A previous video blog entry has the message that we are already evolving to live longer.  But, does evolution set a limit on our lifespans, pre-ordain when we will die so to speak? Please see these videos for views of a few key longevity scientists.  And then I will weigh in with my own opinions. 

Most importantly, it appears that all these researchers and I agree on one central point – that there appears to be nothing about evolution that should prevent us from discovering means for extending our lifespans.  As Aubrey de Grey colorfully puts it “aging can be combated more and more if you throw in more and more elaborate anti-aging machinery.”

Although my views appear to be close to those of Dr. Kenyon, I find myself on disagreement with the other video presenters on the role of evolution in determining lifespans.   Instead of thinking that evolution has nothing to do with lifespans, I think it has everything to do with them.  Being in the minority here, I will elaborate briefly.

The classical view of evolution is indeed that evolution works generally to keep people healthy through childbearing and child-rearing age and is thereafter indifferent to their wellbeing or longevity.  This appears to be the expressed opinion of Dr’s de Grey, Kennedy – and of Austad in the prior video blog.  Further, in the classical view evolution occurs through the processes of “random variation and natural selection” associated with mutations of genes and for humans takes a very very long time – hundreds of thousands or millions of years.  Although over 200 years ago Lamarck had proposed that acquired characteristics could be inherited, this idea became rejected in part because of its seeming incompatibility with genetics.

A newer and increasingly popular view of evolution, the view I subscribe to, is that evolution takes place not just through genetic mutations but also via inheritable changes in the epigenome.  Lararckism is back in a new sophisticated context!  This kind of evolution can proceed vastly faster, in as little as a few generations, and still have major impacts.  Further, I submit that the changes in the epigenome are driven by the external environment, both physical and social.  As the physical environments of humans evolve – such as by providing cleaner disease-free water – so does our epigenome change and do we evolve biologically.   As the social environment evolves – such as by requiring much more time for kids to become educated and get up to speed so they can participate effectively in an ever-more complex society – so does our epigenome change and do we evolve biologically.     Dr Kenyon suggests this point in her presentation.

The classical theory of evolution cannot explain many observed phenomena which the newer view explains convincingly. One is why do human heights seem to vary so much by population circumstances and time frames? Canadians are now taller than Americans, who have suddenly plateaued — but all trail the towering Dutch. So what’s their secret?(ref)” No way these up-and-down trends in average heights could occur so fast through mutations in genes. Another example is given by the opossums talked about in the earlier blog.  They too doubled their lifespans in response to a changed environment far too fast to be explained by plain genetics.  But the important example for this discussion is that our average from-birth lifespans in Western and US countries are increasing by about two months for every year that goes by.  Why?

(a)  Our epigenomes are adopting to longer lifespans because of changed physical circumstances: freedom from predators, near-elimination of infectious diseases and better public health and diet.  We are living longer not just because of better circumstances of the moment but mainly because of our epigemomes’ adoption to those circumstances.  For example, relative freedom from predators means there is a lessened requirement for constant hyper vigilance implying much less chronic expression of cortisol, the “fight or flight”  hormone that enhances responses to emergencies but suppresses the immune system and bone formation.   So less chronic cortisol associated with freedom from predators can lead to evolution of stronger body defenses against disease, better bones, and consequently, longer lives.

b) Our epigenomes are adopting to longer lifespans because an increasingly complex society requires much more learning before people can effectively participate in it, and this demands longer lifespans.  I laid out this viewpoint in the blog entries Social evolution and biological evolution – another dialog with Marios Kyriazis and Social ethics of longevity.

In the following video on Infection and Mortality, Dr. Kirkwood’s speaks powerfully supporting point (a) above.

So, evolution has had everything to do with lifespans.  Evolution has always cared about how long we live.  The good news is that as we find mechanisms to expand lifespans as Aubrey suggests, those mechanisms will become part of social evolution that drives biological evolution.  We are not prisoners of an inexorable process of biological evolution.  We can affect our evolution via research and applying knowledge.  We have been doing that as long as we have been humans.  Discovering how to start fires was an example, and applying the discoveries of  Louis Pasteur was another of very very many.  And I believe we can shape evolution so we live much longer lives.  There will be more blog entries to come related to this point.

This video blog entry, like previous ones, is being brought to you in close collaboration with the filmmaker Robert Kane Papas.  I expect we will generate more of these blog entries structured around short video segments on aspects of longevity science.  Robert is the filmmaker who produced the recently-released film To Age or Not to Age. Robert captured hundreds of hours of interesting video in shooting the film over a 4-year period, including extensive interviews with a number of prominent aging-science researchers.  It was possible to incorporate only a small fraction of that interesting material in the film itself.  However, Robert will be identifying short but remarkable segments of materials both in the film and not in the film, and I will be remarking on them just as in this blog entry.  I expect the videos and the remarks will appear on both this site and on the film site To Age or Not to Age.

Age reversal appears to be a subject for science fiction, like the alchemist’s vision of turning lead into gold.  Yet, it can be induced on the cellular level.  If fact, for certain of our cells aging-avoidance or age-reversal is absolutely  necessary for the continuation of life.

Please see this short video segment.

How our germline cells can be passed on for hundreds of thousands or millions of years without aging is only now being unraveled.  Those cells don’t age.  Many questions can be raised about all this.  Here is my take on a few of them.

·        Is aging necessary for other than germline cells?  My answer is YES, for otherwise cells could not differentiate into specialized tissue cells to create whole animals like we are.  My skin cells, heart cells, muscle and all other cells are products of aging.  Cells of each type embody an epigenetic “memory” of who they are, thank goodness. So, when a skin cell divides it divides into more skin cells, not bladder or liver cells.   And in that respect all normal body cells are aged in comparison to pristine germline cells.  Germline cells manage not to age by not differentiating except on conception.  There is no clear point when development of an animal stops and aging starts.  Aging starts way back just after conception and is lifelong. 

·        Can aging be reversed in our ordinary body cells?  Breakthrough research developments over the last 10 years say the answer is YES.  Practically any cell in your body can be reverted to become an induced pluripotent stem cell (iPSC), virtually identical to your original embryonic stem cells.  These iPSC cells can in turn be induced to differentiate into any normal body cell type.  I have written about a dozen blog entries about these iPSCs so far.  Some of the most-recent posts are Additional 2010 research progress with induced pluripotent stem cells (December 2010),   A breakthrough in producing high-fidelity induced pluripotent stem cells (October 2010), Induced pluripotent stem cells – developments on the road to big-time utilization (July 2010),  and  A near-term application for iPSCs – making cell lines for drug testing (June 2010).       

·         Can aging be reversed in whole body organs?  I think the answer will turn out again to be YES.  This is the hope of the field of research called regenerative medicine, and there is much ongoing research in this area.  Many of the approaches are based on using stem cells.  See for example the blog entry      Interesting recent stem cell research on the prevention of muscle aging by adult stem cell transplantation.

·        Can aging be reversed in whole animals like we are?  This remains a completely open question.  It is my guess, only a guess for now, that within 15-20 years we will discover means for significant life extension.  I also think that in the same time frame we will very-possibly discover means for reversing many of the phenotypic signs of aging in older people.  The blog entry Mouse age reversal – very interesting but misrepresented research describes recent research in which prematurely-aged mice exhibiting various kinds of tissue degeneration associated with aging were made young and vital again through a telomerase-related treatment.  The tissue degeneration associated with aging simply went away.  The theme of age reversal is also in the background in many of my other writings, particularly those relating to epigenetics and in the concept of closing the loop in the stem cell supply chain.

This video blog entry, like the previous blog entry We are evolving to live longer – video blog, is being brought to you in close collaboration with the filmmaker Robert Kane Pappas.  And I expect we will generate several more of these blog entries which are structured around short video segments on aspects of longevity science.  Robert is the filmmaker who produced the recently-released film To Age or Not to Age. Robert captured hundreds of hours of interesting video in shooting the film over a 4-year period, including extensive interviews with a number of prominent aging-science researchers.  It was possible to incorporate only a small fraction of that interesting material in the film itself.  However, Robert is identifying short but remarkable segments of materials both in the film and not in the film, and I will be remarking on them just as in this blog entry.  The videos and the remarks will appear on both this site and on the film site To Age or Not to Age.

Readers/viewers – please share your reactions.  How do you react to the video? Can you point to other research that clearly demonstrates whole-animal age reversal?  Any other highly-relevant research?  And what do you think about this kind of blog entry?   Would you like to see more of them? 

Biological evolution has been traditionally viewed as due to mutations in genes.  However this kind of evolution can require hundreds of thousands or millions of years to take hold   Now we know that evolution can happen much faster, in as little as a few generations.   Further, I see the human species as evolving very fast in the direction of longer lifespans, with the average lifespan from birth in the US and advanced countries increasing about 4 hours each day that goes by. 

Please view this short video segment.  And then comment on us humans evolving to live longer.  And also comment on how interesting and useful you find this video kind of communication compared to the usual text-based blog entries found here. 

I have suggested that the rapid kind of evolution involved is epigenetic evolution which moves far faster than Darwinian genetic evolution.   It is the kind of evolution that has allowed us to grow taller in just a few generations and that is leading to our ever-longer average lifespans.  See the blog entries US falling behind in longevity increases – why?, Social evolution and biological evolution – another dialog with Marios Kyriazis, Social ethics of longevity and a more-technical presentation Stochastic epigenetic evolution – a new and different theory of evolution, aging and disease susceptibility. 

This blog entry and several subsequent ones including short video segments on longevity science are being brought to you in close collaboration with Robert Kane Pappas.  Pappas is the filmmaker who produced the recently-released film To Age or Not to Age. Pappas captured hundreds of hours of interesting video in shooting the film over a 4-year period, including extensive interviews with a number of prominent aging-science researchers.  It was possible to incorporate only a small fraction of that interesting material in the film itself.  However, Robert will be identifying short interesting segments of materials both in the film and not in the film, and I will be remarking on them just as in this blog entry.  The same videos and my same remarks will appear on both this site and on the film site To Age or Not to Age.

Readers/viewers – please share your reactions in comments.  What do you think are the implications of us living longer lives?  Are we like the opossums?  And what is your reaction to this kind of blog entry?   Would you like to see more of them?  

Vince

The actions of folic acid, vitamin B9 are multiple, complex, directly affect the epigenome, and the implications of folic acid supplementation are still not fully known.  Folic acid supplementation appears to be strongly recommended in some circumstances and dangerous in others.  This blog entry reviews some key things known about folate and key findings of both past and current research.

I was set off in this line of research by a comment by the reader Rossi to my blog post Cancer, epigenetics and dietary substances. 

Basic facts about folic acid. 

The Wikipedia entry for folic acid provides an excellent introduction to and initial discussion of the substance.  “Folic acid (also known as vitamin B₉,^[1] vitamin B_c^[2] or folacin) and folate (the naturally occurring form), as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid^[3] are forms of the water-soluble vitamin B₉. Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.^[4] — Vitamin B₉ (folic acid and folate inclusive) is essential to numerous bodily functions. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in biological reactions involving folate.^[5] It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy, as well as in “feeding” some cancers. While a normal diet also high in natural folates may decrease the risk of cancer, there is diverse evidence that high folate intake from supplementation may actually promote some cancers as well as precancerous tumors and lesions. Children and adults both require folic acid to produce healthy red blood cells and prevent anemia.^[6] — Folate and folic acid derive their names from the Latin word folium (which means “leaf”). Leafy vegetables are a principal source, although in Western diets fortified cereals and bread may be a larger dietary source. — A lack of dietary folic acid leads to folate deficiency which is uncommon in normal Western diets. Failures to replenish one’s folates might not manifest themselves as folate deficiency for 4 months because a healthy individual has about 500-20,000 mcg^[7] of folate in body stores.^[8] This deficiency can result in many health problems, the most notable one being neural tube defects in developing embryos. Common symptoms of folate deficiency include diarrhea, macrocytic anemia with weakness or shortness of breath, nerve damage with weakness and limb numbness (peripheral neuropathy), pregnancy complications, mental confusion, forgetfulness or other cognitive declines, mental depression, sore or swollen tongue, peptic or mouth ulcers, headaches, heart palpitations, irritability, and behavioral disorders. Low levels of folate can also lead to homocysteine accumulation.^[5] DNA synthesis and repair are impaired and this could lead to cancer development.^[5] Supplementation in patients with ischaemic heart disease may also lead to increased rates of cancer.^[9 “  

Continuing, “A  2010 opinion article in the New York Times^[10] named micronutrients, especially folic acid, the “world’s most luscious food,” since absence of folic acid and a handful of other micronutrients causes otherwise preventable deformities and diseases, especially in fetal development. Folic acid can be used to help treat Alzheimer’s disease, depression, anemia, and certain types of cancer. The article claims adding folic acid and micronutrients to the food supply of developing countries could be more cost effective than any other single action in improving world health.”

The term folate is slightly more generic than folic acid.  “Folate is a water-soluble B vitamin that occurs naturally in food. Folic acid is the synthetic form of folate that is found in supplements and added to fortified foods [1](ref).”

Folic acid is included in my suggested anti-aging supplement firewall and I have personally been taking it for several years.  In the blog entry Epigenetics, Epigenomics and Aging I reported “In one experiment at Duke University, two genetically identical mother mice were fed different diets, one a normal diet, the other a diet enriched with choline, betaine, folic acid and vitamin B-12.  The offspring mice looked and were very different.  For one thing the offsprings of the normally fed mice had white hair while the offsprings of the supplemented mother had rich brown hair.  The differences were epigenomic.  Despite genetic identity, the physical characteristics of the offsprings depended on the environment and behavior of the mothers.”  

 Epigenetic impacts of folate – One-carbon metabolism  

One of the key actions of folate is methylation of DNA(ref)(ref).  The biochemistry involved is complex and has to do with a pathway known as One-carbon metabolism.  

   “This one-carbon metabolism pathway is centered around folate. Folate has two key carbon-carbon double bonds. Saturating one of them yields dihydrofolate (DHF) and adding an additional molecule of hydrogen across the second yields tetrahydrofolate (THF). Folates serve as donors of single carbons in any one of three oxidation states: 5-methyl-THF (CH3THF; reduced), 5,10 methylene-THF (CH2THF; intermediate) and 10-formyl-THF (CHOTHF; oxidized). The single carbon donor CH3THF is used to convert homocysteine into methionine which can then be used to methylate DNA, the donor CH2THF is used (along with a molecule of hydrogen at the site of one of the double bonds) to convert dUMP (deoxyuridylate) into dTMP (thymidylate) and the donor CHOTHF is used to set up ring closure reactions in de novo purine synthesis. CH3THF is the primary methyl-group donor for processes such as DNA methylation reactions. Purines are used both in RNA synthesis and in DNA synthesis and dTMP is synthesized srtictly for DNA synthesis, be it for DNA repair or DNA replication. The folate pathway is central to any study related to DNA methylation, dTMP synthesis or purine synthesis. — Differential methylation (e.g. hypermethylation of tumor suppressors) as well as disturbances in nucleotide synthesis and repair, are associated with several forms of cancer. There are also indications that hypermethylation is involved in the progression of adenomas to cancer. — The pathway is also illustrative of the role of a number of B vitamins, including vitamin B12 (cobalamine) which is important for the sythesis of folate (vitamin B9) and of methionine(ref).”  

For those of you interested in the molecular biology, on heartfixer.com I located a diagram of methylation pathway cycles which shows how the folate cycle fits in.  It is the third loop from the left.  The biochemical and epigenomic processes of one-carbon metabolism are extremely complicated in ways beyond those illustrated in this diagram.  This link leads to a very large collection of diagrams and images related to one-carbon metabolism, illustrating that complexity.

Many disease processes involve folate and 1-carbon metabolism     

  The 2009 publication One-carbon metabolism-genome interactions in folate-associated pathologies reports “Impairments in folate-mediated 1-carbon metabolism are associated with several common diseases and developmental anomalies including intestinal cancers, vascular disease, cognitive decline, and neural tube defects. The etiology of folate-associated pathologies involves interactions among multiple genetic risk alleles and environmental factors, although the causal mechanisms that define the role of folate and other B-vitamins in these complex disorders remain to be established. Folate and other B-vitamins fundamentally differ from other nutrients that interact with the genome in determining health and disease outcomes in that their interaction is reciprocal. Common gene variants influence the activity of folate-dependent enzymes and anabolic pathways; folate-mediated 1-carbon metabolism is essential for the high-fidelity synthesis of DNA and activated methyl groups that are required for DNA methylation and regulation of chromatin structure. This review focuses on the regulation of folate-mediated 1-carbon metabolism and its role in maintaining genome integrity and on strategies for establishing the metabolic pathways and mechanisms that underlie folate-associated pathologies.”

