AGINGSCIENCES™ – Anti-Aging Firewalls™

Animals which live extraordinary long lives can provide insight regarding the various theories of aging.  The longevity of the African naked mole rat seems to fly in the face of the the oxidative damage theory of aging, for example(ref).  This little critter is the size of a tiny mouse but lives about eight times longer.  Living up to 28 years,  it is the longest-living rodent.  Its secret to longevity is not known but there are clues.  For example they are very cool, they can all but shut down their metabolism, and they spend a great deal of their life sleeping.  Surprisingly, the markers of oxidative damage in these tiny rats exceed those of mice when they are relatively young.   However the rate of accrual of oxidative damage in these rats does not appear to markedly ramp up with age as it does with mice.  They change very little as they age and females more than 20 years old can give birth.  It seems that the mole rat has a powerful long-lived antioxidant defense system which mice do not have.  I suspect that this observation is just the tip of the iceberg and real insights will come from looking at genes and protein expression and how the rat mitochondria work.  Anyway, if you want a little critter pet that is cool and will not die off on you in a few years, here is your pet.  The only downside is that you won’t see much of your pet since it lives underground..

A recently reported research study seems to throw the whole the the oxidative damage theory of aging into question, at least for C. elegans, a nematode roundworm.  The researchers created a mutant species by individually knocking out five genes in these worms that confer a natural antioxidative effect, e.g. the production of SOD a detoxifying enzyme.  The worms lived just as long despite the compromise in their ability to handle oxidative damage.  And when one of the genes was knocked out the worms lived actually longer, probably due to alteration of mitochondrial function. Does this kill the venerable Oxidative damage aging theory, the granddaddy of all the aging theories?  Should we stop taking oxidants? Not at all.  There is too much evidence behind that theory and over the years it has provided too useful a model for many aging phenomena.  And the beneficial effects of taking antioxidants are well established.

Longevity is not the only area of science where it is useful to keep multiple theories alive despite the fact that they are sometimes inconsistent with evidence and with each other. The prime example is relativity theory and quantum theory in physics, both of which have enabled enormous strides in physics, engineering, astronomy and technology for over a century now.  These two theories have never been reconciled despite prodigious mathematical efforts to do so.  In an interesting article in The March 2009 Scientific American, A Quantum Threat to Special Relativity, it is argued that the quantum theory and special relativity theory are in fact incompatible and contradictory at the most basic level.  No way either of these theories will be thrown out however – not until a more comprehensive theory comes along that subsumes it.  The theories are just too useful.  I think the same is true with theories of aging – all 14 theories covered in my Anti-Aging Firewalls treatise.  It will be incredible, in fact, if we can manage to get those theories down to two or three more basic ones.

Since I first drafted the Anti-Aging Firewalls treatise in May of 2008 my perspective on the Telomere shortening theory of aging has become considerably more sophisticated.  Today, in a fairly major update of the treatise I have rewritten much of the section on that theory highlighting a new evolving perspective on that theory and the role of telomerase activation in an anti-aging regimen.

I often feel like a lucky soldier participating in a long and deadly battle, a soldier whose closest comrades and friends are constantly being wounded or killed.  The battle, of course, is against the ravages of old age and the challenge is to stay alive and healthy.  All my relatives and many of my friends in my age cohort are already dead.  One of my closest college friends is going in for heart bypass surgery Monday; another has diabetes, has experienced unexplained heart stoppages and is having a pacemaker installed Monday; a close friend is having a hip replacement also on Monday; and two more friends are being treated for deadly cancers.  And the problems are increasingly with people 10-25 years younger than I am.  A son in law has already had two knee replacements and is scheduled to have a shoulder replacement.  I, on the other hand, have had a few less-serious orthopedic problems in the last 10 years like a rotator cuff tear from heavy lifting.  But I seem to be free of the debilitating diseases of old age – cancers, dementias, diabetes, cardiovascular problems, etc.  I just had my blood lipids and C-reactive protein checked and they all came in normal.  My annual physical exams are boring.   I ask myself is this the result of blind luck, having a good initial set of genes, or following my anti-aging regimens?  I clearly can’t say for sure.  However if I am as active, alert, productive and disease-free at the age of 109 as I am now at 79, I will then know the answer.   The anti-aging firewalls will get most of the credit.  And, by that time the firewalls should be far more sophisticated and enable me to keep going for a long additional time.  I am betting on it and have to be careful not to ruin the program by getting run over by a bus.

This news item is retro rather than forward looking, being concerned with life re-creation rather than life extension.  Life-extension may pose ethical problems, but how about bringing an extinct near-human species back to life?  German scientists have finished identifying the genome of Neanderthal Man, now extinct for 30,000 years. Further, there is discussion of creating a new live Neanderthal male (or female or both) using available technology.  A modern human genome would be modified so that its DNA matches the Neanderthal version. This DNA would be inserted into a chimpanzee cell which would then be reprogrammed to an embryonic state, and then introduced into a chimpanzee’s womb.  The chimp would give birth to a Neanderthal humanoid.

