“We added life to their years, as well as years to their life,” says Withers.
The effects of disabling S6K1 were similar to those of caloric restriction, though less pronounced. Female mice without S6K1 lived up to 20 percent longer than normal mice; the longevity increase with caloric restriction can reach 50 percent. “That probably means that deleting S6 kinase is not capturing all the effects of caloric restriction,” says Withers, “but the range of health benefits is similar.”
Withers’s findings follow on the heels of a study published in July that showed that the drug rapamycin–which interferes with the same pathway by inhibiting TOR–extends lifespan in mice. Although rapamycin had a pronounced effect on longevity and health, the drug’s potential in humans is limited by its potent immunosuppressant effects. (Rapamycin is already used to prevent organ rejection in transplant patients.) Targeting S6K1 directly–effectively bypassing TOR, which acts on a number of other proteins–may circumvent this dangerous side effect.
“We’ve triaged out one of the downstream rapamycin targets, S6K1, and we appear to have a lot of the benefits without major side effects,” says Withers.
The new study also implicated the protein AMPK, a component of the TOR pathway even further downstream than S6K1, as a key potential drug target. The role of AMPK is especially intriguing because it is activated by metformin, a widely prescribed drug for treating type 2 diabetes. Withers says this means it may be possible in the next few years to design clinical trials that would test metformin’s ability to prevent or treat age-related diseases.
In future studies, Withers and his colleagues hope to begin teasing out the details of the link between TOR signaling and aging. Based on the new paper and other recent studies, it is increasingly clear that throwing a wrench into the TOR pathway can have powerful effects on the aging process across a wide variety of species. And it seems likely that caloric restriction achieves its benefits in part by tapping into the TOR pathway. But it’s not yet obvious why that is.
The TOR pathway is known to act as a kind of fuel gauge, sensing nutrient availability and responding by altering how efficiently proteins are manufactured. For instance, when food is scarce, the TOR pathway responds by scaling back protein synthesis. One hypothesis, according to Kaeberlein, is that while protein manufacture is reduced overall, a small subset of proteins might actually be upregulated. “It’s pretty speculative,” he says, but identifying the functions of those select few proteins could lead to new insights into the way aging works.