David A. Sinclair

Last updated
David A. Sinclair
David Sinclair.jpg
Sinclair in 2020
Born (1969-06-26) 26 June 1969 (age 55) [1] [2]
Sydney, New South Wales, Australia
Citizenship
  • Australia
  • United States
Alma mater University of New South Wales (BSc, PhD)
Known forResearch on aging
Awards
Scientific career
Fields Molecular genetics
Institutions Harvard Medical School [3]
Doctoral advisor Ian Dawes
Other academic advisorsLeonard Guarente

David Andrew Sinclair AO (born June 26, 1969) is an Australian-American biologist and academic known for his research on aging and epigenetics. Sinclair is a professor of genetics at Harvard Medical School and the founding director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard. He is the co-author of Lifespan: Why We Age – and Why We Don't Have To.

Contents

Early life and education

David Andrew Sinclair was born in Australia in 1969 and grew up in St Ives, New South Wales. His paternal grandmother had emigrated to Australia following the suppression of the Hungarian Uprising of 1956, and his father changed the family name from Szigeti to Sinclair. [2] Sinclair studied at the University of New South Wales, Sydney, obtaining a BSc in biochemistry with honours in 1991 and a Ph.D. in molecular genetics in 1995, focusing on gene regulation in yeast. He also won the Australian Commonwealth Prize. [3] [2] [4]

Career

Sinclair met Massachusetts Institute of Technology professor Leonard P. Guarente in 1993. Guarente had studied yeast as a model of aging, and after meeting him Sinclair, interviewed for a post-doc position in Guarente's lab. [2]

He worked as a postdoctoral researcher for Guarente for four years and in 1999 he was hired at Harvard Medical School. In 2004, Sinclair met with the philanthropist Paul F. Glenn who donated $5 million to Harvard to establish the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard, of which Sinclair became the founding director. [2] In 2004, Sinclair founded Sirtris Pharmaceuticals along with Andrew Perlman, Christoph Westphal, Richard Aldrich, Richard Pops, and Paul Schimmel. [5] [6]

Sirtris was focused on developing Sinclair's research into activators of sirtuins, work that began in the Guarente lab. [5] The company was specifically focused on resveratrol formulations and derivatives as activators of the SIRT1 enzyme; Sinclair became known for making statements about resveratrol like: "(It's) as close to a miraculous molecule as you can find. ... One hundred years from now, people may be taking these molecules on a daily basis to prevent heart disease, stroke, and cancer." [5] Most of the anti-aging field was more cautious, especially with regard to what else resveratrol might do in the body and its lack of bioavailability. [5] [7] The company went public in 2007 and was subsequently purchased by and made a subsidiary of GlaxoSmithKline in 2008 for $720 million. Five years later, GSK shuttered the Sirtris program without successful drug development. [8] [9] [10] [11]

In 2006, Sinclair co-founded of Genocea Biosciences, a company founded based on the work of Harvard scientist Darren E. Higgins around antigens that stimulate T cells and the use of these antigens to create vaccines; [12] [13] The company delisted from the NASDAQ and closed in 2022 due to lack of funding. [14]

In 2008, Sinclair was promoted to tenured professor at Harvard Medical School. [15] A few years later, he also became a conjoint professor at the School of Medical Sciences at the University of New South Wales. [15] In 2008, he also joined the scientific advisory board of Shaklee and helped them devise and introduce a product containing resveratrol called "Vivix". He later disputed the use of his name and words to promote the supplement, and resigned from the board. [16]

In 2011, Sinclair co-founded OvaScience along with Michelle Dipp, Aldrich, Westphal, and Jonathan Tilly. The company was based on scientific work done by Tilly concerning mammalian oogonial stem cells and work on mitochondria by Sinclair. [17] [18] The company merged with Millendo Therapeutics in 2018. [19] In 2011, he also co-founded CohBar along with Nir Barzilai and other colleagues. CohBar aimed to discover and develop novel peptides derived from mitochondria. [20] CohBar delisted from the NASDAQ upon belief that it was a public shell. [21]

