Another cross-species pathway has been discovered that allows interventions to lengthen life in primitive organisms, C. elegans nematode worms in this case.  The pathway is related to the hypoxic response, how cells respond to protect themselves when there is insufficient oxygen.  It turns out that if the hypoxic response can be turned on when normal oxygen is present, nematodes live significantly longer.  A recent research report indicates that this was experimentally accomplished by breeding nematodes that could not produce the protein VHL-1which destroys another protein called HIF which keeps the hypoxic response turned off when oxygen is present.  Also, it appears that the cells in such long-lived nematodes are relatively free of lipofuscin and toxic age-related protein aggregations such as seen in Alzheimer’s, Huntington’s and other age-related diseases(ref).  So, as is the case for dietary restriction the increase appears to be not only in lifespan but also in healthspan.  The hypoxic response pathway is different than that which is involved in calorie restriction.  “VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin/IGF-1-like signaling.”  As of yet, however, just how HIF works downstream to extend longevity is still unclear.  The hypoxic response appears to operate in higher animals as well, including humans.  However, Dr. Matt Kaeberlein, University of Washington assistant professor of pathology and the senior author on the study is reported to caution that “mutation of VHL-1 is associated with a variety of tumors, and any therapies targeted toward activation of HIF would most likely need to be specific for cells that are not rapidly dividing, such as brain cells or muscle cells.”  It is too early to know if a practical human anti-aging intervention can be tied to the hypoxic response but the possibility is intriguing.

The conventional wisdom has been that cell division in heart muscle cells (cardiomyocytes) stops at or shortly after birth and that the cardiomyocytes of an 80 year-old are the same ones he started out with.  The technology of radioactive carbon-dating has been recently applied to study this issue and shows that this conventional wisdom is wrong.  Heart muscle cells are slowly but constantly renewing throughout life. 

Radioactive carbon-dating has long been used as the primary technology for establishing the age of archeological artifacts.  A recent study applied radioactive carbon-dating based on carbon-14, generated by nuclear bomb tests during the Cold War to analyzing the issue of heart muscle renewal.  The study looked at the integration of carbon-14 into human cardiomyocyte DNA to establish the age of cardiomyocytes. Nuclear bombs were tested above-ground between 1955 and 1963.  So, looking at the carbon-14 content in cardiomyocyte DNA from people born before 1955 it is possible to tell how many are original and the rate of cardiomycyte renewal..  “We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span.”  So, when someone reaches the age of 50, about 55% of his or her heart muscle cells date back to birth and the rest are newer(ref). 

The study is interested in that it opens the possibility for interventions that greatly accelerate the rate of renewal of heart muscle cells.  Such could be useful for treating a number of cardiac pathologies and for helping extend the working lifetimes of hearts.

It has been pointed out to me that this Blog and my Anti-Aging Firewalls treatise sites are now experiencing enough Internet traffic that I could generate revenue by accepting advertisements such as for proprietary dietary supplements, health cures, anti-aging treatments, anti-wrinkle creams, etc.  While the money would be nice, I will continue to follow a non-commercial model such as that of a professional scientific journal.  There are several reasons for this.  First of all, many advertisements seen on other longevity-related sites make me uncomfortable.  They claim anti-aging results based on science that is shaky at best or nonexistent at worst.  They go against the messages I am trying to deliver.  Services that automatically place advertisements on my site would not give me the option of filtering these out.  Second, I don’t like the idea that any one substance or approach is the central key to longevity today based on the state of science as it is.  And third, I want it to be crystal clear to my readers that my commitment is to the science of longevity and that I will not beholden to any commercial interest.  I think many longevity-related articles appearing on commercial sites are very good.  But I am in this game for the long run and do not want to go in a commercial direction at this point.  So, no advertising.

Longevity research keeps showing up in unexpected places.  The US Army is pursuing research related to the third theory of aging in my Anti-Aging firewalls treatise, Mitochondrial Damage. They have an anti-aging research program called “Optimized Human Performance: Mitochondrial Energetics” The stated objective of the program is “Develop metabolic supplements to optimize adenosine triphosphate production in eukaryotes.”  Of course, optimizing adenosine triphosphate production in humans is one of the prime objectives of the supplements in the firewall for this theory of aging.  But the Army is out to see how the job can best be done. The project involves screening libraries of compounds for their effects “that increase mitochondrial copy number and/or the efficiency of mitochondrial oxidative phosphorylation.”  One intended outcome of the project is to identify supplements which would allow older experienced soldiers to have the same physical and mental performance capabilities as a 20 year-old. This could allow for later retirement of experienced soldiers and significantly increase the human resource capability of the army.

Whatever else you may think about Henry Ford, I think you will agree he knew what he wanted and in large part got it.  I spent most of yesterday with cousins in Greenfield Village, a large historical theme park founded by Henry Ford in 1929, the year I was born.   Greenfield Village, part of a Ford historical complex in Dearborn Michigan, presents the lifestyle and technology of the mid-industrial era 1880 – 1920.  The artifacts are authentic and are presented in original or replica buildings of the times.    What I saw set me off thinking about technology, including the technology of life extension. 

Greenfield Village has numerous buildings full of the massive machines of the mid-industrial era – giant piston steam engines, a massive Edison-designed DC power generator used for the first commercial electricity production in New York City.  Massive machines weighing tens of tons, giant foundation castings, 20-foot flywheels, 12-foot pistons, giant belts and man-eating gears seemed to be everywhere.  Many of the machines are fully installed and still can be run. 

