A Programmed Aging Guide to Cellular Senescence
Amongst the figures of the aging research community - which is pretty much still so small that everyone knows everyone else - there is one fairly prolific author of papers who argues that the mTOR gene is a major regulator of aging. This is an example of someone who sees aging as largely programmed rather than the result of stochastic damage at the level of cells and cellular protein machinery. I think that those folk have a tall hill to climb in order to make their case, based on present evidence, and this particular mTOR specialist might be seeing nails everywhere when the tool to hand is a hammer. But intelligent people can differ, and an important part of reading the scientific literature is to understand that there are ongoing and important differences of opinion under the hood - points are being argued, and most of those positions will ultimately be shown to be incorrect in some way, shape, or form.
In this open access paper, the fellow outlines his view of cellular senescence and how it emerges from a cell that has entered cell cycle arrest due to failing its checkpoints. You'll recall that cellular senescence is the fate awaiting old cells that someone are not removed - either by destroying themselves or being destroyed by the immune system. They are damaging to surrounding tissue and contribute to degenerative aging; their numbers grow rapidly in advanced age, probably due to decline in other systems and a rising level of damage in the body. The paper quoted below is educational and well worth reading, while bearing in mind that the overall case that he makes with regard to mTOR and programmed aging seems weak on the face of it.
Cell cycle arrest is not yet senescence. When the cell cycle is arrested, an inappropriate growth-promotion converts an arrest into senescence (geroconversion). ... As discussed in the article, cell cycle arrest is not yet senescence and senescence is not just arrest: senescence can be driven by growth-promoting pathways such as mTOR, when actual growth is impossible. ... This mechanism connects cellular senescence, organismal aging and age-related diseases....
You might notice that an accumulation of molecular damage was never mentioned in this article. It was unneeded. Cellular aging and geroconversion is not caused by accumulation of random molecular damage. Although damage accumulates, I suggest that the organism does not live long enough to suffer from this accumulation
...
One definition of organismal aging is an increase in the probability of death. Gerogenic cells (due to their hyper-activity and signal-resistance) may slowly cause atherosclerosis, hypertension, insulin-resistance, obesity, cancer, neurodegeneration, age-related macular degeneration, prostate enlargement, menopause, hair loss, osteoporosis, osteoarthritis, benign tumors and skin alterations. These conditions lead to damage - not molecular damage but organ and system damage. Examples include beta-cell failure, ovarian failure (menopause), myocardial infarction, stroke, renal failure, broken hips, cancer metastases and so on. These are acute catastrophes, which cause death. I suggest that by suppressing geroconversion, gerosuppressants will prevent diseases and extend healthy life span.
The part that stands out to me is this:
Cellular aging and geroconversion is not caused by accumulation of random molecular damage.
That is a claim that I think is already readily refuted by the available evidence. But don't let that stop you reading the paper; it's an interesting view on the accumulation of senescent cells, which are demonstrated to be an important factor in aging and worthy of more research attention - they do in fact contribute to the long list of conditions provided by the author above, and more besides.
Excuse an ignorant question. Why can't the programmed-aging and accumulating-damage views both be right? The mechanism of aging is accumulated damage, and genes have been selected that build a body that accumulates damage.
What is a prediction on which the two theories differ?
The important predictions, to my eyes, are those that suggest it will be more effective to extend human life by working to repair damage versus working to change the way in which metabolism works.
The strong programmed aging theories, which I don't think hold water based on current evidence, would suggest that repairing damage is only going to have a limited effect.
I think we can repair the "damage" as much as we want, but if "core blueprints" (the patterns of gene expression, which are the main basis for a phenotype, youth or senescence..) will be whacked - the damage will continue to accumulate, and various different forms of it will appear, new forms, etc.. M.Rose've demonstrated by experiments that programmed aging theory is most likely the most reliable one to date, and that's no good, from the standpoint of "just repair the damage", as we'd be doing a similar thing as currently is done with disseases: the effects are attacked, NOT the main causes. So if main cause is the drift of an epigenetic patterns (due to the lack of selective pressure for a specie, after the certain time) - we either need to: get back these "patterns" to an optimal state, or "create new, maybe even more effective ones".
