AGINGSCIENCES™ – Anti-Aging Firewalls™

Back in 1995 my friends mostly humored me when I told them I was planning to live 165 more years and the secret to my success would be connected with future research that would allow me to extend my telomeres.  “Tele-what?” they said.  “Does that have to do with communications?” This was 10 years after the discovery of telomerase in 1985 by Elizabeth H. Blackburn and Carol W. Greider.   In 1995, the roles of telomeres and telomerase in cell biology was sometimes thought by scientists to be interesting but mostly thought to be of rather peripheral interest.  That is, except for a few visionaries like Michael Fossel who grasped the importance of these topics early-on. Now we know that telomeres and telomerase are of central relevance with respect to cancers, stem cell differentiation and longevity.  And of course Telomere shortening is one of the most important theories of aging covered in my Anti-Aging Firewalls treatise.  

Today, Rockefeller University announced the winners of the fifth annual Pearl Meister Greengard Prize to Blackburn, Greider and Vicki Lundblad of the Salk Institute for Biological Studies.  The prize is being awarded for the discovery of telomerase and for studies of its regulation.  In 2008 Blackburn and Greider received the Paul Erlich and Ludwig Darmstaedter Prize, the leading science prize in Germany, for the same work.  Greider won the 2007 Dickson Prize in Medicine for her contribution. Blackburn and Greider also received the Wiley Prize in Biomedical Sciences in 2006.  The two shared the Louisa Gross Horwitz Prize 1n 2007, and with Jack W. Szostak received the Lasker Prize in 2006.  The honors and prizes are likely to keep rolling in.  It is interesting that it has required more than 20 years for the seminal work of Blackburn and Greider to receive the acknowledgement it deserves.  Some of the other advanced longevity research going on today may likewise not be fully acknowledged until 20 or more years from now.

The suggestions in my Anti-Aging Firewalls treatise, for following certain lifestyle patterns and taking certain supplements for longevity, are based on scientific research rather than simply on folk remedy lore or conventional wisdom.  But what is the nature of this scientific research on which I base my suggestions?  It can be of several different kinds, including:

1.     Macroscopic studies of large populations.  These studies involve looking for correlations among selected factors.  An example is a study of centenarians on Okinawa, an island where an unusual number of people live a long time.  This study of some 900 centenarians, their families and control groups helped identify specific genes and gene polymorphisms that appear to contribute to longevity as well as contributing lifestyle factors, including eating relatively few calories, exercising and not smoking or consuming alcohol.  And of course in Okinawa people eat lots of fish and drink green tea.  These studies can reveal interesting correlations and clues.  For example, the Okinawa study established that the centenarians studied have genetic polymorphisms that place them at lower risk for inflammatory and autoimmune diseases. 

2.     Large population cohort studies.  These are studies that follow coherts of thousands, tens of thousands or even hundreds of thousands of people over 10-20 or longer year periods, like the Woman’s Health Initiative or the Framingham Heart Study or the Bogalusa Heart Study.  Again, they look for correlations such as the effect of smoking or being overweight on cancer incidence or longevity. These studies have been particularly useful for establishing the validity of conventional wisdom as related to longevity, such as clearly documenting the effect of having a positive mental attitude on longevity.

3.     Controlled clinical trials.  These are carefully controlled double-blind studies typically pursued for drug certification that proceed in phases.  They may typically  involve anywhere from a few dozen to thousands of carefully selected people over a test periods of several months for the final phase.  They are usually very narrowly focused and yield limited information with respect to longevity.  For example, a list of clinical trials for patients diagnosed with gliablastoma, an incurable brain disease, can be found here.  These trials are very specific with respect to substance being tested, patient conditions and their relationship to other therapies.  Clinical trials typically cost tens or hundreds of millions of dollars so there is no incentive for a drug company to study a promising natural substance that is in the public domain. Also, for longevity purposes, a six-month study is not likely to tell much.  If we wanted to test some kind of longevity concoction that we thought would double human lifespans, a clinical trial would have to be run for 40-100 years to yield meaningful results.   

4.     Animal experiments.  Mice and rats are genetically very similar to humans but live only 2-3 years, so are excellent subjects for longevity-related experiments.  The studies can be quite technical.  Here is an example relevant to the cell nuclear factor NF-kappaB known to be relevant to human longevity: Maintenance of NF-κB Activation in T-Lymphocytes and a Naive T-Cell Population in Autoimmune-Prone (NZB/NZW)F1 Mice by Feeding a Food-Restricted Diet Enriched with n-3 Fatty Acids We know of several approaches that can extend the normal lifespan of mice by 30% to 50%  We are not sure how many of these approaches will scale-up to work for humans but these experiments are providing valuable clues and are a source of optimism for longevity aficionados like me.

