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NIH grant 1K99AG101344-01: Protein Carbonylation as a Mechanistic Driver and Biomarker of Sarcopenia
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Edwin Ray Miranda. Award: $144053.
Start: 2026-09-11T00:00:00.
ABSTRACT
By 2050 the number of individuals over the age of 80y will triple to reach 426 million. Unfortunately, the rate of
age-related comorbidities has also increased precipitously as our global population has continued to age.
Currently, there is no clinically approved treatment for age-related functional decline creating demand for the
development of such treatments. Carbonyls are reactive electrophilic metabolites that accumulate in contexts of
increased oxidative stress, such as aging. This carbonyl stress damages macromolecules such as proteins,
lipids, and DNA. Our lab demonstrated that carbonyl stress is exacerbated in muscles during a hindlimb
unloading (HU) model of inactivity. Importantly, the accumulation of proteins modified by the reactive lipid
carbonyl 4HNE, as well as muscle dysfunction and atrophy, were attenuated in HU mice treated with the
carbonyl-scavenging dipeptide N-acetyl-carnosine (N-Ac-Carn). Therefore, we hypothesize that N-Ac-Carn
could prevent carbonyl stress in aging muscle. Our preliminary data demonstrates preserved muscle function in
24-month-old male and female mice that had been treated with N-Ac-Carn over six months compared to control.
The current proposed project will test the efficacy of genetically overexpressing the lipid-hydroperoxide detoxing
enzyme GPx4 and N-Ac-Carn treatment to attenuate muscle decline with age. I also aim to elucidate the
mechanisms by which carbonyl stress impairs muscle function during aging by using a novel mass spectrometry
method to comprehensively characterize the carbonyl proteomes in muscle with age. N-Ac-Carn is an
endogenously produced dipeptide that is safe for human consumption and affordable making it a promising
therapeutic strategy for the mitigation of age-related functional decline. In addition, our novel proteomics
approach will uncover which carbonylation events on proteins are most relevant to manifestations of features of
sarcopenia in mice and in humans.document fetched 2026-09-20 02:42