Many factors may interact in complex ways in folate-related disease processes

“Impairments in the folate-dependent 1-carbon network can arise from a primary folate deficiency, secondary B-vitamin nutrient deficiencies, and genetic variations that influence cellular folate accumulation and/or utilization. Many studies have shown that folate cofactors are limiting in the cell and that the concentration of folate-dependent enzymes and folate-binding proteins exceeds the concentration of folate cofactors, which is estimated to be in the range of 25–35 μmol/L (21,22). Given that folate-dependent enzymes and folate-binding proteins exhibit binding constants (K_d values) in the nanomolar range, all cellular folate cofactors are expected to be protein bound, and folate-dependent anabolic pathways must compete for a limiting pool of folate cofactors (23). Therefore, all folate anabolic pathways are anticipated to be sensitive to primary folate deficiency. Furthermore, genetic variation that alters the partitioning of folate cofactors through any folate-dependent pathway influences the entire 1-carbon network. For example, the common 677 C→T human variant of MTHFR results in decreased MTHFR specific activity, elevated homocysteine, and depressed levels of nuclear methylcytosine but potentially enhances rates of de novo thymidylate biosynthesis (19). Last, secondary nutrient deficiencies can also impair folate-dependent pathways. Vitamin B-12 deficiency diminishes MTR activity and methionine synthesis but also impairs nucleotide biosynthesis through the accumulation of cellular folate cofactors such as 5-methyl-THF. This accumulation of 5-methyl-THF, referred to as a “methyl trap,” results because the MTHFR reaction is essentially irreversible in vivo, and MTR is the only enzyme that can regenerate THF from 5-methyl-THF. Therefore, it is often not possible to establish which biomarkers are “causal” in folate-associated pathologies and which biomarkers are bystanders(ref).” 

The epigenetics of one-carbon (folate) metabolism is likely implicated in Alzheimer’s disease

The 2010 publication One-carbon metabolism and Alzheimer’s disease: focus on epigenetics relates:  “Alzheimer’s disease (AD) represents the most common form of dementia in the elderly, characterized by progressive loss of memory and cognitive capacity severe enough to interfere with daily functioning and the quality of life. Rare, fully penetrant mutations in three genes (APP, PSEN1 and PSEN2) are responsible for familial forms of the disease. However, more than 90% of AD is sporadic, likely resulting from complex interactions between genetic and environmental factors. Increasing evidence supports a role for epigenetic modifications in AD pathogenesis. Folate metabolism, also known as one-carbon metabolism, is required for the production of S-adenosylmethionine (SAM), which is the major DNA methylating agent. AD individuals are characterized by decreased plasma folate values, as well as increased plasma homocysteine (Hcy) levels, and there is indication of impaired SAM levels in AD brains. Polymorphisms of genes participating in one-carbon metabolism have been associated with AD risk and/or with increased Hcy levels in AD individuals. Studies in rodents suggest that early life exposure to neurotoxicants or dietary restriction of folate and other B vitamins result in epigenetic modifications of AD related genes in the animal brains. Similarly, studies performed on human neuronal cell cultures revealed that folate and other B vitamins deprivation from the media resulted in epigenetic modification of the PSEN1 gene. There is also evidence of epigenetic modifications in the DNA extracted from blood and brains of AD subjects. Here I review one-carbon metabolism in AD, with emphasis on possible epigenetic consequences.” 

Shift in cancer research – from the genome to the epigenome

Before discussing the epigenomic effects of folic acid in relationship to cancer, I would like to highlight the existence of a major shift in cancer research itself, from concentrating on genes and the genome to sharing concentration also on the epigenome and epigenetic effects.  Multiple genome-wide association studies relating genetic abnormalities to cancers have generally yielded only weak associations.  The July 2010 publication Time to Think Outside the (Genetic) Box relates “Many patients develop cancers that have clinical features of inherited syndromes (e.g., young age of onset and unique pathology) but lack mutations in the genes characteristic of the disease. In this issue of the journal, Wong et al. report that somatic epigenetic inactivation could explain some such cases in the setting of BRCA1-associated breast cancer. Here, we discuss the implications of this work in terms of the etiology, risk, and potential prevention of cancer.” 

The December 2010 publication Linking Epidemiology to Epigenomics—Where Are We Today? relates: “Cancer is the consequence of genetic and epigenetic alterations.  Genetic mutations likely result in part from exposure to environmental carcinogens, giving rise to a large field of cancer-prevention study of these carcinogens and ways to develop strategies to avoid them. Our understanding of regulatory epigenetic mechanisms associated with DNA methylation, histone modifications, and microRNA production is increasing rapidly. The involvement of these processes in carcinogenesis raises the possibility that environmental exposures may promote or prevent cancer through affecting the epigenome. Modifying the epigenome to prevent cancer is particularly intriguing because epigenetic alterations are potentially reversible, unlike gene mutations, and because certain dietary factors, such as the B-vitamin folate, may affect genes’ DNA methylation status (as reported by Wallace et al., beginning on page 1552 in this issue of the journal). Rapidly improving techniques for assessing epigenetic alterations promise to yield important insights for cancer prevention.”

Folic acid and cancer risk – when considering supplementation, pay attention to the details and judge for yourself

It appears that on the one hand folic acid supplementation can reduce cancer risk but, on the other hand, supplementation can speed the progress of a once-established cancer.  And taking too much can also enhance cancer risk.   I start out with a report that lays out the varying behaviors of folate. The 2004 publication Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies reports: ‘Folate, a water-soluble B vitamin and cofactor in one-carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer (CRC). Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with CRC risk. Collectively, these studies suggest an approximately 40% reduction in the risk of CRC in individuals with the highest dietary folate intake compared with those with the lowest intake. Animal studies using chemical and genetically predisposed rodent models have provided considerable support for a causal relationship between folate depletion and colorectal carcinogenesis as well as a dose-dependent protective effect of folate supplementation. However, animal studies also have shown that the dose and timing of folate intervention are critical in providing safe and effective chemoprevention; exceptionally high supplemental folate levels and folate intervention after microscopic neoplastic foci are established in the colorectal mucosa promote, rather than suppress, colorectal carcinogenesis. These animal studies, in conjunction with clinical observations, suggest that folate possesses dual modulatory effects on carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect, whereas folate supplementation has a promoting effect on the progression of established neoplasms. In contrast, folate deficiency in normal epithelial tissues appears to predispose them to neoplastic transformation, and modest levels of folate supplementation suppress the development of tumors in normal tissues. Notwithstanding the limitations associated with animal models, these studies suggest that the optimal timing and dose of folate intervention must be established for safe and effective chemoprevention in humans. Folate is an important factor in DNA synthesis, stability, and integrity, the repair aberrations of which have been implicated in colorectal carcinogenesis. Folate may also modulate DNA methylation, which is an important epigenetic determinant in gene expression (an inverse relationship), in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. A mechanistic understanding of how folate status modulates colorectal carcinogenesis further strengthens the case for a causal relationship and provides insight into a possible chemopreventive role of folate.’ 

Essentially the same message is conveyed in the 2007 publication Folate and colorectal cancer: an evidence-based critical review by the same author.  “Currently available evidence from epidemiologic, animal, and intervention studies does not unequivocally support the role of folate, a water-soluble B vitamin and important cofactor in one-carbon transfer, in the development and progression of colorectal cancer (CRC). However, when the portfolio of evidence from these studies is analyzed critically, the overall conclusion supports the inverse association between folate status and CRC risk. It is becoming increasingly evident that folate possesses dual modulatory effects on colorectal carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on the progression of established colorectal neoplasms. In contrast, folate deficiency in normal colorectal mucosa appears to predispose it to neoplastic transformation, and modest levels of folic acid supplementation suppress, whereas supraphysiologic supplemental doses enhance, the development of cancer in normal colorectal mucosa. Several potential mechanisms relating to the disruption of one-carbon transfer reactions exist to support the dual modulatory role of folate in colorectal carcinogenesis. Based on the lack of compelling supportive evidence and on the potential tumor-promoting effect, routine folic acid supplementation should not be recommended as a chemopreventive measure against CRC at present.” The 2010 report Plasma folate, related genetic variants, and colorectal cancer risk in EPIC backs off from the notion that folic acid supplementation has anything to do with risk for colorectal cancer.  “BACKGROUND: A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. We investigate the associations between plasma folate, several relevant folate-related polymorphisms, and CRC risk within the large European Prospective Investigation into Cancer and Nutrition cohort.  — METHODS: In this nested case-control study, 1,367 incident CRC cases were matched to 2,325 controls for study center, age, and sex. Risk ratios (RR) were estimated with conditional logistic regression and adjusted for smoking, education, physical activity, and intake of alcohol and fiber. —  RESULTS: Overall analyses did not reveal associations of plasma folate with CRC. — CONCLUSIONS: This large European prospective multicenter study did not show an association of CRC risk with plasma folate status nor with MTHFR polymorphisms. — IMPACT: Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions.” 

Folic acid and cancer risk is associated with GPC island methylation

The theory behind seeing folic acid as inducing cancer risk is that an epigenetic effects of folate is inducing GPC island methylation and that GPC island methylation is associated with many cancers.  The research has largely been associated with prostate and colorectal cancer and goes back 25 years or so..  The 1998 publication Methylation of the 5′ CpG Island of the Endothelin B Receptor Gene Is Common in Human Prostate Cancer¹ n.  The 2006 review publication The emerging roles of DNA methylation in the clinical management of prostate cancer. “Aberrant DNA methylation is one of the hallmarks of carcinogenesis and has been recognized in cancer cells for more than 20 years. The role of DNA methylation in malignant transformation of the prostate has been intensely studied, from its contribution to the early stages of tumour development to the advanced stages of androgen independence. — Herein we discuss the major developments in the fields of prostate cancer and DNA methylation, and how this epigenetic modification can be harnessed to address some of the key issues impeding the successful clinical management of prostate cancer.”

An additional relevant publication is the 2008 report The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer. “A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many processes including apoptosis. To date, studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast, colon and stomach, with only limited data available on prostate cancer. Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer. The most significant advances have involved the discovery of apoptotic gene targets of methylation, including XAF1, (fragile histidine triad (FHIT ), cellular retinol binding protein 1 (CRBP1), decoy receptor 1(DCR1), decoy receptor 2 (DCR2 ), target of methylation-induced silenceing 1 (TMS1), TNF receptor superfamily, member 6 (FAS), Reprimo (RPRM) and GLI pathogenesis-related 1 (GLIPR1). These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers.”  Further relevant discussion is provided in the  2009 report Promoter Methylation in APC, RUNX3, and GSTP1 and Mortality in Prostate Cancer Patients.

 More on GPC island methylation and folic-acid induced cancer risk

The relationship between GPC island methylation by folates and susceptibility to cancers is being actively investigated.  Current research suggests that folic acid supplementation by older adults may incur increased risk of colorectal cancer.  The December 2010 publication Association between Folate Levels and CpG Island Hypermethylation in Normal Colorectal Mucosa reported “Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. — Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.” 

So, does folic acid supplementation decrease risk of subsequent cancer or increase it?  The answer appears to depend on the research studies you find most credible.

A commentary on the aforementioned publication Viewing the Epigenetics of Colorectal Cancer through the Window of Folic Acid Effects states “Wallace and colleagues shed new light on the epigenetics of colorectal cancer by exploring the role of changes in DNA methylation in normal-appearing colon biopsies collected during a chemoprevention trial of folic acid. This study and the parent clinical trial will potentially further elucidate the long-studied role of folate in colon cancer development. In particular, the focus on the intermediate biomarker DNA methylation could provide a mechanistic link between folate exposure and colon cancer. Dietary or supplemental folate has complex interactions with important processes that may alter colon cancer development or progression, but this influence is likely altered by supplementation’s timing and duration and whether in the setting of depleted or more typical, higher levels of folate. Despite decades of epidemiologic, molecular, and animal studies, answers to what effects these interactions have are complex, often contradictory. This perspective will place this study in context, looking at what it tells us and what it does not.”   

The gist of this citation appears to be that, while there appears to be some agreement in the literature about whether dietary intake of folate affects methylation levels, the implications with respect to cancer progression in the colon appear to be shrouded in complexity and uncertainty.  The 2010 publication Folate and one-carbon metabolism and its impact on aberrant DNA methylation in cancer is similarly cautious about drawing conclusions, this time as to whether insufficient folate may create a predisposition to colon cancer:  “Folate deficiency may be implicated in the development of genomic DNA hypomethylation, which is an early epigenetic event found in many cancers, particularly colorectal cancer (CRC). Numerous studies employing in vitro systems, animal models, and human interventional studies have tested this hypothesis. Here, we describe the role of folate as a methyl donor in the one-carbon metabolism cycle, and the consequences of cellular folate deficiency. The existing evidence on folate and its relationship to DNA methylation is discussed using CRC as an example. While there remain numerous technical challenges in this important field of research, changes to folate intake appear to be capable of modulating DNA methylation levels in the human colonic mucosa and this may potentially alter CRC risk.” 

High folate intake may increase predisposition to breast cancer for some women

It you are confused by these findings, it is probably because they are confusing.  Here is a 2009 study report that suggests that high folate intake may contribute to risk of breast cancer for some women: Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women.  “BACKGROUND: Several studies have determined that dietary intake of B vitamins may be associated with breast cancer risk as a result of interactions between 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) in the one-carbon metabolism pathway. However, the association between B vitamin intake and breast cancer risk in Brazilian women in particular has not yet been investigated. — METHODS: A case-control study was conducted in São Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B6, and vitamin B12 were derived from a validated Food Frequency Questionnaire (FFQ). — CONCLUSION: MTHFR polymorphisms and dietary intake of folate, vitamin B6, and vitamin B12 had no overall association with breast cancer risk. However, increased risk was observed in total women with the MTR 2756GG genotype and in premenopausal women with high folate intake.”

Folic acid inhibition is an established strategy for cancer chemotherapy

The idea of targeting folate metabolism as an anti cancer strategy goes back some time.  The 1991 review article Compartmentation of folate-mediated one-carbon metabolism in eukaryotes reports “Folate coenzymes supply the activated one-carbon units required in nucleic acid biosynthesis, mitochondrial and chloroplast protein biosynthesis, amino acid metabolism, methyl group biogenesis, and vitamin metabolism. Because of its central role in purine and thymidylate biosynthesis, folate-mediated one-carbon metabolism has been the target of many anticancer drug therapies.”

Antifolate drugs are now routinely used for treating certain cancers  “Folate is important for cells and tissues that rapidly divide.^[25] Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate methotrexate is a drug often used to treat cancer because it inhibits the production of the active form of THF from the inactive dihydrofolate (DHF). However, methotrexate can be toxic,^[84][85][86] producing side effects, such as inflammation in the digestive tract that make it difficult to eat normally. Also, bone marrow depression (inducing leukopenia and thrombocytopenia), and acute renal and hepatic failure have been reported(ref).”

The 2010 publication Cancer chemotherapy: targeting folic acid synthesis gives a current overview on antifolate drugs.  “Antifolates are structural analogs of folates, essential one-carbon donors in the synthesis of DNA in mammalian cells. Antifolates are inhibitors of key enzymes in folate metabolism, namely dihydrofolate reductase, β-glycinamide ribonucleotide transformylase, 5′-amino-4′-imidazolecarboxamide ribonucleotide transformylase, and thymidylate synthetase. Methotrexate is one of the earliest anticancer drugs and is extensively used in lymphoma, acute lymphoblastic leukemia, and osteosarcoma, among others. Pemetrexed has been approved in combination with cisplatin as first-line treatment for advanced non-squamous-cell lung cancer, as a single agent for relapsed non-small-cell lung cancer after platinum-containing chemotherapy, and in combination with cisplatin for the treatment of pleural mesothelioma. Raltitrexed is approved in many countries (except in the United States) for advanced colorectal cancer, but its utilization is mainly limited to patients intolerant to 5-fluorouracil. Pralatrexate has recently been approved in the United States for relapsed or refractory peripheral T-cell lymphoma. This article gives an overview of the cellular mechanism, pharmacology, and clinical use of classical and newer antifolates and discusses some of the main resistance mechanisms to antifolate drugs.”

The 2008 publication New data integrating multitargeted antifolates into treatment of first-line and relapsed non-small-cell lung cancer is concerned with the therapeutic actions of the antifolate Pemetrexed  “The cytotoxic action of antifolates is mainly related to their ability to inhibit several different folate-dependent enzymes involved in DNA synthesis. Pemetrexed is a novel multitargeted antifolate that inhibits at least 3 of the enzymes involved in purine and pyrimidine synthesis: thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). Pemetrexed was approved for the treatment of relapsed NSCLC as it produced equivalent response and survival rates and less toxicity compared with docetaxel.”

Dietary folate is unlikely to promote tumorgenesis via methylation of the P53 tumor suppressor gene.

The 2003 publication The effect of dietary folate on genomic and p53-specific DNA methylation in rat colon  suggests that folate-induced P53 activation is not a major factor in folate-related carcinogenesis.  “Folate is an important mediator in the transfer of methyl groups for DNA methylation, abnormalities of which are considered to play an important mechanistic role in colorectal carcinogenesis. This study investigated the time-dependent effects of dietary folate on genomic and p53 (in the promoter region and exons 6-7) DNA methylation in rat colon, and how these changes are related to steady-state levels of p53 transcript. Despite a marked reduction in plasma and colonic folate concentrations, a large increase in plasma homocysteine (an accurate inverse indicator of folate status), and a progressive decrease in colonic S-adenosylmethionine (SAM; the primary methyl donor for methylations) to S-adenosylhomocysteine (SAH; a potent inhibitor of methylations) ratio, isolated folate deficiency did not induce significant genomic DNA hypomethylation in the colon. Paradoxically, isolated folate deficiency increased the extent of genomic DNA methylation in the colon at an intermediate time point (P = 0.022). Folate supplementation did not modulate colonic SAM, SAH and SAM to SAH ratios, and genomic DNA methylation at any time point. The extent of p53 methylation in the promoter and exons 6-7 was variable over time at each of the CpG sites examined, and no associations with time or dietary folate were observed at any CpG site except for site 1 in exons 6-7 at week 5. Dietary folate deprivation progressively decreased, whereas supplementation increased, steady-state levels of p53 transcript over 5 weeks (P < 0.05). Steady-state levels of p53 mRNA correlated directly with plasma and colonic folate concentrations (P = 0.41-0.49, P < 0.002) and inversely with plasma homocysteine and colonic SAH levels (r = -0.37-0.49, P < 0.006), but did not significantly correlates with either genomic or p53 methylation within the promoter region and exons 6-7. The data indicate that isolated folate deficiency, which significantly reduces steady-state levels of colonic p53 mRNA, is not associated with a significant degree of genomic or p53 DNA hypomethylation in rat colon. This implies that neither genomic or p53 hypomethylation within exons 6-7 nor aberrant p53 methylation within the promoter region is likely a mechanism by which folate deficiency enhances colorectal carcinogenesis in the rat.” 

