AGINGSCIENCES™ – Anti-Aging Firewalls™

In my earlier post How am I doing I said “All of this is just a start though.  I not only want a full head of hair; I want it to be black instead of gray.”   Also, in an earlier post Why does your hair turn gray? I described research that pointed to hydrogen peroxide as the culprit for hair turning gray.   Newly-reported research looks in a different direction and deeper, shedding light on the underlying cell-level cause of graying hair. Melanocytes are cells that live in hair follicles of mammals that produce melanin, the pigment responsible for hair color. Normally, the melanocytes gives hair its characteristic color of youth – black in my case.  (Melanin is also responsible for skin color and the color in moles, freckles, suntan and the cancer melanoma.  Older people may develop light or dark patches on their skin due to too-little or too-much melanin.)

The new research suggests that gray or white hair is due to age-related depletion of melanocytes which is a direct result of depletion of melanocyte stem-cells(MSCs) which in turn is the result of DNA damage.  It has been known for some time that “ – hair graying is caused by defective self-maintenance of MSCs(ref).”  These stem cells, also living in hair follicles, can normally both reproduce making new stem cells and differentiate into mature color-producing melanocytes. The new research based on experimentation with mice suggests that DNA damage to MSCs causes them to stop reproducing and instead terminally differentiate into melanocytes.  As the melanocytes in hair follicles die off, there are no new melanocytes to replace them because there are no more MSCs to make them.  The result is loss of hair color, in other words, white or gray hair.  The researchers discovered that when mice were exposed to intense radiation, MSCs stopped self-reproducing and terminally differentiated into melanocytes.  Consequently, the fur on the mice turned from brown to gray.  It is thought that the cessation of self-reproduction of genetically damaged MSCs could be an evolutionary protection against cancers.

Wanting black hair, this poses a challenge for me.  If my hair follicle MSCs have died off, how do I get them back?  There seems to be no short term answer though there may be one in the longer term.

It appears that there is a larger issue at stake here when it comes to aging.  The reader may want to review my discussion of the 14^th theory of aging Decline in Adult Stem Cell Differentiation.  What the new research says with respect to that theory is 1. that there is not only the issue of decline in differentiation to be concerned with as part of aging but also an issue of stem cell self-renewal, and 2.  At least some stem cells stop self-renewal in the presence DNA damage.

Both immediate and long-term anti-aging interventions appear to be suggested.  In the immediate outlook the obvious approach is to use antioxidants to minimize DNA damage.  Millions of people are already doing this.  See the Cell DNA Damage theory of aging in my treatise as well as the associated firewall discussion.  For the longer term, it may be possible to induce Pluripotent Stem Cells (iPSC) to selectively differentiate in a controlled manner into adult stem cells, including MSCs.  See the earlier post on this Blog Rebooting cells and longevity.  If a practical iPSC approach could be found to generating MSCs in hair follicles, I might get my black hair back.  Meanwhile I stay tuned for more research in this area.  I do not plan to use shoe polish.

Personally I love spicy foods, and ginger, curcumin and garlic have long been parts of my Anti-Aging Firewalls dietary supplement regimen.  There is an extensive body of literature supporting the health and potential anti-aging effects of spices.  Sage (salvia officinalis), thyme (thymus vulgaris), oregano (oreganol) and rosemary (rosmarinus officinalis) all have antioxidant properties(ref)(ref).  But the basic “reasoning for seasoning” appears to be inhibition of NF-kappaB(ref).  Control of expression of NF-kappaB is of course a major strategy for longevity proposed in the firewall for the Programmed Epigenomic Changes theory of aging.

To start off, hot chili peppers (capsaicin), ginger (gingerol) and turmeric (curcumin) are all inhibitors of NF-kappaB, and thereby regulate COX-2 and inflammation(ref)(ref)(ref)(ref).  The same general statements can be made for black pepper (piperine); it inhibits NF-kappaB expression, is an anti-inflammatory, etc.(ref).  The list goes on to include cloves, anise, cumin, fennel and garlic (ref).  Many of the active ingredients in these spices are also thought to be chemopreventative of cancers(ref) and have numerous other health benefits, curcumin being an example(ref).  “Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, and of liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain(ref).”