In 2015, co-founded Metro Biotech along with Washington University professor Dr. Rajendra Apte. The pharmaceutical company focused on NAD+ precursors such as NMN. [22] He also co-founded Animal Bioscience in 2017 along with his brother Nick. The company focuses on small molecule-based therapy for the pet industry. [23]

In 2022, Metro Biotech successfully urged the FDA to take actions to take NMN off the market as a supplement because Metro Biotech had registered NMN in investigational new drug applications. [24] The following year, he co-founded Tally Health, a supplement company with a stated goal to "change the way we age" at the cellular level. [25]

In 2024, Sinclair resigned as the President of The Academy for Health and Lifespan Research, an organization made up of a group of scientists that Sinclair had co-founded. [26] The resignation came after what The Wall Street Journal described as a "cascade" of resignations from outraged members of The Academy after Sinclair and his brother announced that Animal Biosceince had proven that a supplement for dogs with undisclosed ingredients reversed aging. The claim was also met with criticism and skepticism from other longevity researchers. [27] [26]

Research

Sinclair has expressed the view that there is no limit to human lifespan, and that there is a backup copy of the genetic and epigenetic information in us. [28]

While Sinclair was in Guarente's lab, he discovered that sirtuin 1 (called sir2 in yeast) slows aging in yeast by reducing the accumulation of extrachromosomal rDNA circles. Others working in the lab at the time identified NAD as an essential cofactor for sirtuin function. [2] In 2002, after he had left for Harvard, he clashed with Guarente at a scientific meeting at Cold Spring Harbor Laboratory, challenging Guarante's description of how sir2 might be involved in aging; this set off a scientific rivalry. [5]

In 2003, Sinclair learned that scientists at a Pennsylvania biotech company called Biomol Research Laboratories had developed a biochemical assays in which they thought that polyphenols including resveratrol activated SIR2. [2] This led to publications authored in part by Sinclair in both Nature and Science in 2003. [5] However, by 2005, it became clear that the biochemical assay consists of a fluorescent probe that interacts nonspecifically with resveratrol and that resveratrol is not a SIR2 activator [11] Despite the scientific debunking of resveratrol, Sinclair maintains an outspoken advocacy for resveratrol as an anti-aging drug and supplement. [2] [5] [29] High-profile papers claiming age reversal of mice have also come under intense scrutiny. [30] Sinclair's lab has continued to work on resveratrol and analogues of it as part of their research program in anti-aging. [29]

In December, 2020, Sinclair's group published that three Yamanaka transcription factors, Oct4, Sox2, and Klf4, when delivered together in a virus, could safely reverse the age of human and mouse cells, and restore the vision of old mice and mice with glaucoma. [31] In 2023, with Bruce Ksander's lab at Mass Eye and Ear, they presented a poster at the annual ARVO conference accompanied by a company press release claiming that vision could be restored in non-human primates. [32]

In January 2023, Sinclair's lab published research in Cell purporting to support his Information Theory of Aging, the idea that mammalian aging is due to the loss of epigenetic information, and that Yamanaka factors could exert a degree of artificial control over senescence and rejuvenation in mice. [33] [34] The paper received a formal reply pointing out that the treatment used in the paper is known to produce p53-dependent cell death in a 30-day period in which the mice were not observed. [35] Sinclair's claims of reverse aging have received criticism from other scientists. [26]

Bibliography

Books

In September 2019, Sinclair published Lifespan: Why We Age – and Why We Don't Have To co-written with journalist Matthew LaPlante and translated into 18 languages. [36] This was also released as an audiobook on Audible and read by Sinclair. [37] Sinclair broadly discusses his longevity practices on social media and includes them in his book. They include daily doses of nicotinamide mononucleotide (NMN) and resveratrol, which Sinclair claims are activators of SIRT1. [38]

Selected publications

Related Research Articles

<span class="mw-page-title-main">Life extension</span> Concept of extending human lifespan by improvements in medicine or biotechnology

Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled biological limit of around 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

Calorie restriction is a dietary regimen that reduces the energy intake from foods and beverages without incurring malnutrition. The possible effect of calorie restriction on body weight management, longevity, and aging-associated diseases has been an active area of research.

<span class="mw-page-title-main">Sirtuin</span> Enzyme

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast.