Excessive alcohol consumption can lead to folate malabsorption and deficiency

The 2009 publication New perspectives on folate transport in relation to alcoholism-induced folate malabsorption–association with epigenome stability and cancer development reports “Folates are members of the B-class of vitamins, which are required for the synthesis of purines and pyrimidines, and for the methylation of essential biological substances, including phospholipids, DNA, and neurotransmitters. Folates cannot be synthesized de novo by mammals; hence, an efficient intestinal absorption process is required. Intestinal folate transport is carrier-mediated, pH-dependent and electroneutral, with similar affinity for oxidized and reduced folic acid derivatives. The various transporters, i.e. reduced folate carrier, proton-coupled folate transporter, folate-binding protein, and organic anion transporters, are involved in the folate transport process in various tissues. Any impairment in uptake of folate can lead to a state of folate deficiency, the most prevalent vitamin deficiency in world, affecting 10% of the population in the USA. Such impairments in folate transport occur in a variety of conditions, including chronic use of ethanol, some inborn hereditary disorders, and certain diseases. Among these, ethanol ingestion has been the major contributor to folate deficiency. Ethanol-associated folate deficiency can develop because of dietary inadequacy, intestinal malabsorption, altered hepatobiliary metabolism, enhanced colonic metabolism, and increased renal excretion. Ethanol reduces the intestinal and renal uptake of folate by altering the binding and transport kinetics of folate transport systems. Also, ethanol reduces the expression of folate transporters in both intestine and kidney, and this might be a contributing factor for folate malabsorption, leading to folate deficiency. The maintenance of intracellular folate homeostasis is essential for the one-carbon transfer reactions necessary for DNA synthesis and biological methylation reactions. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. Ethanol, a toxin that is consumed regularly, has been found to affect the methylation of DNA. In addition to its effect on DNA methylation due to folate deficiency, ethanol could directly exert its effect through its interaction with one-carbon metabolism, impairment of methyl group synthesis, and affecting the enzymes regulating the synthesis of S-adenosylmethionine, the primary methyl group donor for most biological methylation reactions. Thus, ethanol plays an important role in the pathogenesis of several diseases through its potential ability to modulate the methylation of biological molecules. This review discusses the underlying mechanism of folate malabsorption in alcoholism, the mechanism of methylation-associated silencing of genes, and how the interaction between ethanol and folate deficiency affects the methylation of genes, thereby modulating epigenome stability and the risk of cancer.”

Folic acid supplementation is widely recommended during pregnancy

Folic acid is often prescribed or recommended as a supplement for pregnant women to prevent neural tube defects.  Health practioneers and Internet sites for pregnant women recommend it.  For examples BabyCenter’s article Folic acid in your pregnancy diet counsels “Why you need folic acid during pregnancy — Women who are pregnant or might become pregnant need folic acid (vitamin B9 or folate, as it’s known in its naturally occurring state) for a number of compelling reasons:

·        Folic acid helps prevent neural tube defects (NTDs) – serious birth defects of the spinal cord (such as spina bifida) and the brain (anencephaly). Neural tube defects occur at a very early stage of development, before many women even know they’re pregnant. They affect about 3,000 pregnancies a year in the United States.

·        The Centers for Disease Control and Prevention (CDC) reports that women who take the recommended daily dose of folic acid starting at least one month before they conceive and during the first trimester of pregnancy reduce their baby’s risk of neural tube defects by 50 to 70 percent.

·        Some research suggests that folic acid may help lower your baby’s risk of other defects as well, such as cleft lip, cleft palate, and certain types of heart defects.

·        Your body needs folate to make normal red blood cells and prevent anemia.

Folate is essential for the production, repair, and functioning of DNA, our genetic map and a basic building block of cells. So getting enough folic acid is particularly important for the rapid cell growth of the placenta and your developing baby. Some research suggests that taking a multivitamin with folic acid may reduce your risk of preeclampsia, a complex disorder that can affect your health and your baby’s.”

More-technically put, “Neural tube closure defects (NTD), which include the birth defects anencephaly and spina bifida, arise from the failure of neurulation during early human embryonic development. NTD are among the most common human birth defects and have a heterogeneous and multifactorial etiology with interacting genetic and environmental risk factors. Clinical trials and folic acid fortification initiatives indicate that up to 70% of NTD can be prevented by maternal folic acid supplementation, and human gene variants in the folate-mediated 1-carbon network have been identified as risk factors (10,12). However, the metabolic pathways and associated mechanisms underlying the association between folate-mediated 1-carbon metabolism and NTD pathogenesis are still unknown(ref).” 

In fact provision of folic acid to pregnant woman is often seen as a public health measure.  A news report appearing today Feb 15, 2011 is headlined Low-income women received thousands of free multivitamins with folic acid.  “Charlotte – Nearly 40,000 low-income women have received free multivitamins with folic acid in an effort to reduce birth defects thanks to a bill passed by the N.C. General Assembly. The Bill provided funding in 2010 for the statewide distribution of multivitamins with folic acid to low income, non-pregnant women of childbearing age through health departments and other safety net providers. — Research shows that if all women consume the recommended amount of folic acid before and during early pregnancy, up to 70 percent of all neural tube defects, serious birth defects of the brain and spinal cord, could be prevented. This one-time appropriation led to the state’s largest multivitamin distribution program on record. — The North Carolina Folic Acid Campaign at the March of Dimes and the Department of Public Health’s Women’s Health Branch administered the program and worked together to ensure that vitamins were shipped to participating agencies. Two hundred thirty-four agencies signed up for the program. The agencies consisted of all 88 county health departments, and numerous community health centers and safety-net clinics.” 

A significant number of pregnant women may take too much folic acid 

The January 211 publication Folic acid supplementation before and during pregnancy in the Newborn Epigenetics Study (NEST) indicates BACKGROUND: Folic acid (FA) added to foods during fortification is 70-85% bioavailable compared to 50% of folate occurring naturally in foods. Thus, if FA supplements also are taken during pregnancy, both mother and fetus can be exposed to FA exceeding the Institute of Medicine’s recommended tolerable upper limit (TUL) of 1,000 micrograms per day (ug/d) for adult pregnant women. The primary objective is to estimate the proportion of women taking folic acid (FA) doses exceeding the TUL before and during pregnancy, and to identify correlates of high FA use. — METHODS: During 2005-2008, pre-pregnancy and pregnancy-related data on dietary supplementation were obtained by interviewing 539 pregnant women enrolled at two obstetrics-care facilities in Durham County, North Carolina. — CONCLUSIONS: Fifty-one percent of women reported some FA intake before and 66% during pregnancy, respectively, and more than one in ten women took FA supplements in doses that exceeded the TUL. Caucasian women were more likely to report high FA intake. A study is ongoing to identify possible genetic and non-genotoxic effects of these high doses.”

Folic acid supplementation does not prevent premature births

A series of news reports appeared a few days ago based on a study of 73,000 Norwegian women indicating that folate supplementation does not protect against premature births.  Of course, I am not sure that anyone has ever said it should.   

Some personal observations

·        The pathways of operation of folate and related epigenetic effects are extremely complex, for me mind-bewildering in how they might interact under in-vivo conditions. 

·        While the individual studies cited above seem to yield definite results, as a collection these studies leave me feeling dissatisfied since so many of them come to mixed or contradictory conclusions.  There seem to be few if any simple unifying hypotheses.

·        In particular, the studies relating dietary folate to cancer risk or cancer progression seem confusing or contradictory.  For now, I prefer the simple interpretation that maintaining an adequate folate level and avoiding hypomethylation may be a good cancer-preventative strategy for someone free of cancer and decreasing folate levels and avoiding folate-induced hypermethylation is probably a good strategy if someone has an incipient or active cancer. 

·        A number of advanced issues relevant to aging are raised in these publications that I may want to explore in future blog entries.  An example is folate-related regulation of chromatin structure.  Another, suggested by my reader Rossi, is whether dietary choline might avert excess hypermethylation brought about by folate.

·        On a personal level, I will continue to eat green leafy vegetables when I can and will continue with my supplementation at the level of 900 mcg a day.

·        Should I become aware of any signs of incipient or developing cancers, I will stop the folic acid supplementation.

This blog entry is personal, about my history relevant to longevity science.   It tells a bit about my earlier history with health and longevity science.   And it describes how my views regarding longevity science have evolved during my years of most-intensive engagement in the field.  I also discuss the continuing evolution of this blog.  This blog post updates my July 2010 post Three years exploring longevity science and my January 21 2010 blog entry The evolution of this blog.

A little personal back history

Trained basically as a physicist and mathematician, I paid little or no attention to the biological sciences until the summer of 1970 when a single event propelled me into the world of dietary supplements.  The event was a knockout case of Hepatitis A from consumption of contaminated shellfish in an offbeat country restaurant.  At the time I was working as a consultant in the Oak Ridge National Laboratory in Tennessee on a temporary summer project.  The sickness hit me suddenly on a Sunday when I was visiting Cumberland Caverns with my family and girlfriend.  I became dizzy and weak and literally had to crawl on my hands and knees up and out of the caverns and across a field to the car to catch up with my family which had gone ahead.  My urine was dark purple.  The doctor told me I had hepatitis. The off-the-scale bilirubin score, the swollen liver and my symptoms were definitive indicators.  Further, the doctor said I would have to rest in bed for a couple of months.  There was no cure or medicine that would work.  This was completely unacceptable to me since I was depending on the daily consulting income.  Somehow, I had to get back to work fast to make ends meet.

Shortly after I got home from the doctor’s office, my girlfriend visited a health food store and brought home a copy of a book by Adelle Davis.  She purchased the book because in browsing she had found a short section on hepatitis in it.  Later that day I started on 4 grams of vitamin C a day.  A week later I was fine and back to work, completely flummoxing the doctor.  So fast a cure was impossible according to him.  During the week I read the rest of the book, and that was my powerful kick-start learning about nutrition and nutritional supplements. Adelle was “a pioneer in the fledgling field of nutrition during the mid-20th century. She advocated whole unprocessed foods, criticized food additives, and claimed that dietary supplements and other nutrients play a dominant role in maintaining health, preventing disease, and restoring health after the onset of disease(ref).”  At the time her views were viewed by the medical establishment as fringe and even dangerous.  The scientific bases for many of her views were only established much later, and only now do we understand the rock-hard science behind many of them.  See for example my last blog entry on Cancer, epigenetics and dietary substances.

Over the years I learned more about nutritional supplements and by the 90s had used them to vanish some bad attacks of rheumatoid arthritis and was taking 8 or so daily supplements.  In 1994 at the age of 65 I decided that, far from retiring, I wanted to keep contributing.  I formulated an intention to live a very long productive life. 

In 1997 I came across Michael Fossel’s book Reversing Human Aging, an eloquent early presentation of the Telomere Shortening and Damage theory of aging  The book strongly suggested the possibility of life extension.  This started me occasionally reading in the longevity research literature, particularly research related to telomeres and telomerase and the supplements I was taking.  By 2003 I was reading the research literature more frequently and had added a number of additional supplements to my dietary regimen. I thought they might keep me healthy and living longer.   My Internet consulting practice was winding down then so I was finding more time for studying the research.  I became amazed at how many different theories of aging there were and how researchers in one area seemed to ignore relevant progress in another area.  I started writing articles related to health and aging topics at that time though I did not publish them.

A new career and the treatise

In 2007 I formulated an intention to pursue a full-time new career as a longevity scientist, not one who does lab research but one who integrates research findings across multiple disciplines and areas of research.  In part, I was driven to see what there is out there that could possibly lead to the holy grail of life extension.  By then it was clear that research in telomeres and telomerase was revealing an area of great significance and complexity, but that there was much more out there related to molecular and cell biology and stem cells that had to be considered. There were many theories of aging and, curiously enough, each seemed to be correct within its own framework of reference.   I started researching and writing my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY and the first version went online early in 2008.  I have since continued to update the treatise frequently, the last update being two days ago.

The blog

By the end of 2008 I was getting more and more in touch with the vast amount of knowledge relevant to longevity and how incredibly complex some of the areas are.  It became clear that there is far too much going on in the longevity science field for me to shoehorn it all into my treatise.  I decided to initiate this blog in early 2009.  Although the blog’s original purpose was to report currently on longevity-related research news, a second more-important purpose soon emerged. That is, to position the new research developments into larger contexts relevant to aging and longevity. The daily press and sources like Science Daily do good jobs at reporting important new research developments and publications. Unfortunately, however, the press too-often reports new research findings as “breakthroughs” when they are actually just pieces in a complex puzzle. (Note the blog entry When reading press releases and newspaper articles about research discoveries, beware!).  What was needed to understand those news items was context.  So, more and more of my blog entries have become in-depth discussions of whole areas of science relevant to longevity, citing and quoting from multiple research publications. The blog now contains 345 posts and 799 comments, with many of the posts being mini-treatises dealing with important health and longevity issues.

I have picked the “lowest hanging fruit” of topics to write about, the easiest ones for me to grasp and present, and have gradually been shifted to creating ever-longer and more comprehensive blog posts on ever-more complex topics.   I am now spending a lot more time on a typical blog entry and the frequency of posts has therefore been going down. When I started the blog I was putting out shorter posts almost every day.  Now I typically produce 1-2 posts a week.   

Based on information collected by my ISP and user registrations:

·        Number of substantive postings: 336

·        Number of daily user accesses (unique users who view 2 or more articles): average 2,000

·        Estimated total number of regular blog readers: 15,000

·        Number of comments: 799

·        New user registrations: average about 20 a day, more than half from outside the US

·        Reader demographics:  heavier in US, Europe and Eastern Europe, sparser in other parts of world. 

I believe a main usage of the blog is as a reference resource.  This is because most comments relate to past, not current blog entries, some current comments relate to blog posts well-more than a year old.  This is not surprising to me since many of the blog posts pull materials from up to a dozen or more research publications together in a fairly understandable way, saving readers having to locate and read multiple publications to cover the same ground.  I am very happy with the ever-growing popularity of this blog. 

Besides researching and generating the blog, in 2010 I attended six longevity-science conferences, offered a presentation Towards a Systems View of Aging at the American Aging Society and appeared in the longevity science film To Age or Not to Age which has been shown multiple times on national TV. 

Changes in my perspective over the last 4 years 

Monitoring the torrent of literature potentially relevant to aging,  going to research conferences, interacting with key longevity scientists, and researching and writing specific blog entries continues to be an intense learning process for me.  The more I go on, the more I am humbled by what I don’t know. Here, I review some of my original views that remain the same and other views that have evolved.

1.     Several of my original views were correct:

·        There are multiple theories of aging, viewpoints that are correct in their own domains. 

·         Newer theories like Programmed Epigenomic Changes  provide deeper explanations of the phenomena of and interrelationships among multiple older theories like Oxidative damage and Chronic inflammation.

·        Proper attention to lifestyle and diet and consuming certain dietary supplements can significantly contribute to the probability of health and longevity.  With the exception of a few additions, I have made relatively few modifications to my suggested lifestyle  and dietary supplement anti-aging regimens over the last 3 years.  As I mentioned, the scientific research basis for those appear clear and I have devoted a number of specific blog entries to such dietary subjects as extra-virgin olive oil,  avocados and curcumin.   

2.     I was naïve about seeing the Telomere Shortening and Damage theory of aging as primary and probably providing the best approach for extending longevity.  Despite of the importance of telomeres and telomerase in cell biology, I no longer see exogenous extension of telomeres as a promising approach to life extensions.  Telomeres are made longer or shorter by other factors and are responders to aging rather than drivers of aging(ref)(ref)(ref).

3.     It became progressively clear that there are a lot of theories about what drives aging.  In my treatise I cover 14 main ones and an additional 6 additional candidate ones.  And this blog describes additional ones, such as Stochastic epigenetic evolution.  Most of these theories are somewhat compatible, others less so.  Further, some are pessimistic with respect to the options for life extension, others optimistic.  For example The Nuclear DNA Damage/Mutation Theory of Aging described in a guest posting says you can do little about aging created by trillions of gene mutation events except live with it.  However, the Programmed Epigenomic Changes suggests that the really important aging changes are epigenomic and reversible.

4.     Three newer areas of science cut across these theories and provide integrative frameworks of underlying knowledge mostly unifying them.  These are molecular biology, epigenetics/epigenomics and stem cell science.  These are the hot areas of contemporary research, each with multiple specialized branches, areas where much progress is being reported.  I see induced pluripotent stem cells as having incredible potential for regenerative medicine and, in the longer term, expanding lifespans.