So, in general I feel free to spice-up my foods as much as I want.  If you haven’t already read it, see the blog post Red wine, hot peppers and my uncle Gigi.

If you are used to reading research abstracts full of abbreviations for genes and proteins, how about this one?  Do you think you get the general idea?  Or do you just tune out on anything that sounds so technical?  The title actually relates to the Battle of Britain (BOB) during the early 1940s, particularly how US-built fighter planes intercepted German bombers over the English Channel when the Luftwaffe was mounting daily raids on London.  The P38, P39 and P40 were US WWII fighter planes, the BF-110, HE111 and HE177 were German bomber planes and (SC)1000 was a one-ton German Sprengbombe Cylindrich general demolition bomb.  The fact reported had to do with the longevity of hundreds of thousands of people and the fate of Western Civilization was possibly at stake.  The message is that when reading biomolecular-genetic research reports, you can be badly mistaken if you think you get the general idea but don’t really understand what is going on. 

Increasingly, researchers are investigating genetic fixes for otherwise intractable conditions.  For example, see the recent blog entry A genetic fix for obesity?  Now, a possible genetic fix is suggested that addresses HIV, a fix that undoes an ancient mutation present in humans.   

The work is reported in a recent online publication Reawakening Retrocyclins: Ancestral Human Defensins Active Against HIV-1.  The good news is that primates including us humans have a gene that produces retrocyclin, antiviral peptide proteins in the defensin family of proteins.  Retrocyclin is a powerful anti-viral substance and “was recently shown to strongly inhibit HIV entry into human cells by blocking the interaction of viral proteins with their cellular receptors(ref).”  The bad news is that way back in evolutionary history our branch of primates, including gorillas and chimps, experienced a  “nonsense mutation” in the retrocyclin gene, so it fails to do its job and produce the retrocyclin proteins.  A nonsense mutation is one where a codon encoding an amino acid is changed into a premature stop codon.  This means the protein-making machinery in the cell ribosomes reading mRNA instructions as if they were on a tape stops before it should resulting in an incomplete protein being made or no protein at all.  

The research challenge was to see if repairing the 7 million-year old nonsense mutation in the human retrocyclin gene could restore retrocyclin production and block entry of HIV into human cells like it does in Old World monkeys. “To determine whether human cells have retained the capacity to make retrocyclin protein, Venkataraman et al. corrected the premature stop codon mutation in a copy of the human retrocyclin gene. Next, they inserted the corrected gene into human promyelocytic cells, and looked to see if protein was produced from the gene. They found that cells harboring the corrected gene could make a protein similar to the monkey version of retrocyclin. But could human retrocyclin block HIV infection? Indeed, extracts made from cells containing the corrected gene could reduce HIV growth, and so could the retrocyclin protein purified from these extracts. Collectively, these results suggest that human cells have a potentially important—but latent—mechanism to protect against HIV(ref).” 

So, there is a possibility that a genetic fix could be created to mobilize retrocyclin to protect against HIV.  But the researchers identified an alternative and much easier approach, and that is to use aminoglycosides instead to override the erroneous stop signals in human retrocyclin protein production. “An aminoglycoside is a molecule composed of a sugar group and an amino group.  Several aminoglycosides function as antibiotics that are effective against certain types of bacteria. They include amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin, and apramycin(ref).”  Aminoglycosides “– don’t block protein creation in human cells but cause ribosomes to make occasional errors—like missing stop codons. The authors found that treating human cells with aminoglycosides allowed the cells to make retrocyclin at sufficiently high levels to inhibit infection by HIV(ref).”

Hmm.  What this seems to say is that taking one or several of those antibiotics might help protect against HIV infection.  The research says “– we exploited the ability of aminoglycoside antibiotics to read-through the premature termination codon within retrocyclin transcripts to produce functional peptides that are active against HIV-1(ref).”  One possibility would be to make topical creams containing such antibiotics to inhibit sexual transmission of HIV.  Of course there are likely to be other disease risks associated with ignoring protein-making stop instructions and taking these antibiotics.  In any event, human activation of retrocyclin seems to be a promising avenue of research for prevention of HIV infections and AIDS.  If it can be done safely and economically, tens of millions of lives and billions or trillions of dollars could be saved.