Leonard Pershing Guarente is an American biologist best known for his research on life span extension in the budding yeast Saccharomyces cerevisiae, roundworms, and mice. He is a Novartis Professor of Biology at the Massachusetts Institute of Technology.

<span class="mw-page-title-main">Sirtuin 1</span> Protein

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.

<span class="mw-page-title-main">Sirtuin 3</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity.

<span class="mw-page-title-main">Sirtuin 5</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Sirtuin 7</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin 7 is an enzyme that in humans is encoded by the SIRT7 gene. SIRT7 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

<span class="mw-page-title-main">Sirtuin 6</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Sirtuin 4</span> Protein-coding gene in the species Homo sapiens

Sirtuin 4, also known as SIRT4, is a mitochondrial protein which in humans is encoded by the SIRT4 gene. SIRT4 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT4 exhibits NAD+-dependent deacetylase activity.

Sirtris Pharmaceuticals, Inc. was a biotechnology company based in Cambridge, MA that developed therapies for type 2 diabetes, cancer, and other diseases. Conceived in 2004 by Harvard University biologist David Sinclair and Andrew Perlman, and founded that year by Sinclair and Perlman, along with Christoph Westphal, Richard Aldrich, Richard Pops, and Paul Schimmel, the company was focused on developing Sinclair's research into activators of sirtuins, work that began in the laboratory of Leonard P. Guarente where Sinclair worked as a post-doc before starting his own lab.

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Christoph Westphal is an American biomedical businessman.

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Extrachromosomal rDNA circles are pieces of extrachromosomal circular DNA (eccDNA) derived from ribosomal DNA (rDNA). Initially found in baker's yeast, these self-replicating circles are suggested to contribute to their aging and found in their aged cells. Like ordinary eccDNA, they are created by intra-molecular homologous recombination of the chromosome. The process for intra-molecular homologous recombination is independent of chromosomal replication. The de novo generated circles had exact multiples of tandem copies of 2-kb fragments from cosmid templates. The tandem organization is essential to circle formation. Looping out of organized ribosomal genes in intergenic nontranscribed spacers yielded either large or small repeat circles dependent on large or short repeats of the spacer.

SilentInformationRegulator (SIR) proteins are involved in regulating gene expression. SIR proteins organize heterochromatin near telomeres, ribosomal DNA (rDNA), and at silent loci including hidden mating type loci in yeast. The SIR family of genes encodes catalytic and non-catalytic proteins that are involved in de-acetylation of histone tails and the subsequent condensation of chromatin around a SIR protein scaffold. Some SIR family members are conserved from yeast to humans.

<span class="mw-page-title-main">Nicotinamide mononucleotide</span> Chemical compound

Nicotinamide mononucleotide is a nucleotide derived from ribose, nicotinamide, nicotinamide riboside and niacin. In humans, several enzymes use NMN to generate nicotinamide adenine dinucleotide (NADH). In mice, it has been proposed that NMN is absorbed via the small intestine within 10 minutes of oral uptake and converted to nicotinamide adenine dinucleotide (NAD+) through the Slc12a8 transporter. However, this observation has been challenged, and the matter remains unsettled.

OvaScience was a publicly traded biotechnology company, focused on female infertility. It was founded in 2011 by Michelle Dipp, Richard Aldrich, Christoph Westphal, Jonathan Tilly, and David Sinclair and is based on scientific work done by Tilly concerning mammalian oogonial stem cells and work on mitochondria by Sinclair. Tilly's work was expectedly met with skepticism, as it warranted a paradigm-shift; however, many labs across the world have been able to reproduce his results over several decades.

