David Sinclair (biologist)
Encyclopedia
David A. Sinclair PhD is a biologist
best known for his research on the biology of lifespan extension and driving research towards treating diseases of ageing.
.
or "ERCs" in determining the lifespan of yeast. Subsequent research showed that ERCs are unique to aging in a particular yeast strain, and not involved in aging in any other organisms. ERCs were subsequently shown to be suppressed by the SIR2
gene, the founding member of the sirtuin
gene family, as well as deletion of the FOB1
gene. With Kevin Mills and Lenny Guarente, he also showed that the Sir2 protein relocalizes to DNA breaks and mediates repair. These two discoveries led his lab to discover that genomic instability induces changes in gene regulation may drive the aging process in mammals.
In 2002, Sinclair's lab at Harvard discovered a key role of NAD+ biosynthesis in aging. In 2003, his lab published that nicotinamide is a non-competitive inhibitor of Sir2 and SIRT1, and proposed the molecule as a physiological regulator of Sirtuins.
Sinclair is also credited with the "Mitochondrial Oasis Hypothesis" which states that the energetics and NAD+ content of mitochondria determines cell survival in the face of genotoxic stress (i.e. DNA damage), independent of the state of the cytoplasm or nucleus. He is also known for his hypothesis developed with Konrad Howitz called the "Xenohormesis
Hypothesis" which states that animals have evolved to sense stress signalling molecules in other species, in order to gain advance warning of a deteriorating environment.
Sinclair is credited with co-discovering Sirtuin
activating compounds STACs with Konrad Howitz of Biomol Inc. In September 2003, Howitz and Sinclair et al., published a highly cited paper reporting that polyphenols such as resveratrol
activate human SIRT1 and extend the lifespan of budding yeast (Howitz et al., Nature, 2003). In collaboration with two Drosophila aging experts, Marc Tatar and Steven Helfand (Brown U.), he co-published that resveratrol extends the lifespan of worms and flies in a SIR2-dependent manner. This effect was found not reproducible by other investigators (Linda Partridge
and David Gems
). In a more recent study by Sinclair, published in November 2006 by the journal Nature
indicated that resveratrol
had life-extending activity in mice fed a high fat Western diet (60% fat). These obese mice lived considerably shorter than normally fed mice, and that obese mice treated with resveratrol lived an average of 15% longer than obese mice not treated with resveratrol. A later study showed that resveratrol mimics the diets known as calorie restriction (CR) in normally fed mice and slowed down diseases of aging such as cardiovascular disease, cataracts, and diabetes (however, no effect on overall lifespan was evident). Molecules that are orders of magnitude more potent that resveratrol have been developed and shown efficacy in mouse models of obesity and diabetes (Milne et al., Nature, 2007; Feige et al., Cell Metabolism, 2008). However, key results from these studies have proved irreproducible by independent investigators. When queried on these, Sinclair questioned the ability of these independent investigators to synthesize these compounds. The first of these potent STACs is in Phase I human trials.
with Christoph Westphal
, to develop drugs that harness the body's own defenses against diseases of ageing. Sirtris was featured on the cover of Fortune magazine in Jan 2007.
Michelle Dipp
since led the acquisition of Sirtris by GlaxoSmithKline
in 2008 for $720 million.
Biologist
A biologist is a scientist devoted to and producing results in biology through the study of life. Typically biologists study organisms and their relationship to their environment. Biologists involved in basic research attempt to discover underlying mechanisms that govern how organisms work...
best known for his research on the biology of lifespan extension and driving research towards treating diseases of ageing.
Current position
Sinclair is Professor of Pathology and Co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School. Dr. Sinclair obtained a Bachelors of Science (Honors Class I) at the University of New South Wales, Sydney, and received the Australian Commonwealth Prize. In 1995, he received a Ph.D. in Molecular Genetics then worked as a postdoctoral researcher at MIT with Leonard Guarente before being recruited in 1999 to Harvard Medical SchoolHarvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
.
Research
One of Sinclair's discoveries was in the lab of Leonard Guarente where he identified the key role of rDNA circlesExtrachromosomal rDNA circle
Extrachromosomal rDNA circles are self replicating circles of ribosomal DNA found in some strains of yeast and thought to contribute to their aging.The ERC accumulate in the mother cell during the budding process....
or "ERCs" in determining the lifespan of yeast. Subsequent research showed that ERCs are unique to aging in a particular yeast strain, and not involved in aging in any other organisms. ERCs were subsequently shown to be suppressed by the SIR2
Sir2
Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied...
gene, the founding member of the sirtuin
Sirtuin
Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes...
gene family, as well as deletion of the FOB1
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
gene. With Kevin Mills and Lenny Guarente, he also showed that the Sir2 protein relocalizes to DNA breaks and mediates repair. These two discoveries led his lab to discover that genomic instability induces changes in gene regulation may drive the aging process in mammals.
