There is no doubt that the work represents a major breakthrough for systems biology, the study of complex biological cellular systems in multiple media: in vivo, in vitro etc. The subject at hand is telomeres, the protective caps on chromosomes and the shortening of which has long been held as a kind of countdown clock to cell death. Like other theories on aging, it comes in and out of fashion. The important key to the new work is that it establishes a kind of dynamic feedback loop of free radicals and telomere shortening, suggesting a more complex death clock, and one related to other proposed theories on aging.
Since several people who have not read my book yet — or who have obvious telomere vested interests — have reamed Eternity Soup
for the (non)omission, here are my troubles with this latest telomerific work as it relates to human aging:1. Many cells in the body divide indefinitely — a substantial and long standing objection to the universality of programmed cell death and any suggestion that it is the primary agent of human aging.
2. The last spike in interest in t-theory and age-retardation came in the late 1990s, with the discovery of the telomere-lengthening enzyme telomerase. There was a huge inflow of capital to firms like Geron — until it was discovered that telomerase might cause cancer by undermining the body’s natural defense against unchecked cell proliferation.
To be fair, the other big aging theories have similar tradeoffs: Anti-oxidants may check damaging free radical production, but free radicals themselves are key to healthy cell function. Small note: Lab mice with their endogenous anti-oxidants knocked out do not display any reduction of lifespan.
Hormesis theory — the notion that caloric restriction (the only intervention that expands maximum lifespan in mammals — mice) works by putting the body in a kind of energy-saving hibernation state, is promising. But the pathway by which it seems to work—ratcheted down Insulin-like Growth Factor 1 (IGF-1), does not seem implicated in exceptional human longevity; in one recent study only 6 of 220 human centenarians had the mutated IGF -1 receptor. Also, human beings do very badly on low IGF 1. They get sick and die.
Tellingly, the principal commercial work using T-theory now focuses on telomerase inhibition — the maintenance of cell death capacity. Cancer is an age-related disease, yes. That suggests that t-theory-based therapies might work to boost life expectancy, but not maximum lifespan - i.e. “the end of aging.”
3.The principal lab animal used to explore the age-telomere dynamic is the black 6 mouse—which has, for its size, a huge telomere cap — totally out of proportion to that in human cells. It can be a great model, as Harrison, Effros et al have shown, for T-cell support and hence immune system maintenance. Thats pretty important for aging. But immune system decline is only one of four (or more) big age-related pathologies: the loss of the ability to maintain healthy blood pressure, healthy blood sugar, and a reserve of naïve stem cells. In other words, to borrow from the Great Hayflick, “The loss of the capacity to maintain cellular harmony.”
4.The study describes a complicated pathway by which extrinsically-induced DNA damage leads to cellular senescence. No connection gets made to how this affects a whole organism—the actual living thing.
The new report should nonetheless be hailed for what it says about systems biology, now coming of age after decades of starts and stops. We now have a better understanding of senescence and the complex, dynamic systems behind our decline over chronological time. It may push those studying cellular aging out of their theoretical silos and launch a new era of gerosystem biology.
And maybe, just maybe, it may end up supporting the most radical thesis of all: that aging — and longevity — are random processes, driven by inner and outer events of completely unknown symbiosis.
Greg Critser’s new book is Eternity Soup: Inside The Quest To End Aging
(Harmony 2010)
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