References

  1. ↑ Sinclair, David (2023-06-28). "David A Sinclair". Twitter. Retrieved 2023-06-28.
  2. 1 2 3 4 5 6 7 8 Duncan, David Ewing (August 15, 2007). "The Enthusiast". MIT Technology Review. Archived from the original on April 30, 2020. Retrieved August 17, 2017.
  3. 1 2 "David Sinclair". The Sinclair Lab, Harvard Medical School, Department of Genetics. Archived from the original on 17 August 2017. Retrieved 17 August 2017.
  4. ↑ Molecules discovered that extend life in yeast, human cells
  5. 1 2 3 4 5 6 7 Couzin, J (27 February 2004). "Scientific community. Aging research's family feud". Science. 303 (5662): 1276–9. doi:10.1126/science.303.5662.1276. PMID   14988530. S2CID   161459205. Archived from the original on 17 August 2017. Retrieved 17 August 2017.
  6. ↑ "Sirtris S-1 Registration for IPO". Sirtris via SEC Edgar. March 1, 2007. Archived from the original on February 13, 2017. Retrieved August 17, 2017.
  7. ↑ Wade, Nicholas (17 August 2009). "Tests Begin on Drugs That May Slow Aging". The New York Times. Archived from the original on 17 August 2017. Retrieved 17 August 2017.
  8. ↑ Carroll, John; McBride, Ryan (Mar 12, 2013). "Updated: GSK moves to shutter Sirtris' Cambridge office, integrate R&D". FierceBiotech. Archived from the original on April 28, 2019. Retrieved August 17, 2017.
  9. ↑ "GSK absorbs controversial 'longevity' company: News blog". Nature Blog. Archived from the original on 2013-12-17. Retrieved 2017-08-17..
  10. ↑ McBride, Ryan (12 August 2010). "Former Sirtris Execs' Nonprofit Starts Selling Resveratrol with Potential Anti-Aging Effects Online". Xconomy. Archived from the original on 27 March 2019. Retrieved 17 August 2017.
  11. 1 2 Kaeberlein, Matt; McDonagh, Thomas; Heltweg, Birgit; Hixon, Jeffrey; Westman, Eric A.; Caldwell, Seth D.; Napper, Andrew; Curtis, Rory; DiStefano, Peter S.; Fields, Stanley; Bedalov, Antonio; Kennedy, Brian K. (2005-04-29). "Substrate-specific activation of sirtuins by resveratrol". The Journal of Biological Chemistry. 280 (17): 17038–17045. doi: 10.1074/jbc.M500655200 . ISSN   0021-9258. PMID   15684413.
  12. ↑ Richtel, Matt (16 May 2007). "Warding Off Diseases, Many Vaccines at a Time". The New York Times. Archived from the original on 17 August 2017. Retrieved 26 August 2017.
  13. ↑ McBride, Ryan (May 1, 2008). "Polaris' Bitterman is humble about his early VC success". Boston Business Journal. Archived from the original on August 17, 2017. Retrieved August 17, 2017.
  14. ↑ Bayer, Max (24 May 2022). "Genocea closes up shop after failing to find a buyer, delists from Nasdaq". Fierce Biotech. Retrieved 9 December 2024.
  15. 1 2 "Professor David Sinclair | School of Medical Sciences". medicalsciences.med.unsw.edu.au. Archived from the original on 2017-12-01. Retrieved 2017-11-26.
  16. ↑ Goldstein, Jacob (26 December 2008). "Harvard Researcher Tied to Shaklee 'Anti-Aging Tonic' Vivix". WSJ. Archived from the original on 1 December 2017. Retrieved 27 November 2017.
  17. ↑ "OvaScience S-1". OvaScience via SEC Edgar. August 29, 2012. Archived from the original on May 14, 2017. Retrieved August 17, 2017.
  18. ↑ Weintraub, Karen (December 9, 2016). "Can fertility startup OvaScience really help women conceive late in life, as promised?". MIT Technology Review. Archived from the original on February 14, 2017. Retrieved August 17, 2017.
  19. ↑ "Once a multibillion dollar company, OvaScience ends a pennystock vehicle for Millendo's reverse merger".
  20. ↑ Grant, Bob (May 1, 2015). "Follow the Funding". The Scientist. Archived from the original on April 11, 2018. Retrieved January 8, 2022.
