大卫·安德鲁·辛克莱

大卫·安德鲁·辛克莱（David Andrew Sinclair，1969年6月26日在悉尼出生）是一名澳大利亚生物学家，主要研究遗传学中如何有效令人类生命延长和治疗老年疾病。^[1]

辛克莱是哈佛医学院保罗·格伦实验室老化生物学机构的共同指导者。辛克莱在悉尼新南威尔士大学获得了理学学士（荣誉I级），并获得了澳大利亚联邦奖。1995年，他获得分子遗传学博士学位，然后前往美国麻省理工学院与李纳德·瓜伦特（英语：Leonard P. Guarente）共同担任博士后研究员。

自1999年起，他成为哈佛医学院遗传系的终身教授。

辛克莱的一项研究成果是在李纳德·瓜伦特的实验室确定了染色体外rDNA环（英语：Extrachromosomal rDNA circle）（或“ERCs”）在决定酵母寿命中的关键角色。^[2]随后的研究表明，ERCs在特定酵母菌株中，对衰老有一种特别的反应。他还表明Sir2蛋白质重新定位于DNA断裂和介导修复。^[3]这两个发现导致他的实验室发现基因组不稳定性诱导基因调节的变化，可能驱动哺乳动物的衰老过程。^[4]

2002年，辛克莱在哈佛的实验室发现NAD⁺于细胞在衰老过程中的起关键作用。^[5]

2003年，他的实验室公布，NAD⁺是Sir2和SIRT1的非竞争性抑制剂，并提出该分子作为去乙酰化酶的生理调节剂。^[6]

辛克莱归因于“线粒体绿洲假说”，其中指出线粒体的能量和诺加因子含量决定细胞面对基因毒性侵略（即DNA损伤）的存活率。^[7]辛克莱也以他与孔拉德·霍维兹（Konrad Howitz）共同发展的“异种毒物兴奋效应假说”而闻名。

2003年9月，霍维兹和辛克莱等人发表了一篇外界高度关注的论文，报告称白藜芦醇等多酚能激活人类的SIRT1从而延长细胞的寿命（Howitz等人，Nature，2003）。其后与两个研究果蝇的抗衰老专家马克·鞑靼（Marc Tatar）和史蒂芬·赫尔芳德（Stephen Helfand，布朗大学）合作，共同发表了以白藜芦醇激活SIR2的方式延长蠕虫和苍蝇的寿命的报告。但这项报告不被其他研究者重现。

2006年11月，辛克莱于Nature杂志发表的一项研究表明，通过对体脂率（60%脂肪）喂饲提升诺加因子(NAD+)的物质,具有延长生命的效果。这些肥胖小鼠比正常饲养的小鼠存活时间短得多。　研究发现，以提升NAD⁺的物质治疗的肥胖小鼠比未用白藜芦醇治疗的肥胖小鼠平均寿命长15％。证实以提升NAD⁺的物质在模拟正常喂养的小鼠中能有效限制卡路里，并减慢老化疾病的影响，例如心血管疾病，白内障和糖尿病（然而，对总体寿命没有影响）。

2013年12月，辛克莱和UNSW的一个团队发现，通过应用烟酰胺单核苷酸，可以令细胞内的分子得到修复，令线粒体和细胞核之间的通信迅速恢复诺加因子到年青的水平（被认为是衰老的其中一个原因）。^[8]^[9]^[10]

辛克莱已经收到了超过25个奖项，包括澳大利亚联邦奖、海伦·惠特尼奖学金、内森休克奖、白血病和淋巴瘤会士、国立卫生研究院MERIT奖、默克奖、阿米姆奖学金、Genzyme优秀成就生物医学科学奖、埃里森医学高级会士、生物创新奖及40岁以下顶尖科学家明亮火花奖。

[1]
Stop, rewind: the scientists slowing the ageing process. BBC News. January 26, 2011 [2017-05-15]. （原始内容存档于2020-11-11）.
[2]
(Guarente and Sinclair, Cell, 1997)
[3]
Mills KD, Sinclair DA, Guarente L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.. Cell (Print). May 28, 1999, 97 (5): 609–20. PMID 10367890. doi:10.1016/S0092-8674(00)80772-2. 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
[4]
(Oberdoerffer, Cell, 2008)
[5]
(Anderson, JBC, 2002)
[6]
(Bitterman et al., JBC, 2003)
[7]
(Yang et al., Cell, 2007)
[8]
Sinclair, David A. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell. 19 December 2013, 155 (7): 1624–1638 [14 April 2015]. PMC 4076149 . PMID 24360282. doi:10.1016/j.cell.2013.11.037. （原始内容存档于2019-09-23）.
[9]
Bellman, Gary. New Elixir of Youth? Researchers Develop a Drug That Can Reverse Aging in Animal Models. Male Anti-Aging Institute. [14 April 2015]. （原始内容存档于2017-04-14）.
[10]
Cameron, David. A New—and Reversible—Cause of Aging. Harvard Medical School. 19 December 2013 [14 April 2015]. （原始内容存档于2017-08-03）.

[1] [1]
Stop, rewind: the scientists slowing the ageing process. BBC News. January 26, 2011 [2017-05-15]. （原始内容存档于2020-11-11）.

[2] [2]
(Guarente and Sinclair, Cell, 1997)

[3] [3]
Mills KD, Sinclair DA, Guarente L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.. Cell (Print). May 28, 1999, 97 (5): 609–20. PMID 10367890. doi:10.1016/S0092-8674(00)80772-2. 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

[4] [4]
(Oberdoerffer, Cell, 2008)

[5] [5]
(Anderson, JBC, 2002)

[6] [6]
(Bitterman et al., JBC, 2003)

[7] [7]
(Yang et al., Cell, 2007)

[8] [8]
Sinclair, David A. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell. 19 December 2013, 155 (7): 1624–1638 [14 April 2015]. PMC 4076149 . PMID 24360282. doi:10.1016/j.cell.2013.11.037. （原始内容存档于2019-09-23）.

[9] [9]
Bellman, Gary. New Elixir of Youth? Researchers Develop a Drug That Can Reverse Aging in Animal Models. Male Anti-Aging Institute. [14 April 2015]. （原始内容存档于2017-04-14）.

[10] [10]
Cameron, David. A New—and Reversible—Cause of Aging. Harvard Medical School. 19 December 2013 [14 April 2015]. （原始内容存档于2017-08-03）.

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大卫·安德鲁·辛克莱

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