Pushing on 80 I am still quite young compared to my intended target age.  But I am already experiencing a major downside of longevity – and that is experiencing the sadness of death or debilitating illness of dear relatives and friends.  I am writing this in Michigan where Marlene, the long-time wife of my dear cousin and virtual-brother Eddie Max, died Sunday.  I flew into Detroit Tuesday and the church ceremony and celebratory dinner were yesterday.  The burial this morning was simple but the feelings shared with Marlene’s descendents were profound. 

I seem to be the last member alive in my generation of my birth family.  Almost all of my dead blood relatives and their spouses died younger than I am now.  Papa, Mamina, Eddie Max, Marlene, Elios, Edward my father, Iris, uncle Edward. my aunts and uncles and cousins Lila, Gigi, Flip, Eros, Laurice, Flora, Elia, – and the list goes on.  An exception was my mother who lived to 93.  And it’s not just about deceased relatives.  My best childhood friend Bobby passed away over 20 years ago and his much-younger wife passed away a few years ago too. 

My sadness and feeling of impotency is sometimes more acute because so many of my younger living friends and relatives are beset with cancers, heart disease, diabetes and the other main killer diseases of our times.  Almost everybody I know is younger than me and most are much younger.  Some a dozen or more years younger than me have already had strokes and heart attacks, stents installed, or multiple bypass surgeries, or have had a lung removed or chemotherapy or surgery for cancers that are still active or could come back.  Some can no longer walk or work and others are incoherent with dementia. 

Do I think many or most of these deaths or illnesses could have been forestalled or at least postponed if these people had taken better care of themselves, had followed the lifestyle and dietary supplement recommendations in my Anti-Aging Firewalls treatise?  Yes, definitely. But I cannot fault them for they followed the patterns and norms of our culture.  Some smoked when they were younger, some were obese and did not exercise, some were consistently unhappy or stressed out or lived on junk food.  And some, perhaps, suffered from bad luck in the genetic draw.  All to my knowledge have had good medical care, but it has been the kind of care that happens after a major problem is discovered, usually too late to correct the basic problem.  

I think I have a health and anti-aging message now that could have helped many of these people if they had received it and taken it to heart five or ten years ago, before they experienced any cancer, heart disease, Alzheimer’s or Parkinson’s Disease, etc.  But I also realize that I did not have the message back then to communicate. 

So much for my thoughts.  Getting back to my feelings, there is a mixture there of sadness,  hope and drive.  The sadness is for the loss of those I loved deeply and who are now gone.  And it is for the suffering and pain of those I now love deeply and see slowly sinking into disease.  There is even a little guilt since I seem to be free of such problems and as active as ever.  I ask myself “why do I deserve such good luck?” even though I know there is more than luck involved.  The hope is of two kinds, first for the recovery of those suffering now – that they should somehow get better.  And second, the hope is that such misery and death can be postponed for others – by an anti-aging program such as mine. 

Finally the drive is to make a difference in the lives of others by my anti-aging activities – to prevent some of the suffering and extend the times of death.  This is an extremely powerful motivator of the work seen in this blog and in my Anti-Aging Firewalls treatise.  A key issue for me now is how to reach my dearest family members and friends who are still relatively healthy with health messages that work.  I want very much to reach them in a way that will empower them to decide they want to live healthier and longer lives and lead them to take the necessary actions.  This will likely not turn out to be easy but it is a task I am taking on.

There seems to be no end to news stories about people 100 and over reporting their secrets to longevity.  Here is a sample from today’s news:

:·        Being kind to people and eating healthy food (age 102)

·        Exercise (age 100)

)·        Taking one day at a time (age 106)

A table of 86 validated supercentenarians – living people 110 years or more older (78 females, 8 males)  – is maintained by a Gerontology Research Group.  I conjecture that in advanced countries the human epigenome is continuing to evolve to support greater general longevity.  Yet, there still seems to be an absolute human lifespan limit of 123 years and breaking through that will require powerful new anti-aging interventions.  So, in addition to daily exercise, eating good food, being kind to people and taking one day at a time, we have a lot of hard research still to do.