5.     I now see the topic of life extension as a more nuanced topic than before. 

First of all, when talking about lifespan extension, only averages are meaningful.  Even if I take a pill absolutely guaranteed to extend my life 10 years, I can still get run over by a bus or struck by lightning tomorrow. It is essential to specify the population the average applies to.  “Life extension of an average of 15 years” means one thing when I am talking about “from birth” and something quite different when I am talking about people 80 to start with.  And it is important to specify the demographic being talked about: men, women, Caucasians, “average” Americans, Swedes in Sweden, Swedes in the US, Latin Americans, Ashkenazi Jewish centenarians living in the US, people who have recovered from cancer, etc. 

Second, I see life extension as roughly divisible into four categories:

a.     General expected lifespan extension of more than 2 months for every year that passes in the US and advanced countries for lifespan from birth(ref).  The number is a little less in the US than in  other advanced countries.  See the blog entriy US falling behind in longevity increases – why?  This pattern of increasing lifespans has been going on for hundreds of years now and is accelerating.  It is probably explainable by epigenomic changes associated with social evolution(ref)(ref)(ref).

b.     Expected lifespan extension due to observing good dietary and lifestyle patterns and taking certain supplements. Here, I am thinking of following suggestions such as those contained in my lifestyle  and dietary supplement supplement anti-aging regimens.  I do not know how to estimate this effect but a wild guess is that an average US 40 year-old non-smoker in good health can gain 10-12 more years life expectancy this way.

c.      Average lifespan extension due to pharmacological interventions, perhaps of up to 15 years, again for an average US 40 year-old non-smoker in good health.  I am thinking here of drugs likely to come onto the market soon designed to affect well-studied longevity pathways such as SIRT1, mTOR and IGF1.  I conjecture such pharmacological interventions may be available within 5 years from now. Whether such life extension will overlaps that of b) above or add to it is unknown.  My guess is overlaps, meaning that taking such a drug may only add a few average years of lifespan beyond those achievable via the lifestyle and dietary interventions of b) above.  However, such a drug may add significant number of years to those not willing to follow all of the lifestyle and dietary interventions.

d.     Drastic future life-extension interventions associated with techniques of regenerative medicine.   I am thinking of interventions that deeply reverse eipigenomic markers of aging or that utilize stem cell technology.  A good example is described in my blog entries having to do with Closing the loop in the stem cell supply chain.  I conjecture that such techniques could be available within 10 to 20 years and, as perfected, could possibly lead to lifespans of up to several hundred years. 

If these conjectures sound wild, consider the following:  In 1952 I was working with a then “giant brain” computer the size of a large truck trailer.  Some futurists then spoke of possible future computers with 100 or even 1,000 times the power.  These people were dismissed as crazy ungrounded visionaries, even by me.  Few paid any attention to such nonsense.  However, the $859 notebook computer being used to write this blog post is easily 100,000 times more powerful than that 1952 computer.  And even the wildest visionaries back then could not imagine their grandsons and granddaughters running around with tiny computers 20,000 times as powerful in their little smartphones.

I am afraid that history will judge these conjectures on life extension as far too conservative rather than too radical.    

6.     Historically, public health measures have been more important than medical breakthroughs in assuring longevity.  So I will be generating more blog entries like Public health longevity developments – focus on foods and US falling behind in longevity increases – why?

7.     As time progresses I am seeing a much larger unfolding social picture in which see longevity research is only one component.  Now, as we are in the beginning of the 21st century, profound changes are already happening connected with lengthening lifespans.  Marriage and the start of careers has been postponed by a dozen or more years since when I was young .   Instead of having babies when they are 17-23, middle class women are having babies in their 30s and 40s.  And other changes are needed.  For example, we are on the average living 15 years longer from birth now than we were in 1935 when Social Security and a standard retirement age of 65 was established.  Back then, 65 was more than average expected lifespan from birth.  That is, the average person was not expected to live long enough to retire.  Now it is 14 years less.  We have a big job to do to prepare our society for the life extension going on now and the more-radical  life extension likely to happen in the near future.  I anticipate the ramifications will be even more profound than those wrought by electronics, computers and Internet in the 20^th century.  So occasionally I will be writing blog entries on the social facets of longevity, blog entries like Social evolution and biological evolution – another dialog with Marios Kyriazis.

8.     I am not sure how much longer I can keep up with the central research developments relevant to longevity.  The pace of research is increasing and many of the key discoveries are increasingly technical.  I find myself having to be more selective in picking topics for blog entries.  And I am struggling harder and harder to understand what is going on in the areas of some of my blog entries.  Popular writers like Ray Kurtzweil are predicting a future “singularity” likely to occur when there is more highly relevant knowledge than humans can grasp.  I may well at some point run into a personal “singularity” with regard to the longevity research literature.  I think this point is likely to be several years in the future, however, and I am determined for now to keep going with my intent to stay on top of it.  I love it that “Kurtzweil is now 60 but intends to be no more than 40 when the singularity arrives(ref).”  I am now 81 but intend more or less the same.

I invite comments and suggestions, particularly for this blog.   I do have one specific question for readers.  As a policy for the blog, in addition to linking to large numbers of research publications I have been providing backwards hyperlinks to previous relevant postings and to my treatise. I believe this has contributed significantly to the usefulness of both the blog and treatise.  Also in selected cases I have linked from the treatise to blog entries.   As of now, however, I have not gone back to past blog entries to provide forward linking.  For example, I have not gone back to put links in my earlier articles on telomeres and telomerase to multiple subsequent articles on the same topic.  It would take a substantial effort for me to do this kind of linking across the board.  Do you think that would be worthwhile if I were to do it?

Green tea, olive oil, blueberries, garlic and broccoli are among foods that work to reverse epigenetic changes that create susceptibility to cancers. A number of recent research publications relate to complex epigenetic conditions that lead to cancers – conditions that typically involve DNA methylation and histone acetylation.  A number of other recent publications point out how many of these conditions are reversible via dietary inputs of substances that are old friends to many of my readers – substances like olive oil, blueberries, garlic, green tea, curcumin and resveratrol.  Indeed, this new research is providing deep insight into why certain dietary polyphenols are effective in preventing cancers via their epigenetic actions.  After a little background, I quote relevant passages from a number of these publications. 

Background: Plant polyphenols and cancer

We have long known from large population studies that regular consumption of certain dietary substances and supplements like green tea, olive oil, blueberries, oregano, ginger and hot chili peppers can negatively impact on incidences of cancer.  We also know from multiple studies that certain plant-based polyphenol substances like rosmarinic acid, curcumin, lycopene, caffeic acid, resveratrol and gingerol inhibit the development of certain cancers.  Indeed this research has been the basis for my suggested lifestyle  and dietary supplement anti-aging regimens.  The October 2009 blog entry Nrf2 and cancer chemoprevention by phytochemicals  provides a specialized but interesting introduction to the topic of cancer chemoprevention by certain dietary substances.  It also lists a number of literature citations on this subject.  The present blog entry goes into the basic epigenetic mechanisms involved. 

Background: Epigenetics of cancer

The December 2010 blog entry Epigenetics of cancer and aging provides a well-focused introduction to and explanation of this topic for readers.  It also contains numerous links to relevant previous blog entries and research publications.  This current blog entry picks up where that one leaves off. 

Epigenetic mechanisms of dietary substances  that avert cancers 

Getting to the main meat of this blog post, a good place to start is with the December 2010 publication Epigenetic targets of bioactive dietary components for cancer prevention and therapy.  “The emergent interest in cancer epigenetics stems from the fact that epigenetic modifications are implicated in virtually every step of tumorigenesis. More interestingly, epigenetic changes are reversible –.  Dietary agents consist of many bioactive ingredients which actively regulate various molecular targets involved in tumorigenesis. We present evidence that numerous bioactive dietary components can interfere with various epigenetic targets in cancer prevention and therapy. These agents include curcumin (turmeric), genistein (soybean), tea polyphenols (green tea), resveratrol (grapes), and sulforaphane (cruciferous vegetables). These bioactive components alter the DNA methylation and histone modifications required for gene activation or silencing in cancer prevention and therapy. Bioactive components mediate epigenetic modifications associated with the induction of tumor suppressor genes such as p21WAF1/CIP1 and inhibition of tumor promoting genes such as the human telomerase reverse transcriptase during tumorigenesis processes. —  Here, we present considerable evidence that bioactive components and their epigenetic targets are associated with cancer prevention and therapy which should facilitate novel drug discovery and development. — The bioactive components of dietary phytochemicals most often shown to be effective against cancer are tea polyphenols, genistein, curcumin, resveratrol, sulforaphane, isothiocyanates, silymarin, diallyl sulfide, lycopene, rosmarinic acid, apigenin, and gingerol.”  

The basic concepts here are simple:

1.                 Cancers and cancer growth are facilitated by or caused by environmentally-conditioned and possibly inheritable epigenetic modifications, and

2.                 Many such epigenetic modifications are reversible by selected dietary inputs.  The genome is programmed by the epigenome and the epigenome in turn is largely programmed by the social and physical environment(ref)(ref).

“Cancer is a multi-step process derived from combinational crosstalk between genetic alterations and epigenetic influences through various environmental factors (Ducasse and Brown 2006; Esteller 2008; Ellis et al. 2009). Moreover, it has been well documented that environmental exposure to nutritional, dietary, physical, and chemical factors could alter gene expression and modify individual genetic susceptibility through changes in the epigenome (Issa 2008; Suter and Aagaard-Tillery 2009; Herceg 2007). Several distinct but intertwined mechanisms are known to be part of the epigenome which includes DNA methylation, histone acetylation, poly-ADP-ribosylation and ATP-dependent chromatin remodeling(ref).”  Further, “The link of lifestyles, such as dietary patterns and physical activity, to the risk of developing cancer and other diseases has received support from a plethora of epidemiological and biochemical studies. In line with this, a report from the World Health Organization (WHO) states that cancer causes 7.1 million deaths annually (12.5% of the global total) and dietary factors account for about 30% of all cancers in western countries and approximately up to 20% in developing countries(ref).” 

Among numerous other factors affecting the epigenetic-related risks of cancers are insufficient exercise, smoking and exposure to environmental toxins.  And reversible epigenetic changes can lead to other disease and degenerative processes.  For example, some pesticides in the environment work to cause neuron loss via histone acetylation, as pointed out in the 2010 publication Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. 

“Growing evidence suggests that bioactive dietary components impact epigenetic processes often involved with reactivation of tumor suppressor genes, activation of cell survival proteins, and induction of cellular apoptosis in many types of cancer (Landis-Piwowar et al. 2008; Li et al. 2010; Paluszczak et al. 2010; Majid et al. 2008). In addition to transcriptional silencing of tumor suppressor genes and protein expression, noncoding microRNAs (miRNAs) can regulate expression of a myriad of cellular proteins by affecting mRNA stability and translation by epigenetic processes in cancer progression (Esteller 2007; Ducasse and Brown 2006).” [You can also see my blog entries MicroRNAs in cancers and aging and MicroRNAs, diseases and yet-another view of aging.]  “Interestingly, these miRNAs can control the expression of various epigenetic modifying enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), and histone deacetylases (HDACs) involved in carcinogenesis processes (Guil and Esteller 2009; Saito and Jones 2006). Recent evidence suggests that bioactive dietary components can also target various oncogenic or tumor suppressive miRNAs to alter the gene expression profile in cancer prevention (Parker et al. 2009; Sun et al. 2009; Li et al. 2009b). In fact, miRNA profiles are now being used to classify human cancers (Calin et al. 2004). Further, miRNAs can directly or indirectly regulate cancer progression either by acting as tumor suppressors or by altering epigenetic modifying enzymes, respectively. In particular, miRNA-221 and miRNA-222 target KIT, an oncogene, and therefore function as tumor suppressors in erythroblastic cells and other human solid tumors (Croce 2009). Furthermore, the miRNA-29 family can directly regulate the expression of DNMTs and increase expression of DNMT3a and DNMT3b thereby causing a global genomic hypermethylation and silencing of methylation-sensitive tumor suppressor genes such as FHIT and WWOX (Fabbri et al. 2007)(ref).”

DNA methylation

The 2010 publication Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components relates “It is well established that aberrant gene regulation by epigenetic mechanisms can develop as a result of pathological processes such as cancer. Methylation of CpG islands is an important component of the epigenetic code and a number of genes become abnormally methylated during tumorigenesis.”  These include tumor suppressor genes like p16/INK4a, turning them off(ref).  Continuing, “Some bioactive food components have been shown to have cancer inhibition activities by reducing DNA hypermethylation of key cancer-causing genes through their DNA methyltransferase (DNMT) inhibition properties. The dietary polyphenols, (-)-epigallocatechin- 3-gallate (EGCG) from green tea, genistein from soybean and possibly isothiocyanates from plant foods, are some examples of these bioactive food components modulated by epigenetic factors. The activity of cancer inhibition generated from dietary polyphenols is associated with gene reactivation through demethylation in the promoters of methylation-silenced genes such as p16INK4a and retinoic acid receptor beta. The effects of dietary polyphenols such as EGCG on DNMTs appear to have their direct inhibition by interaction with the catalytic site of the DNMT1 molecule, and may also influence methylation status indirectly through metabolic effects associated with energy metabolism. Therefore, reversal of hypermethylation-induced inactivation of key tumor suppression genes by dietary DNMT inhibitors could be an effective approach to cancer prevention and therapy(ref).”

In more detail “DNA methylation, occurring primarily at cytosine-guanine (CpG) dinucleotides, is a heritable, tissue- and species-specific modification of mammalian DNA [5, 6]. CpG dinucleotides are frequently clustered into CpG islands, regions that are rich in CpG sites. These islands extend about 0.5–3 Kb, occur on average every 100 Kb in the genome and are found in approximately half of all genes in humans [7]. DNA methylation often occurs at the regulatory sites of gene promoter regions and involves an enzymatic process by addition of a methyl group to the 5-position of the cytosine ring of CpG dinucleotides (Fig. 1). It is an important epigenetic determinant in gene expression, maintenance of DNA integrity and stability in many biological processes such as genomic imprinting, normal development and proliferation [8–10]. DNA hypermethylation of CpG islands is usually associated with silencing of the expression of genes in contrast to loss of methylation which often leads to gene reactivation. Abnormal patterns of DNA methylation may ultimately lead to genetic instability and cancer development through epigenetic inactivation of certain critical cancer-related genes by promoter hypermethylation [11] (Fig. 1). These altered genes include tumor suppressor genes, such as the cell cycle checkpoint genes, p21^WAF1/CIP1 and p16 ^INK4a, and growth regulatory genes, such as RAS association domain family 1A (RASSF1A) and retinoic acid receptor β (RARβ). Furthermore, promoter hypomethylation-induced oncogene activation contributes to the processes of tumorigenesis [12]. Aberrant DNA methylation occurs at specific genes in almost all neoplasms, suggesting that this alteration may be a molecular marker in cancer prevention and therapeutic approaches(ref).”

Continuing, – “Numerous studies have demonstrated that certain dietary components inhibit cancer proliferation by affecting epigenetic signaling pathways both in vitro and in vivo [37, 38]. The green tea polyphenol, EGCG, is believed to be a key active ingredient for cancer inhibition through epigenetic control. It has been found that EGCG can reverse CpG island hypermethylation of various methylation-silenced genes and reactivate these gene expressions through inhibition of DNMT1 enzymatic activity [39]. Moreover, EGCG has been proposed to regulate gene expression through the mechanism of chromatin remodeling suggesting that EGCG could exert its anticancer ability through both epigenetic mechanisms. Another well-known bioactive dietary compound is the soybean isoflavone, genistein, which has also been found to inhibit tumorigenesis through epigenetic control in several cancer cell lines [40, 41](ref).”

Lysine(K) acetylation

Another related set of mechanisms by which dietary substances affect epigenomics so as to prevent cancers involves lysine (K) acetylation.  The October 2010 e-publication Dietary, metabolic, and potentially environmental modulation of the lysine acetylation machinery reports: “Epigenetic changes play a key role in defining gene expression patterns under both normal and pathological conditions. As a major posttranslational modification, lysine (K) acetylation has received much attention, owing largely to its significant effects on chromatin dynamics and other cellular processes across species. Lysine acetyltransferases and deacetylases, two opposing families of enzymes governing K-acetylation, have been intimately linked to cancer and other diseases. These enzymes have been pursued by vigorous efforts for therapeutic development in the past 15 years or so. Interestingly, certain dietary components have been found to modulate acetylation levels in vivo. Here we review dietary, metabolic, and environmental modulators of the K-acetylation machinery and discuss how they may be of potential value in the context of disease prevention.” 

“As a key component of the epigenetic makeup, lysine acetylation is now recognized as one fundamental posttranslational modification exerting profound effects on chromatin dynamics and other cellular processes in different species [2–4]. This modification transfers the acetyl moiety from acetyl-CoA to the ε-group of a lysine residue (Figure 1), which is reversible and dynamically governed by two groups of counteracting enzymes known as lysine acetyltransferases (KATs) and deacetylases (KDACs) [5–7]. Due to historical reasons, KDACs have almost exclusively been referred to HDACs (histone deacetylases), –.   Acetylation of specific lysine residues on histones is generally associated with transcriptional activation, whereas histone deacetylation results in transcriptional repression [8, 9](ref).”

At least one acetyltransferase is a longevity factor required for calorie restriction-mediated life span extension(ref).

