The good news for the burger and fries crowd is that the entire pathway----AMPK, calcineurin, and CRTC1----and a host of interacting factors may operate similarly in worms and humans. In fact, one well-characterized protein partner of CRTC1 is the gene regulator CREB. The group found that worms lacking the worm version of CREB lived longer, similar to worms lacking CRTC1, suggesting that both factors conspire to antagonize longevity.
"CREB is involved in a suite of physiological processes-from memory to drug addiction, to energy homeostasis," says William Mair, Ph.D., a postdoctoral fellow in the Dillin lab and the study's first author. "CRTC factors may regulate CREB's ability to activate targets specifically involved in aging."
Circumstantial evidence already suggests that factors downstream of AMPK impact aging-related human diseases: both metformin, widely used to treat type II diabetes, and age-retardant resveratrol, red wine drinkers' best excuse for having just one more glass, are activated by AMPK.
"This pathway is evolutionarily conserved biochemically-that single phosphorylation site on the CRTC1 protein, which is critical for longevity in worms, is conserved as an AMPK target site in CRTC1-like genes from worms to mammals," says Shaw, suggesting that inducing that site pharmacologically was a goal worth going after. This study also dovetails nicely with a number of key studies on the function of the CRTC family in mammals by Marc Montminy, M.D., Ph.D, a professor in the Clayton Foundation Laboratories for Peptide Biology and a co-author on the current study.
"Whether you are talking about yeast, worms, Labradors, or rhesus monkeys-dietary restriction is the best intervention we have so far against age-related conditions like neurodegeneration, cancer and diabetes," says Mair. "Our goal now is to use information we have derived from worm studies to find a way to treat many of these diseases with one magic bullet." With any luck, that magic bullet will be maximally effective when taken on a full stomach.
SOURCE Salk Institute for Biological Studies