This blog entry is intended to clarify what aging, life extension and anti-aging are about. It suggests a new way of looking at the theories of aging in my treatise ANTI-AGING FIREWALLS THE SCIENCE AND TECHNOLOGY OF LONGEVITY.
It is easiest to start out with distinguishing between life extension and postponing aging (or anti-aging), which are not quite the same things. Aging is the most difficult of these matters to define and I will get to it a bit later.
First of all, life-extension approaches are not sure things; they negatively affect the probability of death of a member of a defined population. Even if you could halt and reverse all causes of aging, the next day you could get run over and killed by a bus. A lot of things will extend the average lifespan of a population, including quality sewage systems, unpolluted air, and living where there is a law-abiding citizenry. Included in this list can be pursuance of personal choices such as exercising daily, eating a Mediterranean diet and taking certain supplements. However, not all things that extend average lifespans also postpone aging. For example requiring people to wear seatbelts in cars and observe speed limits can extend average lifespans but not affect aging which I see to be a biological process.
In this blog, I have mainly been concerned with life extension approaches that involve biological processes and that slow, stop or reverse aging. So, the next question is “What is aging?” Aging starts with birth (actually before birth) and lasts through life. The part of it I have mainly been concerned with is post-maturational aging, aging that happens after an organism reaches reproductive age. This later-stage aging is characterized by a number of degenerative processes that accelerate with advancing age, and these are the degenerative processes described by the 14 theories of aging in my treatise and an additional 7 “candidate” theories of aging:
11. Susceptibility to Cardiovascular Disease
12. Telomere Shortening and Damage
13. Programmed Epigenomic Changes
14. Stem Cell Supply Chain Breakdown
17. Gene mutations leading to hellicase abnormalities
19. Declining hypoxic response
20. Epigenomic changes in DNA methylation and histone acetylation
21. Micronutrient triage with aging
As pointed out in the treatise and many blog discussions, many of these “theories of aging” are highly interdependent, existing in feedback loops where one promotes another, or are results of one or more common underlying processes. In fact, it is possible to add additional theories of aging in the same spirit such as
22. Metabolic degradation affecting the expression of sirtuins(ref)(ref), and
23. Decline in effectiveness of autophagy(ref), and, probably many more yet.
A few key points are:
· These are not so much theories of aging as they are corollaries of aging or processes that go on during aging. They are all processes that, once one of them is started, it can then can affect multiple body systems and unchain rapid aging in each of them.
· There are many more corollaries of aging everyone is familiar with such as bone loss, grey hair, loss of hair, wrinkled skin, far-sightedness, loss of teeth, eyesight, hearing, and balance, etc. While these are not usually seen as theories of aging because they each seem to involve only one system, this is not strictly true in all cases. Hair stem cells, for example, can differentiate into epidermal and other kinds of cells(ref) and the same is true of stem cells living in tooth pulp(ref). Bone marrow houses important mesenchymal and haemopoietic stem cells needed for renewal of cells in the blood and other parts of the body. So, loss of hair or bone or even natural teeth could affect body renewal elsewhere.
.· It might be possible to extend expected lifespan by interventions that address only one or several of these processes, just as it is possible to do so by diligently wearing seatbelts in a car. Wearing eyeglasses and hearing aids may extend the lives of those who wear them by preventing accidents. So, life-extension does not need to address fundamental aging.
· Since body systems and the theories of aging are so inter-related, a biologically-oriented antiaging intervention addressed to one theory, such as taking antioxidants(ref), is likely to affect aging with respect to several other theories as well, such as tissue glycation, inflammation and susceptibility to cancers. The actions in my anti-aging lifestyle regimen affect aging with respect to several of the theories. The same is true of almost all of the supplements in the supplement regimen. For this reason I call them anti-aging interventions though individually they may not slow or halt aging according to all the corollary theories.
· The life extension interventions of most interest to me are the ones that slow or halt aging from the viewpoint of most of the 23 theories of aging listed. In that category appear to be systematic exercise, weight management, and most of the other interventions suggested in my lifestyle regimen.
