We have identified a functional role for Myc-related transcription factors of C. elegans in the process of aging. This family consists of two different heterodimers, the MDL and MML complexes, respectively, which have opposing roles in transcription and longevity control. The MML complex can extend lifespan and activate target gene transcription, whereas the MDL complex shortens lifespan and represses gene activity. These complexes interact genetically and molecularly with both insulin/IGF signaling and with dietary restriction. Thus, the Myc family of transcription factors represents a newly discovered convergence point for these central aging related pathways. We will investigate the molecular mechanisms by which the MML and MDL complexes influence longevity. Orthologous mammalian transcription factors have been linked to nutrient sensing, metabolic control, and disease. We will use metabolomics to discover the specific metabolic pathways that are altered by the MDL/MML complexes and link those metabolic changes to longevity using genetic and functional genomic approaches. The MML and MDL transcriptional complexes represent an evolutionarily conserved entity for coupling nutrient sensing, metabolism, and aging. Characterizing the newly discovered role of Myc transcription factors in the dynamic interplay between distinct longevity signals, in the experiments proposed here, may facilitate the development of rationale strategies for the treatment of age-associated disease and metabolic disorders (e.g. diabetes, glucose intolerance, and insulin resistance) to promote human health.

Public Health Relevance

Obtaining the goal of aging research: to ameliorate the negative consequences of advanced age and to prevent or cure age-associated diseases, one must understand the genetic pathways that alter longevity along with the underlying biology. We have discovered an evolutionarily conserved transcriptional network that regulates C. elegans aging. Understanding aging signaling pathways in C. elegans provides targets for intervention of human aging and age-associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG043421-03
Application #
9017903
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2014-07-01
Project End
2019-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627