DEFINING THE LANDSCAPE AND MECHANISMS OF REDOX REGULATION OF METABOLISM DURING AGING - PROJECT SUMMARY: MAM…

Assistance award details

Assistance award identifier

ASST_NON_R00AG073461_075

FAIN

R00AG073461

Recipient

THE LELAND STANFORD JUNIOR UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$496,708

Period

May 15, 2022 – Dec 31, 2027

Fiscal year

2025

Place of performance state

CA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

DEFINING THE LANDSCAPE AND MECHANISMS OF REDOX REGULATION OF METABOLISM DURING AGING - PROJECT SUMMARY: MAMMALIAN TISSUES ENGAGE IN SPECIALIZED PHYSIOLOGY THAT IS REGULATED THROUGH REVERSIBLE MODIFICATION OF PROTEIN CYSTEINE RESIDUES BY REACTIVE OXYGEN SPECIES (ROS). DESPITE THE LONGSTANDING LINKS BETWEEN ROS DYSREGULATION AND AGING, TECHNOLOGICAL LIMITATIONS HAVE RESULTED IN A PERSISTENT ABSENCE OF INFORMATION ON THE EXACT PROTEIN CYSTEINES ARE MODIFIED BY ROS THAT EXPLAIN THE MOLECULAR BASIS FOR THIS DYSFUNCTION IN VIVO. USING THE CYSTEINE-PHOSPHO TAG (CPT) PROTEOMICS TECHNOLOGY THAT I DEVELOPED, I HAVE DETERMINED THAT A FUNDAMENTAL REMODELING OF PROTEIN CYSTEINE OXIDATION NETWORKS OCCURS WITH CALORIC RESTRICTION (CR) IN AGING. BUILDING ON THIS, I WILL DETERMINE THE FUNCTIONAL ROLE OF REDOX REGULATION OF NEWFOUND PROTEIN NETWORKS THAT ARE LINKED TO THE LIFESPAN AND HEALTHSPAN BENEFITS OF CR IN AGING. I HAVE ALSO EXTENDED OXIMOUSE TO DIVERSITY OUTBRED (DO) MOUSE POPULATIONS TO RECAPITULATE THE GENETIC DIVERSITY OF HUMAN POPULATION, IN SEARCH FOR REDOX SIGNALING TARGETS THAT HAVE HIGH TRANSLATIONAL POTENTIAL. PRELIMINARY DATA FROM THIS EFFORT HAS IDENTIFIED CONSERVED REDOX SIGNALING TARGETS ON PROTEINS THAT MAY HAVE CRITICAL IMPLICATIONS IN AGE-DEPENDENT DECLINE OF THERMOGENESIS LEADING TO AGE-RELATED OBESITY. I WILL STUDY METABOLIC REDOX SIGNALING NODES UNDERLYING LONGEVITY- MODIFYING INTERVENTIONS AND DELINEATE THE MECHANISMS THROUGH WHICH THESE TARGETS ARE REDOX-REGULATED WITH AGE THAT LEAD TO A DECLINE IN THERMOGENIC ACTIVITY. THE PROTEOMICS DATA WILL PROVIDE A RICH RESOURCE FOR THE COMMUNITY TO EXPLORE ROS AND AGING. THE MECHANISTIC STUDIES WILL VALIDATE REDOX SIGNALING NODES THAT CAN POTENTIALLY BE MANIPULATED TO EXTEND LIFESPAN AND HEALTHSPAN, IN LINE WITH THE MISSION OF THE NATIONAL INSTITUTE OF AGING. OBJECTIVES: (1) DEFINING MITOCHONDRIAL CYSTEINE OXIDATION MECHANISMS UNDERLYING THE HEALTH BENEFITS OF CR. (2) DETERMINING ADIPOSE METABOLIC REDOX SIGNALING N