In earlier blog entries I have related how inhibition of expression of NF-kappaB is a mechanism through which a number of phytochemicals like curcumin and resveratrol work to inhibit cancers(ref)(ref).  The 2010 publication Acetylation of p65 at lysine 314 is important for late NF-k(kappa)B-dependent gene expression links (K) acetylation to inhibition of NF-kappaB.  “BACKGROUND: NF-k(kappa)B regulates the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation and survival. We have earlier reported that p65, a subunit of NF-k(kappa)B, is acetylated in vitro and in vivo at three different lysines (K310, K314 and K315) by the histone acetyltransferase p300. RESULTS: In this study, we describe that site-specific mutation of p65 at lysines 314 and 315 enhances gene expression of a subset of NF-k(kappa)B target genes including Mmp10 and Mmp13. Increased gene expression was mainly observed three hours after TNFa(alpha) stimulation. Chromatin immunoprecipitation (ChIP) experiments with an antibody raised against acetylated lysine 314 revealed that chromatin-bound p65 is indeed acetylated at lysine 314. CONCLUSIONS: Together, our results establish acetylation of K314 as an important regulatory modification of p65 and subsequently of NF-k(kappa)B-dependent gene expression.” 

Relevant to this last factor and the subject of this post, I remind my readers that 39 of the supplements in my Anti-Aging Firewalls regimen are inhibitors of NF-kappaB expression or binding.  It is likely that (K) acetylation plays a key role in the actions of many if not all of these.

“Delicate control is required for maintaining an appropriate acetylation profile for normal cellular functions. An imbalance has been associated with various diseases. As a result, many KAT and HDAC inhibitors, as well as activators, have emerged as promising agents for modulating this modification and treating diseases whose roots originate from altered K-acetylation. Several HDAC inhibitors have received approval from the US Food and Drug Administration (FDA) for treating cutaneous T-cell lymphoma [20]. In addition, scientists have discovered that some dietary components modulate KAT and HDAC activities (Figure 2), and have analyzed lifestyles to determine factors that may influence the functioning of these enzymes](ref).”  For example, resveratrol is a HDAC inhibitor(ref).

Interestingly, HDAC inhibitors can provide a number of other health effects.  For example, they can serve as anti-depressants(ref) and can be used to enhance learning and memory following traumatic brain injury(ref).

Epigenetic activities of specific cancer-inhibiting foods

This table relates dietary components that inhibit cancer to their epigenetic activities, lists target genes and research references.  The table is from the publicationmentioned earlier Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components .  This paper explains the key epigenetic roles of the DNMT methyltransferases, and details how several classes of food chemicals operate on an epigenetic level to inhibit cancers.  It has sections describing  the epigenetic anti-cancer activities of Tea polyphenols, Soy isoflavone genistein, Other polyphenols, Selenium, and Isothiocynates.  I comment here only selectively on the actions of some of these and other selected dietary compounds.

Isothiocyanates and allyl compounds

“Isothiocyanates, metabolites of glucosinolates, are found naturally in cruciferous vegetables, such as broccoli, cabbages, and watercress and have been reported to reduce the incidence of prostate cancer (Table 2) [99]. Phenethyl isothiocyanate (PEITC), a hydrolytic product of glucosinolate gluconasturtin, has been proposed to reduce cell growth of prostate cancer both in vivo and in vitro [100, 101].”

The 2009 publication Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds reports. “– Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic.  Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention.”

Resveratrol

The 2010 publication Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex describes a mechanism by which resveratrol acetylates and therefore turns on the apoptosis gene P53 gene in cancer cells to kill them.

More relevant publications

Among of the other recent publications relevant to this blog entry are

·        Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells.

·        The dietary histone deacetylase inhibitor sulforaphane induces human β-defensin-2 in intestinal epithelial cells·        Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines

·        Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention

·        Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds.

·        A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase

·         Dietary agents as histone deacetylase inhibitors

·        Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 

·        Synergistic effects of a combination of dietary factors sulforaphane and (-) epigallocatechin-3-gallate in HT-29 AP-1 human colon carcinoma cells

·         Histone deacetylases as targets for dietary cancer preventive agents: lessons learned with butyrate, diallyl disulfide, and sulforaphane

·        Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter

·        Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? 

·        Cancer-preventive peptide lunasin from Solanum nigrum L. inhibits acetylation of core histones H3 and H4 and phosphorylation of retinoblastoma protein (Rb)

·        The cancer preventive peptide lunasin from wheat inhibits core histone acetylation

·        Inhibition of core histone acetylation by the cancer preventive peptide lunasin

·        Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription

·        Cytotoxic benzophenone derivatives from Garcinia species display a strong apoptosis-inducing effect against human leukemia cell lines

·        Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells

·        Curcumin-induced histone hypoacetylation: the role of reactive oxygen species

·        Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression 

·        Inhibition of lysine acetyltransferase KAT3B/p300 activity by a naturally occurring hydroxynaphthoquinone, plumbagin 

I could go on with this list, and there are many other relevant publications.  You can hyperlink out from these links to a number of others.  The subject of epigenetic dietary interventions to prevent cancers is very hot. 

As usual I am afraid that I have just scratched the surface in this blog entry.  Systematic epigenomic changes appear to be associated with far-flung health issues such as chronic alcohol consumption(ref)(ref) and cocaine addiction(ref).   In fact, epigenomics is emerging as a powerful new lens for looking at all our disease processes and aging.   So, I expect to be writing ever-more blog entries relating to epigenomics.  And, if you are a regular reader of this blog, you already know that one of my most-favorite theories of aging is Programmed Epigenomic Changes.

Important research published in late 2010 and 2011 relates to a protein JDP2 that plays a key role in cell-cycle processes.   JDP2 is involved with epigenetic modifications to histones relevant to age-related changes in stem cell differentiation and cell senescence.  Like the previously-discussed Smurf2 gene, JDP2  is involved in the regulation of the differentiation and proliferation of cells.  Its presence or absence affects whether cells differentiate or become senescent.  The new research has implications related to organismal aging and for the Programmed Epigenomic Changes  theory of aging.  I review some of the new publications here and relate new findings to matters I have discussed previously.  The subject is highly technical and the actions of JDP2 are complex   So, I have framed some of the explanations  and interpretations I put forward here in simplified terms.

I start with the abstract of the 2011 electronic publication Jun dimerization protein 2 controls senescence and differentiation via regulating histone modification, and then go on to interpret and amplify certain key points.  “Transcription factor, Jun dimerization protein 2 (JDP2), binds directly to histones and DNAs and then inhibits the p300-mediated acetylation both of core histones and of reconstituted nucleosomes that contain JDP2 recognition DNA sequences. JDP2 plays a key role as a repressor of adipocyte differentiation by regulation of the expression of the gene C/EBPδ via inhibition of histone acetylation. Moreover, JDP2-deficient mouse embryonic fibroblasts (JDP2(-/-) MEFs) are resistant to replicative senescence. JDP2 inhibits the recruitment of polycomb repressive complexes (PRC1 and PRC2) to the promoter of the gene encoding p16(Ink4a), resulting from the inhibition of methylation of lysine 27 of histone H3 (H3K27). Therefore, it seems that chromatin-remodeling factors, including the PRC complex controlled by JDP2, may be important players in the senescence program. The novel mechanisms that underline the action of JDP2 in inducing cellular senescence and suppressing adipocyte differentiation are reviewed.” 

JDP2 is an epigenetic modifier, a transcription factor that inhibits gene expression

In binding to histones and preventing acetylation of core histones, JDP2 keeps the corresponding chromatin tightly wrapped up inhibiting accessibility of promoter regions of certain genes and therefore inhibiting expression of those genes.  “We found that acetylation by p300 is inhibited in a dose-dependent manner by JDP2, when added exogenously. We also found that JDP2 was not acetylated by p300 under our experimental conditions. The inhibitory effect of JDP2 was detected on histone acetylation induced by p300, CREB-binding protein (CBP), p300/CBP-associated protein (PCAF), and general control nonrepressive 5 (GCN5). The overexpression of JDP2 apparently represses the RA-induced acetylation of lysines 8 and 16 of histone H4 and some amino terminal lysine residues of histone H3(ref).”

JDP2 is a repressor of cell differentiation

As stated in the 2010 publication Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging, “Thus JDP2 plays a key role as a repressor of cell differentiation by regulating the expression of genes with an activator protein 1 (AP-1) site via inhibition of histone acetylation and/or assembly and disassembly of nucleosomes.”  Going back to the 2007 publication JDP2 suppresses adipocyte differentiation by regulating histone acetylation, “–JDP2 inhibited both the acetylation of histone H3 in the promoter of the gene for C/EBPdelta and transcription from this promoter. Our data indicate that JDP2 plays a key role as a repressor of adipocyte differentiation by regulating the expression of the gene for C/EBPdelta via inhibition of histone acetylation.”   Additional insight is provided in the November 2010 publication Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2.  “Fibroblasts derived from embryos of Jdp2KO mice proliferated faster and formed more colonies than fibroblasts from wild-type mice. JDP2 was recruited to the promoter of the gene for cyclin-A2 (ccna2) at the AP-1 site. Cells lacking Jdp2 had elevated levels of cyclin-A2 mRNA. Furthermore, reintroduction of JDP2 resulted in the repression of transcription of ccna2 and of cell-cycle progression. Thus, transcription of the gene for cyclin-A2 appears to be a direct target of JDP2 in the suppression of cell proliferation.” JDP2 is a driver of cell senescence, and does by activating the gene p16(Ink4a)The 2010 publication Epigenetic regulation of p16Ink4a and Arf by JDP2 in cellular senescence recapitulates the complex mechanisms through which JDP2 is a regulator of cellular senescence.   “In response to accumulating cellular stress, cells protect themselves from abnormal growth by entering the senescent stage. Senescence is controlled mainly by gene products from the p16^Ink4a/Arf locus. In mouse cells, the expression of p16^Ink4a and Arf increases continuously during proliferation in cell culture. Transcription from the locus is under complex control. p16^Ink4a and Arf respond independently to positive and negative signals, and the entire locus is epigenetically suppressed by histone methylation that depends on the Polycomb repressive complex-1 and -2 (PRC1 and PRC2). In fact, the PRCs associate with the p16^Ink4a/Arf locus in young proliferating cells and dissociate in aged senescent cells. Thus, it seems that chromatin-remodeling factors that regulate association and dissociation of PRCs might be important players in the senescence program. Here, we summarize the molecular mechanisms that mediate cellular aging and introduce the Jun dimerization protein 2 (JDP2) as a factor that regulates replicative senescence by mediating dissociation of PRCs from the p16^Ink4a/Arf locus.” 

According to the 2009 publication JDP2 (Jun Dimerization Protein 2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence “Senescence protects normal cells from abnormal growth signals and oncogenic transformation by interrupting the cell cycle. Senescence is induced not only by cellular aging but also by the forced activation of the MAPK³ pathway and by genotoxic stressors, such as peroxide and certain DNA-damaging compounds. There is evidence to suggest that, in mice, two inhibitors of progression of the cell cycle, p16^Ink4a and p19^Arf (Arf and p14^ARF in humans), are the main regulators of senescence. These proteins are encoded by overlapping reading frames at the CDKN2A (MTS1) locus (1–3).  The expression of both p16^Ink4a and p19^Arf is enhanced in rodent cells with aging (1, 2). By contrast, in human cells, senescence is generally associated with the increased expression of p16^Ink4a but not of Arf (1–3).” 

The same publication reports “JDP2 (Jun dimerization protein 2, an AP-1 transcription factor) is involved in the regulation of the differentiation and proliferation of cells. We report here that JDP2-deficient mouse embryonic fibroblasts (Jdp2(-/-) MEF) are resistant to replicative senescence. In the absence of JDP2, the level of expression of p16(Ink4a), which is known to rise as normal fibroblasts age, fell significantly when cells were cultured for more than 2 months. Conversely, the overexpression of JDP2 induced the expression of genes for p16(Ink4a) and p19(Arf). Moreover, at the promoter of the gene for p16(Ink4a) in Jdp2(-/-) MEF, the extent of methylation of lysine 27 of histone H3 (H3K27), which is important for gene silencing, increased. Polycomb-repressive complexes (PRC-1 and PRC-2), which are responsible for histone methylation, bound efficiently to the promoter to repress the expression of the gene for p16(Ink4a). As a result, JDP2-deficient MEF became resistant to replicative senescence. Our results indicate that JDP2 is involved in the signaling pathway for senescence via epigenetic regulation of the expression of the gene for p16(Ink4a).” 

The October 2010 publication Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging relates “Senescent cells show a series of alterations, including flatten and enlarged morphology, increase in nonspecific acidic β-galactosidase activity, chromatin condensation, and changes in gene expression patterns. The onset and maintenance of senescence are regulated by two tumor suppressors, p53 and retinoblastoma proteins. The expression of p53 and retinoblastoma proteins is regulated by two distinct proteins, p16(Ink4a) and Arf, respectively, which are encoded by cdkn2a. JDP2 inhibits recruitment of the polycomb repressive complexes 1 and 2 (PRC-1 and PRC-2) to the promoter of the gene that encodes p16(Ink4a) and inhibits the methylation of lysine 27 of histone H3 (H3K27). The PRCs associate with the p16(Ink4a)/Arf locus in young proliferating cells and dissociate from it in senescent cells. Therefore, it seems that chromatin-remodeling factors that regulate association and dissociation of PRCs, and are controlled by JDP2, might play an important role in the senescence program.” 

JDP2 contributes to aging via activation of p16(Ink4a)

I have discussed the role of p16(Ink4a) as an epigenetic driver of aging before in this blog and in my treatise as part of the discussion of the Programmed Epigenomic Changes theory of aging.  Specifically, levels of p16(Ink4a) increase with aging and p16(Ink4a) inhibits the differentiation of adult stem cells.  “Buildup of levels of Ink4a/P16 associated with aging slows down the rate of differentiation of adult stem cells.  “Recent evidence shows that loss of Bmi-1, a polycomb transcriptional repressor of the Ink4a-Arf locus, results in progressive loss of HSCs in adult mice with subsequent failure of hematopoiesis.” – “ These results show that either both p16Ink4a and p19Arf can inhibit HSC self-renewal in a serial transplant setting, or that only p16(Ink4a) is necessary(ref).“

The new research suggests that the smoking gun driving p16(Ink4a) expression and therefore cell senescence is JDP2. 

The 2009 publication Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging relates “Expression of the p16(INK4a) tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age-induced functional decline of certain self-renewing compartments. These observations have suggested that p16(INK4a) expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16(INK4a) expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T-lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationship with donor characteristics. Expression of p16(INK4a), but not other INK4/ARF transcripts, appeared to exponentially increase with donor chronologic age. Importantly, p16(INK4a) expression did not independently correlate with gender or body-mass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16(INK4a) expression was associated with plasma interleukin-6 concentration, a marker of human frailty. These data suggest that p16(INK4a) expression in PBTL is an easily measured, peripheral blood biomarker of molecular age.”

The usefulness  of p16(INK4a) as a biomarker of aging is also related in the 2008 publication p16INK4A is a robust in vivo biomarker of cellular aging in human skin.  “To determine whether p16INK4A expression in human skin correlates with donor age, p16INK4A expression was analyzed by immunohistochemistry as well as the expression of the p16INK4A repressor BMI1. Samples from the age groups 0-20, 21-70, and 71-95 years were selected from a bank of healthy human skin. We show that the number of p16INK4A positive cells is significantly higher in elderly individuals compared to the younger age groups. The number of p16INK4A positive cells was found to be increased in both epidermis and dermis, compartments with strictly different proliferative activities. BMI1 gene expression was significantly down-regulated with increasing donor age, whereas no striking age differences were observed for Ki67.  — In conclusion, we provide for the first time evidence that p16INK4A expression directly correlates with chronological aging of human skin in vivo. p16INK4A therefore is a biomarker for human aging in vivo. The data reported here suggest a model for changes in regulatory gene expression that drive aging in human skin.” 

JDP2 affects responses of cells to stress and growth signals by repressing ATF3 

The 2009 publication The ubiquitously expressed bZIP inhibitor, JDP2, suppresses the transcription of its homologue immediate early gene counterpart, ATF3 reports “JDP2 is a ubiquitously expressed bZIP repressor protein. JDP2 binds TPA response element and cyclic AMP response element located within various promoters. JDP2 displays a high degree of homology to the immediate early gene ATF3. ATF3 plays a crucial role in the cellular adaptive response to multiple stress insults as well as growth stimuli. We have identified ATF3 as a potential target gene for JDP2 repression. JDP2 regulates the ATF3 promoter potentially through binding to both the consensus ATF/CRE site and a non-consensus ATF3 auto-repression DNA-binding element. Expression of ATF3 protein in wild-type mouse embryo fibroblast (MEF) cells is below the detectable levels, whereas, JDP2 disrupted MEF cells display noticeable level of ATF3 protein. Following either serum or ER stress stimulation, ATF3 expression is potentiated in JDP2-KO fibroblast cells as compared with wild-type cells. Mice with either JDP2 over-expression or JDP2 disruption display undetectable level of ATF3 protein. However, ATF3 induction in response to either growth or stress signals is dependent on JDP2 expression level. ATF3 induction is attenuated in JDP2 over-expressing mice whereas is potentiated in JDP2-KO mice as compared with the corresponding wild-type mice. Collectively, the data presented strongly suggest that JDP2 plays a role in the determination of the ATF3 adaptive cellular threshold response to different stress insults and growth stimuli.”  

