(BEING CONTINUED FROM 26/04/17)
Through the 1990s researchers learned much more about the gene’s roles in cells and the body as a whole —many of which ultimately turned out to have a bearing on aging. They found, notably, that the gene encodes an enzyme, or catalytic protein, that combines
in the cytoplasm with several other proteins to form a complex, called TORC1, which supervises a whole slew of growth- related activities in cells.
Rapamycin mainly affects TORC1. A less well-understood, second complex, called TORC2, also incorporates the TOR enzyme.
The teams further demonstrated that TOR is a nutrient sensor. When food is abundant, its activity rises,prompting cells to increase their overall production of proteins and to divide. When food is scarce, TOR settles down, and the resulting reduction in overall protein manufacture and cell division conserves resources. At the same time, a process called
autophagy amps up: cells break down defective components such as misshapen proteins and dysfunctional mitochondria (the cell’s energy powerhouses), generating by-products that can be exploited as fuel or building materials; newborn mice rely on autophagy to supply energy before they start nursing. When food returns the seesaw relation
between TOR and autophagy swings back again: TOR activity rises and autophagy slows.
Researchers also discovered that the signaling pathways headed by TOR and insulin in animals are intertwined; signaling pathways are sequences of molecular interactions that control a cell’s activities. Insulin is the hormone released by the pancreas after meals to signal muscle and other cells to absorb glucose from the blood for energy. But that is not all insulin does. It is a growth factor; both it and related proteins help to rev up the TOR pathway, a behavior that helps induce cells throughout the body to grow and proliferate in response to nutrient intake. In another feature important for health, the wiring between the TOR and insulin pathways includes a negative feedback loop: stimulating TOR makes cells less sensitive to insulin’s signals. Chronic overeating.
then, will activate TOR excessively and make cells increasingly deaf to insulin: this insulin “resistance,” in turn, can lead to high blood sugar levels and diabetes and can also contribute to other age-related disorders such as heart problems.
TOR also reacts to cellular stresses beyond nutrient shortages, including low oxygen levels and DNA damage. In general, when cells sense threats to survival, TOR activity dials back. The consequent slowing of protein production and cell proliferation frees up resources so that cells can channel them into DNA repair and other defensive measures. Studies in
fruit flies indicate that as protein synthesis gets broadly curtailed in this red-alert mode, protein manufacturing also shifts in a way that leads to selective production of key mitochondrial components, perhaps helping cells rejuvenate their energy systems. No doubt this multifaceted “stress response” evolved to help cells cope with harsh
conditions, but it may also inadvertently harden them against the ravages of time.
FINDING THE AGING LINK
THE IDEA THAT TOR influences aging dates fromfindings in the mid 1990s indicating that nutrientstarved cells curtail growth by reducing TOR activity.
Gerontologists had seen something like this before: in 1935 Cornell University nutritionist Clive McCay showed that putting young rats on near-starvation diets made them slow- growing and extraordinarily longlived.
Calorie restriction has since been shown to extend maximum life span in species ranging from yeast to spiders to dogs; preliminary evidence suggests that it also does so in monkeys. Cutting normal calorie intake by about a third early in life generally boosts
maximum life span by 30 to 40 percent, apparently by postponing the deterioration of aging; elderly rhesus monkeys in long-term studies of calorie restriction are
extraordinarily healthy and youthful-looking for their ages.
The approach does not always work—in some strains of lab mice, it actually shortens life—but mounting evidence implies that calorie restriction can promote healthy aging in people just as it does in monkeys.
Thus, identifying compounds that evoke calorie restriction’s effects without inducing hunger is a grail for scientists who study aging.
By the early 2000s researchers knew enough about TOR’s functions to suspect that blocking its influence in cells might mimic calorie restriction. In 2003 Tibor Vellai, a Hungarian researcher visiting at the University of Fribourg in Switzerland, led a roundworm study offering the first evidence that inhibiting TOR may oppose aging: by genetically suppressing TOR synthesis in worms, he and his colleagues more than doubled the worms’ average life span.
