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.
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.
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|Ondracek, Caitlin R; Frappier, Vincent; Ringel, Alison E et al. (2017) Mutations that Allow SIR2 Orthologs to Function in a NAD+-Depleted Environment. Cell Rep 18:2310-2319|
|Guarente, Leonard (2014) Linking DNA damage, NAD(+)/SIRT1, and aging. Cell Metab 20:706-707|
|Imai, Shin-ichiro; Guarente, Leonard (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464-71|
|Chang, Hung-Chun; Guarente, Leonard (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25:138-45|
|Sinclair, David A; Guarente, Leonard (2014) Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol 54:363-80|
|Herskovits, A Zara; Guarente, Leonard (2014) SIRT1 in neurodevelopment and brain senescence. Neuron 81:471-83|
|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|
|Fendt, Sarah-Maria; Bell, Eric L; Keibler, Mark A et al. (2013) Reductive glutamine metabolism is a function of the ?-ketoglutarate to citrate ratio in cells. Nat Commun 4:2236|
|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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