Molecular mechanisms of aging
Aging, mitochondria, resveratrol, sirtuins, metabolism, longevity, mTOR, rapamycin
The Baur lab is interested in the basic mechanisms that lead to aging. Age is the most important risk factor for many of the diseases affecting Western society today, including cancer, cardiovascular disease, and neurodegenerative disorders. Although the causes of aging are not known, it can be delayed experimentally in rodents by decreasing energy intake in the absence of malnutrition (caloric restriction, CR). Elucidating the mechanism(s) by which CR extends lifespan is expected to yield insights into the causes of aging and to highlight new therapeutic approaches to the prevention and treatment of age-related disease.
One current project in the lab uses a transgenic mouse approach (overexpression of Nampt) to mimic the changes in NAD+ metabolism that occur during CR. Changes in NAD+ metabolism are thought to be the driving force that activates SIRT1 and other sirtuins, but are likely to affect a host of other processes as well. Thus, Nampt-overexpression may be a more effective strategy to mimic the full effects of CR than previous approaches, such as SIRT1-overexpresion or resveratrol (a SIRT1 activator).
Another area of interest is the role of mitochondrial biogenesis in CR. Although it has been studied since the 1930s, CR was shown only recently to paradoxically increase the number of mitochondria in many tissues. The consequences of this increase on reactive oxygen species generation, stress resistance, and insulin sensitivity are not known and cannot easily be distinguished from other effects of CR in vivo. Fortunately, the increase in mitochondrial biogenesis can be recapitulated in cell culture using serum from CR animals. We plan to use this system to functionally characterize cells with increased mitochondrial content and to isolate the serum factor that mediates the effect.
Recently, we have been investigating the mechanisms by which rapamycin affects metabolism in mice. Rapamycin is the only compound that has been unambiguously shown to extend the maximum lifespan of a mammalian species. However, the underlying mechanisms remain unknown, and side effects including immunosuppression and the elevation of cardiovascular risk factors are likely to limit the utility of the drug in humans. Together with our collaborators in the Sabatini lab (Whitehead Institute), we have shown that in addition to inhibiting its canonical target, mTOR complex 1, chronic rapamycin treatment disrupts mTORC2, resulting in insulin resistance. Several current lines of investigation will test whether mTORC2 disruption is responsible for other detrimental or beneficial effects of rapamycin, and whether the effects of the drug on longevity are separable from its undesirable side effects.
Cassie Tran, PhD Postdoctoral Fellow
Tony Davila, PhD Postdoctoral Fellow
Karthi Chellappa, PhD Postdoctoral Fellow
David Frederick, Graduate Student
Carrie Sims, MD Graduate Student
James Davis, PhD, Research Specialist
Sarmistha Mukherjee, PhD Researcher
Lamming Dudley W, Ye Lan, Katajisto Pekka, Goncalves Marcus D, Saitoh Maki, Stevens Deanna M, Davis James G, Salmon Adam B, Richardson Arlan, Ahima Rexford S, Guertin David A, Sabatini David M, Baur Joseph A: Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science (New York, N.Y.) 335(6076): 1638-43, Mar 2012 Notes: Featured in a commentary and recommended by the Faculty of 1000.
Miller Richard A, Harrison David E, Astle C M, Baur Joseph A, Boyd Angela Rodriguez, de Cabo Rafael, Fernandez Elizabeth, Flurkey Kevin, Javors Martin A, Nelson James F, Orihuela Carlos J, Pletcher Scott, Sharp Zelton Dave, Sinclair David, Starnes Joseph W, Wilkinson J Erby, Nadon Nancy L, Strong Randy: Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice. The journals of gerontology. Series A, Biological sciences and medical sciences 66(2): 191-201, Oct 2010.
Baur Joseph A: Resveratrol, sirtuins, and the promise of a DR mimetic. Mechanisms of ageing and development 131(4): 261-9, Feb 2010.
Armour Sean M, Baur Joseph A, Hsieh Sherry N, Land-Bracha Abigail, Thomas Sheila M, Sinclair David A: Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging 1(6): 515-28, Jun 2009.
Pearson Kevin J, Baur Joseph A, Lewis Kaitlyn N, Peshkin Leonid, Price Nathan L, Labinskyy Nazar, Swindell William R, Kamara Davida, Minor Robin K, Perez Evelyn, Jamieson Hamish A, Zhang Yongqing, Dunn Stephen R, Sharma Kumar, Pleshko Nancy, Woollett Laura A, Csiszar Anna, Ikeno Yuji, Le Couteur David, Elliott Peter J, Becker Kevin G, Navas Placido, Ingram Donald K, Wolf Norman S, Ungvari Zoltan, Sinclair David A, de Cabo Rafael: Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell metabolism 8(2): 157-68, Aug 2008.
Kim Dohoon, Nguyen Minh Dang, Dobbin Matthew M, Fischer Andre, Sananbenesi Farahnaz, Rodgers Joseph T, Delalle Ivana, Baur Joseph A, Sui Guangchao, Armour Sean M, Puigserver Pere, Sinclair David A, Tsai Li-Huei: SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. The EMBO journal 26(13): 3169-79, Jul 2007.
Yang Hongying, Yang Tianle, Baur Joseph A, Perez Evelyn, Matsui Takashi, Carmona Juan J, Lamming Dudley W, Souza-Pinto Nadja C, Bohr Vilhelm A, Rosenzweig Anthony, de Cabo Rafael, Sauve Anthony A, Sinclair David A: Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130(6): 1095-107, Sep 2007.
Baur Joseph A, Pearson Kevin J, Price Nathan L, Jamieson Hamish A, Lerin Carles, Kalra Avash, Prabhu Vinayakumar V, Allard Joanne S, Lopez-Lluch Guillermo, Lewis Kaitlyn, Pistell Paul J, Poosala Suresh, Becker Kevin G, Boss Olivier, Gwinn Dana, Wang Mingyi, Ramaswamy Sharan, Fishbein Kenneth W, Spencer Richard G, Lakatta Edward G, Le Couteur David, Shaw Reuben J, Navas Placido, Puigserver Pere, Ingram Donald K, de Cabo Rafael, Sinclair David A: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117): 337-42, Nov 2006.
Baur JA., Sinclair DA.: Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews in Drug Discovery 5(6): 337-342, 2006.
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Last updated: 07/14/2016
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