The discovery that rapamycin extends the life span of diverse organisms has triggered a flurry of studies aimed at identifying the underlying molecular mechanisms and potential ways to prevent aging and age-related diseases. It has been suggested that the mammalian target of rapamycin complex 1 (mTORC1) controls growth and aging by regulating mRNA translation. However, how a decrease in protein synthesis can extend lifespan remains an unresolved issue. Protein homeostasis refers to a proper balance between synthesis, maturation, and degradation of cellular proteins. Despite the crucial role of protein homeostasis in growth and aging, the mechanistic connection between nutrient signaling and protein homeostasis is poorly understood. In addition, little is known about aging-associated proteome changes due in large part to technical limitations. The goal of this project is to establish the functional connection between nutrient signaling and protein homeostasis at the level of translation, and to determine aging-associated alternative translation. The rationale for this proposal grew out of the preliminary results that nutrient signaling not only controls protein quantity, but also negatively regulates the quality of translational products. Using high resolutio ribosome profiling technique, we uncovered a prevailing alternative translation controlled by nutrient signaling. These findings led to the central hypothesis that nutrient signaling coordinates with protein homeostasis in controlling the aging process. The following specific aims are proposed to test this hypothesis: 1) Dissect the molecular linkage between nutrient signaling and protein homeostasis by focusing on translational aspects of different mTORC1 down- stream targets. 2) Define the role of nutrient signaling in co-translational events of nascent chains, including co-translational folding, degradation, and chaperone interaction. 3) Determine translational re-programming in mammalian aging, in particular the nutrient signaling-controlled selective translation and alternative translation initiation. Our newly-developed global translation initiation sequencing technique (GTI-Seq) will serve as an excellent tool to investigate the genome-wide translational re-programming in response to nutrient signaling and aging. This proposal integrates innovative approaches into fundamental studies of translational control. Successful completion of the proposed studies will transform our knowledge about the biology of aging. A comprehensive understanding of aging-associated proteome changes will ultimately lead to new therapeutic strategies for combating aging and age-related pathologies.

Public Health Relevance

Aging is a major risk factor for several common diseases including cancers, cardiovascular, metabolic and neurodegenerative diseases, which pose a daunting challenge to public health. This proposal aims to elucidate the mechanistic connection between protein homeostasis and nutrient signaling pathway, as well as its implication in growth and aging. A mechanistic understanding of protein synthesis regulation will facilitate the development of new therapeutic strategies for combating aging and age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG042400-01A1
Application #
8501929
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$312,161
Indirect Cost
$107,161
Name
Cornell University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Liu, Botao; Qian, Shu-Bing (2014) Translational reprogramming in cellular stress response. Wiley Interdiscip Rev RNA 5:301-15
Wan, Ji; Qian, Shu-Bing (2014) TISdb: a database for alternative translation initiation in mammalian cells. Nucleic Acids Res 42:D845-50