Living long on less? Mouse and human cells respond to slim diets.

Scientists have known since the 1930s that mice and other animals live 30 to 50 percent longer when placed on a diet that's low in calories yet nutritionally complete. The unanswered question has been whether calorie restriction has the same life-extending effect on people.

Direct proof of a payoff for human longevity would take decades. But scientists have now shown that people on a calorie-restricted diet experience many of the cellular changes reported in mouse studies.

"The experimental results [in mice] mirror the results we found," says Anthony E. Civitarese of the Penning-ton Biomedical Research Center in Baton Rouge, La. Whether those changes would extend a person's life remains uncertain, he notes.

As people get older, energy-converting organelles called mitochondria decrease in number and generate greater amounts of harmful by-products called free radicals. Many scientists hypothesize that DNA damage from these by-products can cause chronic diseases of old age such as cancer.

Civitarese and his colleagues randomly assigned 36 overweight people to one of three groups. The first group was instructed to follow a diet with 25 percent fewer calories than the individuals' initial energy expenditures. Each participant in the second group followed a diet with 12.5 percent fewer calories than he or she had initially expended, while exercising to burn another 12.5 percent. Both diets contained adequate nutrition. People in the third group ate a weight-maintenance diet, the researchers report in the March PLoS Medicine.

During the 6-month study, participants in both calorie-restricted groups showed a 20 to 35 percent increase in the number of mitochondria in their muscle cells and a 60 percent decrease in DNA damage. The mitochondria appeared to become more youthful and efficient.

People in the calorie-restricted groups also showed increased activity of several genes related to mitochondial function. Scientists have long considered one of these genes, SIRT1, to be crucial for animals' responses to calorie restriction.

"Not only is it a good study, but it's the only kind that we can do" practically, comments David Sinclair of Harvard Medical School in Boston. Several companies, including one cofounded by Sinclair, are developing drugs to activate SIRT1.

"It's exciting to see SIRT1 in the middle of this," says Leonard Guarente of the Massachusetts Institute of Technology, a cofounder of a competing company. However, he says that interpretation of the results of the Baton Rouge study is limited because the participants were overweight, a condition that can accelerate tissue aging.

The researchers enrolled overweight people in part because they would be motivated to follow a strict diet, Civitarese says. His team is planning a test that will focus on people of normal body weight and last 2 years.