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 David
Sinclair, Ph.D. -
is Co-Director
of the Paul F.
Glenn
Laboratories for
the Molecular Biology
of Aging, an Associate
Professor of Pathology
at Harvard Medical
School, Associate
Member of the Broad
Institute for Systems
Biology, and co-founder
of Sirtris Pharmaceuticals,
Waltham, MA. Dr.
Sinclair's research
aims to identify
conserved longevity
control pathways
and devise small
molecules that
activate them,
with a view to
preventing and
treating diseases
caused by aging.
His lab was the
first to identify
small molecules
called STACs that
can activate the
SIRT pathway and
extend lifespan
of a diverse species.
They also discovered
key components
of the aging regulatory
pathway in yeast
and is now focused
on finding genes
and STACs that
extend the healthy
lifespan of mice.
Dr. Sinclair obtained a BS with first-class honors at the University
of New South Wales, Sydney, and received the Commonwealth Prize for his
research. In 1995, he receive d a Ph.D. in Molecular Genetics and was
awarded the Thompson Prize for best thesis work. He worked as a postdoctoral
researcher with Dr. Leonard Guarente at M.I.T. being recruited to Harvard
Medical School at the age of 29. Dr. Sinclair has received several additional
awards including a Helen Hay Whitney Postdoctoral Award, and a Special
Fellowship from the Leukemia Society, a Ludwig Scholarship, a Harvard-Armenise
Fellowship, an American Association for Aging Research Fellowship, and
is currently a New Scholar of the Ellison Medical Foundation. He recently
won the Genzyme Outstanding Achievement in Biomedical Science Award for
2004.
Selected
Publications:
Yu
MC,
Lamming
DW,
Eskin
JA,
Sinclair
DA,
Silver
PA
(2006).
The
role
of
protein
arginine
methylation
in
the
formation
of
silent
chromatin.
Genes
Dev 20(23):3249-54.
Yang H, Baur
JA, Chen A, Miller
C, Sinclair DA
(2006). Design
and synthesis
of compounds
that extend yeast
replicative lifespan.
Aging
Cell PMID:
17156081
North BJ, Sinclair
DA (2006). Sirtuins:
a conserved key
unlocking AceCS
activity. Trends
Biochem Sci 32(1):1-4.
Baur JA, Pearson
KJ, Price NL,
Jamieson HA,
Lerin C, Kalra
A, Prabhu VV,
Allard JS, Lopez-Lluch
G, Lewis K, Pistell
PJ, Poosala S,
Becker KG, Boss
O, Gwinn D, Wang
M, Ramaswamy
S, Fishbein KW,
Spencer RG, Lakatta
EG, Le Couteur
D, Shaw RJ, Navas
P, Puigserver
P, Ingram DK,
de Cabo R, Sinclair
DA (2006). Resveratrol
improves health
and survival
of mice on a
high-calorie
diet. Nature 444(7117):337-42.
Yang H, Lavu
S, Sinclair DA.
Nampt/PBEF/Visfatin:
a regulator of
mammalian health
and longevity?
Exp Gerontol 41(8):718-26.
Baur JA, Sinclair
DA. Therapeutic
potential of
resveratrol:
the in vivo evidence.
Nat Rev
Drug Discov 5(6):493-506.
Mai A, Massa
S, Lavu S, Pezzi
R, Simeoni S,
Ragno R, Mariotti
FR, Chiani F,
Camilloni G,
Sinclair DA.
Design, synthesis,
and biological
evaluation of
sirtinol analogues
as class III
histone/protein
deacetylase (Sirtuin)
inhibitors. J
Med Chem 48(24):7789-95. Lin, S-J, Sinclair,
DA (2005) HST2 mediates SIR2-independent
lifespan extension
by calorie restriction. Science,
July 28 epub SciExpress.
Wood, J, Rogina,
B, Lavu, S, Howitz,
KT, Helfand,
SL, Tatar, M,
Sinclair, DA.
(2004). Sirtuin
activators mimic
calorie restriction
and delay aging
in metazoans. Nature,
430(7000):686-9.
Cohen, HY, Miller,
C, Bitterman,
KJ, Wall, NR,
Hekking, B, Kessler,
B, Howitz, KT,
Gorospe, M, de
Cabo, R Sinclair,
DA. (2004) Calorie
restriction promotes
cell survival
by inducing SIRT1. Science,
305(5682):390-2
Howitz,
KT., Bitterman,
KJ., Cohen, HY.,
Lamming, DW., Lavu,
S., Wood, JG.,
Zipkin, RE., Chung
P., Kisielewski,
A., Zhang, L.,
Scherer, B., Sinclair
DA. (2003) Small
molecule sirtuin
activators that
extend S. cerevisiae
lifespan. Nature,
425:191-196
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 Bruce
A. Yankner, M.D.,
Ph.D is
Professor of Pathology
and Neurology at
Harvard Medical School
and Co-Director of
the Paul F. Glenn
Laboratories for
the Molecular Biology
of Aging. Dr. Yankner
graduated from Princeton
University, received
his M.D. and Ph.D.
from Stanford, and
did his residency
at the Massachusetts
General Hospital.
