New evidence implicates telomere loss as primary trigger
Scientists at Dana-Farber Cancer Institute say they have identified
the root molecular cause of a variety of ills — waning energy, failure
of the heart and other organs, metabolic disorders like diabetes —
brought on by advanced age.
"What we have found is the core pathway of aging connecting several
age-related biological processes previously viewed as independent of
each other," said Ronald A. DePinho, MD, senior author of a report posted online by the journal Nature. The first author, Ergun Sahin, MD, is a member of the DePinho lab.
DePinho, who is the director of Dana-Farber's Belfer Institute for Applied Cancer Science,
said that although the studies were conducted in mice, "The findings
bear strong relevance to human aging as this core pathway can be
directly linked to virtually all known genes involved in aging as well
as current targeted therapies designed to mitigate the toll of aging on
The scientists found that the basic cause of age-related health
decline is malfunctioning telomeres — the end-caps on cells' chromosomes
that protect them against DNA damage. As cells reach their
pre-determined limit of times that they can divide, the telomeres become
shortened and frayed, making the chromosomal ends vulnerable to
increased rates of unrepaired DNA damage.
Faced with this increasing reservoir of injured DNA, cells activate a
gene, p53, that sounds an alarm and shuts down the cells' normal growth
and division cycle, ordering them to rest until the damage can be
repaired or, if not, to self-destruct.
Scientists previously had blamed this emergency shutdown and cell
death for the age-related deterioration of organs whose cells divide
rapidly and are rejuvenated by reserves of adult stem cells. Such
tissues include skin, intestinal lining and blood cells, among others,
which generate trillions of new cells each day of life.
However, left unanswered is how cells with less cell division, such
as the heart or the liver, sustain equivalent levels of aging. The
scientists felt if they could answer this mystery, they might gain new
insights into how DNA damage might lead to age-related decline across
The new findings demonstrate that the telomere dysfunction and
activation of p53 also trigger a wave of cellular and tissue
degeneration that links telomeres to well-known mechanisms of aging that
are not simply related to rapid growth and division. In other words,
telomere dysfunction is not just one culprit in the declining health of
advanced age — it's the kingpin, according to DePinho and his
(DePinho published a study in Nature in January that demonstrated that it was possible to reverse the symptoms of
extreme aging in mice by increasing their levels of telomerase, the
enzyme that maintains health of the telomeres.)
In this new larger role, that telomere dysfunction also sets off an
array of reactions leading to diminished health and longevity. For
example, muscles suffer a loss of mitochondria — a cell's chemical power
plant — causing waning vitality and failure of the heart and other
organs. Risks of metabolic disorders such as diabetes are increased.
In addition, the process weakens the body's antioxidant defenses
against the damaging molecules known as reactive oxygen species, or
"free radicals" that accumulate with age and exposure to stress. Until
now, some researchers had labeled the decline in mitochondria or the
buildup of free radicals as the primary causes of age-related ills. The
new work integrates these seemingly disparate mechanisms into one
unified theory of aging.
Telomere dysfunction causes this wave of metabolic and organ failure,
the scientists found, because when the p53 gene is activated, it
represses the functions of two master regulators of metabolism —
PGC1?alpha and PGC1?beta. This dialing down of the regulators diminishes
metabolic processes needed to provide energy and resist stress. In the
mouse experiments, the scientists showed that "knocking out" p53 in mice
released the brakes on PGC1?alpha and PGC1?beta.
"This is the first study that directly links telomere dysfunction to
regulators of the mitochondria and anti-oxidant defense via p53,"
DePinho said. "The discovery of this new pathway of aging integrates a
lot of different ideas people have had and gives us a better
understanding of the aging process." By unifying several major aging
pathways under the umbrella of telomere dysfunction, he said the
findings may yield new targets for therapies.
The discoveries also may underlie the relatively sudden and rapid failure of the body leading to the end of life.
"Because telomere dysfunction weakens defenses against damage by free
radicals, or reactive oxygen species," DePinho explained, "we think
this exposes telomeres to an accelerated rate of damage which cannot be
repaired and thereby results in even more organ deterioration. In
effect, it sets in motion a death spiral."
The research was funded in part by the National Cancer Institute and the Robert A. and Renee E. Belfer Foundation.
In addition to DePinho and Sahin, the paper's other authors include
faculty members from Dana-Farber, the Belfer Institute for Applied
Cancer Science at Dana-Farber; Boston University School of Medicine;
Brigham and Women's Hospital; Harvard University; University of
Massachusetts, Worcester; Harvard Medical School; and St. Vincent's
Hospital, University of Melbourne, Australia.
The Belfer Institute for Applied Cancer Science at Dana-Farber Cancer
Institute consists of leading academic and industry seasoned scientists
working as multidisciplinary teams supported by powerful platforms in
computational science, oncogenomics, engineered model systems,
clinicopathological analyses, and drug discovery. The Belfer Institute's
mission is to convert insights gleaned from cancer genomics and deep
biology research into the next generation of highly effective drugs and
drug combinations, as well as breakthrough diagnostics for improved
patient management. The Belfer Institute technology has launched a new
biotechnology companies and has enabled cancer drug discovery through
highly productive strategic alliances within the pharmaceutical sector,
including Merck and Sanofi-Aventis.