Rapamycin target and aging: new data
The mammalian aging process is associated with hyperactivity of the mTORC1 cellular pathway
LifeSciencesToday based on Whitehead Institute for Biomedical Research:
Mammalian aging process linked to overactive cellular pathway
Scientists at the Whitehead Institute have linked the hyperactivity of the mTORC1 cellular pathway (the mechanistic target of rapamycin complex 1, the mechanistic target of rapamycin complex 1) with a decrease in ketone production, which is a known sign of aging in mice. The results of their latest study are presented in the journal Nature: mTORC1 controls fasting-induced ketogenesis and its modulation by aging.
"This is the first paper that shows from a genetic point of view that the mTORC1 pathway in mammals has an effect on the phenotype of aging," says David Sabatini, the head of the work. "It gives us the molecular basis for studying aging-related processes at a deeper level."
When we think about aging, flabby skin, poor eyesight and brittle bones come to mind. But Sabatini's lab is more interested in the changes in cells that occur during the aging process. One of the cellular pathways, mTORC1, is known to function as a sensor of the level of nutrients, growth factors and energy in the cell and coordinates its growth. Previous studies have shown that when this pathway is suppressed, many animals, including worms, flies and mice, tend to live longer.
Although the observed increase in life expectancy suggests that mTORC1 is involved in the development of aging, this cannot explain its exact role in this process.
One of the signs of aging is a decrease in ketogenesis, or the ability to produce ketones. During sleep and under other conditions of low carbohydrate intake, the liver converts fatty acids into ketones, which are vital sources of energy during fasting, especially for the brain and heart. As we age, the ability to synthesize ketones in response to starvation in animals decreases. The cause of this phenomenon remains unknown.
To determine whether mTORC1 mediates ketogenesis in mice, Shomit Sengupta, a former graduate student in Sabatini's lab and the first author of a paper in Nature, studied the effect of induced hyperactivity in the mTORC1 pathway in the liver of starving mice. He found that while the levels of most liver and blood metabolites did not change significantly, ketone levels dropped.
Having established that activation of the mTORC1 pathway reduces ketogenesis, Sengupta tried to determine the exact site of action of mTORC1. Knowing that alpha replicators activating proliferation of peroxisomes (peroxisome proliferator-activated receptor alpha, PPAR-alpha), or PPAR-alpha, are activators of hepatic ketogenesis, Sengupta decided to start the process by stimulating them. Interestingly, it was not possible to increase ketone levels – direct evidence that mTORC1 interferes with the action of PPAR-alpha receptors.
"This makes mTORC1 the main regulator of ketogenesis," says Sengupta, who is currently a research associate at Harvard Medical School. "It is necessary and sufficient to suppress PPAR-alpha receptors and ketogenesis."
The next step in the study was to establish the connection of the mTORC1 pathway with an age-related decrease in ketogenesis. If activating mTORC1 is responsible for lower ketone levels due to aging, turning on mTORC1 in older mice should have no effect on its already low levels – it's like trying to turn off an already off switch. Sengupta compared ketone production in old and young mice during fasting. If in young mice activation of the mTORC1 pathway during fasting reduced ketone levels, then in old mice its levels remained the same low. And when the mTORC1 pathway was turned off in very young mice who subsequently aged, they did not experience a decrease in ketogenesis characteristic of normal mice. The level of their ketogenesis corresponded to the level of younger animals, confirming that the constant inhibition of the mTORC1 pathway prevents an age-related decrease in ketone production.
It is possible that suppression of mTORC1 can slow down aging, and, as some believe, the drug rapamycin, an mTOR inhibitor used to treat cancer and prevent rejection of transplanted organs, may indeed have anti-aging properties.
"Rapamycin is definitely being aggressively advertised as an anti–aging agent," says Sabatini, who is also a professor of biology at the Massachusetts Institute of Technology and a researcher at the Howard Hughes Medical Institute. "Having worked a lot with this molecule, I am not sure that I will take it for long periods of time precisely to slow down the aging process."
Instead, Sabatini focuses on a number of more practical issues, including why ketogenesis is suppressed during aging and how aging contributes to the activation of the mTORC1 pathway.
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24.12.2010