His early work contributed
to the understanding
of the pathology
of Alzheimer’s
disease, and included
the discovery of
beta amyloid neurotoxicity,
the elucidation of
cell death mechanisms
in Down’s syndrome,
and the biology of
the presenilin genes.
His more recent work
has defined molecular
features of the aging
process in the brain,
onstrated
a genetic signature
of brain aging characterized
by changes in genes
that are critical
for learning and
memory. His laboratory
has also demonstrated
that gene damage
may contribute to
the aging of the
brain, and may start
in middle age. He
has received a number
of awards, including
the Major Award for
Medical Research
from the Metropolitan
Life Foundation,
the Derek Denny-Brown
Award from the American
Neurological Association,
the Zenith Award
from the Alzheimer’s
Association, and
the Ellison Medical
Foundation Senior
Scholar Award in
Aging.
Selected
Publications:
Xu J, Kao S-Y, Lee FJS, Song W, Jin L-W and Yankner BA (2002) Dopamine-dependent
neurotoxicity of alpha-synuclein: A mechanism for selective neurodegeneration
in Parkinson’s disease. Nature Medicine 8:600-606.
Lu T, Pan Y, Kao S-Y, Li C, Kohane I, Chan J and Yankner BA (2004). Gene
regulation and DNA damage in the ageing human brain. Nature 429:833-891.
Epub 2004 Jun 09.
Xu J Zhong N, Wang H, Elias JE, Kim CY, Woldman I, Pifl C, Gygi SP, Geula
C and Yankner BA (2005). The Parkinson’s disease-asssociated DJ-1
protein is a transcriptional co-activator that protects against neuronal
apoptosis. Human Molec. Genetics 14:1231-1241. |
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 Marcia
Haigis, Ph.D. -
Assistant Professor
of Pathology at Harvard
Medical School. Dr.
Haigis's lab is focused
on understanding the
role that mitochondria
play in mammalian aging
and disease. Mitochondria
are dynamic organelles
that provide cells
with energy even during
dramatic changes in
diet, stress and development.
Mitochondria are also
a major site for reactive
oxygen species production,
ion homeostasis, and
apoptosis. Not surprisingly,
mitochondrial dysfunction
has been implicated
in aging, neurodegeneration
and metabolic diseases,
such as diabetes.
The regulation of aging is highly conserved. For example, an extra copy of
SIR2 (silent information regulator; sirtuins) significantly increases the lifespan
of yeast, worms and flies. Mammals have seven homologs of SIR2, three of which
are found in mitochondria. Recent studies have shown that sirtuins affect mitochondrial
biogenesis and energy production. Our lab is interested in understanding how
sirtuins mediate the interplay between mitochondrial activity and aging.
The main goals of the lab's research are: 1) to identify signals generated
by mitochondria that contribute to aging and to identify those regulated by
mammalian sirtuins, 2) to determine molecular mechanisms for these signals,
and 3) to understand how these pathways regulate biological functions that
decline during normal aging. To accomplish these goals, the lab's research
integrates biochemistry, proteomics, cell biology and mouse genetics. These
studies have the potential to lead to novel therapies that could treat a spectrum
of human diseases.
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Direct
Contact:
Harvard
Medical School
NRB-954C
77 Ave Louis Pasteur
Boston, MA 02115
Telephone: 617-432-6865
Fax: 617-432-6562
Email: marcia_haigis@hms.harvard.edu
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Selected
Publications:
Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy
AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla
TA, Weindruch R, Alt FW, Guarente L. SIRT4 inhibits glutamate dehydrogenase
and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;
126:941-54.
Haigis MC and Guarente L. Mammalian sirtuins – emerging
roles in physiology, aging and calorie restriction, Genes
and Development 2006; 20:2913-21.
Lin SJ, Ford E, Haigis MC, Liszt G, Guarente L. Calorie restriction
extends yeast life span by lowering the level of NADH. Genes
and Development 2004; 18:12-16.
Leissring M, Farris W, Wu, Christodoulou D, Haigis MC, Guarente
L, Selkoe D. Alternative translation initiation generates a novel
isoform of insulin-degrading enzyme targeted to mitochondria. Biochemical
Journal 2004; 116:313-24.
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