5.     In-vitro and in-vivo studies of cell populations.  There is a great numer of experimental studies going on that look at specific cell populations under particular conditions that that have a bearing on longevity.  For example, many such studies look at neurogenesis and adult stem cell differentiation as impacted by specific gene activation cascades and particular proteins, or as stimulated by certain dietary substances.  These studies can yield specific nuggets of insight such as the roles of key proteins and activation factors like INK4a, P-53, and NF-kappaB. Again, there are very many of these studies and they can be quite technical each yielding a single piece of the immense longevity puzzle.  An example related to eating pigmented fruits is A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer PC3 cells in vitro and in vivo: involvement of nuclear factor-kappaB signaling.

6.    Synthesis and review studies.  These are studies that consider results together from possibly many experiments and look at them in terms of the powerful forefront areas of genetics, cell signaling cascades, gene activation, genomics and epigenomics.  They also draw on knowledge from related areas, such as computational genomics, epigenomic and protein-folding databases.   Some of these studies are starting to link gene expression factors to longevity, such as in SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF- B-Dependent Gene Expression and Organismal Life Span.  We have identified various signaling cascades directly related to longevity such as the Insulin Growth Factor 1 axis.  This axis seems to be the one that is involved in achieving longevity via calorie restriction.  And it also seems to be activated by taking the supplement resveratrol. 

All the actions and supplements in the anti-aging firewalls are based on one or more of these kinds of research. Most are supported by several of these kinds of research and, for a few firewall elements, supporting research exists on all of the above levels.  For example, the value of green tea as a cancer preventative is established on all of the above levels as is the value of regular hard exercise for longevity in general. 

It is clear that radical life extension—to beyond age 110—must depend on knowledge associated with the newer and more sophisticated ongoing studies in epigenetics, molecular biology, and medical research.  Research suggests that certain substances already in the anti-aging regimen may act powerfully toward this end, but what they can actually do for human life extension will not be clearly known for many years.  These substances include:

–         Use of r-alpha lipoic acid and acytl-l-carnitine to address cell mitochondrial longevity and inhibit unwanted cell apoptosis (self-destruction).

–         Use of resveratrol or resveratrol homologs to activate the SIRT1 and FOXO3 “longevity” genetic pathway, the pathway known to confer life extension due to calorie restriction

.–         Use of astragaloside IV or cycloastragenol  to activate telomerase expression in body cells, possibly immortalizing these cells and conferring longevity to the associated organs.

.–         Use of combinations of green tea, curcumin, and other phyto-substances for their powerful cancer-preventative effects and cardiovascular benefits that operate through genetic mechanisms.

Longevity research is a ride into uncharted territory.  The ride is moving faster and faster and I believe we will see breaking the 120-year ultimate human age limit in my lifetime.  As a matter of fact, I am planning to be one of the breakers.  

There were a number of press reports this morning on a finding based on the Woman’s Health Initiative data, a study of over 100,000 woman that started in 1994.  The study shows that a piece of conventional wisdom often found in touchie-feely books is in fact correct: positive mental attitude enhances longevity; negative attitude reduces it.  Pessimistic woman, those with a dim outlook on life, were 30 percent more likely to die from heart disease and 14 percent more likely to die from any cause than optimistic ones.  Cynically hostile women, ones who tend to mistrust people, were 23 percent more likely to die from cancer and 16 percent more likely to die from any cause.   Optimistic women were also less likely to smoke cigarettes or have high blood pressure or, diabetes.  Yet again, the message is that your mental state can create epigenomic modifications, DNA methylation on your chromosomes and histone acetylation/deacetylation modifications, and therefore alter your gene expression pattern and therefore affect your longevity.  There is no more mystery to it.

The first P is Perspective.  To start, you need to have a perspective that a very long and healthy life is possible, that you want it and that you are willing to take whatever actions as are necessary to have it. 

The second P is Participation.  Participate actively in managing your health and creating your longevity.  This involves being knowledgeable about your own conditions and the options available to you and seeking out and taking advantage of resources needed for your wellbeing and longevity.  These could include securing good foods, companionship, intellectual challenges, exercise, dietary supplements and knowledgeable medical assistance, to start the list. 