A year later a study at the California Institute of Technology led by Pankaj Kapahi, now at the Buck Institute for Research on Aging in Novato, Calif.,demonstrated that quelling TOR activity in fruit flies extended their average life span, too, and protected them from the consequences of rich diets, just as calorie restriction does. And in 2005 Brian Kennedy,
then at the University of Washington, and his colleagues hammered home the link between TOR and aging by showing that disabling various TOR pathway genes in yeast cells increased longevity.
These studies, along with others on TOR, were especially intriguing because they suggested that inhibition of TOR mimics not only calorie restriction but also mutant genes known to extend life span. The first such “gerontogenes” had been discovered about a
decade earlier in roundworms whose mean and maximum life spans were doubled by mutations later shown to interrupt their species’ version of insulin signaling. The discovery that aging, previously thought to be intractably complex, could be dramatically slowed by altering a single gene had helped make gerontology a hot topic; among other things, it suggested that human aging might be retarded with drugs. That idea was reinforced by the
discovery of various mouse gerontogenes in the late 1990s and early 2000s that block growth signals,including ones conveyed into cells by insulin and a closely related hormone called insulinlike growth factor 1. In 2003 a mouse with one such mutation set the record for its species’ longevity: nearly five years.
Lab mice generally live less than 30 months.
You might think the connections between TOR,calorie restriction and gerontogenes would have ispired a heated race to test rapamycin’s life-extending effect in mammals. Yet experts on mammalian aging “didn’t really take TOR seriously” before the late
2000s, says Steven Austad, a gerontologist at the Barshop Institute for Longevity and Aging Studies at the University of Texas Health Science Center at San Antonio. The reason is that rapamycin was known as an immunosuppressant; hence, long-term administration, it was widely assumed, would be toxic to mammals. Still, Zelton Dave Sharp, one of Austad’s independent- minded colleagues at the Barshop Institute, concluded otherwise after studying the TOR literature. In 2004 he instigated a major study on life span in mice that were chronically dosed with rapamycin.
Funded by the National Institute on Aging, the study seemed to go badly at first—trouble formulating the drug in mouse chow delayed the initiation of doses until the study’s rodents were 20 months old, the human equivalent of 60 years. At that point, Austad says, “no one—and I mean no one—really expected it to work.” Indeed, not even calorie restriction reliably extends life span in such old animals. But in 2009 three gerontology labs that jointly conducted the study —Randy Strong’s at the Barshop Institute, David E.Harrison’s at the Jackson Laboratory and Richard A.Miller’s at the University of Michigan at Ann Arbor—made history by reporting that the drug had upped life expectancy by an astounding 28 percent in the aged male rodents and 38 percent in the females versus control animals. Maximum life span was increased by 14 percent in females and 9 percent in males.
The galvanizing mouse results were quickly followed by others highlighting TOR’s importance in aging.
Researchers at University College London reported that disabling a gene called S6K1, which gives rise to an enzyme that mediates mTOR’s control of protein manufacturing, makes female mice resistant to agerelated diseases and extends their maximum life span.
(Mysteriously, males showed scant benefit.) And the three U.S. labs that first tested raparnycin in mice reported that initiating doses in the rodents at nine months of age extended their life spans by about the same amount that starting them at 20 months did—suggesting that rapamycin mainly confers benefits after midlife, possibly because that is when the deterioration it opposes mostly occurs.
The fact that inhibiting TOR prolongs life across species now stands out like a beacon in the molecular murk surrounding aging. That prominence does not mean, however, that other aging- related pathways are unimportant for longevity. Indeed, gerontologists increasingly picture the pathways that calorie restriction affect as belonging to a complex, manypronged network that can be tweaked in various ways to promote healthy aging. The network’s components include insulin-related enzymes and proteins called FoxOs that activate stress responses in cells.
Considerable evidence also indicates that sirtuins help to induce calorie restriction’s benefits in mammals and may, in some circumstances, participate in TOR inhibition. At this point, though, TOR appears to be the closest thing to the network’s central processing
unit, integrating various inputs to control the rate of aging, at least in various animal species and perhaps humans, too.
(to be continued)
By David Stipp
source Scientific American