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Senior Citizen Longevity & Statistics
Calorie Restriction Prolongs Life and Scientist Find
Genes that May Cause It
SIRT3 and SIRT4 may be targets for drug treatments
to stimulate fight against aging
 Sept. 20, 2007 - For nearly 70 years scientists
have known that caloric restriction prolongs life. In everything from
yeast to primates, a significant decrease in calories can extend
lifespan by as much as one-third. In a new study, however, scientists
have focused on two genes they think come out fighting against the
diseases of aging, when provoked by something like calorie restriction.
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Longevity & Statistics on Senior Citizens |
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Getting under the hood of the molecular machinery
that drives longevity has remained elusive. Now, reporting in the
September 21 issue of the journal Cell, researchers from Harvard Medical
School, in collaboration with scientists from Cornell Medical School and
the National Institutes of Health, have discovered two genes in
mammalian cells that act as gatekeepers for cellular longevity.
When these cells experience certain kinds of
stress, such as caloric restriction, these genes rev up and help protect
cells from diseases of aging.
"We've reason to believe now that these two genes
may be potential drug targets for diseases associated with aging," says
David Sinclair, associate professor of pathology at Harvard Medical
School and senior author on the paper.
The new genes that Sinclair's group have
discovered, in collaboration with Anthony Sauve of Cornell Medical
School and Rafael de Cabo of NIH, are called SIRT3 and SIRT4. They are
members of a larger class of genes called sirtuins. (Another gene
belonging to this family, SIRT1, was shown last year to also have a
powerful impact on longevity when stimulated by the red-wine molecule
resveratrol.)
In this paper, the newly discovered role of SIRT3
and SIRT4 drives home something scientists have suspected for a long
time: mitochondria are vital for sustaining the health and longevity of
a cell.
Mitochondria, a kind of cellular organ that lives
in the cytoplasm, are often considered to be the cell's battery packs.
When mitochondria stability starts to wane, energy is drained out of the
cell, and its days are numbered. In this paper, Sinclair and his
collaborators discovered that SIRT3 and SIRT4 play a vital role in a
longevity network that maintains the vitality of mitochondria and keeps
cells healthy when they would otherwise die.
When cells undergo caloric restriction, signals
sent in through the membrane activate a gene called NAMPT. As levels of
NAMPT ramp up, a small molecule called NAD begins to amass in the
mitochondria. This, in turn, causes the activity of enzymes created by
the SIRT3 and SIRT4 genes--enzymes that live in the mitochondria--to
increase as well. As a result, the mitochondria grow stronger,
energy-output increases, and the cell's aging process slows down
significantly. (Interestingly, this same process is also activated by
exercise.)
"We're not sure yet what particular mechanism is
activated by these increased levels of NAD, and as a result SIRT3 and
SIRT4," says Sinclair, "but we do see that normal cell-suicide programs
are noticeably attenuated. This is the first time ever that SIRT3 and
SIRT4 have been linked to cell survival."
In fact, the mitochondria appear to be so essential
to the cell's life that when all other energy sources inside the
cell--including the nucleus--are wiped out, yet the mitochondria are
kept intact and functional, the cell remains alive.
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Hebrew SeniorLife Researchers Suggest Other Aging
Genes
Researchers at Hebrew SeniorLifes Institute for
Aging Research (IFAR) have examined close to 100,000 genetic markers for
aging and low bone mass to help determine which genes are responsible
for the development of osteoporosis and longevity.
In the search for genes related to longevity and
aging traits, the HSL investigators worked with Boston University
colleagues in a genome-wide association study (GWAS).
Two candidates they found are FOXO1a, which is
associated with age at death, and PON1, which is associated with age at
death and illness-free survival. These findings, if replicated in others
studies, may help scientists understand better the mechanisms
responsible for aging and, in turn, aid in health promotion and disease
prevention.
The studies, published as part of a 17-paper
supplement to the online, open-access journal BMC Medical Genetics,
examined the genetic differences that potentially affect the risk for
certain diseases, using data collected from the landmark Framingham
Heart Study (FHS).
The studies evaluated DNA at 100,000 sites along
the human genome where people are known to commonly differ. Researchers
then looked for associations between the genotypes (the genetic makeup
encoded in an individuals DNA) and hundreds of clinical phenotype
measures (observable, physical characteristics) from nearly 60 years of
FHS data, including biomarkers for cardiovascular disease, cancer,
osteoporosis, longevity and aging, and renal and endocrine function,
among others.
It is important to remember, says David Karasik,
Ph.D., an associate scientist at IFAR and co-author of the HSL papers,
that we need to replicate our findings in other studies. We havent
found the genes for osteoporosis and aging, but weve generated a
hypothesis for future work.
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"Mitochondria are the guardians of cell survival,"
says Sinclair. "If we can keep boosting levels of NAD in the
mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4,
then for a period of time the cell really needs nothing else."
Sinclair and his colleagues have coined a phrase
for this observation: the Mitochondrial Oasis Hypothesis.
SIRT3 and SIRT4 may now also be potential drug
targets for diseases associated with aging. For example, in recent years
scientists have become increasingly aware of the importance of
mitochondrial function in treating diseases such as cancer, diabetes,
and neurodegeneration.
"Theoretically, we can envision a small molecule
that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the
mitochondria," says Sinclair. "Such a molecule could be used for many
age-related diseases."
According to Suave of Cornell, "This study also
highlights how advanced technological methods can help resolve
fundamental biological questions in ways that were hard to achieve as
recently as a few years ago."
Editors Notes:
This study is supported by the National Institutes
of Health and the Paul F. Glenn Laboratories for the Biological
Mechanisms of Aging. Sinclair and Suave are consultants to Sirtris
Pharmaceuticals, a company aiming to treat diseases by modulating
sirtuins. Sinclair is also a cofounder of Sirtris Pharmaceuticals and
sits on their advisory board and board of directors.
Full Citation: Cell, Volume 130, Issue 5, September
21, 2007
"Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival"
Harvard Medical School (www.hms.harvard.edu)
has more than 7,000 full-time faculty working in eight academic
departments based at the School's Boston quadrangle or in one of 47
academic departments at 18 Harvard teaching hospitals and research
institutes. Those Harvard hospitals and research institutions include
Beth Israel Deaconess Medical Center, Brigham and Women's Hospital,
Cambridge Health Alliance, The CBR Institute for Biomedical Research,
Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth
Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge
Baker Children's Center, Massachusetts Eye and Ear Infirmary,
Massachusetts General Hospital, Massachusetts Mental Health Center,
McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute,
Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
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