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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015339-13
Application #
8220804
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
1999-05-01
Project End
2015-01-31
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
13
Fiscal Year
2012
Total Cost
$422,197
Indirect Cost
$170,889
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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
Sinclair, David A; Guarente, Leonard (2014) Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol 54:363-80
Chang, Hung-Chun; Guarente, Leonard (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25:138-45
Herskovits, A Zara; Guarente, Leonard (2014) SIRT1 in neurodevelopment and brain senescence. Neuron 81:471-83
Herskovits, Adrianna Z; Locascio, Joseph J; Peskind, Elaine R et al. (2013) A Luminex assay detects amyloid β oligomers in Alzheimer's disease cerebrospinal fluid. PLoS One 8:e67898
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
Yao, Hongwei; Hwang, Jae-woong; Sundar, Isaac K et al. (2013) SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD. Am J Physiol Lung Cell Mol Physiol 305:L615-24
Guarente, Leonard (2013) Sirtuins and ageing--new findings. EMBO Rep 14:750
Simic, Petra; Williams, Eric O; Bell, Eric L et al. (2013) SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep 3:1175-86

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