By disabling a gene involved in an important biochemical signaling pathway, scientists have discovered a way to mimic the well-known anti-aging benefits of caloric restriction, allowing mice to live longer and healthier lives. This finding, published online today in Science, offers a promising drug target for combating the many health problems associated with aging.
“This research points the way to potential pharmacological approaches to treating aging-related diseases in humans,” says senior author Dominic Withers, professor of diabetes and endocrinology at University College London.
“It really defines this as a pathway that’s affecting aging all the way from yeast to mammals, which I think is pretty striking,” says Matt Kaeberlein, professor of pathology at the University of Washington and coauthor of a commentary accompanying the new study.
Caloric restriction has long been known to extend lifespan and reduce the incidence of age-related diseases in a wide variety of organisms, from yeast and roundworms to rodents and primates. Exactly how a nutritionally complete but radically restricted diet achieves these benefits has remained unclear. But recently several studies have offered evidence that a particular signaling pathway, involving a protein called target of rapamycin (TOR), may play a pivotal role. This pathway acts as a sort of food sensor, helping to regulate the body’s metabolic response to nutrient availability.
Withers and colleagues noticed that young mice with a disabled version of the protein S6 kinase 1 (S6K1), which is directly activated by TOR, bore strong resemblance to calorie-restricted mice: they were leaner and had greater insulin sensitivity than normal mice. The researchers wondered whether these benefits would persist into middle and late age, and whether the mice would live longer.
To find out, they bred two large groups of “knockout” mice that lacked a functional version of the gene for S6K1. One group lived out their lives undisturbed, providing a measure of the group’s natural lifespan. The other group was put through extensive testing of cognitive and motor performance and metabolic health.
In female mice, the results were profound. Knockout females lived substantially longer than their normal counterparts. At 600 days–the mouse equivalent of human middle age–they excelled at motor performance tests, outdoing normal mice at tasks requiring balance, strength, and coordination. They were also more inquisitive and apt to explore new environments, suggesting improved cognitive function. Physiological measures also pointed to better health: the knockout mice had stronger bones, better insulin sensitivity, and more robust immune cells. While male knockout mice did not have extended lifespans, they did have the same array of health benefits as females.