July 2011

The findings cast doubt on long-held scientific and cultural beliefs regarding the inevitability of the body's decline. They also suggest that other interventions, which include new drugs, may retard aging even if the diet itself should prove ineffective in humans. One leading candidate, a newly synthesized form of resveratrol -- an antioxidant present in large amounts in red wine -- is already being tested in patients. It may eventually be the first of a new class of anti-aging drugs. Extrapolating from recent animal findings, Dr. Richard A. Miller, a pathologist at the University of Michigan, estimated that a pill mimicking the effects of calorie restriction might increase human life span to about 112 healthy years, with the occasional senior living until 140, though some experts view that projection as overly optimistic.

Researchers at Louisiana State University reported in April in The Journal of the American Medical Association that patients on an experimental low-calorie diet had lower insulin levels and body temperatures, both possible markers of longevity, and fewer signs of the chromosomal damage typically associated with aging.

These studies and others have led many scientists to believe they have stumbled onto a central determinant of natural life span. Animals on restricted diets seem particularly resistant to environmental stresses like oxidation and heat, perhaps even radiation. "It is a very deep, very important function," Dr. Miller said. Experts theorize that limited access to energy alarms the body, so to speak, activating a cascade of biochemical signals that tell each cell to direct energy away from reproductive functions, toward repair and maintenance. The calorie-restricted organism is stronger, according to this hypothesis, because individual cells are more efficiently repairing mutations, using energy, defending themselves and mopping up harmful byproducts like free radicals.

"The stressed cell is really pulling out all the stops" to preserve itself, said Dr. Cynthia Kenyon, a molecular biologist at the University of California, San Francisco. "This system could have evolved as a way of letting animals take a timeout from reproduction when times are harsh."

In a series of studies, Dr. Kenyon, of the University of California, San Francisco, has created mutant roundworms that live six times longer than normal, largely because of a mutation in a single gene called daf-2. The gene encodes a receptor on the surface of cells similar to a receptor in humans that responds to two important hormones, insulin and the insulin-like growth factor 1 or IGF-1.

Insulin is necessary for the body to transport glucose into cells to fuel their operations. Dr. Kenyon and other researchers suggest that worm cells with mutated receptors may be "tricked" into sensing that nutrients are not available, even when they are. With its maintenance machinery thereby turned on high, each worm cell lives far longer -- and so does the worm.

Many experts are now convinced that the energy-signaling pathways that employ insulin and IGF-1 are very involved in fixing an organism's life span. Some researchers have even described Type 2 diabetes, which is marked by insensitivity to the hormone insulin, as simply an accelerated form of aging.

In yeast, scientists have discovered a gene similar to daf-2 called SIR2, that also helps to coordinate the cell's defensive response once activated by calorie restriction or another external stressor. The genes encode proteins called sirtuins, which are found in both plants and animals.

A mammalian version of the SIR2 gene, called SIRT1, has been shown to regulate a number of processes necessary for long-term survival in calorie-restricted mice.

Scientists are now trying to develop synthetic compounds that affect the genes daf-2 and SIRT1.

Several candidate drugs designed to prevent age-related diseases, particularly diabetes, are on the drawing boards at biotech companies. Sirtris Pharmaceuticals, in Boston, already has begun testing a new drug in patients with Type 2 diabetes that acts on SIRT1 to improve the functioning of mitochondria, the cell's energy factories.

While an anti-aging pill may be the next big blockbuster, some ethicists believe that the all-out determination to extend life span is veined with arrogance. As appointments with death are postponed, says Dr. Leon R. Kass, former chairman of the President's Council on Bioethics, human lives may become less engaging, less meaningful, even less beautiful.

Dr. Kass recently wrote. "Mortality makes life matter."

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