[tt] SIRT3-4 mediates caloric restriction's impact on mitochonrial health, longevity

[Hughes, James J.]

http://www.eurekalert.org/pub_releases/2007-09/hms-rfc091707.php

Researchers find connection between caloric restriction and longevity

BOSTON, Mass. (September 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. But getting under the hood of the molecular
machinery that drives this 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 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.

"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."

###

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.

For a copy of the paper, please contact public_affairs at hms.harvard.edu

Full Citation:
Cell, Volume 130, Issue 5, September 21, 2007
"Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival"
Hongying Yang(1,6), Tianle Yang(2), Joseph A. Baur(1), Evelyn Perez(3),
Takashi Matsui(5), Juan J. Carmona(1), Dudley W. Lamming(1), Nadja C.
Souza-Pinto(4), Vilhelm A. Bohr(4), Anthony Rosenzweig(5), Rafael de
Cabo(3), Anthony A. Sauve(2), and David A. Sinclair(1)

1-Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical
School, Bo