In 2009 scientists discovered that a drug called rapamycin could significantly extend life span in mice, doing so by interfering with the activity of a protein called mammalian TOR, or mTOR. The finding is the most compelling evidence to date that mammalian aging can be slowed pharmaceutically, and it galvanized interest in mTOR’s role in the aging process. The result also highlighted a mystery: Why would suppressing cellular growth and replication—one effect of interfering with mTOR—extend life span? Research into that question could lead to medicines that postpone or mitigate aging-related disorders— from Alzheimer’s disease to cancer to heart failure— and perhaps even extend how long humans can live.

David Stipp is a Boston science writer who has focused on gerontology since the late 1990s. His book on the subject, The Youth Pill: Scientists at the Brink of an Anti-Aging Revolution, was published in 2010. He blogs about aging science at


in trying to better understand how TOR inhibition and calorie restriction extend life span in so many species, researchers have come up against a long-standing mystery: Why would any mechanism evolve to retard aging? The issue has evolutionary biologists scratching their heads because natural selection works to foster successful reproduction, not to enable organisms to go into overtime in the game of life by remaining vibrant at ages when members of their species have typically been wiped out by predators, infections, accidents, and the like. Because of such “extrinsic” risks to survival, evolution effectively equips creatures to live long enough to reproduce before the environment does them in; then, as their odds of continued survival decline, they deteriorate like abandoned houses. Yet calorie restriction retards late-life decline in widely differing species, which implies that it evokes an ancient, conserved mechanism that has been shaped by natural selection to slow aging under some circumstances.

A frequently cited solution to the puzzle holds that calorie restriction taps an evolved starvation response that brakes organisms’ aging during lean times so they can last long enough to reproduce when conditions improve. Skeptics, such as the Barshop Institute’s Austad, counter that there is no evidence that low-calorie diets make animals in the wild live longer; calorie restriction has been observed to extend life span only in pampered lab animals. Already lean wild animals weakened by hunger may have little chance of surviving long enough to benefit from, and pass on, genes that slow aging and thus give rise to an evolved starvation response. Some gerontologists think another solution to the conundrum makes more sense: calorie restriction extends life span as a side effect of responses evolved for purposes unrelated to aging. Austad, for example, theorizes that during lean times, animals branch out and eat unfamiliar things in the wild, exposing themselves to toxic substances not present in their regular food. Such “hard foraging” might have selected for a tendency to rev up inner defenses against poisons as hunger sets in, activating the cellular stressresponse and repair processes that accompany it and thereby inadvertently slowing aging. A few years ago Mikhail V. Blagosklonny, a cancer researcher at the Roswell Park Cancer Institute in Buffalo, N.Y., seized on discoveries about TOR to propose another theory that explains calorie restriction’s magic as a kind of accident.

A native of Russia whose work has ranged widely across cancer research and cell biology, he was inspired by an unorthodox idea: the capacity for growth, which seems the very essence of youthfulness, drives us into the grave later in life. Calorie restriction prolongs life, he posits, by interfering with the untoward, late-life effects of growth pathways, TOR’s most important among them. Blagosklonny’s theory holds that TOR, which is essential for development and reproduction, becomes the engine of aging after maturity is reached. Because of its progrowth signaling, it abets proliferation of smooth muscle cells in arteries (a key step in atherosclerosis), accumulation of fat (which helps to spur bodywide inflammation), development of insulin resistance, multiplication of cells called osteoclasts that break down bones, and growth of tumors. Further, by diminishing autophagy, TOR favors the buildup of aggregation-prone proteins and of dysfunctional mitochondria, which spew DNA-damaging free radicals and hurt cells’ energy metabolism. It also contributes to the accumulation of degradation-resistant proteins in neurons, a process that plays a part in Alzheimer’s and other forms of neurodegeneration. Blagosklonny has shown that, late in life, TOR’s signals can also help trigger cell senescence, a kind of night-of-the-living-dead state that damages nearby cells and saps tissues’ regenerative capacity.