What the heck does this mean?  It means an additional jigsaw-puzzle piece of knowledge relevant to the 14^th theory of aging in my Anti-Aging Firewalls treatise, which is Decline in Adult Stem Cell Differentiation.  In this instance Sonic hedgehog (Shh) is not a video game character but is a protein in the hedgehog family named after that videogame character. Shh plays an important role in the division of stem cells and in the formation of organs.  Cell proliferation during development and tissue patterning are in part controlled by the hedgehog pathway and Shh is implicated in the organization of human tissues including the brain.  Proteoglycans are heavily glycosylated glycopoteins which, roughly put, are a class of proteins that have a lot of sugar side chains.  Chondroitin sulphate is a proteoglycan which is an important structural component of cartilage and is also a dietary supplement commonly used to ward off osteoarthritis.  The quoted headline for this posting is from a recent report on research that indicates that Shh contains a proteoglycan-binding domain and that during neural development Shh-proteoglycan interactions regulate tissue growth. If Shh is to induce cell proliferation there apparently must be proteoglycan interactions involved.  However, without additional provisions for proper tissue patterning the proliferation may be without proper cell differentiation, a characteristic of oncogenesis.  What does this mean for longevity?  We don’t exactly know yet. That will depend on how this piece of the jigsaw puzzle fits in with a lot of other pieces to define a pattern that leads eventually to some kind of effective anti-aging intervention. 

A large number of substances in the combined anti-aging firewalls dietary regimen such as green tea extract, ashwagandah, curcumin, resveratrol, olive leaf extract and boswellia seratta are herbal in origin and contain multiple phytochemicals that have pluripotent antiaging effects. Caffeic acid is one such phytochemical, found naturally in coffee and many fruits and herbs.  Studies  show that caffeic acid and its phenethyl ester (CAPE) have multiple positive health and anti-aging impacts.  It has anti-oxidant, anti-inflammatory and anti-bacterial capabilities.  It inhibits the growth of tumor cells and is an inhibitor of nuclear factor kappa beta (NF-kappaB)(ref,ref,ref,ref). CAPE protects brain against oxidative stress and inflammation induced by diabetes in rats(ref).   

Thus, caffeic acid is part of the Anti-Aging Firewalls against Oxidative Damage, Chronic Inflammation, Susceptibility to Cancers and Programmed Epigenomic Changes for starters. It is probably best to get caffeic acid through drinking coffee, foods and herbal supplements rather than taking it directly as a supplement, however, since some earlier studies suggest that the substance may not be completely free of side effects. In the anti-aging firewalls supplements, caffeic acid is found in green tea extract, ginger extract, olive leaf extract and curcumin.  It is also found in cayenne pepper, celery, thyme, tarragon, black tea, cucumbers, apples, potatos, radishes, cabbage, grapefruit, bell peppers and of course coffee.  List of plants containing caffeic acid can be found here and, at the bottom, here.  

Caffeic acid is only one of a large list of phytochemicals with well-researched positive health and anti-aging capabilities.  I may feature others on this blog in the future.

It is now approximately 11 months since I posted the first version of the Anti-Aging Firewalls treatise and it is interesting to identify how the current version of the treatise (which might  be considered to be Version 1.9) is different from the original one.  I have been updating the treatise frequently, sometimes weekly, sometimes daily.  There have been at least a dozen major upgrades and additions over the period including one made today which includes a new section on the Relationships among the theories of aging. Compared to the original, the treatise now:

·        Embodies three additional theories of aging beyond the original 11 ones, Telomere Shortening and Damage, Programmed Epigenomic Changes, and Decline in Adult Stem Cell Differentiation,

·        Embodies significant discussions throughout on the relationships among the theories of aging including the new section on that topic,

·        Has a summary section describing the Combined Lifestyle Regimen,

·        Has a revised  Combined Dietary Supplement regimen with a few substances added to the original list, a deletion or two and revised dosages for a few supplements,

·        Embodies considerable discussion on selected topics including stem cell differentiation, neurogenesis, telomerase-related developments and the role of NF-kappaB,

·        Provides a much larger number of research literature research links backing up key points,

·        Provides considerable more discussion on the roles of certain of the dietary supplements, and

·         Embodies a series of technical notes on subjects like protein folding, telomerase binding proteins, and the firewall against osteoarthritis

These changes reflect two factors: first, developments reported in the research literature during the 11-month period that came to my attention, and second, continuing increase in my own awareness and comprehension.  I believe the net result is improvement in the scientific integrity and comprehensiveness of the treatise.  This Blog, started in January 2009, now includes some 55 major postings and is an important complement to the treatise.  Specifically, I have explored certain topics here that are peripheral to the main treatise, topics like epigenomics, population longevity studies, the economics of longevity and the prospects for living very long. A complete list of postings can be found by clicking on the left on Site Admin and then on the Manage tab.  You might have to be a registered user and login in order to access the entire list.