JDP2 may play mixed roles in cancer processes.   

“It is also interesting that JDP2 is one of the candidate oncoproteins that collaborate in the oncogenesis associated with the loss of p27 as the result of insertional mutations [29]. Recent study of tumor cells demonstrated that JDP2 was a tumor suppressor [30](ref).”  The 2002 publication Identification of oncogenes collaborating with p27Kip1 loss by insertional mutagenesis and high-throughput insertion site analysis reported “This analysis identified a remarkable number of putative protooncogenes in these lymphomas, which included loci that were novel as well as those that were overrepresented in p27-/- tumors.  We found that Myc activations occurred more frequently in p27-/- lymphomas than in p27+/+ tumors. We also characterized insertions within two novel loci: (i) the Jun dimerization protein 2 gene (Jundp2), and (ii) an X-linked locus termed Xpcl1. Each of the loci that we found to be frequently involved in p27-/- lymphomas represents a candidate oncogene collaborating with p27 loss.”  The 2004 publication The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene reported “we show for the first time the potential role of JDP2 in inhibition of cell transformation and tumor suppression. The mechanism of tumor suppressor action of JDP2 can be partially explained by the generation of inhibitory AP-1 complexes via the increase of JunB, JunD, and Fra2 expression and decrease of c-Jun expression.” 

The 2010 publication The AP-1 repressor protein, JDP2, potentiates hepatocellular carcinoma in mice provides a later take: “RESULTS: JDP2-transgenic mice display normal liver function. JDP2-transgenic mice displayed potentiation of liver cancer, higher mortality and increased number and size of tumors. The expression of JDP2 at the promotion stage was found to be the most critical for enhancing liver cancer severity.– CONCLUSIONS: This study suggests that JDP2 expression may play a critical role in liver cancer development by potentiating the compensatory proliferative response and increased inflammation in the DEN liver cancer model.” 

Comments

There is much more to the literature of JDP2 than I have been able to cover.  However, it is clear that JDP2 is an important actor in the epigenetic cell-cycle regulatory system that relaters to stem cell differentiation capability, cell senescence and aging.   I believe this literature tends to support the Programmed Epigenomic Changes  theory of aging.  According to this theory, aging involves progressive and somewhat systematic changes in the chromatin.  JDP2 is a key player in the program as are the polycomb repressive complexes, P16(INK4a), Arf, P53  and a number of other regulatory proteins.  Yet, the extent and exact functioning of the program remains far from clear.  Most of the literature I have reviewed was focused on what JDP2 does and I saw little if any discussion of what promotes or inhibits JDP2 itself in-vivo.  Do any of the sirtuins impact on JDP2 expression?  Is JDP2 expression conditioned by exercise, by diet, by phytochemicals?  I saw no answers to these questions or a host of others I can think of.  So, I expect there will be much more to report as time progresses.

The US is falling behind other advanced countries in longevity gains.  This is the essential content of stories that appeared this week in almost every major newspaper.  The stories are based on a carefully-crafted study released by the National Academy of Sciences.   I first comment on where the US stands compared to other countries in terms of a few key health statistics.  Then I go on to summarize key findings of the new report.  Finally, largely in an editorial mode I comment on some of the deep-seated cultural factors that are involved, factors that may contribute to the US falling even further behind other leading countries when it comes to health and longevity.

Health statistics –where does the US stand?

Many US citizens like to think of our country as “having the most advanced medical system in the world.”  In terms of health statistics, however, we are very far from a leader.  We are in the middle of the pack and in some cases worse off than developing countries.  Here are a few example statistics:

–         Infant mortality:  According to the CIA World Factbook (2009 statistics) the US ranks 46^th, just below Cuba and Guam.  We have 6.26 deaths per thousand births, nearly three times as many as the first ranking nation Singapore with 2.31 deaths per thousand births.  Other countries doing better than us include Slovenia, the Czech Republic and Iceland.

–         Maternal mortality: 41 countries do better than the US in terms of deaths of mothers upon giving birth according to World Health Organization statistics.  Among the countries with fewer deaths per 100,000 births are Belarus, Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Kuwait  and Iceland.

–         Percent of rural population having access to improved drinking water:  57 countries rank better than the US including the Ukraine, Tuvalu, Turkey, Tonga, Slovinia, Slovakia, Egypt, Malasia, Macedonia, Thailand, Serbia, Qatar, Greece, Guyana and Montenegro, and the Democratic People’s Republic of Korea according to WHO statistics.

–         People living with HIV or AIDS.  According to the CIA World Factbook we have the world’s 8^th largest population of these people, 1.2 million.  Russia, China and India rank way below us.

Changes in life expectancy

A few days ago the National academy of Sciences issued a report “Explaining Divergent Levels of Longevity in High-Income Countries.”  The findings should be disturbing to US citizens.  We are trailing other advanced countries in both longevity and rate of increase of longevity.

According to the introduction to the report “Over the last 25 years, life expectancy at age 50 in the U.S. has been rising, but at a slower pace than in many other high-income countries, such as Japan and Australia. This difference is particularly notable given that the U.S. spends more on health care than any other nation. Concerned about this divergence, the National Institute on Aging asked the National Research Council to examine evidence on its possible causes. — According to Explaining Divergent Levels of Longevity in High-Income Countries, the nation’s history of heavy smoking is a major reason why lifespans in the U.S. fall short of those in many other high-income nations. Evidence suggests that current obesity levels play a substantial part as well. The book reports that lack of universal access to health care in the U.S. also has increased mortality and reduced life expectancy, though this is a less significant factor for those over age 65 because of Medicare access. For the main causes of death at older ages — cancer and cardiovascular disease — available indicators do not suggest that the U.S. health care system is failing to prevent deaths that would be averted elsewhere. In fact, cancer detection and survival appear to be better in the U.S. than in most other high-income nations, and survival rates following a heart attack also are favorable.”

The report was covered widely in the popular press with headlines like Why is America’s life expectancy lagging?  “Despite spending more on health care than any other country in the world, the U.S. is lagging in life expectancy. American men and women do not live as long as people in France, Japan, and other wealthy nations, and the gap is widening. Now, the National Research Council has attempted to find out why that is. Here, a quick guide to their findings:  — How much does our life expectancy lag? We rank 36th in the world, behind even South Korea and Cuba, with an average life expectancy of 78.3 years. Japan, whose citizens can expect to live to the ripe old age of 83, ranks first. But what is especially worrying is how we’re failing to keep up with other developed nations. Between 1980 and 2006, the life expectancy for men born in the U.S. rose by only 5.5 years — a lower rate than in 21 other developed countries. Women didn’t fare much better, gaining six years in life expectancy since the 1950s, while women from nine other high-income countries gained eight years. — What did the National Research Council say was behind the gap? Smoking, primarily. Even though only about 21 percent of U.S. adults smoke these days, reports Katherine Hobson in The Wall Street Journal, that number was closer to 37 percent back in 1980. “Smoking-related illnesses such as lung cancer can take decades to have an impact on mortality rates.” Men will likely see their average longevity increase in the next few years, as their “smoking habits are well past the peak,” says NPR. Women, however, “took longer to cut back, and the toll of smoking will be around longer.”  — Are there other factors? Obesity also plays some part, but just how much is a “controversial” question, says The Boston Globe. The NRC estimates that obesity could “account for up to a third of the shortfall compared with other rich nations.” Lack of exercise is also a factor. Americans are “among the most sedentary people” in the developed world, says Nathan Seppa at Science News, “vying with Poland for the dubious status of topping that category.”

Looking deeper

The picture is that we are falling behind other advanced countries in both health and longevity.  These statistics are not static.  A few years back the US was at or near the top of the list in most categories of health as well as longevity.  I do not think we in the US are getting worse off; in fact we have been improving.  However, much of the rest of the world is moving a lot faster.   We are falling further and further behind the leaders.   Even some countries we have thought of as “third world” are catching up with and surpassing us when it comes to health and longevity.    I note that the same trends apply to a number of other specific public health measures as well as levels and effectiveness of education, investment in public infrastructure and general quality of life. 

The report described above and most of the press articles blame our relatively poor longevity performance on smoking, a sedentary lifestyle, a non-universal medical system and poor nutrition.  I agree these are the important proximate causes.  However, I believe understanding what is really going on requires looking deeper.   Our society is subject to underlying operating conditions having to do with the cultural situation in the US, conditions rooted deeply in our mindsets and systems that will not go away easily.  I comment editorially on some of these conditions here.

Though the US cultural picture is complex and multi-faceted, it contains strong remnants of a frontier culture, valuing individual initiatives and private solutions over public ones.  While many cultural traditions such as in Europe and Japan value community initiatives to address shared problems, we have tended to value individualistic initiatives.  Distrust of government-based public solutions runs deep in many of us.  And initiatives of giant corporations, even ones bigger than many governments, are seen by many to be preferable to government initiatives.  This value system can be seen very clearly as prevalent in a large sector of our political system.  It also shows up in many dimensions that affect the public health and longevity pictures:

–         Compared to European countries we have fewer and smaller public spaces and a transportation system which is automobile-based with much poorer public transportation options.  This translates into many fewer opportunities or requirements for walking, less exercise, and poorer health in many dimensions(ref)(ref)(ref)(ref).    There is less opportunity for exercise-related stress that lead to cardiovascular and other exercise-related health benefits and hormesis-derived  longevity-enhancing effects. 

 –         Powerful lobbying groups representing private economic interests keep our health care system fragmented, non-universal, and far less cost-effective than single-payer health care systems.  So, many people who cannot afford expensive insurance or private health care do not get their basic health needs taken care of and die early.  We are virtually the only advanced country that does not have universal health care.

     –         There is a general reluctance to invest in infrastructure, be that in education, public spaces, clean water systems or sanitary landfills.  There is a preference for privatized solutions wherever possible – or no solutions at all.  

–         The media system, particularly TV, being commercial puts great emphasis on expensive proprietary drugs for treating diseases and relatively little emphasis on general health, good diet, lifestyle elements and dietary supplements. 

 –         We do not know how effective dietary supplements are as compared to expensive drugs because nobody is willing to underwrite the expensive clinical trials required to find out. –         There is a premium on as little regulation as possible and substantial delays in public health regulations when those regulations affect important industries and economic interests having important political lobbying power:            

o   High-taxation of tobacco products and effective regulation of tobacco use were delayed many decades after the public health issue and life-shortening effect of tobacco use were first identified.  The article Tobacco Smoking and Longevity was published in 1938.  And smoking is still largely condoned and second-hand smoke in the homes of tobacco smokers is still an issue.

               o   The coal industry and electric utilities that burn dirty high-sulphur  coal have effectively lobbied for decades against clean air regulations.  The result is a relatively high incidence of a variety of sometimes-fatal lung diseases, including lung cancer. 

            o   Only in recent years has there been limited control of toxic pollution, and many rivers and lakes and tracks of land remain with high concentrations of toxic substances.  Thousands of toxic waste sites remain not cleaned up threatening water supplies.  Airborn mercury from burning coal and mercury in fish remain largely-unaddressed issues.  The life-shortening effects of toxins are well documented. 

            o   Even the practice of medicine has clearly unhealthy elements such as a drastic increase in CATscan diagnostic X-rays despite the known life-shortening effects of radiation.  See my article Protection Against Radiation – The Second Line of Defense.

             o   Regulation of clearly-unhealthy foods, certain processed foods and junk foods,  is now only getting started and may take decades before it is completely implemented.  Again, poor diets translate into higher prevalence of diseases like diabetes and cardiovascular failure and the consequence is shorter average lifespans.  See the previous  blog entry Public health longevity developments – focus on foods.

Our political system is now deeply divided between those who seek greater government participation for the common good and those who seek less.  At stake is whether we look to government for improving public spaces and our public transportation system, for improving our educational system, for deeper research in the life sciences, for implementing  further health-promoting regulations and for a host of related matters.  The alternative is to reduce government involvements in public health issues, continue to allow industries to regulate themselves and to look to private industries for our solutions.  In my opinion, following this second course is likely to cause us to fall further and further behind the rest of the world with regard to the health and wellbeing of our citizens – eventually into third-world status.

Public health measures like cleaner water, public sanitation systems, cleaner air and barriers to cigarette smoking have been major contributing to longevity in the last 200 years. These measures have contributed significantly to the average lifespan in the US more than doubling during that period. High-tech end-of-life medical developments have had only minor impacts on overall longevity compared to these public initiatives. How do such public health longevity-enhancing interventions get put into place? There is usually first a long period of scientific awareness and then growing public awareness that something can and should be done. After that, what typically follows are initial efforts that are only partially effective, an example being small warnings that were first placed on cigarette boxes. Finally, as a result of innovative leadership, effective action steps are taken, often steps that are controversial like outright smoking bans. In the final phases, the public health issue is often characterized as an economic one where the cost of proposed public health measures are very small compared to the costs of inaction. Here, I review several news items that appeared only during the last week describing the states of public health initiatives related to mass-distributed foods.

Dangerous foods, diet, obesity, disease and shortened lifespans

Research over decades has established the life-shortening impacts of obesity(ref) (ref)(ref) and the roles of saturated fats, trans-fats and excess sugar in soft drinks and processed foods in promoting obesity, cardiovascular diseases, diabetes and cancers, and leading to shorter lives(ref)(ref)(ref)(ref)(ref)(ref). Countless blogs and websites are devoted to these issues and to dietary advice(ref). My focus in this blog entry is not to review that research, but rather to discuss what is being done about these issues from a public health viewpoint. Major public health focus has been on foods likely to lead to an alarming increase in childhood obesity including sweetened sodas, fast foods containing saturated and trans-fats, and on unhealthy school lunches.

Sin taxes

One of the ways of dealing with public health problems associated with marketed substances is to impose “sin taxes” on products that generate public health problems. The idea is that raising the cost of an unhealthy item will result in lesser consumption of that item. The two primary current examples are high taxes on tobacco products and on alcoholic beverages.

The this-week article Tax sugar-sweetened beverages in a British Columbia newspapers is one on a many that have called for an extra tax on sugary soda pop.

But sin taxes tend not to work unless they are set painfully high. An April 2010 Science Daily article Small Soda Taxes Insufficient to Curb onsumption Among Children, Study Finds reports “Small sales taxes on soft drinks in the range currently in force in some states are insufficient to reduce consumption of soda or curb obesity among children, according to a new RAND Corporation study. — Such small taxes may reduce consumption in some subgroups such as children at greater risk for obesity, but reducing consumption for all children would require larger taxes, according to the study published by the journal Health Affairs. — “If the goal is to noticeably reduce soda consumption among children, then it would have to be a very substantial tax” said Roland Sturm, the study’s lead author and a senior economist at RAND, a nonprofit research organization. “A small sales tax on soda does not appear to lead to a noticeable drop in consumption, led alone reduction in obesity.” — Taxes on soft drinks and other sugar-sweetened beverages have been proposed as part of many anti-obesity efforts, with the goal being to discourage consumption of the high-calorie drinks in order to curb excess weight gain. — Researchers estimated the potential effect of soft drink taxes on children’s consumption and weight by examining differences in existing sales taxes on soft drinks between states. Details about state soda taxes were compared to information about weight and soda consumption among 7,300 children enrolled in the Early Childhood Longitudinal Study, which has been gathering information about a national group of children for many years. — Children studied reported drinking an average of six sodas per week, but there was wide variation among the group. Fifteen percent reported drinking no sodas in the prior week, while 10 percent consumed two or more sodas per day.  The amount of soda purchased at school was small. — The analysis could find no significant link between the consumption of soda or weight gain among children and differential taxes on sodas versus other foods. Existing differential taxes (taxes that are imposed on sodas and not other food items sold in grocery stores) are small, averaging 3.5 percent and none are larger than 7 percent.”

Nutrition labels do not necessarily affect eating patterns and can be misleading

Another approach favored by the food industry and the US government up to this point has been nutritional labeling. The logic seems very reasonable: “Tell consumers what they are getting and let them make their own choices.” This approach may be good for a few people who have the knowledge, eyesight and patience to read labels. But the approach tends to be relatively ineffective when it comes to the general public. Just like cigarette warning labels did not initially scare off many smokers, last week’s news reports indicate that calorie listing on restaurant menus have virtually no impact.

A publication appearing in the February 2011 issue of American Journal of Preventative Medicine is Mandatory menu labeling in one fast-food chain in King County, Washington: “As part of a comprehensive effort to stem the rise in obesity, King County, Washington, enforced a mandatory menu-labeling regulation requiring all restaurant chains with 15 or more locations to disclose calorie information at the point of purchase beginning in January 2009. The purpose of this study is to quantify the impact of the King County regulation on transactions and purchasing behavior at one Mexican fast-food chain with locations within and adjacent to King County. To examine the effect of the King County regulation, a difference-in-difference approach was used to compare total transactions and average calories per transaction between seven King County restaurants and seven control locations focusing on two time periods: one period immediately following the law until the posting of drive-through menu boards (January 2009 to July 2009) and a second period following the drive-through postings (August 2009 through January 2010). Analyses were conducted in 2010. No impact of the regulation on purchasing behavior was found. Trends in transactions and calories per transaction did not vary between control and intervention locations after the law was enacted. In this setting, mandatory menu labeling did not promote healthier food-purchasing behavior.”

