10-Fold Life Span Extension Reported

01/14/08
Record longevity for baker's yeast suggests strategies for helping humans
live longer and healthier, says USC study leader Valter Longo.
By Carl Marziali

Longo's group next plans to further investigate life span extension in mice.

Photo/S. Peter LopezBiologists 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 USC
study leader Valter Longo.

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 redirect 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.