Researchers discover life-extending agent
Leaving no stone unturned
The giant monoliths of Easter Island are worn, but they have endured for centuries. New research hints that a compound first discovered on the South Pacific island might one day help us stand the test of time, too.
In Nature this summer, the Health Science Center and collaborating centers reported that the Easter Island compound – called “rapamycin” after the island’s Polynesian name, Rapa Nui – extended the expected lifespan of middle-aged mice by 28 percent to 38 percent. In human terms, this would be greater than the predicted increase in extra years of life if cancer and heart disease were both cured and prevented.
The rapamycin was given to the mice at an age equivalent to 60 years old in humans.
The studies were part of the National Institute on Aging (NIA) Interventions Testing Program, which seeks compounds that might help people remain active and disease-free throughout their lives. The Sam and Ann Barshop Institute for Longevity and Aging Studies at the Health Science Center is one of the three NIA Interventions Testing Centers, along with the University of Michigan and the Jackson Laboratory in Bar Harbor, Maine.
“This study has identified a potential therapeutic target for development of drugs that might prevent age-related diseases and extend healthy lifespan,” said Randy Strong, Ph.D., a professor of pharmacology who directs the Interventions Testing Center for the Barshop Institute. He is a senior research career scientist with the South Texas Veterans Health Care System (VA).
Discovered in the 1970s, rapamycin has been used to prevent organ rejection in transplant patients. It also is used in stents and is in clinical trials for treatment of cancer. The Texas, Michigan and Maine sites for the aging experiments each found it extended the life of mice.
“We believe this is the first convincing evidence that aging can be slowed and lifespan can be extended by a drug therapy starting at an advanced age,” Dr. Strong said. Study co-author Z. Dave Sharp, Ph.D., director of the university’s Institute of Biotechnology, said the findings have “interesting implications for our understanding of the aging process.”
Aging researchers currently acknowledge only two life-extending interventions in mammals: calorie restriction and genetic manipulation. Rapamycin appears to partially shut down the same molecular pathway as restricting food intake or reducing growth factors. It does so through a cellular protein called mTOR (mammalian target of rapamycin), which controls many processes in cell metabolism and responses to stress.
A decade ago, Dr. Sharp proposed to his colleagues that mTOR might be involved in calorie restriction. In 2004, a year after the NIA Interventions Testing Program began, he submitted a proposal that rapamycin be studied for anti-aging effects. The proposal was approved, and the three testing centers began to include rapamycin in the diets of mice. The male and female mice were cross-bred from four different strains of mice to more closely mimic the genetic diversity and disease susceptibility of humans.
Dr. Strong soon recognized a problem: Rapamycin was not stable enough in food or in the digestive tract to register in the animals’ blood level. He worked with the Southwest Research Institute in San Antonio to microencapsulate the compound and solve these problems.
The goal was to begin feeding the mice at 4 months of age, but because of the delay caused by the stability issue, the mice were not started until they were 20 months old – the equivalent of 60 human years. “I did not think it would work because the mice were too old,” said Arlan G. Richardson, Ph.D., director of the Barshop Institute, professor of cellular and structural biology, Methodist Hospital Foundation Chair and VA senior research career scientist. “Most reports indicate calorie restriction doesn’t work when implemented in old animals. The fact that rapamycin increases lifespan in relatively old micewas totally unexpected.”
Dr. Strong summarized possible implications of this discovery: “If rapamycin or drugs like it work as envisioned, the potential reduction in overall health cost for the world will be enormous.” Indeed, such an intervention would cast an enormous shadow, just like the well-worn monoliths of Easter Island.