By Vince Giuliano
June 27 1017
Once in a while over the years I take a break from blog research and writing as I have done recently. When I come back to the research and writing after such a break, I sometimes see aging from a broader view than I allow myself to see when my mind is wrapped up in the devilish technical details of one specific topic. Such is the case right now, and I want to share that broader view here. In this case, the view is about aging itself.
There still is a lot of disagreement among gerontologists and aging scientists about exactly what aging is, how to measure it, and what to do about it. Despite this, what is meant by aging is taken for granted in almost all of the hundreds of thousands of papers and treatises about it. The consequences include a general lack of agreement about how to even think about aging, and multiple disjointed and confusing perspectives and views of anti-aging interventions.
I have recently come to embrace some simple but important distinctions related to aging that provide me significant clarity in thinking about the topic and its ramifications. This finally, after 10 years as a researcher in the area! I share and discuss these distinctions here. Then I discuss critical questions including the nature and causes of aging and types and levels of anti-aging interventions.
KEY DISTINCTIONS RELATED TO AGING
I start out by distinguishing between 1. Chronological aging, 2. Biological aging, 3. Diseases and degenerative processes typically associated with aging, and 4. Disease and degenerative process precursor conditions.
- Chronological aging (CA). This is aging as simply measured by years and days on a calendar. There can be little argument about this. It makes no sense to say that something causes or accelerates chronological aging or that anything slows it. CA is by definition synched to the clock and you may no more slow it down or speed it up than you can slow down or speed up time itself. Saying that chronological age causes something like greying hair or cancer is a statistical generalization that applies to only to some people but not to others. Relationships of CA to other factors can only be understood as statistical distribution curves. For example, for a given population you may specify the probability of initiation of Alzheimer’s disease as a function of age. But you can’t say beforehand the age a given person will get it, or even for sure if he or she will ever get it.
- Biological aging (BA). This is the kind of aging of concern in any study where aging is looked at as cause or effect. Sometimes it is called functional aging. BA has been discussed in the literature, though there is no general agreement on how to measure it(ref)(ref), When I talk about aging in the rest of this blog post it is mostly about BA. While difficult to measure, as applied to older people, biological age can be thought of as chronological age adjusted for state of health so as to be the best predictor of mortality. For example, my own chronological age is nearly 88 but I estimate that my biological age is typical of that to be found in a cohort of healthy 68 year-olds who live in comparable social, lifestyle and social circumstances, If we could agree on how to measure biological age, say be identifying accurate biomarkers for it, we would have a much better predictor of mortality than chronological age. Because BA like CA is a whole-body factor, like for CA, relationships of BA to other factors can only be understood as statistical distribution curves.
- Diseases and degenerative processes typically associated with aging (DDPs), The list of these is very long including cancers, diabetes, atherosclerosis, coronary diseases, dementias, loss of balance, loss of hearing, liver and other organ failures, pneumonia, frailty, loss of muscle mass, macular degeneration, etc. People don’t die from “old age.” They die from DDPs. Also, many DDPs as well as therapies for them can induce system-wide modifications to the body which promote biological aging. Cancers, radiation and chemotherapy are examples. Some degenerative processes feed on themselves and accelerate other diseases and biological aging. Joint inflammation can make exercise less attractive because it is painful, leading to cardiovascular diseases, sarcopenia and dementias. Loss of balance can lead to falls which also lead to cessation of physical exercise which leads to acceleration of biological aging.
- DDP precursor conditions (DPCs). A large number of conditions can exist in a person which are precursors to DDPs. I have focused on chronic inflammation. (See for example the recent blog entries in our Series on Inflammation, Part 1, Part 2, and Part 3. (And two additional parts have been drafted and will be published soon.) Chronic inflammation is a consequence of many diseases and degenerative processes and the cause of others. Others of these DPCs can include hormone imbalances, abnormal body redox state, inadequate NAD/NADPH ratio, high levels of IGF-1 and insufficient levels of sirtuins. DPCs can themselves have major influences on DDPs as well as on biological aging.
WHAT IS THE NATURE OF AGING?
