X-Message-Number: 22434
Date: Fri, 29 Aug 2003 20:30:59 -0700 (PDT)
From: Doug Skrecky <>
Subject: sirtuin activating compounds & life extension


Molecules Discovered That Extend Life In Yeast, Human Cells; Group Of
Compounds Found In Red Wine, Vegetables Simulate Benefit Of Low-calorie Diet

BOSTON, MA - Mice, rats, worms, flies, and yeast all live longer on a
low-calorie diet, which also seems to protect mammals against cancer and
other aging-related diseases. Now, in yeast cells, researchers at Harvard
Medical School and BIOMOL Research Laboratories have for the first time
found a way to duplicate the benefits of restricted calories in yeast with
a group of compounds found in red wine and vegetables. One compound
extended yeast life span by up to 80 percent. The molecules are also
active in human cells cultured in the laboratory.
 The findings are reported in the August 24 Nature advanced online
edition. The research suggests a promising route to find and develop
drugs to lengthen life and prevent or treat aging-related diseases.
The molecules belong to a familiar group of compounds known as
polyphenols, such as the resveratrol found in red wine and the flavones
found in olive oil. For these particular polyphenols, the beneficial
effects seem to be independent of their famed antioxidant properties.
Instead, the molecules activate sirtuins, a family of enzymes known to
extend the life span of yeast and tiny lab round worms. In screening
tests, the researchers found 17 molecules that stimulated SIRT1, one of
seven human sirtuins, and the yeast sirtuin SIR2. "We think sirtuins buy
cells time to repair damage," said molecular biologist David Sinclair,
assistant professor of pathology at Harvard Medical School and co-author
of the new study. "There is a growing realization from the aging field
that blocking cell death -- as long as it doesn't lead to cancer --
extends life span."  "The sirtuin stimulation provided by certain, but not
all, polyphenols may be a far more important biological effect than their
antioxidant action," said co-author Konrad Howitz, director of molecular
biology at BIOMOL, a biochemical reagents company in Pennsylvania.
Calorie restriction (in mammals, reducing intake to 60 or 70 percent of
the normal daily calories) may be one of many mild stresses that trigger
beneficial effects, a phenomenon called hormesis. To explain their new
findings, the researchers propose that plant polyphenols, which increase
in response to stressful conditions, cue organisms to prepare for
impending harsh conditions by switching to a more beneficial survival
program. They call their hypothesis "xenohormesis."
The most potent molecule in the study, resveratrol, helped yeast cells
live as much as 60 to 80 percent longer, as measured by the number of
generations. Other studies have linked resveratrol to health benefits in
mitigating age-related diseases, including neurodegeneration, cancer and
clogged arteries. In this study, researchers were surprised to find that
yeast cells treated with small doses of resveratrol lived for an average
of 38 generations, compared to 19 for the untreated yeast. The polyphenol
worked through a known sirtuin molecular pathway to help yeast and human
cells survive environmental stresses.
 In experiments with human cells, resveratrol activated a similar pathway
requiring SIRT1. This enabled 30 percent of the treated human cells to
survive gamma radiation compared to 10 percent of untreated cells. Little
is known about the human sirtuin SIRT1, except that it turns off the
tumor suppressor gene p53. This raises the concern that any promotion of
this pathway might promote cancer even as it switches on a longevity
program. But Sinclair said that calorie-restricted animals in experiments
by others have lower, not higher rates of cancer.  In the paper, the
researchers report that preliminary experiments in flies and worms are
encouraging. Mouse studies are in the works. They are exploring synthetic
variations on the molecules, which they call sirtuin activating compounds
or "STACs," to improve the sirtuin activity. They are also searching for
endogenous activators that may naturally exist in human cells.
In the May 8 Nature, Sinclair's research group reported the first known
genetic link between environmental stresses and longer life in yeast.
Triggered by low salt, heat, or calorie restriction (to as low as 25
percent of normal), a yeast "longevity gene" stimulated Sir2 activity.
Sinclair and his colleagues are testing equivalent genes in humans to see
if they similarly speed up human sirtuin activity.

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