Wistar
Institute team finds key target of aging
regulator
Researchers at The Wistar Institute have
defined a key target of an evolutionarily
conserved protein that regulates the process
of aging. The study, published June 11 in
Nature, provides fundamental knowledge about
key mechanisms of aging that could point
toward new anti-aging strategies and cancer
therapies.
Scientists have long known that a class of
proteins called sirtuins promotes fitness
and longevity in most organisms ranging from
single-celled yeast to mammals.
At the cellular level, sirtuins protect
genome integrity, enhance resistance to
adverse stresses, and antagonize senescence.
However,
the underlying molecular mechanisms have
remained poorly understood.
The team, led by senior author Shelley
Berger, Ph.D., Hilary Koprowski Professor at
The Wistar Institute, demonstrated for the
first time a molecular target for a member
of this class, Sir2, in regulation of aging
in yeast cells.
Sir2
removes an acetyl group attached to a
specific site (lysine at position 16 or K16)
on histone H4—histones are proteins that
package and organize the long strands of DNA
within the nucleus and also are central
regulators in turning genes on and off.
The study reveals that removal of this
acetyl group by Sir2 near the chromosome
ends—the telomeres—is important for yeast
cells to maintain the ability to replicate.
Researchers found that Sir2 levels decline
as cells age, and there is a concomitant
accumulation of the acetylation mark along
with disrupted histone organization at
telomeres.
Deacetylation of H4K16 by Sir2 and
consequent telomere stability play a major
role in maintaining long lifespan in yeast.
Since sirtuins deacetylate many different
proteins, these results clarify a key role
of Sir2 protein in control of lifespan.
"Some modifications on histones, like this
acetylation on histone H4 lysine 16, are
persistent and are maintained through
generations of cell divisions. This
DNA-independent inheritance is called
epigenetics," Berger says.
"Characteristic epigenetic features have
been discovered for various developmental
processes in recent years. Understanding
epigenetic changes associated with aging is
a hugely exciting direction in aging
research.
"It
will provide insights and ideas not only for
new therapies to regulate cells that have
lost control of proliferation, such as
'immortal' cells found in cancers, but also
for new strategies to maintain health and
fitness."
"We plan to continue to search for new
targets of Sir2 and other aging regulators,"
says lead author Weiwei Dang, Ph.D., a
postdoctoral scientist working with Berger.
"We are designing unbiased screens for other
aging targets and mechanisms in chromatin.
Using yeast as our aging model enables us to
do many discovery screens that are
impossible with other, more complex
organisms.
"Yet
it is remarkable that many of these
chromatin mechanisms associated with yeast
could turn out to be relevant even for aging
human cells."
###
Along with senior author Berger and lead
author Dang, other authors include: research
assistants Rocco Perry and Jean A. Dorsey,
from Wistar; graduate student Kristan K.
Steffen, Assistant Professor Matt Kaeberlein,
Ph.D., and Assistant Professor Brian K.
Kennedy, Ph.D., from the University of
Washington, Seattle; Assistant Professor F.
Brad Johnson, M.D., Ph.D., from the
University of Pennsylvania; and Investigator
Ali Shilatifard, Ph.D., from the Stowers
Institute. This work was funded by the
National Institutes of Health and an AFAR
Julie Martin Mid-Career Award in Aging
Research.
The Wistar Institute is an international
leader in biomedical research with special
expertise in cancer research and vaccine
development.
Founded
in 1892 as the first independent nonprofit
biomedical research institute in the
country, Wistar has long held the
prestigious Cancer Center designation from
the National Cancer Institute.
Discoveries at Wistar led to the creation of
the rubella vaccine that eradicated the
disease in the United States, human rabies
vaccines used worldwide, and a rotavirus
vaccine approved in 2006. Today, Wistar is
home to preeminent research programs
studying skin cancer, lung cancer, and brain
tumors.
Wistar Institute Vaccine Center scientists
are creating new vaccines against pandemic
influenza, HIV, and other diseases
threatening global health.
The Institute works actively to transfer its
inventions to the commercial sector to
ensure that research advances move from the
laboratory to the clinic as quickly as
possible. The Wistar Institute: Today's
Discoveries — Tomorrow's Cures. On the Web
at
www.wistar.org.