Having read some of Blagosklonny’s papers with interest, and having been impressed by the coherence of his point of view, I think his work deserves a closer analysis from the staff at fightaging.org.
On reflection, I decided that Blagosklonny may be laboring under the problems described by Kuhn in his now classic work, The Structure of Scientific Revolutions. There Kuhn observed that progress in science is punctuated by paradigm shifts. The accumulation of anomalies creates the need for a new paradigm that accounts for a broader range of evidence. Such new paradigms change the “rules of the game,” the conceptual "map" that directs research, asks new questions of old data, and moves beyond the old framework. See, e.g., en.wikipedia.org/wiki/The_Structure_of_Scientific_Revolutions. How would we know if we're at the point of such a paradigm shift?
Might the ROS paradigm have outlived its usefulness? Anomalies are accumulating. For instance, it’s accepted that CR’s extension of life in fruit flies is NOT linked to protection against somatic DNA damage. 34 (references are to Blagosklonny 9:10 Cell Cycle 1859 (2010)). Likewise, overexpression of major antioxidant enzymes in mice decreases their ROS levels while NOT extending their lifespan. 35. And while SOD reduces oxidative stress in worms, it does not increase their lifespan. 36 These are the kind of intellectual challenges to the ROS theory that signal the need for a new paradigm.
The TOR paradigm states that over-activation of TOR is aging (TOR = Target of Rapamycin, a clinically approved drug used in high doses as a supposed "immunosuppressant.") The TOR paradigm may account for more of the available evidence than does the ROS paradigm. On its face, it seems plausible that aging might be the result of the perpetuation of the signal systems that promote development, but without an “off” switch, continue trying to function long after they’re useless. Why couldn’t aging be the unhappy result of the continued activation of cellular signaling pathways and cellular functions long past their usefulness?
To take this a step further, can the genes that have already been identified in yeast, flies, worms and mice that prolong or shorten life be regrouped into a single development-related TOR pathway? These genes would include insulin/IGF signaling, FOXO transcription factors, sirtulins, TOR, AMPK, PKA and heat-shock proteins. Might they all converge on TOR? Confirming this notion are observations about two main downstream targets of TOR: S6K (for aging) and 4E-BP (for longevity). Deletion of S6K extends mammalian life. 22 4E-BP extends the life of flies. There’s a nice fit, for starters. Whether more of these genes fit nicely with the TOR paradigm is a matter I leave for others better informed than I.
In 2006, Blagosklonny spelled out his TOR theory in 5 Cell Cycle 87. He returned to this article in the 2010 article cited above. As a gedankenexperiment supporting his call for a paradigm shift, he pointed out a series of “predictions” implied by his 2006 article, and tested them against subsequent research.
1. The stimulation of growth-promoting pathways when the cell cycle is blocked causes senescence.
2. Inhibitors of mTOR (mammalian TOR) and PFK pathways will convert senescence into quiescence.
3. Rapamycin will extend life in multicellular organisms, which it is proved to be true in flies, mice and cancer-prone mice.
4. At concentrations that inhibit mTOR, resveratrol suppresses senescence.
5. Rapamycin administered to old mice prolong their life.
6. Rapamycin prevents age-related diseases, like cancer.
7. Rapamycin rejuvenates hematopoietic stem cells.
8. Rapamycin pulsing rejuvenates those hematopoietic stem cells.
9. Rapamycin inhibits TOR by stimulating immunity, e.g., by enabling effective vaccination in old mice.
Every single one of his “predictions,” Blagosklonny found had been subsequently confirmed by research conducted after his 2006 article.
Might it be time for a paradigm shift? Might Blagosklonny be right? Might his TOR paradigm be worth examining whole-heartedly?
Peter van Schaick
PS I'm not a scientist, but am a lawyer interested in Blagosklonny's intriguing notion that the Medicare and Veteran's Administration systems might reduce their immediate treatment costs if they administered a careful program using Rapamycin to reduce the prevalence of medical conditions caused by aging.