The third P is Proactivity.  Simply put, go out there and create your own health and longevity.  And keep creating it. It won’t happen automatically. 

The fourth P is Prevention.  There are multiple ways to avoid diseases and slow or stop aging processes outlined in my Anti-Aging Firewalls treatise.  Take advantage of them while you are healthy.  Once you have a cancer, a serious cardiovascular problem, diabetes or senile dementia, your options will be much narrower and not necessarily very good ones. 

The fifth P is Perplexity.  Yes, perplexity!  The processes required for health and longevity are very complex and many are still poorly understood.  You have to do a lot of things to keep healthy and make it to a very old age.   The roadmaps are relatively poor and frequently change.  There are many options and blind alleys, phony nostrums and cures that can take you off course.  Be prepared to be perplexed and confused along the way.  If you take on your longevity as a serious problem to be solved and grapple with it, this will just by itself enhance your neurogenesis and help you keep going longer.  (See the previous blog entry Tough learning and neuron survivability). 

The sixth P is Personalization.  Your health and possible longevity is a highly personalized matter, different than anyone else’s.  This means you need to get to know and monitor your own body’s health parameters.  To start, get regular lipid and and C-reactive protein profiles.  Monitor your heart rate and blood pressure if appropriate.  If you have a blood glucose level issue, you can monitor that daily too.   And take appropriate actions.   If your CRP is off-scale and indicative of inflammation you can increase your use of anti-inflammatory supplements, for example.  And pay special attention for incipient disease conditions like mild arthritis, trigger finger or carpal tunnel syndrome.  These too indicate inflammatory conditions.  If you are getting frequent colds or suffering from minor infections, these could indicate a weakened immune condition.  You might need more rest or to take immune system strengthening supplements.  If you are gaining weight or feeling lethargic you might want to exercise more, etc. And as the availability of gene-chip profiling for susceptibility to disease conditions increases, be prepared to take advantage of this technology for knowing yourself too. 

The seventh P is perserverence.  You need to persevere with your good eating habits, avoiding junk or bad food, non-smoking, daily exercise and taking your supplements, paying attention to all the factors impacting on your health and lonngevity.  Otherwise you might not live long or healthily enough to take advantage of new longevity breakthroughs from molecular biology or nanomedicine as they come along.

In a previous post Protein origami and aging I mentioned how proteins fold themselves up in complex shapes as soon as they are formed and how stress often leads to the misfolding of proteins, a process that can accelerate with age creating vulnerability to a number of dysfunctional and disease conditions.  Misfolded proteins are generally bad news.  In fact, I asserted that if I were to add a 15th theory of aging to my Anti-Aging Firewalls treatise it would possibly be Misfoldings of proteins.  I have posted a long and rather technical note on the protein folding subject in that treatise.  Some proteins have very complex topologies involving knots and slipknots. It turns out that the processes of folding can involve intermediate configurations with slipknot transition states and the folding trajectory can even involve backtracking.  The presence of these can affect the probability of successful folding.  Modeling of the folding process for complex proteins is starting to yield insight of how it can work. 

The March 2009 issue of Scientific American reports research on what happens to neurons after neurogenesis in rats. Under normal circumstances thousands of new neurons are generated every day in the dendrate gyrus of the hippocampus. Within a few weeks most of those neurons die if the animal’s life is unremarkable. However, if the animal is confronted with a sufficiently daunting and important learning task and successfully learns something complex and new, then many of the neurons will stay alive. This appears to be particularly applicable to learning that affects future behavior. The “use it or lose it” concept for maintaining cognitive capability seems to relate directly to the survivability of neurons.  See the neurogenesis discussion in my Anti-Aging Firewalls paper.

More telomerase tidbits

When I started following telomere/telomerase-related research 15 years ago, this was an arcane subject. Research publications related to it were extremely far-between and only a few far-out thinkers saw it as having a lot to do with human longevity. Nowadays, hardly a day goes by without new research related to telomeres or telomerase coming to my attention. Here are two tidbits.

– Leukocyte telomere length like HDL cholesterol is a predictor of susceptibility to coronary artery disease.