A number of newspaper articles picked up on this research in the last few days.  Here is an excerpt from one in the Daily Mail, Nutrition labels on fast food ‘won’t stop you eating unhealthily: “Making fast food chains print nutritional facts on the packaging of burgers, fries and other fat laden products does not make an ounce of difference to diners’ choices, according to new research. — A 13-month study of restaurants after mandatory labelling legislation was brought in found customer tastes remained just the same. — Professor Eric Finkelstein, of Duke-National University of Singapore, said: ‘Given the results of prior studies, we had expected the results to be small, but we were surprised we could not detect even the slightest hint of changes in purchasing behaviour as a result of the legislation. — Right choice? Mandatory labelling of fast food products did not stop consumers eating them, a survey found ‘The results suggest mandatory menu labelling, unless combined with other interventions, may be unlikely to significantly influence the obesity epidemic.’ — As part of a comprehensive effort to stem the rise in obesity King County in Washington, which includes Seattle and surrounding areas, brought in the regulation on all restaurant chains with 15 or more outlets from January, 2009. Restaurants had to disclose calorie information at the point of purchase. Some companies in the UK, including McDonald’s, now print facts including the fat, salt, calorie and carbohydrate content of its foods to help people make healthy choices. — But Prof Finkelstein and his colleagues monitored a chain of Mexican restaurants called Taco Time for just over a year and found there was no difference in the eating habits of diners at those situated in King County and those who used ones outside the area where the rule was introduced. — No difference: ‘Traffic light’ health label on a pizza. The total number of sales and average calories per transaction were unaffected by the menu labelling, reports the American Journal for Preventive Medicine. — As part of health care reform, the US
government is planning a nationwide launch of mandatory nutrition information
at the point of purchase for fast-food chains with twenty or more outlets.”

Besides confusing fine-print nutrition labeling on supermarket foods, products often feature pseudo-health claims in much larger print on the fronts of packages. A “low fat” desert product may be taken as healthy when in fact it contains a large amount of sugar. An “all natural” product may contain an unhealthily large amount of fructose sugar. And a number of toxins are perfectly natural. Another news story this week was Front-of-Package Labels Hide Truth: 8-of-10 kids’ foods flunk nutrition standards. “Parents want healthy food for their kids, and they want accurate information to guide them. — But parents are being fundamentally misled, says Prevention Institute’s new study, released today through Strategic Alliance. Claiming Health: Front-of-Package Labeling of Children’s Food examined products with front-of-package labeling–those products that food companies choose to identify as healthier. Claiming Health found that 84% of products studied failed to meet basic nutritional standards. — Contrary to the claims on the labels, study findings reveal: – More than half (57%) of the study products qualified as high sugar, and 95% of products contained added sugar. – More than half (53%) were low in fiber. – More than half (53%) of products did not contain any fruits or vegetables; of the fruits and vegetables found, half came from just 2 ingredients – tomatoes and corn. – 24% of prepared foods were high in saturated fats. – More than 1/3 (36%) of prepared foods & meals were high in sodium.”

Banning junk foods in schools and playgrounds

A news story that appeared last week was WHO calls for junk food ban in schools, playgrounds, as reported by AFP: “GENEVA — Junk food should not be sold in schools and playgrounds, the World Health Organization said Friday in a series of recommendations aimed at promoting a healthy diet and cutting child obesity. — However it fell short of calling for a ban on advertising directed at children for foods high in saturated fats, sugars or salt, opting instead to ask member states to “consider the most effective approach to reduce” such marketing. — The non-binding recommendations will be put to a high-level meeting on the prevention and control of non-communicable diseases during September’s General Assembly in New York, WHO officials said. — “Settings where children gather should be free from all forms of marketing of foods high in saturated fats, trans-fatty acids, free sugars or salt,” said the UN health agency. — “Such settings include, but are not limited to, nurseries, schools, school grounds and pre-school centres, playgrounds, family and child clinics and paediatric services and during any sporting and cultural activities that are held on these premises,” it added . — Some 43 million pre-school children are obese or overweight, according to WHO data. — “Children throughout the world are exposed to marketing of foods high in fat, sugar or salt, which increases the potential of younger generations developing noncommunicable diseases during their lives,” it said. — Six out of ten deaths every year are due to cardiovascular diseases, cancers, diabetes and chronic lung diseases, the WHO warned, pointing out that a common factor of the four main diseases is poor diet.”

Another headline this week was USDA Proposes Cutting Fatty Foods From School Lunches. “According to government data, almost a third of all kids under 19 are obese. In an effort to curb the trend, the USDA is proposing new guidelines on the nutritional content of school lunches. — The plan would place a limit on calories, saturated fat content, and sodium on school meals. It would also ban trans-fats entirely. — Servings for starchy foods, like French fries or tater tots would be limited to one per week. — “I probably wouldn’t have school lunches anymore,” said Kya, a student at Turtle Bay School. “I would kind of eat a little bit.” — Other students say they already enjoy the vegetables. — “Really, I wouldn’t care because they’re still good,” said Cloe, another Turtle Bay student. — The school already offers fresh fruits and a salad bar, something Turtle Bay principal Linda Lawhon should make the transition easier. — “For our students, they already have the choices of greens and fruits that are available to them and they usually choose to take from the salad bar almost daily,” said Lawhon. “I don’t think it’ll be much of a change for them.” — Before the guidelines are finalized, the USDA is requesting input from the public on how to make school lunches both healthier and appealing to kids. Those interested in providing input can do so at Regulations.gov.”

A related headline was School nutrition-guideline changes sought to fight obesity. “Calling it not only a national health issue but also a military one, Agriculture Secretary Tom Vilsack on Thursday proposed to overhaul the nutrition guidelines for public school meals for public school meals for the first time since 1995, when Americans were mostly alarmed by the fat content of food. — The proposed rules are far more wide-ranging and would gradually reduce sodium, limit starchy vegetables, ban most trans fats, require fat-free or lowfat milk, increase whole grains, add more fruits and vegetables, and, for the first time, limit the number of calories children consume daily. The guidelines are consistent, Vilsack said, with first lady Michelle Obama‘s Let’s Move initiative, which promotes healthier eating for children. — “The numbers are rather troubling. We have today nearly a third of our youngsters at risk of being obese or, in fact, are obese in our schools,” he said in a conference call Thursday. He added: “If we do not get our hands around the obesity epidemic in the United States by the year 2018, we will face nearly $344 billion of additional health-care costs. That’s money we won’t be able to spend on innovation and creating jobs and improving our education system.”

Another related story was USDA unveils new school lunch rules “– U.S. Department of Agriculture Secretary Tom Vilsack unveiled Thursday what he called a series of “fundamental changes” his agency plans to make to the country’s school nutrition program. The changes are designed to stem the effects of childhood obesity. — Recognizing the financial burden the nutrition guidelines can place on a school system, in terms of increased equipment, personnel and ingredient costs, Vilsack said his agency has set aside more than $380 million of additional nutrition program funding each year for schools that comply with the new rules. — That funding increase mainly comes in the form of a 6 cent per meal increase in the amount of money the government pays schools through its free- and reduced-price lunch program, which helps students from low-income families across the country eat the meals served in their cafeteria. The government currently pays schools in the 48 contiguous states between $2.32 and $2.89 for each lunch they serve through the program and $1.18 and $1.76 for each breakfast.” It is not clear to me whether this program will be funded by congress.

The guidelines are just guidelines and are not necessarily followed. The Boston Globe in a January 23 2011 Sunday editorial School lunches get healthier commented “While the USDA deserves a pat on the back for updating its guidelines for the first time in 15 years, it should consider further updates, including restrictions on the amount of sugar and processed foods a school can serve. Increasing the number of apples kids consume is beneficial, but not if they are covered in caramel sauce. In short, the USDA should create incentives, and provide encouragement, for schools to provide healthy meals with fresh ingredients, without tilting too far toward food-police tastelessness. — That may be harder than it would appear. According to the USDA’s own estimates, up to 35 percent of schools are out of compliance with even current federal regulations. While schools that follow the new guidelines will get an extra 6 cents per meal from the agriculture department, some school-lunch advocates doubt this rate will cover the extra cost of healthier lunch options. Schools that already meet national standards will surely adapt to the new guidelines, and their students will be healthier for it. But those struggling to keep up with even the outdated regulations may need more help — and a stronger nudge — to stop dishing out so many fries.”

I suspect that these approaches related to school lunches are likely to have a slow but growing effect. Already a number of school districts have moved to better diets and some have even thrown out their soft drink machines. On the other hand, needed change is slow and partial and it may take 20-30 more years for a full effect to be felt. The food industry has traditionally been very effective in blunting USDA regulations they don’t like.

Banning junk food advertising

Another approach involves banning advertising of junk foods, advertising that appears in vast quantities on TV programs viewed by children. One headline that appeared in the press last week was World leaders to discuss junk food ad ban at UN. “The U.N. health agency says world leaders will discuss efforts to clamp down on junk food marketing to children when they meet in New York on Sept 19-20. — The World Health Organization says heads of state will use the U.N. General Assembly meeting to talk about limiting the number and type of ads that children are exposed to. — WHO says 43 million preschool children around the world are overweight or obese. Experts talk of a “fat tsunami” that is already causing millions of premature deaths each year. –Bjorn-Inge Larsen of the Norwegian Directorate of Health told reporters Friday that he expects voluntary measures limiting junk food advertising to eventually evolve into laws banning the practice in the same way that has occurred with tobacco.”

Another headline was Health officials eye junk food ad ban. “It may be time to ban ads for foods high in salt, sugar and trans fats that target children, international health officials say. — Voluntary measures to limit junk food ads eventually could evolve into legislated bans just as tobacco bans did, Bjorn-Inge Larsen of the Norwegian Directorate of Health told reporters Friday in Geneva. — Domestic laws might not work since so many ads reach children through international TV channels, Larsen said. — Non-communicable diseases such as cancer, diabetes and heart and lung disease will top the agenda when heads of state meet at the United Nations General Assembly in New York on Sept. 19 to 20. — About 43 million children aged five and under around the world are overweight or obese, according to the UN health agency. — WHO officials are consulting with food makers such as Coca-Cola, General Mills, Kellogg, Kraft, McDonald’s, Mars, Nestle, Pepsico, Unilever and the World Federation of Advertisers on drawing up a code of conduct that restricts marketing of unhealthy products to children under the age of 12.”

Despite the horrors of the situation involved for 43 million children, I suspect this approach of banning advertising will not get very far. That is because the advertising at stake is worth billions of dollars to gigantic media companies and because the product sales are worth many tens (or hundreds) of billion dollars to the food giants involved. Do I think these companies are more influential in political circles than the World Health Organization and all the nutritional do-gooders in the world combined? Yes, I do.

Wal-Mart move to healthier foods

It takes a giant to influence other giants like food packagers, and Wal-Mart is definitely a giant, the world’s largest retailer with about half of its sales in foods. “Retailing behemoth Wal-Mart Stores, Inc., operates 4404 stores in the U.S. (including Sam’s Club) and 8838 worldwide, at last count(ref).” The news was all over the world’s press three mornings ago. From a Bloomberg news report Wal-Mart to Stock Healthier, More Affordable Foods to Help Fight Obesity: “Wal-Mart Stores Inc., the world’s largest retailer, said it is joining first lady Michelle Obama’s anti-obesity campaign by stocking healthier foods. — The company said it will reformulate thousands of packaged food items by 2015, reducing the salt content by 25 percent and sugar content by 10 percent, and will remove all remaining industrially produced trans fats and partially hydrogenated oils. — “No family should have to choose between food that is healthier for them and food they can afford,” Bill Simon, chief executive officer of U.S. stores for Bentonville, Arkansas-based Wal-Mart, said in a statement. — With more than 140 million customer visits each week, Wal- Mart “is uniquely positioned to make a difference” by making healthy foods more affordable, said Simon, who joined Mrs. Obama for an event today in Washington. — The first lady said Wal-Mart’s initiative is a victory for parents and children that will give families more information and more opportunities to eat more healthy foods. She said that because of company’s size, the move “has the potential to transform the marketplace.” — Wal-Mart said it plans to reduce prices to save customers about $1 billion a year on fresh fruits and vegetables. The company said it would develop “strong criteria” for simple front-of-package seals that would help consumers identify healthier foods, including whole-grain cereals, whole-wheat pastas or unsweetened canned fruit. — Andrea Thomas, Wal-Mart’s senior vice president of sustainability, said lower costs will come in part from planned efforts to make the entire supply chain more efficient, including steps to stock more produce from local farmers to reduce shipping costs.”

I am not claiming the step will make all or even most of Wall Mart foods healthier. For example, it appears the company is doing nothing about sugar-infused soft drinks. But I believe it is an important step that is likely to have immense impact. Wal-Mart suppliers will have to modify their manufacturing processes and product mixes to meet Wal-Mart’s criteria. Once they do this to produce healthier products they will want to sell those products through other retailers as well. Everybody will benefit from more efficient supply chains for healthier food. And other retailers are likely to want to sell foods even healthier than Wal-Mart’s. A health-positive feedback loop is likely to be set off.

Wrapping it up

Almost all the above-quoted news stories appeared in the course of only one week, last week. So my take is on the whole optimistic:

– Obesity is now recognized as a major public health issue and there is good general awareness of what has to be done to address the situation. It seems displacing unhealthy foods is the next big public health issue after slowing tobacco smoking.

– A vital and growing health food industry offers affluent consumers many choices (over $3 billion in 2011 for the health food and supplement store sector alone(ref)). The public-health crosshairs are now on low-cost mass-distributed foods and on the fast food and school lunch sectors.

– The public health issue of foods is being tied to economic issues like future health care costs and national defense, and to the emotional issue of wellbeing of our children.

– Public health measures for providing healthier foods for children and adults are in the advanced planning and initial action phases involving all levels of government, giant corporations and tiny businesses, school systems of every size and households such as my own.

– Even fast-food companies are opting into the push for better nutrition. Three weeks ago McDonalds added oatmeal to their breakfast menu. “But now the stakes are much higher. The government is beating on their door, telling them that it is no longer politically correct to serve greasy, high in fat foods to the general public(ref).”

– For now, dietary suggestions are contained in the anti-aging anti-aging lifestyle regimen in my treatise. Also, for comments on a number of healthy as well as unhealthy foods, see my blog entry Diabetes Part 2: Lifestyle, dietary and supplement interventions

– The food industry is likely to play a mixed role, progressive as well as regressive. Providers of more healthy foods will exercise influence counterbalancing the influence of providers of unhealthy and junk foods. And, big food companies do not want to find themselves facing gigantic lawsuits in the future like cigarette companies are facing now.

– While we are seeing the start concerted action there is a long way to go. Further measures are likely to identified and implemented throughout the century as our science and knowledge and public awareness related to nutrition improves. The point is, the healthier-food train has already left the station.

Those of you who have put together jigsaw puzzles know that every once in a while a piece is found that links together several seemingly unrelated chunks of the puzzle.  The sirtuin SIRT3 is doing that for several chunks of the aging/longevity puzzle, showing a key way in which the Oxidative Damageand the Mitochondrial Damagetheories of aging fit together and how these fit with the known life-extending properties of calorie restriction, with the role of exercise, response to stress and PGC – 1alpha, cell metabolism, several age-related diseases including obesity, diabetes and Alzheimer’s Disease, the FOXO gene family, and actions of P53,  and with the actions of the dietary polyphenol resveratrol.  Much of the relevant research is quite recent. 

Preamble  

(From the introduction to Mitochondrial SIRT3 and heart disease) “The desire to live longer and probably forever has long fascinated mankind. Concoctions to prevent ageing and maintain youth have been described in medical books of ancient civilizations, including Charaka Samhita, the most ancient textbook of Ayurveda (an Indian system of traditional medicine), which is believed to have been written centuries before the birth of Christ. It seems our forefathers found a way to live longer and healthy by undergoing calorie restriction, a diet regimen that is considered to be impractical for modern society where food is surplus and time is scarce. Even though vaccination, antibiotics, better child care, and early disease-detection techniques in combination with modern drugs have helped us to increase our average lifespan, the quest to increase maximal lifespan still remains elusive. The major advances in ageing research that we have witnessed in the past two decades are the rediscovery of benefits of calorie restriction, and the delineation of the molecular mechanism involved in its protective effects. Many studies have proposed that the beneficial effect of calorie restriction is mediated through a set of genes collectively called sirtuins (SIRT1–7).1” 

Mitochondrial sirtuins – focus on SIRT3 

In humans, there are at least seven sirtuins (SIRT1–7), proteins  with diverse actions including the regulation of metabolism and chromatin structure, DNA repair and preservation of genomic integrity.  I have discussed actions of SIRT1 and SIRT6 in several previous blog entries (ref)(ref)(ref)(ref).   Lifespan extension has been linked to actions of sirtuins in various publications(ref).   

SIRT3 is a mitochondrial protein that serves to deacetylate acetyllysine-modified proteins in mitochondria 

From the 2010 publication Mitochondrial sirtuins  “Three sirtuins, SIRT3, 4 and 5, are located within the mitochondrial matrix. SIRT3 and SIRT5 are NAD(+)-dependent deacetylases that remove acetyl groups from acetyllysine-modified proteins and yield 2′-O-acetyl-ADP-ribose and nicotinamide. SIRT4 can transfer the ADP-ribose group from NAD(+) onto acceptor proteins. Recent findings reveal that a large fraction of mitochondrial proteins are acetylated and that mitochondrial protein acetylation is modulated by nutritional status. This and the identification of targets for SIRT3, 4 and 5 support the model that mitochondrial sirtuins are metabolic sensors that modulate the activity of metabolic enzymes via protein deacetylation or mono-ADP-ribosylation.” 