In 2002, Sinclair's lab at Harvard discovered a key role of NAD+ biosynthesis in aging. In 2003, his lab published that nicotinamide is a non-competitive inhibitor of Sir2 and SIRT1, and proposed the molecule as a physiological regulator of Sirtuins.
Sinclair is also credited with the "Mitochondrial Oasis Hypothesis" which states that the energetics and NAD+ content of mitochondria determines cell survival in the face of genotoxic stress (i.e. DNA damage), independent of the state of the cytoplasm or nucleus. He is also known for his hypothesis developed with Konrad Howitz called the "Xenohormesis
Xenohormesis
Xenohormesis explains how certain molecules such as plant polyphenols, which indicate stress in the plants, can have a longevity-conferring effect in consumers of plant . It was first used in the paper "Small molecules that regulate lifespan: evidence for xenohormesis." by Dr. David Sinclair and...
Hypothesis" which states that animals have evolved to sense stress signalling molecules in other species, in order to gain advance warning of a deteriorating environment.
Sinclair is credited with co-discovering Sirtuin
Sirtuin
Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes...
activating compounds STACs with Konrad Howitz of Biomol Inc. In September 2003, Howitz and Sinclair et al., published a highly cited paper reporting that polyphenols such as resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
activate human SIRT1 and extend the lifespan of budding yeast (Howitz et al., Nature, 2003). In collaboration with two Drosophila aging experts, Marc Tatar and Steven Helfand (Brown U.), he co-published that resveratrol extends the lifespan of worms and flies in a SIR2-dependent manner. This effect was found not reproducible by other investigators (Linda Partridge
Linda Partridge
Dame Linda Partridge DBE is a British geneticist, who studies the biology and genetics of ageing and age-related diseases, such as Alzheimer's disease and Parkinson's disease....
and David Gems
David Gems
David Gems FRS is a British biogerontologist and Reader in the Biology of Ageing at UCL where he is also Deputy Director of the Institute of Healthy Ageing. His work concerns understanding aging through the genetics of C. elegans....
). In a more recent study by Sinclair, published in November 2006 by the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
indicated that resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
had life-extending activity in mice fed a high fat Western diet (60% fat). These obese mice lived considerably shorter than normally fed mice, and that obese mice treated with resveratrol lived an average of 15% longer than obese mice not treated with resveratrol. A later study showed that resveratrol mimics the diets known as calorie restriction (CR) in normally fed mice and slowed down diseases of aging such as cardiovascular disease, cataracts, and diabetes (however, no effect on overall lifespan was evident). Molecules that are orders of magnitude more potent that resveratrol have been developed and shown efficacy in mouse models of obesity and diabetes (Milne et al., Nature, 2007; Feige et al., Cell Metabolism, 2008). However, key results from these studies have proved irreproducible by independent investigators. When queried on these, Sinclair questioned the ability of these independent investigators to synthesize these compounds. The first of these potent STACs is in Phase I human trials.
Sirtris Pharmaceuticals
In 2004, Dr. Sinclair co-founded Sirtris PharmaceuticalsSirtris Pharmaceuticals
Sirtris Pharmaceuticals, Inc. is a biotechnology company based in Cambridge, MA that is developing therapies for type 2 diabetes, cancer, and other diseases. Founded in 2004 by a Harvard University biologist, Drs. David Sinclair, and venture capitalist Christoph Westphal, the company went public in...
with Christoph Westphal
Christoph Westphal
Christoph Westphal, M.D., Ph.D., co-founded Sirtris Pharmaceuticals in 2004 with David Sinclair and served as Chief Executive Officer until April 2010. Dr...
, to develop drugs that harness the body's own defenses against diseases of ageing. Sirtris was featured on the cover of Fortune magazine in Jan 2007.
Michelle Dipp
Michelle Dipp
Michelle Dipp, M.D., Ph.D., is a co-founder and CEO of OvaScience, a company focused on improving the success of IVF, as well as a founder and partner of Longwood Fund, a healthcare venture capital firm that founds and invests in healthcare companies....
since led the acquisition of Sirtris by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
in 2008 for $720 million.