A study of 662 males and females followed over a a 29.8 year period, the Bogalusa Heart Study, showed that a) longer telomere length is positively correlated with higher levels of HDL cholesterol, b) shorter telomere length and lower levels of HDL: are highly correlated with increase in the risk for atherosclerosis and susceptibility to coronary artery disease, and c) shortening of longer telomeres is significantly reduced when higher levels of HDL is present. The simplest explanation is that low levels of HDL increase the level of oxidative risk and that cell reproduction is accelerated to replace cells damaged by oxidation and therefore average telomere lengths are higher when there is more HDL. I suspect there may be more to it than that. Namely, telomere lengths may also affect cholesterol levels. Another analysis of data from the Heart and Soul Study looked at patients with stable coronary artery disease. “ — patients in the lowest quartile of (leukocyte) telomere length remained at significantly increased risk of death compared to those in the highest quartile. Patients in the lowest quartile of telomere length were also at significantly increased risk of HF (Heart Failure) hospitalization –. This study suggests that leukocyte telomere length may be a predictor of mortality risk that provides information not included in the usual predictors such as cholesterol levels. These studies stop short of stating what to me seems obvious – that active intervention to maintain telomere lengths could possibly reduce the risk of susceptibility to coronary artery disease and the death rate of those that already have it.

– The longest living birds have very long telomeres and manage to keep them long. This was brought to my attention by reader of this blog Res and is covered in the discussion under the Naked Mole Rat item. Because of its importance I repeat the substance here. Res brought to my attention these citations relevant to the telomere lengths of different bird species and storm petrels in particular:
–
– http://mbe.oxfordjournals.org/cgi/content/abstract/msm244v1
http://www.bucknell.edu/x45446.xml
http://biblioteca.universia.net/ficha.do?id=22484361

My initial response to Res was: Extremely interesting articles. I get the following messages: 1. Since the storm petrels are tiny birds always on the go and live up to 40 years, this tends to knock out the theory that lifespan is centrally shaped by rate of metabolism. One explanation given for the long lifespan of the naked mole rat is that its existence is very laid back and it mostly sleeps. It is the opposite for the bird. 2. The accumulated oxidative damage theory of aging also does not seem very applicable for these birds since high metbolism generates a lot of free radicals. 3. The evidence connected with these and other birds is that long initial telomere lengths and telomere length maintenance are factors very correlated with longevity, e.g. a boost to the telomere shortening theory of aging. 4. Despite telomere lengths growing with age and low cancer rates these birds still die, suggesting that some other form of aging is operational and life-limiting for them.

About a week ago I updated the telomerase section in the Anti-Aging Firewalls treatise with a new perspective on the Telomere shortening theory of aging.

I can’t say that you can.  But I also can’t say that you can’t.  Actually everything that you think and feel can change your biochemical makeup and could affect your longevity.  That is one message of the previous post on Epigenetics and Epigenomics.  It has long been a part of conventional wisdom that a positive mental attitude can contribute to stress minimization and therefore longevity.  The message of Epigenomics is that your mental state can affect the DNA methylation and histone modifications on your chromosomes and therefore alter your gene expression pattern and therefore affect your longevity.  I go for that but of course also go for the active program for longevity laid out in my Anti-Aging Firewalls treatise.

Human traits and gene expression are affected by signals that can result from interaction with our environment, including what a mother eats and the social conditioning received by a young child.  Imagine a control system of biomolecular switches that can turn expression of genes on or off.  And imagine that those switches can be controlled by what we eat, do or experience in any way or even think.  Further imagine that the positions of those switches, genes being turned on or off, can be inherited.  If you can imagine those things you have imagined the science called Epigenetics.  Epigenetics and epigenomics are concerned with the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence in DNA.  The subjects are a bit dense but are of considerable and growing importance for disease and aging research.  Here is a primer:

Epigenetics may be concerned with both heritable and non-heritable changes in gene activity and expression and also stable, long-term alterations in the gene transcriptional potential of a cell.  While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome(ref). 

Events in the early development of an organism can affect the phenotype (observable characteristics and traits) creating biological changes in the epigenome (the overall epigenetic state of a cell or organism).   This is a way of saying that genes by themselves do not determine our destinies or the diseases we get or the way we age.  Simply put, there is a lot more going on in a higher organism than can be explained by genetics.  Humans physical traits are determined not only by what is in our genes but also by factors that affect gene expression and changes in gene regulation such as are evident in the growth of an embryo or in differentiation of stem cells.  For example, what are the factors that allow a single fertilized human egg to continue dividing into all of the specialized cell types and organs – blood cells, neurons, bone cells, muscle cells, etc.?  That information is both genomic and epigenomic information not provided just by the sequence of genes in a strand of DNA.  Aging itself appears to be an epigenomic phenomenon, with the typical pattern of gene expression changing in the course of a lifetime. 