The 2007 publication Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation reports “Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.”

Expression of SIRT3 is controlled by diet and exercise 

The 2009 publication Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle reports “SIRT3 is a member of the sirtuin family of NAD(+)-dependent deacetylases, which is localized to the mitochondria and is enriched in kidney, brown adipose tissue, heart, and other metabolically active tissues. We report here that SIRT3 responds dynamically to both exercise and nutritional signals in skeletal muscle to coordinate downstream molecular responses. We show that exercise training increases SIRT3 expression as well as associated CREB phosphorylation and PGC-1alpha up-regulation. Furthermore, we show that SIRT3 is more highly expressed in slow oxidative type I soleus muscle compared to fast type II extensor digitorum longus or gastrocnemius muscles. Additionally, we find that SIRT3 protein levels in skeletal muscle are sensitive to diet, for SIRT3 expression increases by fasting and caloric restriction, yet it is decreased by high-fat diet. Interestingly, the caloric restriction regimen also leads to phospho-activation of AMPK in muscle. Conversely in SIRT3 knockout mice, we find that the phosphorylation of both AMPK and CREB and the expression of PGC-1alpha are down regulated, suggesting that these key cellular factors may be important components of SIRT3-mediated biological signals in vivo.”

Cellular stress causes SIRT3 to translocate from the nucleus to the mitochondria and to be highly expressed in brown adipose tissue

The 2007 publication SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress reports “SirT3 levels have been shown to correlate with extended life span, to localize to the mitochondria, and to be highly expressed in brown adipose tissue. — In humans, SirT3 exists in two forms, a full-length protein of approximately 44 kDa and a processed polypeptide lacking 142 amino acids at its N terminus. We found that SirT3 not only localizes to the mitochondria, but also to the nucleus under normal cell growth conditions. Both the full-length and processed forms of SirT3 target H4-K16 for deacetylation in vitro and can deacetylate H4-K16 in vivo when recruited to a gene. Using a highly specific antibody against the N terminus of SirT3, we found that SirT3 is transported from the nucleus to the mitochondria upon cellular stress. This includes DNA damage induced by Etoposide and UV-irradiation, as well as overexpression of SirT3 itself.”

There are two isoforms of SIRT3 (in mice at least) with somewhat different properties

As time progresses more and more of the detailed structure and workings of SIRT3 are being discovered.  The 2010 publication Characterization of the murine SIRT3 mitochondrial localization sequence and comparison of mitochondrial enrichment and deacetylase activity of long and short SIRT3 isoforms relates “SIRT3 is identified as the major mitochondrial deacetylase. Two distinct isoforms of the murine SIRT3 have been identified with the short isoform having no recognizable mitochondrial localization sequence (MLS) and the long isoform having a putative MLS. A recent study questions the mitochondrial deacetylase activity of this short isoform. In contrast, the long isoform has been shown to be predominantly mitochondrial with robust deacetylase activity.  In this study, we investigate whether the amino-terminus of the long SIRT3 isoform is a legitimate MLS and evaluate in-situ mitochondrial deacetylase activity of both isoforms. We confirm the presence of long and short isoforms in murine liver and kidney. —  Despite lower mitochondrial expression of the short isoform, the capacity to deacetylate mitochondrial proteins and to restore mitochondrial respiration is equally robust following transient transfection of either isoform into SIRT3 knockout embryonic fibroblasts. How these alternative transcripts are regulated and whether they modulate distinct targets is unknown. Furthermore, in contrast to exclusive mitochondrial enrichment of endogenous SIRT3, overexpression of both isoforms shows nuclear localization. This overexpression effect, may partially account for previously observed divergent phenotypes attributed to SIRT3.” 

PGC1-alpha is an upstream activator of SIRT3.  Further, SIRT3 suppresses mitochondrial ROS and promotes mitochondrial biogenesis

As discussed in the blog entry PGC-1alpha and exercise, the protein PGC1-alpha (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) appears to be the mediator of the health benefits produced by exercise, and plays an important role in the metabolism of both white and brown fat.  PGC1-alpha also plays a role in the the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination.  This protein also appears to be implicated in the regulation of cellular cholesterol homoeostasis, control of blood pressure, and the development of obesity. 

The 2010 publication Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesisreports “(PGC-1alpha) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1alpha induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.  — RESULTS: Here we show that PGC-1alpha strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. —  Furthermore, Sirt3 was essential for PGC-1alpha-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1alpha in C(2)C(12) myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1alpha on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1alpha on mitochondrial biogenesis in C(2)C(12) myotubes. — CONCLUSION: Our results indicate that Sirt3 functions as a downstream target gene of PGC-1alpha and mediates the PGC-1alpha effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation.”

Calorie restriction results in increased expression of SIRT3 which produces a stronger mitochondrial defense against free radicals resulting in mammals living longer 

A November 2010 publication  Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction links SIRT3 to the longevity benefits of calorie restriction.  “Here, we report that CR reduces oxidative DNA damage in multiple tissues and prevents AHL in wild-type mice but fails to modify these phenotypes in mice lacking the mitochondrial deacetylase Sirt3, a member of the sirtuin family. In response to CR, Sirt3 directly deacetylates and activates mitochondrial isocitrate dehydrogenase 2 (Idh2), leading to increased NADPH levels and an increased ratio of reduced-to-oxidized glutathione in mitochondria. In cultured cells, overexpression of Sirt3 and/or Idh2 increases NADPH levels and protects from oxidative stress-induced cell death. Therefore, our findings identify Sirt3 as an essential player in enhancing the mitochondrial glutathione antioxidant defense system during CR and suggest that Sirt3-dependent mitochondrial adaptations may be a central mechanism of aging retardation in mammals.” 

Thus, actions of SIRT3 link up the Oxidative Damageand the Mitochondrial Damagetheories of aging.  The research strongly suggests that minimizing mitochondrial oxidative damage can extend life spans.  Further, three practical sirtuin-related ways of extending life spans appear to be 1. increasing expression of SIRT3 via exercise, 2.  Promotion of expression of SIRT1 via resveratrol and  3.  calorie restriction which appears to affect both SIRT1 and SIRT3. 

According to the November 2010 Science Daily report on this research Scientists Ferret out a Key Pathway for Aging, “It has been well documented in species ranging from spiders to monkeys that a diet with consistently fewer calories can dramatically slow the process of aging and improve health in old age. But how a reduced diet acts at the most basic level to influence metabolism and physiology to blunt the age-related decline of tissues and cells has remained, for the most part, a mystery. — Now, writing in the Nov. 18 online issue of the journal Cell, a team of scientists from the University of Wisconsin-Madison and their colleagues describe a molecular pathway that is a key determinant of the aging process. The finding not only helps explain the cascade of events that contributes to aging, but also provides a rational basis for devising interventions, drugs that may retard aging and contribute to better health in old age. — “We’re getting closer and closer to a good understanding of how caloric restriction works,” says Tomas A. Prolla, a UW-Madison professor of genetics and a senior author of the new Cell study. “This study is the first direct proof for a mechanism underlying the anti-aging effects we observe under caloric restriction.” — The Wisconsin study focuses on an enzyme known as Sirt3, one of a family of enzymes known as sirtuins, which have been implicated in previous studies in the aging process, gene transcription, programmed cell death and stress resistance under reduced calorie conditions. In mammals, including humans, there are seven sirtuins that seem to have wide-ranging influence on cell fate and physiology. — Sirt3 has been less studied than other members of the sirtuin family, but the new study provides “the first clear evidence that sirtuins have anti-aging effects in mammals,” according to John M. Denu of UW-Madison’s Wisconsin Institute for Discovery and a senior author of the report. — The Sirt3 enzyme, Denu explains, acts on mitochondria, structures inside cells that produce energy and that are the sources of highly reactive forms of oxygen known as free radicals, which damage cells and promote the effects of aging. Under reduced-calorie conditions, levels of Sirt3 amp up, altering metabolism and resulting in fewer free radicals produced by mitochondria. — “This is the strongest and most direct link that caloric restriction acts through mitochondria,” says Prolla, who has studied the effects of reduced calorie diets on aging and health for more than a decade. “Sirt3 is playing a surprisingly important role in reprogramming mitochondria to deal with an altered metabolic state under caloric restriction.”

SIRT3 regulates P53-induced cell senescence

The 2010 publication p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylasereports “A hallmark of p53 function is to regulate a transcriptional program in response to extracellular and intracellular stress that directs cell cycle arrest, apoptosis, and cellular senescence. Independent of the role of p53 in the nucleus, some of the anti-proliferative functions of p53 reside within the mitochondria [1].  p53 can arrest cell growth in response to mitochondrial p53 in an EJ bladder carcinoma cell environment that is naïve of p53 function until induced to express p53 [2]. TP53 can independently partition with endogenous nuclear and mitochondrial proteins consistent with the ability of p53 to enact senescence.In order to address the role of p53 in navigating cellular senescence through the mitochondria, we identified SirT3 to rescue EJ/p53 cells from induced p53-mediated growth arrest. Human SirT3 function appears coupled with p53 early during the initiation of p53 expression in the mitochondria by biochemical and cellular localization analysis. Our evidence suggests that SirT3 partially abrogates p53 activity to enact growth arrest and senescence.  Additionally, we identified the chaperone protein BAG-2 in averting SirT3 targeting of p53 -mediated senescence. These studies identify a complex relationship between p53, SirT3, and chaperoning factor BAG-2 that may link the salvaging and quality assurance of the p53 protein for control of cellular fate independent of transcriptional activity.”

SIRT3 protects in-vitro fertilized embryos against P53-mediated developmental arrest induced by oxidative stress

According to the 2010 publication Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest, “When Sirt3-knockdown embryos were transferred to pseudopregnant mice after long-term culture, implantation and fetal growth rates were decreased, indicating that Sirt3-knockdown embryos were sensitive to in vitro conditions and that the effect was long lasting. Further experiments revealed that maternally derived Sirt3 was critical. Sirt3 inactivation increased mitochondrial ROS production, leading to p53 upregulation and changes in downstream gene expression. The inactivation of p53 improved the developmental outcome of Sirt3-knockdown embryos, indicating that the ROS-p53 pathway was responsible for the developmental defects. These results indicate that Sirt3 plays a protective role in preimplantation embryos against stress conditions during in vitro fertilization and culture.”

SIRT3 affects gene expression in two longevity-related gene families: the sirtuins and FOXO

The 2008 publication SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expressionrelates “Cellular longevity is a complex process relevant to age-related diseases including but not limited to chronic illness such as diabetes and metabolic syndromes. Two gene families have been shown to play a role in the genetic regulation of longevity; the Sirtuin and FOXO families. It is also established that nuclear Sirtuins interact with and under specific cellular conditions regulate the activity of FOXO gene family proteins. Thus, we hypothesize that a mitochondrial Sirtuin (SIRT3) might also interact with and regulate the activity of the FOXO proteins. To address this we used HCT116 cells overexpressing either wild-type or a catalytically inactive dominant negative SIRT3. For the first time we establish that FOXO3a is also a mitochondrial protein and forms a physical interaction with SIRT3 in mitochondria. Overexpression of a wild-type SIRT3 gene increase FOXO3a DNA-binding activity as well as FOXO3a dependent gene expression. Biochemical analysis of HCT116 cells over expressing the deacetylation mutant, as compared to wild-type SIRT3 gene, demonstrated an overall oxidized intracellular environment, as monitored by increase in intracellular superoxide and oxidized glutathione levels. As such, we propose that SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway.”

SIRT3 blocks the cardiac hypertrophic response in mice via a FOXO-related pathway

The 2009 paper Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice states “Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased expression of SIRT3 has been linked to an extended life span in humans. Here, we have shown that Sirt3 protects the mouse heart by blocking the cardiac hypertrophic response. Although Sirt3-deficient mice appeared to have normal activity, they showed signs of cardiac hypertrophy and interstitial fibrosis at 8 weeks of age. Application of hypertrophic stimuli to these mice produced a severe cardiac hypertrophic response, whereas Sirt3-expressing Tg mice were protected from similar stimuli. In primary cultures of cardiomyocytes, Sirt3 blocked cardiac hypertrophy by activating the forkhead box O3a-dependent (Foxo3a-dependent), antioxidant-encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. Reduced ROS levels suppressed Ras activation and downstream signaling through the MAPK/ERK and PI3K/Akt pathways. This resulted in repressed activity of transcription factors, specifically GATA4 and NFAT, and translation factors, specifically eukaryotic initiation factor 4E (elf4E) and S6 ribosomal protein (S6P), which are involved in the development of cardiac hypertrophy. These results demonstrate that SIRT3 is an endogenous negative regulator of cardiac hypertrophy, which protects hearts by suppressing cellular levels of ROS.”

SIRT3 is a tumor suppressor

The 2010 comment in the Journal Cancer Cell A tumor suppressor SIRTainty outlines the story: “Sirtuin deacetylases are linked to longevity, aging, and stress responses. In this issue of Cancer Cell, Kim et al. show that SIRT3 functions as a tumor suppressor by enhancing the expression of mitochondrial MnSOD. Loss of SIRT3 leads to increased mitochondrial ROS, which then enhances cellular transformation and tumor growth.”  The Kim et al. publication is SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress.  “This work demonstrates that SIRT3(-/-) mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3(-/-) MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3(-/-) MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3(-/-) mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.”

I comment that this work is coincident with a rising focus on mitochondrial ROS damage as a possible and even probable cause for cancer as outlined in the 2010 publicationThe causes of cancer revisited: “mitochondrial malignancy” and ROS-induced oncogenic transformation – why mitochondria are targets for cancer therapy.  “— more recent evidence indicates the importance of two additional key factors imposed on proliferating cells that are involved in transformation to malignancy and these are hypoxia and/or stressful conditions of nutrient deprivation (e.g. lack of glucose). These two additional triggers can initiate and promote the process of malignant transformation when a low percentage of cells overcome and escape cellular senescence. It is becoming apparent that hypoxia causes the progressive elevation in mitochondrial ROS production (chronic ROS) which over time leads to stabilization of cells via increased HIF-2alpha expression, enabling cells to survive with sustained levels of elevated ROS. –. Recent evidence also indicates that the resulting mutated cancer-causing proteins feedback to amplify the process by directly affecting mitochondrial function in combinatorial ways that intersect to play a major role in promoting a vicious spiral of malignant cell transformation. Consequently, many malignant processes involve periods of increased mitochondrial ROS production when a few cells survive the more common process of oxidative damage induced cell senescence and death. The few cells escaping elimination emerge with oncogenic mutations and survive to become immortalized tumors. — ”

SIRT3 plays an important role in cardioprotection

The 2008 publication SIRT3 Is a Stress-Responsive Deacetylase in Cardiomyocytes That Protects Cells from Stress-Mediated Cell Death by Deacetylation of Ku70 relates “We show that, like human SIRT3, mouse SIRT3 is expressed in two forms, a 44-kDa long form and a 28-kDa short form. Whereas the long form is localized in the mitochondria, nucleus, and cytoplasm, the short form is localized exclusively in the mitochondria of cardiomyocytes. During stress, SIRT3 levels are increased not only in mitochondria but also in the nuclei of cardiomyocytes. We also identified Ku70 as a new target of SIRT3. SIRT3 physically binds to Ku70 and deacetylates it, and this promotes interaction of Ku70 with the proapoptotic protein Bax. Thus, under stress conditions, increased expression of SIRT3 protects cardiomyocytes, in part by hindering the translocation of Bax to mitochondria.”

The 2010 publication Mitochondrial SIRT3 and heart disease reports “Although the role of SIRT3 in cell biology is only beginning to be understood, initial studies have shown that SIRT3 plays a major role in free fatty acid oxidation and maintenance of cellular ATP levels. In the heart SIRT3 has been found to block development of cardiac hypertrophy and protect cardiomyocytes from oxidative stress-mediated cell death. Similarly, SIRT3 has been reported to have tumour-suppressive characteristics. In this article, we review the known effects of SIRT3 in different tissues and relate them to the protection of cardiomyocytes under stress.”

Pharmaceutical researchers are investigating interventions for disease conditions based on promoting or inhibiting SIRT3 activity

The October 2010 Harvard University Office of Technology Development  posting Regulation of hypoxia and glycolysis through modulation of SIRT3 activity: SIRT3 activators for cancer metabolism and SIRT3 inhibitors for vascular diseaserelates“Pharmaceutical targeting of the SIRT3 activity may provide a novel therapeutic strategy for the treatment and/or prevention of cancer and vascular disease – SIRT3 has tumor suppressive function and acts by destabilizing HIF1? and reducing the glycolytic metabolism. A small molecule, protein or gene therapeutic that upregulates SIRT3 would reduce the level of glycolytic metabolism and deprive solid tumors of energy, without significantly impacting healthy cells that rely mostly on the TCA cycle. — “

Concluding: 

One impact on me of reviewing these documents is observing that the classical Oxidative damage theory of aging, the first one covered in my treatise, is far from dead.  The SIRT3 research is giving this theory new life and connecting it to newer ones. 

I have set out here to cover some of the high points of SIRT3 research.  However, the field is moving very fast.  I have possibly left important material out and, without doubt, soon there will be much more to report.