In anti-aging blog circles the answer seems to be YES, causing endless discussion of how people who want to take these substances and the telomerase activator astragaloside IV should time their doses so the effect of the expensive telomerase activator is not cancelled out.  But what does the actual research say?  I decided to spend a few hours having a fresh look at this question.  Personally, I have resistance to forgoing the cancer protection and other benefits of resveratrol, curcumin and other phyto substances for days at a time in order to benefit from the astragaloside IV.  I decided to focus on published experimental research results, not opinions.

To start with, as far as cancer cells are concerned the answer to the question seems definitely to be YES.  Here are a few of the many relevant citations: “Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro(ref),” “Effect of resveratrol on proliferation and telomerase activity of human colon cancer cells in vitro(ref).” “Curcumin inhibits telomerase activity in human cancer cell lines(ref),” “Curcumin-induced apoptosis in human leukemia cell HL-60 is associated with inhibition of telomerase activity(ref), Inhibition of telomerase activity and induction of apoptosis by curcumin in K-562 cells(ref),” “Molecular mechanism of curcumin induced cytotoxicity in human cervical carcinoma cells(ref),”  “EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells,” leading to suppression of cell viability and induction of apoptosis(ref).” The tea polyphenols EGCG and EGC repress mRNA expression of human telomerase reverse transcriptase (hTERT) in carcinoma cells(ref).”  “Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG(ref).” 

This is just a starting list of research studies for each of these substances that make two central points:  1. The substance leads to apoptosis in the cancer cell line studied, and 2. The substance down-regulates the expression of telomerase in that cancer cell line.  In other words the substance down-regulates the expression of telomerase induced by the cancer itself and leads the cancer to kill itself.  Note that these substances do NOT lead to apoptosis in normal cells.   

Although the research seems to be sparser for other phyto substances in my anti-aging firewalls regimen that are reputed to inhibit telomerase expression [like ginkgo biloba and ashwagandha (Withania somnifera)], the same two central points seem to apply to them as well.

So, what makes us think these substances down-regulate the expression of telomerase in normal cells?  Looking into that question, my first observation is that while there is a great deal of research linking the listed substances to telomerase inhibition in cancer cells, there is very little to no such research on how those substances relate to exogenously activated telomerase in normal cells.  A few studies jump out suggesting that these substances may do the opposite: promote telomerase activity at least in progenitor cells.  For example: “Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms(ref),” “Immortalization of epithelial progenitor cells mediated by resveratrol(ref), “Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity(ref).” A review study on cell growth regulation states “In addition, curcumin also exerts indirect control over cell division such as inhibition of telomerase activity. Remarkably, some studies point toward a selective growth-inhibitory effect of curcumin on transformed cell lines compared to nontransformed cell lines(ref).”

The bottom line of my mini-review is that I found:

1.   What appears to be many dozens or hundreds of articles that answer YES to the question in terms of experimental results but only for cancer cells,

2.   Several statements of YES opinion for normal cells, including opinions from reputable researchers, but without backup experimental evidence.

3.   Virtually NO actual experimental research studies that say YES for normal cells.  Such may well exist.  It is just that I could not find them in the time I set aside for looking.  My guess is that the opinions come from assuming that telomerase-inhibiting research on cancer cells applies to normal cells as well.

4.   A few experimental studies that definitely say NO for normal progenitor cells. At lease resveratrol and ginko activates telomerase expression in some progenitor cell lines.

My personal answer to the question is “I don’t know because there is no published research on what these substances do in normal cells when combined with a telomerase activator.  There seems to be no evidence for answering YES in the case of normal cells and some evidence for answering ‘NO, the opposite is true.’”  So I am not going to worry too much about taking resveratrol, curcumin, green tea, etc. the same day I take astragaloside IV.  Besides, it all seems to be working.  See my recent post How am I doing?

