Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015339-14
Application #
8417687
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
2013-02-01
Budget End
2014-01-31
Support Year
14
Fiscal Year
2013
Total Cost
$398,979
Indirect Cost
$161,491

  Institution

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

  Publications

Das, Abhirup; Huang, George X; Bonkowski, Michael S et al. (2018) Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging. Cell 173:74-89.e20
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
Herskovits, Adrianna Z; Locascio, Joseph J; Peskind, Elaine R et al. (2013) A Luminex assay detects amyloid ? oligomers in Alzheimer's disease cerebrospinal fluid. PLoS One 8:e67898
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

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