- I believe aging (speaking primarily about biological aging) is a species specific lifelong molecular program which takes into account stochastic environmental conditions. It starts with conception and ends with death. Aging is not the consequence of random damage nor is it simply a pseudo program, the consequence of vestigial developmental programs that fail to shut down. There might well, however, be one master program for each species that governs both development and aging, and governs several other aspects of life for that species as well. And vestigial pseudo progams may be part of the overall aging program, like mTOR expression failing to wind down in older people. I refer to biological aging as a “program” because aging is highly regulated and comes to a deterministic conclusion, ie. You die with certainty before the maximum age for your species. Note that I am not saying that the code for this program is separable from the code for other biological programs that govern a live organism. What I am saying is that aging behaves like a program and therefore is likely one, even if we are not completely sure how the program works. It is clear that human embryogenesis and early development are governed by programs, ones that exercise an incredible degree of regulation. Programmatic regulation of life is essential and continues at all ages, including providing multiple forms of homeostasis. Even advanced aging is similarly highly regulated. Further:
- All living species of all kinds have maximum known lifespans, without exception, Nothing ever lives beyond the maximum age for its species. Although stochastic variables exist in the aging program, the program itself is deterministic, surely leading to death.
- The age-vs mortality curves for members of species do not represent those which would exist if aging was caused by random damage or any other random process. It they did we would have a tiny handful of 600+ year old people and 75 year-old house cats, 100 year old dogs and 15 year-old mice. The same would be true if aging was the result of randomly-operating vestigial developmental programs. More precisely, the statistical distribution for any random process results in a Poissonian distribution curve, one with an infinitely long tail. The same is true for distributions representing combinations of random process. The lifespan curves for all species have cut-off tails.
- DNA methylation provides lifelong clocks that can predict BA. DNA methylation is a clear indication of one or more of the critical subroutines of aging, is one of the three major epigenetic mechanisms for gene activation and silencing ,and appears to act as a major causal factor in the overall program of aging., See Jim Watson’s blog entry Aging, health and disease – view from the DNA Methylome. Also, see this list of other entries in this blog related to DNA methylation.
- Over history and also in recent decades there has been a steady increase in average expected human lifespan – by around 4 months for each passing years now in Western societies(ref). This increase appears to be due to constant epigenetic remodeling. It is not known whether maximum human lifespan is experiencing a similar increase.
- In terms of classical evolutionary biology going back to Darwin, nature cares a lot about the preservation of a species, much less about the preservation of members of that species. In fact it has long been thought that there is generally an evolutionary advantage to pruning out the old so they are not competing with the young for resources. Both the Antagonistic Pleiotropy and The Disposable Soma therories explain aging as nature being indifferent to organisms after reproductive age.
- To understand the nature of aging, the best place to start is by considering the most ancient of evolutionary-conserved pathways, ones at least 500 million years old going back to the pre-Cambrian period and before(ref). In the course of evolutionary history, very early on nature had to decide how to handle life, reproduction, death and the preservation of species. Once evolution found a good solution to a problem, It tended to re-use that solution in descendant species. Aging and death of members of a species was one of the first great problems dealt with and solved – and those ancient solutions are still built-in within us.
- Nature cares for the preservation of life even more than for the preservation of species which can come and go. So nature provides mechanisms for accelerating the evolution of any species when its members are too stressed out. See the blog entry Transposable DNA elements – Part 3 TEs and and other key mechanisms of evolution: incRNAs, A to I editing, alternative splicing and exonization. It is about how a mechanism of greatly accelerated evolution kicks in when stress on an organism gets too great.
- The human aging program is inexorable and act ever-more powerfully with advancing age until it kills.
- Only one person in 250,000 lives to 105 years old
- Only one person in five million lives to 110 years old
- Nobody ever lives to be beyond 123 years old
- The program operates differently at different phases of life, though there is little data on this
- Factors related to longevity and what kills organisms are different for different periods in their life cycles. For humans, for example, environmental and epigenetic factors seem to be the most important factors for staying alive for people in their 60s through 80s, while genetic composition is thought to be most important for centenarians,
- The program for humans may vary somewhat by ethnicity and other factors in now-unknown ways.
- My guess is that the aging program for humans contains one or more “cleanup” routines that sense age, probably from a DNA methylation clock, and starts to kill you around some preset age, say around 115, if nothing else has killed you by then.