Suppose a simple genetic fix could allow us humans to gorge on fatty junk foods and avoid obesity.  Something like that has been tried on mice and apparently works according to research reported today(ref).  The idea was to introduce a plant-based genetic pathway in mice that increases metabolism of fatty acids and induces resistance to diet-related obesity.  Certain plants have a set of enzymes called the ‘glyoxylate shunt’ not present in mammals.  A team at UCLA “ —  cloned bacteria genes from Escherichia coli that would enable the shunt, then introduced the cloned E. coli genes into the mitochondria of liver cells in mice; mitochondria are where fatty acids are burned in cells.” 

“The researchers found the glyoxylate shunt cut the energy-generating pathway of the cell in half, allowing the cell to digest the fatty acid much faster than normal.  “Mice expressing the shunt showed resistance to diet-induced obesity on a high-fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation(ref).”

I imagine a similar approach might well work in humans, making us genetically a little more like plants.  I anticipate concerns about the practicality, safety and ethical aspects of such genetic modifications of humans, although the fast food people would probably love to see this one happen.  And it could be a great approach to solving the current obesity epidemic.

A year after first publishing the online treatise Anti-Aging Firewalls – The Science And Technology Of Longevity and six months after initiating this blog, it’s a good time to ask the question “How am I doing with my anti-aging firewalls program?”   First, there is the personal subjective response.  Coming up on 80:

·        I am experiencing high energy, good health and am feeling good about life.

·        My creativity, productivity, ability to think things through and social participation are as high as ever.

·        My level of activity including physical exercise remains high.

·        In photos, I look about the same age as in ones taken 10-20 years ago.

·        I pass my cholesterol, CRP and other annual blood tests and physical exam procedures with flying colors.

·        Compared to a year ago I believe my sexual libido is a bit increased, and my eyesight a bit better and keener.   

·        On the other hand, my hearing has gone a bit downhill.

·         There is definitely more grey hair growing on the top of my scalp now.  I started balding before 50 and there were hardly any hairs left on top a year ago.  At the current rate in another 18 months I will have a full head of hair again, for the first time since I was about 50.  

So, on the whole I feel very good about my anti-aging program so far.  Telomerase activation was one of the big changes in the last year and I think it might largely be responsible for some of the effects including improved eyesight and hair growth.   

From an intellectual viewpoint, I am also satisfied about how my view of aging has been maturing.  Devoting countless hours to reviewing the aging-related research literature, writing over 90 posts in this blog and generating numerous enhancements to my treatise, I have been learning a lot about the advanced sciences that are informing us about aging.  And, drawing on different viewpoints I have been increasingly seeing aging from a systems perspective.   

All of this is just a start though.  I not only want a full head of hair; I want it to be black instead of grey.   I want to look and move and hear like I did when I was 45.  And there is tons more for me to learn about biochemistry, molecular biology, genetics, genomics and the other omics.  And progress over the last year has sharpened my thirst for more basic breakthroughs, more understand of how the theories of aging interrelate and better anti-anti-aging interventions.  Please stay tuned.  There will be more.

In this blog and in my treatise Anti-Aging Firewalls – The Science And Technology Of Longevity I try to steer a mid course between scientific over-simplification and loosing readers because the content is too technical for them to fathom.  I am aware that many readers possibly have to struggle to follow the details of some of my posts.  The purpose of this particular post is to remind my reader that longevity science involves biomolecular and genetic complexity that is much deeper than what I discuss, or for that matter, that I am competent to discuss. 

It is pretty much agreed that extraordinary longevity will require activation of critical longevity-related cell signal transduction pathways. Yet, those pathways are incredibly complex.  As an example, here is a listing of papers in the current online issue of the Journal of Biological Chemistry having to do with Mechanisms of Signal Transduction.  I list the titles to illustrate the naked underlying complexity involved.  And there are thousands of other journals reporting research results every month of equal complexity that have potential relevance for longevity.  I am not suggesting you read these items but you might find the titles interesting for illustrating the biomolecular detail involved.  I am necessarily highly selective in what I cover in this blog. 

