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Scientists Ferret Out a Key Pathway for
Aging
Newswise,
November 22, 2010 — For decades, scientists
have been searching for the fundamental
biological secrets of how eating less
extends lifespan.
It has been well documented in species
ranging from spiders to monkeys that a diet
with consistently fewer calories can
dramatically slow the process of aging and
improve health in old age. But how a reduced
diet acts at the most basic level to
influence metabolism and physiology to blunt
the age-related decline of tissues and cells
has remained, for the most part, a mystery.
Now, writing in the current online issue
(Nov. 18) of the journalCell, a team of
scientists from the University of
Wisconsin-Madison and their colleagues
describe a molecular pathway that is a key
determinant of the aging process.
The finding not only helps explain the
cascade of events that contributes to aging,
but also provides a rational basis for
devising interventions, drugs that may
retard aging and contribute to better health
in old age.
“We’re getting closer and closer to a good
understanding of how caloric restriction
works,” says Tomas A. Prolla, a UW-Madison
professor of genetics and a senior author of
the new Cell study. “This study is the first
direct proof for a mechanism underlying the
anti-aging effects we observe under caloric
restriction.”
The Wisconsin study focuses on an enzyme
known as Sirt3, one of a family of enzymes
known as sirtuins, which have been
implicated in previous studies in the aging
process, gene transcription, programmed cell
death and stress resistance under reduced
calorie conditions. In mammals, including
humans, there are seven sirtuins that seem
to have wide-ranging influence on cell fate
and physiology.
Sirt3 has been less studied than other
members of the sirtuin family, but the new
study provides “the first clear evidence
that sirtuins have anti-aging effects in
mammals,” according to John M. Denu of
UW-Madison’s Wisconsin Institute for
Discovery and a senior author of the report.
The Sirt3 enzyme, Denu explains, acts on
mitochondria, structures inside cells that
produce energy and that are the sources of
highly reactive forms of oxygen known as
free radicals, which damage cells and
promote the effects of aging. Under
reduced-calorie conditions, levels of Sirt3
amp up, altering metabolism and resulting in
fewer free radicals produced by
mitochondria.
“This is the strongest and most direct link
that caloric restriction acts through
mitochondria,” says Prolla, who has studied
the effects of reduced calorie diets on
aging and health for more than a decade.
“Sirt3 is playing a surprisingly important
role in reprogramming mitochondria to deal
with an altered metabolic state under
caloric restriction.”
The lead authors of the new study are
postdoctoral fellows Shinichi Someya, of
UW-Madison and the University of Tokyo, and
Wei Yu of UW-Madison. The work involved a
mouse model that exhibits age-related
hearing loss, a phenomenon associated with
free radical damage to the cells of the
cochlea, a structure in the inner ear that
converts sound vibrations to nerve impulses.
Age-related hearing loss is common in
humans, and is newly exemplified by such
things as ultrasonic cell phone ring tones
that only the very young can hear as the
cells that capture the highest frequencies
are the first to go.
“Hearing loss is associated with the loss of
specific cell types in the cochlea,” notes
Prolla, whose previous work established a
genetic link to cell death and age-related
hearing loss. “And hearing loss is prevented
through caloric restriction.”
In companion experiments in cultured cells
and detailed in the Cell report,
the Wisconsin team and their colleagues show
that elevated levels of Sirt3 protect cells
from cell stress and death caused by free
radicals.
“Sirt3 is sufficient to provide protection
against oxidative damage,” says Denu.
Although sirtuins have been studied
extensively and are believed by many
scientists to play a role in aging, the new
study is the first to conclusively link the
enzymes to slowing the aging process in
mammals.
According to Denu, who is also a professor
of biomolecular chemistry in the UW School
of Medicine and Public Health, knowing the
molecular basis of how the sirtuin enzymes
work may ultimately lead to the rational
development of drugs that activate the
pathways of enzymes like Sirt3 to slow down
the process of aging.
In addition to Denu, Prolla, Yu and Someya,
authors of the study include William C.
Hallows and James M. Vann of UW-Madison;
Jinze Zu and Christiaan Leeuwenburgh of the
University of Florida; and Masaru Tanokura
of the University of Tokyo. The work was
supported by the U.S. National Institutes of
Health; the Ministry of Education, Culture,
Sports, Science, and Technologies of Japan;
and the Marine Bio Foundation.
