David Sinclair (biologist)
Sinclair is Professor of Pathology and Co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School. 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 School.
One of Sinclair's discoveries was in the lab of Leonard Guarente where he identified the key role of rDNA circles 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 that 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 Stephen Helfand (Brown University), 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.
In 2004, Sinclair co-founded Sirtris Pharmaceuticals 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.
- To Age or Not To Age, a documentary film
- "Stop, rewind: the scientists slowing the ageing process". BBC News. January 26, 2011.
- (Guarente and Sinclair, Cell, 1997)
- Mills KD, Sinclair DA, Guarente L (May 28 1999). "MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.". Cell (Printdoi:10.1016/S0092-8674(00)80772-2. PMID 10367890. "The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance. Here, we show that Sir3p is released from telomeres in response to DNA double-strand breaks (DSBs), binds to DSBs, and mediates their repair, independent of cell mating type. Sir3p relocalization is S phase specific and, importantly, requires the DNA damage checkpoint genes MEC1 and RAD9. MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs. This novel mode by which preformed DNA repair machinery is mobilized by DNA damage sensors may have implications for human diseases resulting from defective DSB repair") 97 (5): 609–20.
- (Oberdoerffer, Cell, 2008)
- (Anderson, JBC, 2002)
- (Bitterman et al., JBC, 2003)
- (Yang et al., Cell, 2007)
- (Howitz and Sinclair, Cell, 2008)
- (Wood et al., Nature, 2004)
- About Sirtris Pharmaceuticals
- Fortune archive
- "Michelle Dipp’s interview with Xconomy.com regarding the GSK acquisition of Sirtris". Retrieved 2010-02-18.