A step of progress was reported this week in developing better understanding of the molecular processes underlying Alzheimer’s Disease.  For some time it has been known that beta-amyloid protein shows up in excessive quantities in the brains of Alzheimer’s Disease patients and that this protein causes synaptic damage to neurons.  But the mechanism by which damage was inflicted was unknown.  In the new research it was observed that beta-amyloid protein multimers create excessive production of nitric oxide.  This free-radical substance was shown to attack a mitochondrial protein Drp1 in cultured nerve cells through a process known as S-nitrosylation.  This in turn led to activation of enzymatic activity that induces mitochondrial fragmentation. The reaction damages neuron synapses leading to nerve cell death and eventually to loss of brain function.  It is thought that one avenue of therapy for Alzheimer’s Disease that could come out of this understanding could be blockage of S-nitrosylation.  Or better yet, figure out how to prevent the buildup of beta-amyloid protein in the first place,

Here are a few recent longevity news tidbits derived from studies published in geriatrics journals.  Two of the news reports confuse cause and effect and project a probably-incorrect message. 

·        Seniors can use computerized brain exercises to improve their memory and ability to think faster(ref). My comment is sure, and the best computer brain exercise for me is researching how to live a lot longer.

·        The news article in the Tehran Times is entitled Daily naps may raise older women’s death risk. ‘White women who took a daily siesta were 44 percent more likely to die from any cause, 58 percent more prone to dying from heart problems, and nearly 60 percent more likely to die from non-cardiovascular or non-cancer causes.(ref)’  However, I point out that people who are quite sick may take more naps than those who are healthy.  So, napping itself may not cause increased mortality but may be the result of mortality-inducing illnesses.

·        Specific personality traits are associated with children of centenarians and their longevity including low neuroticism, high extraversion and high agreeableness.  Apparently these traits enable much better management of stress(ref).  My comment is yes and that these characteristics are not only inherited but to some extent can be learned even by us old folks.

·        The news item is entitled Keep Hold of Those Car Keys: Driving May Be Good for Your Health.  A study in Florida of 660 older people, aged aged 63 to 97, showed that people who kept driving were four to six times more likely to still be alive after a three-year period than their counterparts who stopped driving(ref).  I comment again that it is important not to confuse cause with effect.  Most of the people who stopped driving were probably a lot sicker to start with than those who kept driving.  Stopping driving itself was probably the effect of sicknesses and not the cause of the increased mortality.

When lifespans of 160+ years become routinely available it will most likely be due to research results coming out of the “omics:”  genomics, epigenomics, proteomics, etc.  This is a short introduction to some of the most important omics and how they fit in the universe of longevity-related research.

Genomics  This is the granddaddy omics, the study of the genomes of organisms, eg. the chromosomes, genes and so-called non-coding DNA on chromosomes.  Back a dozen years ago when we were starting to decode the human genome some scientists thought that once we got the genes in the human genome down the rest would be easy.  Now we understand that that was just the start of the omics revolution. Clearly, longevity has a lot to do with genes.  Here is a list of genes that have been analyzed for their possible association with human longevity.  As you can see from looking at that long list, the pieces of research evidence gathered so far tend to be scattered fragments.

Epigenomics This is the study of encoded possibly inheritable DNA information acquired in the processes of living that is not in the sequences of genes themselves.  The encoding is via DNA methylation and histone acytelation. (See the Feb 28, 2009 post on this Blog Epigenetics, Epigenomics and Aging.  Also the March 20 2009 post on this Blog DNA methylation, personalized medicine and longevity. Very likely, major gains in longevity will result from epigenetic reprogramming, possibly via nutrigenomic interventions.  The regimen of supplements suggested in Anti-Aging Firewalls is a start.

Proteomics  This is the study of proteins, particularly their structures and functions in relationship to gene activation.  (See the February 26 2009 post on this Blog on Protein origami and aging and the March 6 post Do your proteins get tied up in knots?) Clearly, proteomics is of central relevance to Epigenomics and also to Genomics since genes make proteins and proteins condition the activation of genes.

Transcriptomics This is the global study of gene expression at the RNA level(ref).  It is the study of all messenger RNA (mRNA) molecules, or “transcripts,” produced in a cell, a population of cells or an entire organism.  Since messenger RNA is produced by genes and encodes instructions for making proteins, transcriptomics stands in the middle between Genomics and Proteomics.  As such, it is also central to longevity research.  By now it should becoming clear that all the omics up to this point address different but highly related aspects of fundamental processes that occur in cells.  They share two other very important properties, which are 1. that very large data bases are being built in each of these omics areas and 2. ever-superior tools are being built for creating such databases such as improved microarray and digital gene-expression profiling technology and qualitative real-time polymerase chain reaction systems (ones that can measure the abundance of specific sequences of DNA or RNA in a sample).  These databases and tools increasingly play central roles in basic discoveries related to human longevity.