All this shows, Blagosklonny argues, that evolution has not built a mechanism designed to slow aging. Rather the life-extending effects of rapamycin, calorie restriction and gene mutations that block progrowth hormones are merely accidents of nature—ones that happen to interfere with what he calls the “twisted growth” of aging, causing it to play out more slowly than usual. In effect, the TOR pathway behaves very much like an aging program even though it was built to aid early development. Although Blagosklonny’s theory is novel, one of its key inspirations was a well-regarded hypothesis proposed in 1957 by the late evolutionary biologist George Williams. He theorized that aging is caused by two-faced genes that are beneficial early in life but harmful later on. Such “antagonistic pleiotropic genes” are favored by evolution because, as Williams put it, natural selection is “biased in favor of youth over old age whenever a conflict of interest arises.” Blagosklonny sees TOR as the quintessential example of such genes. Like many novel theories, Blagosklonny’s is controversial. It strikes certain scientists as putting too much weight on TOR, whereas others see aspects of TOR distinct from growth promotion as the key thing—for instance, some regard TOR’s inhibition of autophagy, which renews cellular components, as its dominant influence on aging. Still, some TOR experts find the theory plausible, and Basel’s Hall gives Blagosklonny credit for “connecting dots that others don’t even see”—adding, “and I am inclined to think he is right.”


if tor is a key driver of aging, what are the options for defanging it? Rapamycin’s side effects may rule it out as a candidate antiaging drug in people because, among other things, it can increase blood cholesterol, cause anemia and interfere with wound healing. Another drug, metformin, might be an alternative, although much testing would be needed to evaluate the idea. Metformin is the most widely prescribed diabetes treatment—millions have safely taken it for long periods to lower blood glucose. Its mechanism of action is not well understood, but it is known to inhibit the TOR pathway and to activate another aging-related enzyme called AMPK, which is likewise stimulated by calorie restriction and promotes the stress response in cells. Metformin also has been shown to emulate calorie restriction’s effect on gene activity levels in mice, and some evidence indicates that it may increase maximum life span in the rodents. We are still years away from knowing whether metformin can mimic calorie restriction in people, although rigorous tests of its ability to extend life span in mice are now under way. Boosting human longevity proportional to rapamycin’s enhancement of mouse life span could potentially add, on average, five to 10 years to a human life.

That would be huge. Indeed, life expectancy in the developed world has risen so much over the past century that when it comes to aging, we are like Olympic athletes trying to eke out ever smaller incremental gains—average life span in the U.S. rose by more than 50 percent during the 20th century; over the past decade it rose by less than 2 percent. Because we have cut early-life mortality about as low as it can go, boosting life expectancy much at this point will require pushing back diseases of aging. The exploding costs of geriatric medicine suggest this is a very tall order. But drugs that slowed aging could affordably manage it. In effect, they would serve as preventive medicines that could postpone or retard our late-life ills— dementia, osteoporosis, cataracts, cancer, loss of muscle mass and strength, deafness, even wrinkles—just as medicines that cut blood pressure and cholesterol now help to push off middleage heart attacks. And they would buy us quality time, extending our period of vibrancy before we become frail and die. Developing such drugs would not be easy. One obstacle is the lack of a reliable way to measure the rate of human aging; a good yardstick would enable researchers to test efficacy without having to run untenably long trials. Yet finding safe antiaging medicines would be worth the effort, if only to promote healthy aging irrespective of increasing longevity. Who would have thought that a vial of dirt scooped up almost five decades ago would become such fertile soil for research that could lead to more years of quality life?


TOR Signaling in Growth and Metabolism. Stephan Wullschleger et al. in Cell, Vol. 124, No. 3, pages 471–484; February 10, Growth and Aging: A Common Molecular Mechanism.

Mikhail V. Blagosklonny and Michael N. Hall in Aging, Vol. 1, No. 4, pages 357–362; April 20, 2009. http://www.ncbi.nlm.nih. gov/pubmed/20157523 Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice.David E. Harrison et al. in Nature, Vol. 460, pages 392–395; July 16, 2009.

Aging and TOR: Interwoven in the Fabric of Life. Zelton Dave Sharp in Cellular and Molecular Life Sciences, Vol. 68, No. 4, pages 587–597; February 2011. pubmed/20960025


By David Stipp

source Scientific American /2011

About sooteris kyritsis

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