  21. ↑ "CohBar, Inc.: Notice of Delisting or Failure to Satisfy a Continued Listing Rule or Standard; Transfer of Listing (Form 8-K)". CohBar, Inc. 2023-11-27. Retrieved 2024-05-22.
  22. ↑ Ciardha, Victor (19 June 2024). "A Sneak Peek of Sinclair's MetroBiotech Lab and New NMN Clinical Trials". NMN. Retrieved 9 December 2024.
  23. ↑ Kerwin, Nicole (5 March 2024). "Supplement shows potential to reverse aging in dogs". Pet Food Processing. Retrieved 9 December 2024.
  24. ↑ "In NAC Docket, NAD+ Drug Firm Suggests US FDA Get Serious About Dietary Ingredient Regulations" . Retrieved 2023-01-07.
  25. ↑ "Tally Health — Welcome to a New Age". Tally Health. Retrieved 2023-03-28.
  26. 1 2 3 Marcus, Alex Janin, Dominique Mosbergen and Amy Dockser. "Star Scientist's Claim of 'Reverse Aging' Draws Hail of Criticism". WSJ. Retrieved 2024-04-29.{{cite news}}: CS1 maint: multiple names: authors list (link)
  27. ↑ Molteni, Megan (2024-03-05). "Harvard longevity scientist sparks furor with claim about reversing aging in dogs". STAT. Retrieved 2024-03-26.
  28. ↑ "How scientists want to make you young again".
  29. 1 2 Wallace, Benjamin. "An MIT Scientist Claims That This Pill Is the Fountain of Youth". New York . Archived from the original on 2017-08-14. Retrieved 2017-08-17.
  30. ↑ Gomes, Ana P.; Price, Nathan L.; Ling, Alvin J. Y.; Moslehi, Javid J.; Montgomery, Magdalene K.; Rajman, Luis; White, James P.; Teodoro, João S.; Wrann, Christiane D.; Hubbard, Basil P.; Mercken, Evi M. (2013-12-19). "PUBPEER Dissection of Anomalies with Figures in Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging". PubPeer. Archived from the original on 2021-03-02. Retrieved 2020-11-24.
  31. ↑ Lu, Yuancheng; Brommer, Benedikt; Tian, Xiao; Krishnan, Anitha; Meer, Margarita; Wang, Chen; Vera, Daniel L.; Zeng, Qiurui; Yu, Doudou; Bonkowski, Michael S.; Yang, Jae-Hyun; Zhou, Songlin; Hoffmann, Emma M.; Karg, Margarete M.; Schultz, Michael B. (2020-12-03). "Reprogramming to recover youthful epigenetic information and restore vision". Nature. 588 (7836): 124–129. Bibcode:2020Natur.588..124L. doi:10.1038/s41586-020-2975-4. ISSN   0028-0836. PMC   7752134 . PMID   33268865.
  32. ↑ "Life Biosciences Presents Groundbreaking Data at ARVO Demonstrating Restoration of Visual Function in Nonhuman Primates". Yahoo Finance. 2023-04-23. Retrieved 2024-05-21.
  33. ↑ Yang, Jae-Hyun; Hayano, Motoshi; Griffin, Patrick T.; Amorim, João A.; Bonkowski, Michael S.; Apostolides, John K.; Salfati, Elias L.; Blanchette, Marco; Munding, Elizabeth M.; Bhakta, Mital; Chew, Yap Ching; Guo, Wei; Yang, Xiaojing; Maybury-Lewis, Sun; Tian, Xiao (2023-01-12). "Loss of epigenetic information as a cause of mammalian aging". Cell. 186 (2): 305–326.e27. doi:10.1016/j.cell.2022.12.027. PMC   10166133 . PMID   36638792.
  34. ↑ Park, Alice (2023-01-13). "Scientists Have Reached a Key Milestone in Learning How to Reverse Aging". www.yahoo.com.
  35. ↑ Timmons, James A.; Brenner, Charles (2024-02-29). "The information theory of aging has not been tested". Cell. 187 (5): 1101–1102. doi:10.1016/j.cell.2024.01.013. PMID   38428390.
  36. ↑ Finkel, Toren (2019-09-10). "The enlightenment of age". Nature. 573 (7773): 193–194. Bibcode:2019Natur.573..193F. doi: 10.1038/d41586-019-02667-5 .
  37. ↑ Sinclair, David A (10 September 2019). Lifespan: Why We Age - and Why We Don't Have To. Archived from the original on 22 February 2020. Retrieved 22 February 2020– via Audible.
  38. ↑ "The Anti-Aging Supplements David Sinclair Takes | Skeptical Review". NOVOS. 2022-05-10. Retrieved 2022-11-16.
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