Connecting mTORC1 to the aging-related decline in ketogenesis was the next step. If mTORC1 activation is responsible for lower ketone levels caused by aging, turning on mTORC1 in older mice should not affect their already low ketone levels - it would be like trying to turn off a light switch that is already off. So Sengupta compared the ketone production of old and young mice during fasting. While turning on the mTORC1 pathway during fasting reduced ketone production in the young mice, the old mice maintained the same, low ketone levels. And when the mTORC1 pathway was turned off in very young mice that were subsequently aged, these older mice did not experience the decline in ketogenesis found in normal mice. Their ketogenesis levels were similar to younger mice, confirming that continual inhibition of the mTORC1 pathway prevented the aging-induced decline in ketone production.

It might follow that suppressing mTORC1 could slow aging, and indeed, some have suggested that the drug rapamycin, an mTOR inhibitor used to treat cancer and to prevent organ transplant rejection, might have anti-aging properties.

"Rapamycin definitely has lots of anti-aging hype," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "Having worked with that molecule a lot, I'm not sure I would take it for long periods of time, just for slowing down aging."

Instead Sabatini is focused on a host of more practical questions, including why ketogenesis is suppressed by aging and how aging serves to activate mTORC1.

"We know enough of what's upstream of mTORC1 that I think now we can test different components and ask which one is sort of acting funny in its aged state," says Sabatini.

SOURCE Whitehead Institute