· On the supplement side, to the extent that resveratrol can activate SIRT1 producing the well-studied longevity results of calorie restriction(ref)(ref)(ref), it too affects most of the theories of aging. Some others of the supplements might do that as well.
What is aging?
This is a question I have ducked up to this point: What is aging? Actually, we don’t know for sure. We know all the corollaries of aging as listed, but we are not sure if any of these or any other as-yet unknown process is basic to all of the others. The later could be the case, or it simply could be that we will never know aging except as through its corollaries. More or less the same holds for anti-aging interventions. If we could find an anti-aging intervention that halts or reverses aging according to all of the listed corollaries of aging, then the mechanisms of that intervention would go a long way towards telling us what aging is. As I have mentioned above activation of SIRT1 via taking resveratrol probably comes as close to being a full anti-aging intervention as we have now.
Some of the 23 theories of aging listed are without doubt more fundamental than others as underlying drivers of aging. That is, some of the theories are sufficient to explain what goes on according to some of the other theories of aging. My favorites at the moment are Epigenomic changes in DNA methylation and histone acetylation and Stem Cell Supply Chain Breakdown with Telomere Shortening and Damage being in third place. Since I have discussed each of these extensively elsewhere I comment only briefly on them here. You can follow the hyperlinks to find out more about them.
Epigenomic changes in DNA methylation and histone acetylation is actually a special case of Programmed Epigenomic Changes. It is a global theory relating to changes that accumulate over a lifetime and that are capable of regulating all genes. Anti-aging interventions could involve many specialized approaches to protein or histone demethylation or deacetylation. It is interesting that SIRT1 mentioned above works through being a powerful deacetylase. To see past blog posts related in some respect to this theory of aging start out with Feb 2009 blog entry Epigenetics, Epigenomics and Aging. To see more just enter the phrase “epigenomic changes” into the search box to the left of this main text.
Stem Cell Supply Chain Breakdown is a favorite theory of mine, and not just because because I have formulated it myself. It says that we are charged up with a supply of pluripotent stem cells at conception (cells capable of differentiating into any body cell type), and these differentiate into our normal body cells (somatic cells) as well as various troves of adult stem cells which throughout life differentiate to make new replacement somatic cells. The process runs down when the adult stem cells get old and are not replaced, so old senescent and near-senescent somatic cells are not replaced and aging results. Anti-aging interventions according to this theory could include introduction of embryonic stem cells (ESCs) or “closing the loop” by reverting a few cells taking from a person to induced pluripotent stem cell (iPSC) status(ref)(ref). It too is a global theory that could explain everything. To see multiple past blog posts on this theory of aging just enter the word “supply chain” into the search box to the left of this main post.
Telomere Shortening and Damage is the theory all over the news since the last Nobel prizes were given out, but it has fallen to third place in my listing because 1. It is not clear to me that telomere shortening is the critical factor limiting human lifespans. In a healthy young human if telomeres get too short in a cell and apoptotic processes are working well, the cell dies and is replaced by a new cell that is differentiated from an adult stem cell. The same is not true for adult stem cells because there are no pluripotent cells around to differentiate to replace them, so we are back to the previous theory of aging, and 2. Despite all the commercial hoop-la about supplements that induce “telomerase activation,” there is no published experimental evidence that people, monkeys, rats, mice or even worms live longer when they are subject to telomerase activation. And we know for sure that there are a lot of other interventions that make worms, mice and rats live a lot longer than normal. To see multiple past blog posts related to telomeres and telomerase activation just enter the word “telomerase” into the search box to the left of this main text.
I note that the second and third of these theories could in fact be highly complementary. Adult stem cells could age and beome depleted because of shortening of their telomeres. If controlled telomerase expression could be activated in adult stem cells, in theory at least it might take a lot longer before they become depleted.
I expect that in another year it will be possible to refine or update the above observations in a significant way. I could never have written the above when I first drafted my treatise in May 2008. At that point I had identified only the first dozen of the above 23 theories/corollaries of aging.