- Different species have different aging programs. Mice live typically from 1 to 3 years depending on species and environmental conditions, small bats live to about 20 years on the average, and naked mole rats can live up to 31 years. Yet, all three of these kinds of animals have similar weights and look a lot alike.
- The information repository for aging that drives the aging program is most likely epigenetic information in the nuclii of cells including DNA methylation status and state of chromatin ordering.
- Circadian clocks seem to play important roles in epigenetic regulation and biological aging(see this reference list).
- Although the overall molecular program of aging is still poorly understood, we do know important things about some key subroutines in that program for humans.
- These subroutines relate to key molecular pathways including those associated with mTOR, IGF-1, NAD, REDOX states, and there are probably others in addittion
- The subroutines associated with these pathways in turn affect the DDP conditions mentioned above
- Insight is being gained on how these subroutines interact so as to affect aging is rapidly growing though still primitive.
LEVELS OF ANTI-AGING INTERVENTIONS
The above framework allows sorting out anti-aging interventions, that is:
- Direct interventions on diseases and degenerative processes typically associated with aging (DDPs) already in place: Most of what is done in modern medicine is on this level. You deal with a cancer or Alzheimer’s disease or a failing liver after the disease or degenerative problem is already clearly manifest and diagnosed. If you have a medical condition that seriously threatens your life, interventions on this level sometimes can keep you alive longer – like a heart transplantation or cancer removal surgery. However, much of what can be done on this level is not efficacious or only partially efficacious, i.e. there is no known cure for Alzheimer’s disease or many types of cancer. Or, the best that can be hoped for is a stabilized but still-impaired condition, such being the case when dealing with many organ or system pathologies.
- Inteventions aimed at disease and degenerative process precursor conditions (DPCs): A few things are being done on this level in contemporary medicine, mainly in the domain of blockbuster drugs. An example is prescription of metformin and other anti-diabetic drugs for people showing signs of insulin resistance, to delay or prevent diabetes. Another example is prescription of statins like Lipitor to forestall cholesterol-related cardiovascular problems. Another yet would be to take a statin when eye examination reveals druzen, a precursor condition to AMD macular degeneration. The hope would be to prevent proliferatiom of chlorestrol-rich druzen, assuming they are causal of AMD. To the extent that a deadly disease is prevented or delayed by an intervention on this level, life extension is provided. I believe a lot more can be done on this level using well-researched plant-based substances. Especially when certain herbal extracts are delivered by means that assure high bioavailability. As avid readers of this blog know, I have recently come to favor the control of chronic inflammation via a liposomal concoction of extracts of well-researched Aryuvedic anti-inflammatory herbs.
- Interventions aimed generally at biological aging (BA): These are interventions aimed at slowing or reversing some of the molecular and epigenetic mechanisms of aging itself. These are “hacks” on the program of aging, targeteted to particular subroutines in the overall aging program. They might not be aimed at any particular disease of DDP condition. They are thought to be life-extending because they slow down or even reverse aspects of organismal aging and their application might significantly delay or forestall disease process precursor conditions. These include several interventions known to be life-extending in animals. They address ancient evolutionary-conserved pathways going back hundreds of millions of years to very primitive organisms. So we think they can be efficacious in us humans as well. They go to the root of aging to the extent we know how to do that now. Examples are:
- Use of intermittent rapamycin to inhibit the pro-aging mTOR C1 pathway. It is thought that inhibition of cell senescence is among the benefits. “Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune disease, and arthritis, obesity, diabetes, macula-degeneration, Alzheimer’s and Parkinson’s diseases(ref) See this easier-to-read article by Alan Green and these papers by Blagasklonny. a leading research advocate for rapamycin as an anti-aging substance: Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition (2006), Rapamycin and quasi-programmed aging: four years later (2009), Rapamycin extends life- and health span because it slows aging (2013) and Rejuvenating immunity: “anti-aging drug today” eight years later (2015). Also, numerous other documents in this list.
- Use of dietary supplements, say nicotinimide riboside and pterostilbenenen, to increase NAD+ to affect metabolic, DNA repair and other pathways, largely by up-regulating expression of sirtuins. Other supplements could target the NQ01 gene, again to affect the NAD salvage pathway. See the five-parts series of articles in this blog about the NAD World.