Subhashini Srinivasan, Fozia Mir, Jin-Sheng Huang, Fadi T. Khasawneh, Stephen C.-T. Lam, and Guy C. Le Breton The P2Y₁₂ Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a G_i-independent Increase in cAMP Levels.  J. Biol. Chem. 2009 284: 16108-16117. First Published on April 3, 2009; doi:10.1074/jbc.M809780200 [Abstract] [Full Text] [PDF] 

Matthew J. Betzenhauser, Larry E. Wagner, II, Hyung Seo Park, and David I. Yule ATP Regulation of Type-1 Inositol 1,4,5-Trisphosphate Receptor Activity Does Not Require Walker A-type ATP-binding Motifs
J. Biol. Chem. 2009 284: 16156-16163. First Published on April 22, 2009; doi:10.1074/jbc.M109.006452 [Abstract] [Full Text] [PDF]  

Xiang Li, George S. Baillie, and Miles D. Houslay Mdm2 Directs the Ubiquitination of β-Arrestin-sequestered cAMP Phosphodiesterase-4D5.  J. Biol. Chem. 2009 284: 16170-16182. First Published on April 16, 2009; doi:10.1074/jbc.M109.008078 [Abstract] [Full Text] [PDF] [Data Supplement 1]  

Chunmei Wang, Runzi Qi, Nan Li, Zhengxin Wang, Huazhang An, Qinghua Zhang, Yizhi Yu, and Xuetao Cao Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression
J. Biol. Chem. 2009 284: 16183-16190. First Published on April 17, 2009; doi:10.1074/jbc.M109.002105 [Abstract] [Full Text] [PDF] [Supplemental Data] 

Kam-Leung Siu, Kin-Hang Kok, Ming-Him James Ng, Vincent K. M. Poon, Kwok-Yung Yuen, Bo-Jian Zheng, and Dong-Yan Jin Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKK Complex
J. Biol. Chem. 2009 284: 16202-16209. First Published on April 20, 2009; doi:10.1074/jbc.M109.008227 [Abstract] [Full Text] [PDF]  

David Grandy, Jufang Shan, Xinxin Zhang, Sujata Rao, Shailaja Akunuru, Hongyan Li, Yanhui Zhang, Ivan Alpatov, Xin A. Zhang, Richard A. Lang, De-Li Shi, and Jie J. Zheng Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled
J. Biol. Chem. 2009 284: 16256-16263. First Published on April 21, 2009; doi:10.1074/jbc.M109.009647 [Abstract] [Full Text] [PDF] 

Philip J. Dittmer, Jose G. Miranda, Jessica A. Gorski, and Amy E. Palmer Genetically Encoded Sensors to Elucidate Spatial Distribution of Cellular Zinc
J. Biol. Chem. 2009 284: 16289-16297. First Published on April 10, 2009; doi:10.1074/jbc.M900501200 [Abstract] [Full Text] [PDF] [Supplemental Data]  

Sandra Mueller, Gunnar Kleinau, Mariusz W. Szkudlinski, Holger Jaeschke, Gerd Krause, and Ralf Paschke The Superagonistic Activity of Bovine Thyroid-stimulating Hormone (TSH) and the Human TR1401 TSH Analog Is Determined by Specific Amino Acids in the Hinge Region of the Human TSH Receptor
J. Biol. Chem. 2009 284: 16317-16324. First Published on April 22, 2009; doi:10.1074/jbc.M109.005710 [Abstract] [Full Text] [PDF]  

Alyson C. Howlett, Amy J. Gray, Jesse M. Hunter, and Barry M. Willardson Role of Molecular Chaperones in G Protein β5/Regulator of G Protein Signaling Dimer Assembly and G Protein β Dimer Specificity
J. Biol. Chem. 2009 284: 16386-16399. First Published on April 17, 2009; doi:10.1074/jbc.M900800200 [Abstract] [Full Text] [PDF]    

Petri Ala-Laurila, M. Carter Cornwall, Rosalie K. Crouch, and Masahiro Kono The Action of 11-cis-Retinol on Cone Opsins and Intact Cone Photoreceptors
J. Biol. Chem. 2009 284: 16492-16500. First Published on April 22, 2009; doi:10.1074/jbc.M109.004697 [Abstract] [Full Text] [PDF]    

