[tt] 10-fold life span extension reported for yeast

[Hughes, James J.]

http://www.eurekalert.org/pub_releases/2008-01/uosc-1ls011008.php

10-fold life span extension reported in simple organism
Record longevity for baker's yeast suggests strategies for helping
humans live healthier and longer

Biologists have created baker's yeast capable of living to 800 in yeast
years without apparent side effects.

The basic but important discovery, achieved through a combination of
dietary and genetic changes, brings science closer to controlling the
survival and health of the unit of all living systems: the cell.

"We're setting the foundation for reprogramming healthy life," said
study leader Valter Longo of the University of Southern California.

The study is scheduled to appear in the Jan. 25 issue of the journal
PLOS Genetics. A companion study, showing that the same genetic changes
in yeast reverse the course of an accelerated aging syndrome, appears in
the Jan. 14 issue of the Journal of Cell Biology.

Longo's group put baker's yeast on a calorie-restricted diet and knocked
out two genes, RAS2 and SCH9, that promote aging in yeast and cancer in
humans.

"We got a 10-fold life span extension that is, I think, the longest one
that has ever been achieved in any organism," Longo said. In 2005, the
same research group reported a five-fold life span extension in the
journal Cell. Normal yeast organisms live about a week.

"I would say 10-fold is pretty significant," said Anna McCormick, chief
of the genetics and cell biology branch at the National Institute on
Aging and Longo's program officer.

The NIA funds such research in the hope of extending healthy life span
in humans through the development of drugs that mimic the
life-prolonging techniques used by Longo and others, McCormick added.

Baker's yeast is one of the most studied and best understood organisms
at the molecular and genetic level. Remarkably in light of its
simplicity, yeast has led to the discovery of some of the most important
genes and pathways regulating aging and disease in mice and other
mammals.

A study recently published in Cell (Issue 130, pages 247-258, 2007)
reported that a mouse with a gene mutation first identified by Longo's
group lived 30 percent longer than normal and also was protected against
heart and bone diseases without apparent side effects.

Longo's group next plans to further investigate life span extension in
mice, and also is studying a human population in Ecuador with mutations
analogous to those described in yeast.

"People with two copies of the mutations have very small stature and
other defects," he said. "We are now identifying the relatives with only
one copy of the mutation, who are apparently normal. We hope that they
will show a reduced incidence of diseases and an extended life span."

Longo cautioned that, as in the Ecuador case, longevity mutations tend
to come with severe growth deficits and other health problems. Finding
drugs to extend the human life span without side effects will not be
easy, he said.

An easier goal, Longo added, would be to use the knowledge gained about
life span "in a fairly limited way, to reprogram disease prevention."

In the study appearing in the Jan. 14 Journal of Cell Biology, Longo's
group developed a yeast model for human Werner/Bloom syndromes,
incurable diseases that prematurely age, increase cancer incidence and
eventually kill their victims.

The same mutations that play a central role in the 10-fold life span
extension reversed the premature aging process, the researchers found.

Longo suggested that although a very simple system was used in his
studies, existing drugs targeting analogous anti-aging pathways in
humans - specifically the pathway involving Insulin Growth Factor, or
IGF-1 - should be considered for testing on Werner/Bloom patients.

"Maybe it will do nothing, but having nothing else, I think it's
certainly a good thing to try," Longo said.

In the PLOS Genetics study, Longo's group identified a major overlap
between the genes previously implicated in life span regulation for
yeast and mammals and those involved in life span extension under
calorie restriction.

"We identified three transcription factors ... that are very important
for the effect of calorie restriction, but at the same time, we also
showed that it's not enough because even without these transcription
factors, calorie restriction can still extend life span a little bit,"
Longo said.

"So that means that we've identified a lot of the key players in the
calorie restriction effect but not all of them."

Calorie restriction - in practice, controlled starvation - has long been
shown to reduce disease and extend life span in species from yeast to
mice.

Scientists believe that a nutrient shortage kicks organisms into a
maintenance mode, enabling them to re-direct energy from growth and
reproduction into anti-aging systems until the time they can feed and
breed again.

Calorie restriction is now being tested by other researchers on primates
and even humans, Longo said.

Longo has been studying aging at the cellular level for 15 years and has
published articles in the nation's leading scientific journals. His
laboratory developed a simple and inexpensive method for measuring the
true chronological life span of yeast. Previously, scientists used the
number of a yeast cell's offspring as a proxy for its age.

The so-called replicative life span technique remains in use, and the
NIA's McCormick said that Longo's method was controversial at first.
However, she said, the scientific community now appears to accept its
usefulness. She said Longo's "stationary phase" method is particularly
applicable to studies of cells that do not divide for most of their
life, such as those in the brain or in muscle.

"Stationary phase I think of as normal cell survival," McCormick said.
She added that NIA funds both stationary phase and replicative life span
research.

###

Longo is the Albert L. and Madelyne G. Hanson Family Trust Associate
Professor in Gerontology with a joint appointment as associate professor
of biological sciences at USC College. A native of Italy, Longo came to
the United States to study jazz performance but switched his major to
biochemistry as an undergraduate at the University of North Texas. He
earned his Ph.D. in biochemistry from UCLA in 1997 and completed his
postdoctoral training in neurobiology at USC.

The studies were funded by NIA (part of the National Institutes on
Health) and the American Federation for Aging Research.

USC graduate students Min Wei and Paola Fabrizio were first authors on
the PLOS Genetics paper. USC graduate students Federica Madia and
Cristina Gattazzo were first authors on the Journal of Cell Biology
paper. The other members of Longo's group were USC graduate students
Abdoulaye Galbani, Jesse Smith, Christopher Nguyen, Selina Huey, Lucio
Comai, Jia Hu, Huanying Ge and Chao Cheng, USC computational biologist
Lei Li, and William Burhans and Martin Weinberger of the Roswell Park
Cancer Institute in Buffalo, N.Y.


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