Age-induced changes in mitochondrial turnover in humans

The National Institute on Aging awarded Loyola Marymount University $539,625 on August 15, 2026, under the Aging Research program (CFDA 93.866) to investigate age-induced changes in mitochondrial turnover in humans.

The research project will measure mitochondrial DNA and protein synthesis rates in skeletal muscle across sedentary and exercise-trained populations to determine how changes in mitochondrial turnover govern the bioenergetic capacity of muscle mitochondria during aging. The study addresses a gap in human aging biology by providing direct measures of age-related changes in mitochondrial turnover and will test whether exercise training prevents age-related declines in mitochondrial function. Findings will inform development of interventions targeting age-related mitochondrial dysfunction that contributes to muscle weakness.

The period of performance runs through July 31, 2029. Work is performed in Westchester, California. Loyola Marymount University, a private Catholic institution in Los Angeles, receives the award as a Project Grant, the standard assistance type for investigator-initiated biomedical research under the National Institute on Aging's mission to support research on aging processes and age-related diseases.

Abstract

Declining mitochondrial functions, such as ATP production, contribute to age-related muscle dysfunction. IT is thought that a decline in mitochondrial turnover, the balance between mitochondrial biogenesis and autophagy, contributes to the decline in mitochondrial function. However, there are few direct measures of age-related changes in mitochondrial turnover in humans. There is conflicting data that mitochondrial protein synthesis declines with age in skeletal muscle. Surprisingly, there is no data on mitochondrial DNA synthesis rates in humans in vivo. This is an important GAP in human aging biology that must be addressed to design effective interventions to counteract age-related declines in mitochondrial function. The long-term goal of the proposed project is to understand how the concerted remodeling of mitochondria changes with age in those who are sedentary and those who engage in exercise training, which preserves mitochondrial function with age. The overall objective for this application is to determine how changes in mitochondrial DNA and protein turnover govern bioenergetic capacity of skeletal muscle mitochondria during aging and whether exercise training prevents these age-related changes. The central hypothesis is that there are predictable age-induced changes in mtdna synthesis and mutation burden which heterogeneously affect synthesis of individual mitochondrial proteins that collectively impair function. We hypothesize exercise modifies these processes to maintain mitochondrial integrity and function in aged human muscle. The rationale behind this proposal is that understanding the changes in mitochondrial protein and DNA turnover that govern mitochondrial bioenergetic capacity will enable development of new strategies that target age-related mitochondrial dysfunction. The central hypothesis will be tested by pursuing two specific aims: 1) compare mitochondrial proteome and genome turnover and integrity in skeletal muscle of young and old sedentary humans and 2) determine if lifelong exercise preserves mitochondrial function in older adults by modifying mitochondrial proteome and genome turnover. These aims will be accomplished by combining proteomics and isotope labeling to measure synthesis and abundance of mitochondrial proteins. We will measure mtdna synthesis using a stable isotope and mtdna copy number and mutation burden with digital PCR. We will assess mitochondrial bioenergetic capacity with high resolution respirometry. The proposed research is innovative as we will be the first to simultaneously measure and compare mitochondrial DNA and individual protein turnover in vivo in young and old human skeletal muscle. The proposed research is significant because IT is the first study to evaluate mtdna turnover in human skeletal muscle and characterizes age-related changes that likely contribute to mitochondrial dysfunction and disease. This work will be performed by the PI and a team of undergraduate researchers, providing a transformative research experience for the next generation of scientists.