Like protein folding, a subject I discussed recently, epigenomics is a frontier area where little is yet known compared to what is yet to be learned and where there is a lot of excitement.  It is starting to change the ways we look at many things in biology and medicine.  There is increasing agreement that truly understanding diseases and susceptibilities to diseases is a matter of both genetics and epigenetics seen in the context of environment – and that goes for cancers, neurological and cardiovascular disorders, psychiatric disorders as well as virtually all other diseases.

One area where epigenomic effects are evident is the case of monozygotic twins.  Despite being genetically identical they can be very different in their phenotypes and susceptibilities to many diseases, such as diabetes, schizophrenia and Huntington’s disease and can weigh different amounts even when fed the same diet.  Some of these characteristics may be inherited.  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. The implications of this little experiment and similar ones are staggering for those of us concerned with dietary supplementation.  Dietary supplementation of parents can result in their offsprings having an altered biochemical makeup and altered physical characteristics.  And a corollary is that dietary supplementation can cause permanent as well as temporary changes in ourselves as well.  I will probably take 50 to 100 years before we will know for sure which dietary supplements create what results in our offsprings, and in the meantime we will have to play it by ear or depend on animal studies which are yet to be conducted.

Genetic imprinting is a process that has been known for some time.  For certain genes, either the mother’s version or the father’s version is selected by an offspring.  This process of selection can profoundly affect disease susceptibility and is now believed to be epigenetically controlled instead of a random one. For example the imprinted KCNK9 potassium channel gene is frequently over-expressed in breast cancers.  Some researchers believe that our ability to diagnose and treat many diseases that have a genetic origin will depend on our identifying the human imprinted genes and determining how they are epigenetically regulated.

One area of epigenomic research is looking for where and how epigenomic information is stored in humans.  The study involves both experimental and computational approaches.  Methylation (the chemical replacement of a hydrogen atom with a methyl group) of  DNA on chromosomes is one of the important encoding mechanisms.  A number of projects have been concerned with mapping the methylation landscape of the human genome, commencing with the Human Epigenome Project that was started in 2000.  The Human Epigenome Pilot Project has “  — recently completed a pilot study of the methylation patterns within the Major Histocompatibility Complex (MHC) – a region of chromosome 6 that is associated with more diseases than any other region in the human genome.”  They believe the project will provide unprecedented insight, particularly applicable to autoimmune diseases. A 5-year initiative involving four research centers was funded recently called the NH Epigenome Roadmap and plans to study 100 cell types, and there are a number of other epigenomic study initiatives. New fast sequencers allow rapid analysis of methylation profiles but the challenge is very complex because diseases may correspond to alterations in both genomic and methylation profiles.  Much is being learned but there is very much more yet to be learned.   

Already, certain DNA methylation changes are known to be associated with aging and others associated with certain diseases like lupus and scleroderma.   It is possible that yet-another theory of aging could be added to my Anti-Aging Firewalls treatise at some point called Changes in DNA methylation profiles.

The impact of epigenetic knowledge is expected to be felt across the board in medicine, including in psychiatry.  Stress and aggression are known to induce epigenetic changes in mice, and addiction does too.  Cocaine exposure, for example, is known to create epigenetic changes in specific areas in the brain. How a mother treats her small daughter may generate epigenomic changes that condition how that girl behaves throughout the rest of her life, and also condition the behavior of her daughter’s daughter.

Epigenomics provides a layer of information applicable to diseases and aging beyond that available in genomics, but there are yet-other layers to consider including proteomics (understanding structures and functions of proteins including factors such as folding) and transcriptomics (understanding the set of all messenger RNA molecules, or “transcripts,” produced in one or a population of cells).  The hope is that by mastering genomics, epigenomics, proteomics and transcriptomics and how they work together in specific instances we will gain mastery over all diseases and the process of aging.  We have a ways to go.

If you have a background in molecular biology and genetics, a more technical discussion of epigenetics can be found here. 

If I were to add a 15^th theory of aging to this Anti-Aging Firewalls treatise, it would possibly be Misfoldings of proteins.  The basic notion is that stress often leads to the misfolding of proteins, a process that can accelerate with age creating vulnerability to a number of disease and dysfunctional conditions.  Misfolded proteins cannot perform their intended functions, can create active mischief and probably contribute to aging in multiple ways.  This is a relatively new and complex area of molecular biology that is to a large extent still unexplored.  I have posted a long and rather technical note on the subject here in my Antiaging Firewalls Treatise.