We plan to further the study of the function of SIRT1 in mice.
In Aim 1 we study whether SIRT1 (and other sirtuin) activity declines aging. This study will include a detailed analysis of NAD and NADH levels in cellular compartments of muscle, heart and brain.
In Aim 2 we will determine the effects of depletion or augmentation of SIRT1 in brown fat, muscle, heart and 2-cells.
This aim will employ tissue specific deletion and over- expression of SIRT1 in mice.
In Aim 3 we will study the effects of SIRT1 on bone. This study will use mice knocked out for SIRT1 in osteoblasts or osteoclasts to determine mechanisms by which SIRT1 determines bone density.
This aim will also study how calorie restriction affects bone.
In Aim 4 we will study the role of SIRT1 in T cells. In this aim we will study immune function in T cell-specific SIRT1 knockout mice and determine the mechanism by which SIRT1 functions in these immune cells.

Public Health Relevance

Sirtuins regulate life span in lower organisms and may mediate some of the effects of calorie restriction. We plan to determine the functions of mammalian sirtuins, with emphasis on SIRT1, in multiple cell types in mice. These studies may suggest new strategies to treat diseases of aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Guo, Max
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Chang, Hung-Chun; Guarente, Leonard (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25:138-45
Li, Yu; Wong, Kimberly; Giles, Amber et al. (2014) Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 146:539-49.e7
Imai, Shin-ichiro; Guarente, Leonard (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464-71
Herskovits, A Zara; Guarente, Leonard (2014) SIRT1 in neurodevelopment and brain senescence. Neuron 81:471-83
Sinclair, David A; Guarente, Leonard (2014) Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol 54:363-80
Guarente, Leonard (2013) Calorie restriction and sirtuins revisited. Genes Dev 27:2072-85
Guarente, Leonard (2013) Introduction: sirtuins in aging and diseases. Methods Mol Biol 1077:3-10
Mouchiroud, Laurent; Houtkooper, Riekelt H; Moullan, Norman et al. (2013) The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell 154:430-41
Herskovits, Adrianna Z; Guarente, Leonard (2013) Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res 23:746-58
Chang, Hung-Chun; Guarente, Leonard (2013) SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153:1448-60

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