- Reduction of angiotensin II via drugs which are ACE inhibitors or receptor blockers. These affect actions in the Renin-Angiotensin cascade. This again involves an evolutionary-conserved pathway that goes back to before the Cambrian period, around 500 million years. Possible downstream benefits could include reductions in DPCs. Disrupting angiotensin II results in life extension in animal studies. “Disruption of angiotensin II, prolongs lifespan of mammals. In hypertensive rats, treatment with angiotensin II inhibition with ACEIs or ARBs ameliorated the harmful vascular effects of hypertension and doubled the rats lifespan. In a study of normal rats without hypertension, Enalapril, an ACEi prolonged lifespan by 21.4% and Losartan, an ARB, increased lifespan 12.5%(ref).” See Jim Watson’s 2013 blog entry ACE and Angiotensin II: The “Double Agents” that Play Multiple Roles in the Molecular Story of Life. Also, you can see the 2010 article Angiotensin II revisited: new roles in inflammation, immunology and aging.
- Use compounds such as lithium to inhibit the GSK3β pathway. The pro-healthspan consequence of doing so may be numerous, including inhibition of the mTOR and the Insulin/IGF pathway. See Jim Watson’s 2014 blog entry The Alpha and Beta of GSK-3s – first in the Strange but Powerful Molecules Series, Also, you can see Knockdown of GSK3β increases basal autophagy and AMPK signalling in nutrient-laden human aortic endothelial cells.
About the interventions and aging subroutines
Each of these interventions addresses one or more critical subroutines in the overall aging program, and this list of interventions and the subroutines that can be addressed is far from complete. For example, it could turn out that we would want to target gene methylation with pharmacologic agents as another anti-aging intervention, or a large variety of other candidates . I expect it might be 40-50 years before these critical subroutines are systematically understood and laid out, and fairly complete practical understanding exists of how we can effectively game them. Meanwhile we have to go with what we know, limited though that may be.
I need point out that many of the classical anti-aging interventions that I and others have been following probably impact on major longevity pathways and therefore work by affecting aging itself (BA), as well as disease and degenerative processes associatiated with aging (DDPs). I am thinking of matters like taking melatonin, pregnalone and DHEA to impact hormone regulation of aging, and numerous phytosubstances like curcumin and boswellia to impact on inflammation. As a matter of fact until recently I have relied completely on natural phyto substances to extend my longevity and only now am beginning to add pharmacological agents as I grow ever-older and the challenge of staying healthy and fully vital ever-greater. Jim Watson and I have published blog entries related to impacts of several phytosubstances on histone acetylation and deacetylation (See blog and other entries on this list). These impacts are likely to affect epigenetic encoding of biological age, and possibly exercise profoundly impact the aging program itself. There is very very much we don’t know yet.
It is possible that most or all of the anti-aging interventions I mentioned above are effective mainly within certain age ranges, say before age 100. There is little or no literature on their effectiveness for the very old and centenarians. On the other hand, with extreme aging some or all of the useful interventions of earlier years may prove to be necessary for continuing health, although not sufficient to do so without further interventions. For example, high levels of the sirtuins SIRT1 and SIRT3 are required for DNA damage repair, and the need for effective repair is likely to continue to increase at all advanced ages. So the need for metabolic interventions that insure high sirtuin levels is not likely to ever go away.
Reversability of aging
It has been a conservative habit to think of aging interventions as being ones “which slow or halt aging,” and rather politically incorrect for a serious scientist to even mention reversing aging. Saying that threatens to tag oneself at worst as a quack remedy marketer, or at best someone ignorant of biology. My personal take is that:
- Selective aspects of the aging program can most likely be reversed, leading to significant remodeling of multiple body systems to a younger phenotype. This is consistent with encoding of aging being epigenetic, since epigenetic coding appears to be reversible. And it is consistent with what is seen in small animals on age-extension regimens, such as mice fed with rapamycin(ref) and mice fed NAD+ boosters(ref). It is also consistent with anecdotal reports of a few human self-experimenters, including the lab rat writing this.
- Since the aging program is multi-faceted and employs multiple subroutines for aging which can lead to death, I very much doubt that any one or even a handful of known intervention can keep you or me alive, healthy and active beyond our species age limit of 123 years. As science progresses, I fully expect a time will come when this is no longer true. And I am doing my best to stay alive, healthy, and fully functional until that time and well beyond.