Rosalyn P. Johnson, Ahmed F. El-Yazbi, Morgan F. Hughes, David C. Schriemer, Emma J. Walsh, Michael P. Walsh, and William C. Cole Identification and Functional Characterization of Protein Kinase A-catalyzed Phosphorylation of Potassium Channel Kv1.2 at Serine 449
J. Biol. Chem. 2009 284: 16562-16574. First Published on April 22, 2009; doi:10.1074/jbc.M109.010918 [Abstract] [Full Text] [PDF]  

Jonathan Barroso-González, Nabil El Jaber-Vazdekis, Laura García-Expósito, José-David Machado, Rafael Zárate, Ángel G. Ravelo, Ana Estévez-Braun, and Agustín Valenzuela-Fernández The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities
J. Biol. Chem. 2009 284: 16609-16620. First Published on April 22, 2009; doi:10.1074/jbc.M109.005835 [Abstract] [Full Text] [PDF] [Supplemental Data]  

  Mohammad Husain, Leonard G. Meggs, Himanshu Vashistha, Sonia Simoes, Kevin O. Griffiths, Dileep Kumar, Joanna Mikulak, Peter W. Mathieson, Moin A. Saleem, Luis Del Valle, Sergio Pina-Oviedo, Jin Ying Wang, Surya V. Seshan, Ashwani Malhotra, Krzysztof Reiss, and Pravin C. Singhal Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis
J. Biol. Chem. 2009 284: 16648-16658. First Published on April 21, 2009; doi:10.1074/jbc.M109.008482 [Abstract] [Full Text] [PDF]  

Evgeny A. Zemskov, Elena Loukinova, Irina Mikhailenko, Richard A. Coleman, Dudley K. Strickland, and Alexey M. Belkin Regulation of Platelet-derived Growth Factor Receptor Function by Integrin-associated Cell Surface Transglutaminase
J. Biol. Chem. 2009 284: 16693-16703. First Published on April 22, 2009; doi:10.1074/jbc.M109.010769 [Abstract] [Full Text] [PDF] [Supplemental Data]   

Research reports continue to appear that identify linkages between theories of aging I have covered in the treatise Anti-Aging Firewalls – The Science And Technology Of Longevity.  The latest shows a link between the Telomere shortening and damage, the Programmed epigenomic changes, the Susceptibility to cancers and the Decline in adult stem cell differentiation theories.  The common element is epigenetic modification in the Ink4a-Arf locus.  These genes encode the proteins P16(Ink4a) and P19(Arf) which prevent inactivation of the tumor suppressor RB, and P19ARF, which stabilizes the tumor suppressor P53.    

According to the Telomere shortening and damage theory, when telomeres in somatic cells become too short as a result of successive cell divisions the cell is likely to go into a state of cell senescence where it can no longer divide and does not die. Senescent cells tend to strongly express the anti-cancer genes P16(INK4a) and P19(Arf).   So, these genes offer senescent cells an alternative to becoming malignant.  But senescent cells are likely to become bad neighbors sending out signals that can lead to organ dysfunction or degeneration.  Further, in discussing the Programmed epigenomic changes theory,   I mentioned how p16(INK4a) tends to be increasingly expressed with age and how it tends to inhibit the differentiation of adult stem and progenitor cells.  Thus, P16(INK 4a) plays a central role in the Decline in adult stem cell differentiation theory.  Also, it “induces an age-dependent decline in islet regenerative potential(ref).” Increasing expression of P16(INK4a) with age therefore tends to compromise organ repair and regeneration. P16(INK4a) provides a central defense against cancer in the case of senescent cells and is therefore important in the Susceptibility to cancers theory of aging.  

There is another side to cell senescence, however:   “Senescent cells, particularly senescent stromal fibroblasts, secrete factors that can disrupt tissue architecture and/or stimulate neighboring cells to proliferate. We suggest that senescent cells can create a tissue environment that synergizes with oncogenic mutations to promote the progression of age-related cancers(ref).”  I have mentioned the paradoxical role of P16(INK4a) in the Blog post Dr. Jekyll and-Mister Hyde Proteins. The new research, reported in a publication entitled Polycomb Mediated Epigenetic Silencing and Replication Timing at the INK4a/ARF Locus during Senescence provides a new link between the theories and hints at anti-aging intervention that can address all of these theories. 

