Program Director/Principal Investigator (Last, First, Middle): PI: Alexey G. Ryazanov, Ph.D. Abstract The TOR pathway plays an important role in aging. It has been demonstrated that treatment with rapamycin leads to prolongation of life span in diverse organisms. One of the components of TOR pathway is eEF2 kinase (eEF2K) which regulates the global rate of protein synthesis through phosphorylation of elongation factor 2 (eEF2). Activation of TOR results in the inhibition of eEF2K as a part of the mechanism that increases the rate of protein synthesis. Recently, we generated mice with knockout of eEF2K and found that its inactivation protects stem cells from apoptosis and retards aging. Thus, there exists a paradox: on one hand inhibition of TOR slows down aging, on the other hand inhibition of TOR may accelerate aging through activation of eEF2K. Therefore, the inhibition of TOR by rapamycin results in two opposite signals: inhibition of the TOR pathway slows down aging and at the same time activates eEF2K, which may counteract the anti- aging effect of rapamycin. Thus, we hypothesize that simultaneous inhibition of TOR and eEF2K increases the effect of TOR inhibition on aging. We will test this hypothesis by determining whether inactivation of eEF2K can synergize with rapamycin in producing an anti-aging effect. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page

Public Health Relevance

PI: Alexey G. Ryazanov, Ph.D. Investigation of synergism between mTOR and eEF2 kinase pathways Project Narrative Chronic activation of nutrient sensing pathway mediated by mTOR and the stress response pathway mediated by eEF2K both contribute to aging. This proposal seeks to explore the functional and molecular interrelationship between the mTOR and eEF2K pathways and to determine whether the simultaneous inhibition of these two pathways can have a synergistic effect on slowing down aging processes. The results of this study will have important implication for understanding the mechanisms of aging and may potentially result in therapeutic opportunities in the future. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG042870-03
Application #
8729435
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
2012-09-30
Project End
2014-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$187,819
Indirect Cost
$69,694
Name
Rbhs-Robert Wood Johnson Medical School
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Chu, Hsueh-Ping; Liao, Yi; Novak, James S et al. (2014) Germline quality control: eEF2K stands guard to eliminate defective oocytes. Dev Cell 28:561-72