My revelation came while I was marveling at a 160-ton locomotive built in 1908, one with 12 foot steel wheels that easily weighed 5 or 10 tons each.  I had tarried and my relatives had wandered on so I pulled out my cell phone to call them.  In doing so it came to me that my 1.2 ounce cell phone was vastly more complex and powerful in its own way than the locomotive which was relatively simple despite its massive scale.  Besides having millions transistors on its processor chip, my phone has sophisticated software and personal information that weighs nothing. 

So what happened in technology between1908 and 2009?   One obvious thing is that things have gotten lighter and smaller all along – from the locomotive to the automobile to the cell phone.  Second, they became more personal.   The locomotive served large communities. It could connect you with relatives in another city in a few days.  Henry Ford’s vision was that every family would have an automobile.  It could connect you with relatives in the same city in minutes or hours.  And it is now getting to where everybody has their own cell phone. It can connect you with anyone who wants to be connected with just about anywhere in seconds.  Third, as weight has gone down exponentially, precision and intellectual content has shot up in the same way.  The mechanical tolerances in the engine of a modern car are a hundred times more precise than they were when the locomotive was built.  And the cell phone is only possible because of high-technology chip design and manufacturing which allows packing tens or hundreds of millions of elements on a half-inch chip.  The precision is a thousand times finer than that found in a car engine.  This in turn was only possible because of computers that used earlier-generation chips and software, etc.  

I have mentioned Moore’s Law in an earlier posting, the Law states that every two years the number of transistors on a processor chip will double keeping essentially the same price point. And, led by Intel, the industry has kept that pace for nearly 40 years. This represents an intellectual accumulation of knowledge, an exponential increase in cost effectiveness.  If the same were true of the locomotive you could probably buy one for a dime by now – shipping not included. Intellectual content and technology, unlike industrial-era technology, feeds on itself.  

How do these trends apply to the technology of life extension?  First, consider scale.  Chip manufacturing technology is now getting to be precise below the 90 nanometer size range. Proteins on the other hand are typically 3 to 10 nanometers long and their interaction sites can be much smaller.  So it appears that gene activation and other biomolecular events take place at a size scale an order of magnitude or more smaller than the dimensions involved in current chip manufacturing.  So the shrinking size trend is continuing.  Second, effective life extension interventions will be extremely personal – they will take place inside us and will eventually act in person-specific manners.  Third, longevity is a field of intellectual content absolutely built on the shoulders of the computer and microprocessor revolution.  We would be nowhere near where we are today with respect to our state of longevity knowledge without computers, automated gene sequencers, gene and protein chips, etc..  And, like information-age technology, longevity technology is feeds on itself and expands exponentially. 

In a previous post I proposed Giuliano’s Law for longevity technology, suggesting that it behaves like Moore’s Law. That is: Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period.  That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period.  Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population.  

With regard to the title quote by Henry Ford, I think I can live healthily and productively to the age of at least 235.  And I think his quote which proved correct for him in the industrial revolution will also work for me in the longevity revolution.  Henry Ford wanted people to have cars.  I want the availability of great longevity to be there for everybody who wants it.  One final Henry Ford quote is: “Anyone who stops learning is old, whether at twenty or eighty. Anyone who keeps learning stays young. The greatest thing in life is to keep your mind young.”

A number of proteins in the body play dual roles with respect to longevity – negative roles in some circumstances and good roles under other circumstances.  I mention three substances in this regard: VEGF, telomerase and P16(Ink4a).

–         VEGF stands for vascular endothelial growth factor, a family of growth factors , signaling proteins that play predominant roles in angiogenesis, the proliferation of new blood vessels.    When the angiogenesis facilitates the viability and expansion of a cancer tumor, the result can be very bad for longevity.  Also, VEGF defeats an important avenue the body uses to defend itself against cancer by causing dendritic cells to not work properly.  Bad stuff! Under such circumstances the best thing to do is inhibit VEGF.  On the other hand, when the body is repairing an injury, promotion of VEGF could be good, in fact required for healing to take place. VEGF is important for maintaining glomerular and other capillary integrity(ref), for example.  A component of VEGF plays an important role in the survival of hematopoietic progenitor cells(ref), cells necessary for renewal of blood and other cells and longevity.  Good stuff!

–         Telomerase is a substance I have already discussed extensively, the substance that serves to enlongate the telomere caps at the end of chromosomes and therefore forestall replicative cell senescence.  Some longevity researchers have thought that telomerase activation could be a golden key to enabling life extension since cell senescence may be at the heart of many kinds of diseases including cancers as well as age-related organ degeneration.  Good stuff!  But wait.  Telomerase expression is turned on in most cancer cells, allowing them to replicate indefinitely and be immortal.  So, most research on telomerase today is focused on finding substances that turn its expression off as a way of making cancer cells mortal again(ref)(ref).  Bad stuff!

–         P16(INK4a) is also a substance I have discussed in my Anti-Aging Firewalls treatise.  On the one hand its increasing concentration with age provides a strengthening defense against cancers.  It works by driving cells into senescence through cell cycle arrest as an alternative to them possibly becoming malignant.  Good stuff!  On the other hand, it “induces an age-dependent decline in islet regenerative potential” and reduces the ability of stem cells to proliferate.  Bad stuff!  As I have said before, P16/Ink4a works together with the three other genes to articulate a process of simultaneously protecting against cancers and shutting down adult stem cell function and regenerative capacity in aging tissues.  Good stuff and bad stuff botIh!

These three Dr. Jekyll and Mr. Hyde proteins illustrate a key point with regard to longevity research: many pathways which promote healthy cell proliferation and organ renewal also promote cancer expression.  Likewise, pathways important for inhibiting cancer proliferation also generally inhibit cell and organ renewal.  The key issue is how to achieve the renewal affects without triggering or promoting cancers.

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.