Recent evidence has implicated the TOR pathway as a key modulator of invertebrate aging. Consistently, reduced TOR signaling has been shown to be protective for a variety of age-related disease models, including cardiovascular, neurodegenerative and metabolic syndromes, as well as cancer. The mechanisms by which TOR activity accelerates aging or age-related disease remain to be determined. Preliminary data presented in this proposal, namely the enhanced longevity of mice lacking S6K1, delimits potential mechanisms. In this proposal, we will define the tissue in which loss of S6K1 is beneficial for these phenotypes and test potential functions of S6 kinase that may be linked to aging and age-related disease. Specifically, in Aim 1 (with work to be performed in both the Kennedy and Withers lab), we will generate and characterize four tissue-specific S6K1-/- knockout lines lacking S6K1 in liver, fat, muscle or brain to determine in which tissues loss of S6K1 leads to protection from diet-induced obesity. Studies in Aim 2 (performed in the Withers lab with translation studies performed in the Kennedy lab) we will examine links between S6K1 function and insulin/IGF-1 signaling. That S6K1-/- and Irs1-/- mice are both long-lived is paradoxical since S6K1 exerts feedback inhibition on insulin/IGF-1 signaling through phosphorylation of IRS1. Thus, one long-lived mouse has reduced insulin/IGF-1 signaling and the other has enhanced signaling. We will compare and contrast these two mouse models, examining metabolic parameters as well as markers of insulin/IGF-1 and TORC1 signaling together with analysis of protein translation, to better understand the crosstalk between these two pathways and its potential relevance to aging and age-related disease. Finally, in Aim 3 (performed in the Kennedy lab) we will examine general levels of translation in S6K1-/- tissues and cells in cultures, and monitor translation of specific messages linked to S6K1 regulation. Unlike invertebrate models in which loss of S6K1 leads to reduced translation levels, the data in S6K1-/- mice is limited and equivocal. Studies in Aim 3 will resolve this important question. We will generate cells lines lacking both S6K1 and IRS1 to address genetically the interactions between these pathways. Collectively, these studies will provide insight (1) into the activities of S6K1 linked to aging and age-related disease and (2) preliminary data to dictate longevity studies in S6K1 conditional knockout mice.

Public Health Relevance

Identifying the genes that influence mammalian aging is critical to understanding the biology of aging and to developing interventions which improve healthspan, the age to which an individual remains healthy and productive. We have determined that reduced S6 kinase function leads to lifespan extension in organisms ranging from yeast to mice. In this proposal, we will dissect the mechanisms by which S6 kinase activity accelerates the aging process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG035336-01
Application #
7786663
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (A1))
Program Officer
Finkelstein, David B
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$306,120
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tsai, Shih-Yin; Rodriguez, Ariana A; Dastidar, Somasish G et al. (2016) Increased 4E-BP1 Expression Protects against Diet-Induced Obesity and Insulin Resistance in Male Mice. Cell Rep 16:1903-14
McQuary, Philip R; Liao, Chen-Yu; Chang, Jessica T et al. (2016) C. elegans S6K Mutants Require a Creatine-Kinase-like Effector for Lifespan Extension. Cell Rep 14:2059-2067
Tsai, Shihyin; Sitzmann, Joanna M; Dastidar, Somasish G et al. (2015) Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity. J Clin Invest 125:2952-64
Garelick, Michael G; Mackay, Vivian L; Yanagida, Aya et al. (2013) Chronic rapamycin treatment or lack of S6K1 does not reduce ribosome activity in vivo. Cell Cycle 12:2493-504
Garelick, Michael G; Kennedy, Brian K (2011) TOR on the brain. Exp Gerontol 46:155-63