A well-written article relating mitochondrial health to the use of antioxidants and can be found here.  Mitochondria are particularly susceptible to oxidative damage and such damage is implicated in many debilitating conditions including  cardiovascular disease, stroke, Parkinson’s disease, Alzheimer’s disease, fibromyalgia, schizophrenia, dementia, bipolar disorder, epilepsy, retinitis pigmentosa, and diabetes mellitus.  I continue to strongly believe that there is a central role for anti-oxidants in an effective longevity regimen.  Specifically, Co Q-10. Alpha-lipoic acid and acytl-l-carnitine are important antioxidants for maintaining the health of mitochondria.  An additional report came to my attention today confirming how the use of antioxidants can  support mitochondrial health, this one originated at the Stanford School of Medicine. Blood samples from 20 patients with various mitochondrial diseases uniformly showed depleted glutathione, indicating a lowering of those patients’ antioxidant defenses.  Apparently, mitochondrial disorders generate large numbers of free radicals.  On the other hand, those patients taking antioxidant supplements did not have depleted glutathione, they found, indicating stronger antioxidant defenses.

A reported study about free radicals is radical in its conclusions.  The study was based on disabling five genes in mutant Caenorhabditis elegans worms.  The study’s authors suggest that damage due to free radicals may not be a cause of aging but rather is a consequence of aging and suggest instead that the aging process may originate in the mitochondria.  See my discussion on the Mitochondrial DNA mutation theory of aging.  It would seriously upset the anti-aging establishment’s applecart if oxidative damage turned out to be only a symptom.  However, I hesitate to accept such a broad conclusion given the preponderance of evidence that exposure to strong oxidative stress, such as massive doses of radiation, generates the overt symptoms of aging.  Most likely we are dealing with a chicken-and-egg causative process here where it is both the case that oxidative damage contributes to aging and that aging contributes to oxidative damage.  And the mitochondria play an important role in mediating the aging process.  See the previous blog post as well.

Stress may increase the rate of progression of the most malignant form of melanoma, according to a report on a study conducted in New Zeeland of 1600 people diagnosed with that disease.  Small wonder given what we know about stress and how stress-generated cortisol suppresses the functioning of the immune system. Of course, some of the stress may come from the diagnosis itself.  This study  points again to the importance of the substances in the anti-aging firewalls that encourage regular sleep and mental calm like l-theanine and melatonin as well as a relaxed mental attitude that takes any problems in stride.

I have been quite skeptical of futuristic claims about how nanotechnology will enable immortality.  Specifically, the idea of intelligent nanorobots swimming around freely in my bloodstream diagnosing diseases and repairing cells seems too far off in the future for me to be concerned about it. I have focused more on the growing stream of here-and-now longevity-related discoveries based on genetics and molecular biology. 

Nontheless, an item came to my attention today that leads me to question the severity of my skepticism about the potential contribution of nanotechnology to life extension.  A research study reported in December 2008 indicates that nano-scale substrate surface topography (micro characteristics of the surface on which a cell culture is grown) can significantly affect stem cell differentiation.  The study looked at human mesenchymal stem cells (hMSC) that can differentiate into a variety of cell types including chondrocytes, osteoblasts,  myocytes, and adipocytes.  It was discovered that when the surface consisted of relatively small nanotubes, hMSC adhered to the tubes without noticeable differentiation.  Somewhat larger diameter nanotubes (≈70- to 100-nm diameter)  “elicited a dramatic stem cell elongation (≈10-fold increased), which induced cytoskeletal stress and selective differentiation into osteoblast-like cells.”  The result is relevant to the 14^th theory of aging treated in my Anti-Aging Firewalls treatise which is Decline in adult stem cell differentiation.  The challenge with age is how to assure a continuing high rate of differentiation of adult stem cells to replace depleted body cells without incurring risk of cancer.   The new research result suggests that surface geometry can be an important consideration related to stem cell differentiation, and that control of nanosurface characteristics may prove to be helpful to elicit differentiation.  Another small piece of research in the 2,500,000 piece puzzle that will define aging.

One of the areas of research I track carefully is that related to the Telomere shortening theory of aging.  You will recall that telomeres are like shoestring caps, inert sequences of DNA at the end of chromosomes.   Telomeres provide stability that protects DNA in the chromosomes against getting mixed up in the process of cell reproduction.  Telomeres get shorter as cells divide, and when they get too short a cell can get into big trouble and create trouble for its neighbors – like cancer.  Telomerase is an enzyme that pastes telomere ends back on again, and one theory for life extension is to cause cells to express telomerase so that the telomeres don’t get too short.  You can read about that in my treatise here.  A report appeared yesterday on a Swedish study of changes in telomere lengths in 959 individuals who had contributed blood samples at 9- to 11-year intervals.  The study revealed several interesting findings. 

·         Telomere shortening with age varies significantly between individuals

·         Telomere length at a certain age may not be as good a predictor of future lifespan as previously thought.

·         In general, the rate of telomere shortening appears to depend on the telomeres’ original length.  People starting out with the longest telomeres experienced the fastest rate of telomere shortening and vice versa. 

·         In some individuals, the telomeres measured actually got longer with time. In roughly a third of the subjects, the telomeres actually lengthened over the study period.

These results suggests to me that telomere shortening is a complex process involving a balance of shortening due to cell division, lengthening due to telomerase expression and perhaps cell replacement due to differentiation of stem cells.  And these in turn are affected by many lifestyle and dietary factors.  The new findings also lead to optimism in that they suggests that strategies to keep telomeres from shortening or for making them longer may in fact work.  Readers of the Anti-Aging Firewalls treatise know that I take the supplement astragaloside IV for this purpose as well as pursue other strategies like stress minimization, taking antioxidants, etc.