From: Xiaoguang Li (xli03@emory.edu)
Date: Mon Feb 28 2000 - 12:27:00 MST
---------- Forwarded message ----------
Date: Wed, 23 Feb 2000 19:10:33 PST
From: "UPI / LIDIA WASOWICZ, UPI Science Writer" <C-upi@clari.net>
Newsgroups: clari.tw.science, clari.tw.top, clari.tw, clari.tw.misc,
clari.tw.science+space
Subject: Molecule slows aging by silencing genes
By LIDIA WASOWICZ, UPI Science Writer
SAN FRANCISCO, Feb. 23 (UPI) -- Scientists who have unlocked
the secret of a protein molecule that can slow aging in yeast by turning
off selected sections of its genetic machinery want to know whether the
same key could open the door to longer lifespans for men and women.
"The hope is that researchers may one day be able to intervene
in, and possibly inhibit, the aging process in humans," said lead study
author Leonard Guarente, professor of biology at the Massachusetts
Institute of Technology in Cambridge.
While much work remains, including a corroboration of the
results in animals, "our findings keep this hope alive," he told United
Press International.
The research may provide the missing link that ties together
previous results showing that yeast with extra copies of the protein
Silent Information Regulator, SIR2, live longer, that decreased metabolic
rates extend longevity and that cutting back on calories slows metabolism
and adds years to one's life.
"The new finding connects longevity, the silencing of gene
expression and the slowing of metabolic state," Guarente said in an
interview.
Studies have shown reducing caloric intake can extend
lifespan, although the mechanism for this correlation has been unclear,
the scientists said in the British journal Nature. SIR2 might be the link
between energy metabolism and longevity, turning genes off in response to
reduced energy levels, they suggested.
"So far, we have shown the connection between silencing and
longevity in yeast, a simple system. The silencing is keeping the genome
stable; it is genome instability that causes aging," Guarente said. "We
don't know if this is true in humans."
Before the year is out, the investigators expect to have
gained key insight into whether SIR2 controls aging in animals, notably
mice, which normally live two to three years, and worms, with a
two-to-three-week lifespan. They plan to insert an extra copy of SIR2 in
the animals to determine if it will enable them to live longer.
"With the worm's short longevity, especially, we can get a
view of the aging picture rapidly," Guarente said. "If we find SIR2
regulates aging in animals, we will know we are on track."
Any success in slowing the aging process will have
far-reaching repercussions on human health, the scientists said.
"If we slow down aging, we will slow down the diseases closely
associated with aging, such as osteoporosis. The whole point would be to
reduce the period of morbidity," Guarente said.
"Does this mean we could be immortal? No, but it does mean
some of the diseases of aging could be curtailed so that we could play
tennis and feel healthier and lead more active lives longer."
If the animal tests corroborate the early findings, the next
phase would be to design an anti-aging drug and to test it on worms, he
said, emphasizing any such pill would slow down -- not reverse -- the
aging process.
"Our goals are very much in the spirit of modern medicine --
to increase the human health span," Guarente said.
In the yeast experiment, the researchers found the anti-aging
enzyme has its spell-binding effect by turning off entire sections of the
genome, the complete set of an organism's genes, said study co-author
Shin-ichiro Imai, postdoctoral associate in biology.
The study gives scientists a better understanding of previous
findings that restricting caloric intake to 70 percent of normal levels
significantly extends the lifespans of yeast, earthworms, mice and
possibly primates, the authors said.
"This is the first concrete indication that genome silencing
and metabolism are connected," Guarente said.
Proteins related to SIR2, discovered in the yeast
Saccharomyces cerevisiae -- where it is involved in turning off genes --
have been found in mammals, including man, the scientists said. What
remains to be seen is whether adding extra copies of the molecule to the
higher lifeforms will produce the same life-extending results it did in
the simple system.
The team discovered SIR2 is a type of histone deacetylase, an
enzyme which turns off gene production by modifying the so-called
"chromatin" proteins, those that package and protect chromosomes,
thread-like structures that transmit genetic inheritance from parent to
offspring.
In each cell, some genes are active and others silenced. Skin
and brain cells, for example, are genetically identical -- the difference
lies in their prebirth programming to produce certain genes but not
others. SIR2 can influence which gene groups are permanently silenced,
the end result being prevention of age-related problems that surface late
in life, the scientists said.
"As cells age, genes that had always been turned off sometimes
get turned on, causing problems that can lead to cell death," Guarente
said, noting SIR2 would prevent such activation.
To their surprise, the scientists observed that to carry out
its life-prolonging function, SIR2 requires the ubiquitous energy carrier
nicotinamide adenine dinucleotide, or NAD, which is normally involved in
the breakdown of food molecules, said study co-author Christopher
Armstrong.
Made by all cells, these co-enzymes help transfer electrons
and hydrogen in some reactions that reduce oxidation, said study
co-author Matt Kaeberlein, noting studies have linked food high in
anti-oxidants to lower cancer rates and slowed aging.
"Although NAD and NADH are frequent enzyme co-factors in
oxidation-reduction reactions, this is the first example to our knowledge
in which NAD drives a distinct enzymatic reaction," the authors wrote.
"The NAD connection came out of the blue, but it has an
interesting implication: NAD could well be the signal for the metabolic
status of cells," Guarente said. "If an organism is starved for calories,
the NAD level may go up. More NAD means activating SIR2, which silences
sections of the genome and increases lifespan."
Since genes similar to SIR2 have been found in numerous
organisms, Guarente said, the hope is "if we can keep SIR2 active for
longer, we may slow down aging."
The research was funded by the Human Frontier Science Program
Organization, the National Institutes of Health, the Seaver Foundation,
Ellison Medical Foundation and the Howard and Linda Stern Fund.
--
Copyright 2000 by United Press International.
All rights reserved.
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