Pharmacogenomics This is the study which looks at the influence of genetic variation on drug response in patients by correlating gene expression or gene variations (e.g. single-nucleotide polymorphisms) with a drug’s efficacy, toxicity or unintended effects.  Pharmacogenomics is a branch of pharmacology that looks forward to the day when drugs might be tailor-made for individuals in a way that is adapted to each person’s own genetic makeup(ref). No doubt, by combating age-related diseases those drugs will allow many people to live longer.

Nutrigenomics This is the study of how the bioactive constituents of foods and dietary supplements affect gene expression, again in the light of individual epigenomic history. A practical goal of nutrigenomics is – “to devise genome-based nutritional interventions to prevent, delay, and treat diseases such asthma, obesity, Type 2 diabetes, cardiovascular disease, and prostate cancer(ref).” A more-detailed discussion of this topic was posted on this Blog on March 4.  And I expect to be writing more about it in coming months.

Ecogenomics This is the study of genetic materials as they occur in an environment where there is an ecological system in operation.  It also involves application of such knowledge to ecological and evolutionary processes.  Ecogenomics defines biodiversity at the DNA level and uses molecular techniques to quantify the functions and interactions of organisms at an ecosystem level(ref). Future public health ecosystem interventions are likely to have major impacts on overall longevity as they have historically (e.g., installing sanitation systems, cleaning up rivers).

Agrigenomics This is the study of the genetic makeup of agricultural plants and how all the genes work together to produce a crop(ref).  Possibilities for longevity include the development of much healthier foods.

All together, these omics fields define a new era of both theoretical and applied systems biology.  As we more understand life we will more understand what it takes to live longer and more healthily.  So each of these fields is in fact an area of longevity research.

Nutrigenomics is one of the many latest “omics,” a hybrid of research focused on study of the relationships among nutrition and genomics.  A podcast discussing this emerging field can be found here.  The field is concerned with identifying how the bioactive constituents of foods and dietary supplements affect gene expression.  One of the objectives of nutrigenomics is identifying personalized nutritional interventions for improving health and wellness and interventions for addressing specific disease susceptibilities and conditions like diabetes and arthrosclerosis. The intent is to develop individualized nutrigenomic profiles – profiles that cross-correlate genomic, epigenomic and proteomic markers for an individual to the biomolecular actions to specific nutrients.  Realizing this intent will first require much further research to identify important omics markers to identify key constitutional parameters and specific disease susceptibilities.  Second, it will require much further research in ways in which nutrition can be utilized to affect individual epigenomic profiles and specific gene expression sequences.  Research in both of these domains is already proceeding at an accelerating pace.  The dietary suggestions and regimen of dietary supplements in the Anti-Aging Firewalls treatise can be considered to be a zeroth-order approach to nutrigenomics – one that is to some extent based on known omics interactions but that does not take personal omics differences into account. Nutrigenomics based on individual profiles should provide a much higher-resolution approach to looking at the relevance of foods and dietary supplements than is possible on the basis of overall population studies.  In time, nutrigenomics will see the development of diagnostic tests and dietary and other intervention strategies for specific diseases. It will also allow the development of highly personalized diets and supplement regimens for disease prevention and longevity.  I intend to continue tracking and reporting here on those developments.

Nanotechnology is a wild and unregulated frontier.  It could offer great health benefits.  For example,   Japanese researchers have developed a nanoparticle that fuses with cancer but not normal cells and induces apoptosis in those cancer cells(ref).  On another front, there is concern that nanoparticles in cosmetics and personal care products will end up in the environment where they may have serious adverse effects(ref).

Increasing numbers of consumer products are being based on nanoscale ingredients and among them are over 44 dietary supplements, sometimes called nanoceuticals.  Claims are made by the manufacturers of many of these substances that they offer greatly enhanced bioavailability or offer other unique health benefits.  These nanoceuticals like other dietary supplements are not evaluated by the FDA or any other regulatory organization for either efficacy or safety.  However, nanoparticulate forms of familiar substances like silver have different properties than the conventional forms and the long-term consequences of ingesting them are unknown.  For example are nanoscale silver particles eventually excreted from the body or do they lodge in or next to cells and stay there? What do these nanoparticles do to cell membranes and how do they affect cell signaling?  There could be important benefits to using some nanoceuticals and there could also be serious dangers involved with taking others.  An editorial in the Feb 9 online edition of Chemical and Engineering News points out this situation and the weakness of the FDA regulations in not defining whether a nanoparticulate form of a familiar dietary substance should be treated as a new substance.  Much stronger government oversite of nanoceuticals and other nanoscale consumer products is needed soon, for the numbers of companies producing such products is swelling rapidly(ref).  In the interim I personally would not want to consume or suggest consuming a nanoceutical without seeing ample published research that establishes both its efficacy and long-term safety.  And the same is true for breathing one.