The language of the publication like the title is highly technical, so I attempt a simplified explanation of the basic findings here.  Basically, in young cells, Polycomb group proteins act on the INK4/ARF gene regulatory domain so as to the keep the expression of P16(INK4a) turned off, the gene is silenced.  In senescent cells, however, there are epigenetic modifications (DNA and histone methylation changes) which block the inhibitory actions of the polycomb group proteins, so the P16(INK4a) and Arf genes are activated.  So, cell senescence leads to another pro-aging effect, the activation of the P16(INK4a) and Arf genes. Earlier, in the Anti-Aging Firewalls treatise I identified the increasing expression of P16(INK4a) with aging as a biomarker of aging and possible cause of age-related changes.  In fact, I identified this as possibly one of the major aging mechanisms according to the Programmed epigenomic changes theory.  At that time, however, I had no notion of how possibly to slow or halt the accumulation of INK4/ARF with age. 

The new results suggest two possible routes of intervention.  The first is to slow or stop cell senescence, something I am already attempting to do.  Since too-short telomeres is the primary cause of such senescence, according to the new research telomerase activation may address both the cell senescence and the accumulation of P16(INK4a) issues.  Personally, I am increasing my daily dose of Astragaloside IV to the 100mg a day provided in the new version of the Astral Fruit supplement. 

A second kind of possible anti-aging intervention with respect to slowing buildup of P16(Ink4a) with age comes to my mind as well.  It is to halt or block the cell and histone demethylation and deactylation patterns associated with cell senescence, specifically the histone deactylation patterns in senescent cells that are associated with blocking the inhibitory actions of Polycomb  proteins on expression of P16(Ink4a).  The molecular biology involved in this particular instance is quite complex(ref).  But it could be that histone deactylase promoters could be useful to limit the expression of P16(Ink4a).  See the recent blog post Histone acetylase and deacetylase inhibitors.  This is a speculation on my part but there could be something to it. 

Here is how it might work.  Suppose your child is born with an incurable disease due to a mutated gene.  After diagnosis, the cure would go like this:  Step 1: hair, blood or skin cells are collected from the patient and allowed to replicate.  This is a standard laboratory procedure. Step 2: the mutated genes in cells in the sample are replaced with corresponding normal genes.  This step involves using techniques from the field of gene therapy.  Several possible methods are being researched for deleting and introducing new genes.  Step 3: the cells are reprogrammed to create induced pluripotent cells, iPS cells that for all practical purposes are like patient-specific embryonic stem cells.  Reprogramming of any cells to pluripotent state, was discussed in a previous post on this blog, Rebooting cells and longevity. The resulting iPS cells are functionally equivalent to  the patient’s original stem cells, but no longer have the genetic defect.  They can differentiate into any cell type given the correct signaling conditions.  Step 4:  The iPS cells are introduced back into the body in such a way as to regenerate organs free of the disease.  For example, if an organ such as the heart has been damaged by the disease, the iPS cells could be introduced so as to regenerate healthy heart tissue.  While some success has been achieved with mice, Step 4 will require significant disease-related research if it is to be used in humans.  Introducing iPS cells into a live organism can lead to tumors such as teratomas if the signaling conditions are not correct.     

Research reported a few days ago shows that for one human genetic disease, Fanconi anemia (FA), steps 1-3 have been successful.  “FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C(ref).”  “Caused by mutations in one of 13 Fanconi anemia (FA) genes, the disease often leads to bone marrow failure, leukemia, and other cancers(ref).” 

The researchers started by collecting hair and skin cells from FA patients, and they ended up producing patient-specific iPS cells that were cured of FA.   Since blood cells are some of the worst affected by FA, they “tested whether patient-specific iPS cells could be used as a source for transplantable hematopoietic stem cells. They found that FA-iPS cells readily differentiated into hematopoietic progenitor cells primed to differentiate into healthy blood cells(ref)”  The researchers have set their sights on going forward to achieve Step 4. 

The prospect is for a simple and elegant approach to treating many, perhaps most, genetic diseases.