Researchers Find Pathways Linking Caloric Restriction To Aging Process

As scientists learn more about the biochemical processes that affect lifespan, they might one day be able to target those processes to reduce the effects of age-related diseases like heart disease or diabetes.

The UW researchers conducted a genome-wide screen of yeast cells to find which genes, and their corresponding proteins, affect lifespan. Two of the proteins, called Tor1 and Sch9, are signaling molecules that are linked to nutrient uptake in many different organisms. Their results suggest that the same proteins, or very similar ones, may be related to both nutrient response and the aging process in humans.

"The idea is to identify pathways in yeast that are involved in aging, and take them to higher organisms like mice and eventually people," explained Brian Kennedy, assistant professor of biochemistry at the UW School of Medicine and one of the study's main authors. He collaborated on the project with Matt Kaeberlein, a postdoctoral researcher in the lab of Stanley Fields, professor of genome sciences at the UW and Howard Hughes Medical Institute investigator.

After finding ten genes that regulate lifespan, the researchers tested two -- Tor1 and Sch9 -- to confirm their connection to caloric restriction. One test combined caloric restriction with the genetic mutation to Tor1 that reduced signaling on the TOR pathway. They saw lifespan increases in the resulting yeast cells that were about the same as a cell that had just the Tor1 mutation, indicating that the mutation was doing the same thing as caloric restriction.

"The TOR pathway is evolutionarily conserved, meaning it is common to many lifeforms," said Kaeberlein. "We'd like to know if this is the pathway through which caloric restriction affects lifespan. We think this may be why mice live longer with calorie restriction, because of TOR pathway down-regulation."

The two researchers plan to find out that very thing by studying further the TOR pathway in mice. Unlike yeast, though, that gene is essential for mice to live, so they can't delete the gene entirely. But mice have two copies of the TOR gene, which means the researchers can knock out one copy, essentially cutting activity on the TOR pathway in half. They can then study the lifespan of those mice compared to others, and also look at the progression of age-related conditions in the mutants to see if reducing TOR signaling affects those diseases.

The other signaling protein the researchers found in the yeast study, Sch9, is the yeast version of another signaling protein called AKT, which is found in humans and other mammals. AKT is related to the regulation of the insulin and insulin-like growth factor (IGF-1) pathways, and has also been found to affect lifespan in other model organisms. "Having this pathway implicated in lifespan is consistent with the theory about insulin/IGF-1 response in animals and humans," explained Kaeberlein. "That theory basically says that high nutrient levels make the organism grow faster and bigger, but also reduce lifespan. This may be one reason why calorie-restricted mice live longer, but are smaller than other mice."

The researchers admit that there might be multiple ways to increase the lifespan of model organisms and humans. However, extreme calorie restriction has been shown to be the one process that affects aging universally. It doesn't just make the organism live longer overall, it also reduces the debilitating effects of aging and age-related diseases. Calorie-restricted mice don't just live longer, they live healthier for longer.

"Caloric restriction is acting at the root level of the aging mechanism," said Kennedy. "If we can understand how that works, then maybe you can target the genes or proteins that regulate those processes, and you can alter aging and its effects without reducing caloric intake."