mTOR is Something of a Hot Topic in Longevity Science

The study of mTOR, mechanistic target of rapamycin, in the context of aging and longevity in mammals has been gathering pace and funding in recent years. I expect that there will be a brace of well-funded biotech startups running through the standard, expensive, old-school path to building and commercializing drugs over the next ten years, much akin to what has been happening for suirtuin research - and with just about as little to show for it in the end, I'd imagine, although mTOR is a much better and more proven target for modestly slowing aging than are the sirtuins.

Drugs to slow aging by poking around with metabolism are not the future of longevity science; even if successful, they'll take decades to produce end results, and those end results will be largely useless for people already old. The only future with any future in it for us is SENS research and similar targeted approaches to repairing the damage of aging: ways to produce actual rejuvenation of the old. All the rest is just a distraction, and possibly a lethal one if it keeps on dominating the mainstream of research funding.

There are some quite prolific authors writing papers on the subject of mTOR, many of whom fall into the programmed aging camp. They theorize aging to be an evolved genetic and metabolic program of changes that are beneficial in youth but then run amok to cause damage and dysfunction in old age. This is as opposed to the presently more mainstream view of aging as being caused at root by a stochastic accumulation of cellular and molecular damage that then in turn leads to epigenetic and metabolic changes as our biology tries (and ultimately fails) to cope. Cart, horse, horse, cart: it is a measure of the sheer complexity of the data that the current research community can (more or less) support two completely opposite interpretations of what is actually taking place.

I favor the damage based theories (and hence SENS as a course of research and development). I think it's hard to reconcile programmed aging with the reliability theory view of aging, and the success of reliability theory in general, not to mention the large body of evidence that points toward damage repair strategies like SENS as the best step forward.

The programmed aging researchs see mTOR as a potential central mechanism to fit into their theories - something that can be adjusted and aging changes its pace. In particular, it fits in with the hyperfunction hypothesis on aging put forward of late by researchers of the programmed aging camp. This is a point of view that might gain ground in part because the cancer research community, a large force when it comes to funding and promotion of work within the life sciences, can make use of it:

Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes

It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the "hyperfunction theory", which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin).

Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age-related diseases. As was emphasized by the author of the "hyperfunction model", many (or actually all) of them also play roles in cancer. So these "participants" in pro-aging signaling pathways are actually very well acquainted to cancer researchers. A cancer-related journal [is] the perfect place for publication of such experimental studies, reviews and perspectives, as it can bridge the gap between cancer and aging researchers.

As you might guess from reading between the lines, no small amount of politicking takes place in the trenches when it comes to putting forward one's theories, gathering supporters, claiming more support than there might actually be, and so forth. Here is another recent paper on the topic of mTOR as a therapeutic target to slow aging:

Rapalogs and mTOR inhibitors as anti-aging therapeutics

Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling.

The fundamental problem with programmed ageing theories is that there is no plausible evolutionary driver for the emergence of aging as a genetic process.

Posted by: Abelard Lindsey at March 13th, 2013 6:19 PM

@Abelard Lindsey:- That is indeed a problem for some "programmed ageing" hypotheses, specifically those that propose ageing is somehow adaptive. As I understand it, however, the hyperfunction hypothesis doesn't entail that, since ageing would be a side-effect of processes that were beneficial in youth and run amok in later life, rather than something that was selected for itself.

My hunch (take it for what you will) is that the hyperfunction idea is ~80% wrong. Ageing as damage is the most persuasive theory overall, but there's no reason why hyperfunction can't explain some of the things that go wrong in ageing and there are suggestive clues that it might operate in some areas of age-related pathology. It's not totally incompatible with the damage focused view of ageing.

Posted by: José at March 14th, 2013 1:07 AM
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