# The role of mitochondrial redox stress in the impaired Nrf2 response to contraction in aged muscle > **NIH NIH F32** · UNIVERSITY OF WASHINGTON · 2024 · $74,284 ## Abstract Abstract Aging is associated with impaired stress resilience defined as a loss of the ability of cells, organs, and organisms to adapt to physiological or pathological stressors. Evidence suggests that this loss of resilience arises before any overt pathology, and eventually contributes to the loss of function, disease, and death. However, the cellular mechanisms that drive this process are poorly understood. In order for cells to adapt to environmental and endogenous stressors they need to be able to communicate the stress signal through signal transduction mechanisms. However, in order for transient stress signals to be effective, they should be low under resting conditions. The Nrf2 antioxidant response element activates early changes in gene expression to enhance redox protective mechanisms in response to acute redox stress associated with muscle contraction. In healthy individuals this leads to an adaptive response to restore redox balance and increased cellular resilience to future stresses. We have found that Nrf2 is chronically activated under basal conditions and has an attenuated response to muscle contraction in human aged skeletal muscle. In addition, we have found that aging is associated with elevated reversible oxidation of the thiol proteome, a primary signal transduction mechanism driving redox adaptation, and that reducing mitochondrial redox stress restores the thiol proteome to that found in young adults. Here we hypothesize that mitochondrial redox stress in aging muscle is the chronic low-level stress that impairs the signal transduction communication in the cell underlying the impaired Nrf2 response to muscle contraction. Aim 1 tests whether decreasing mitochondrial redox stress in aged or increasing mitochondrial redox stress in young improves or impairs the Nrf2 activation to acute muscle contraction. Aim 2 tests whether the manipulation of mitochondrial redox stress and basal Nrf2 activation improves the adaptive responses to exercise training in aged mice. This research uses skeletal muscle contraction as a model to generate new insights into the molecular mechanisms underlying reduced resilience with age. A more complete mechanistic understanding of this phenomenon will provide therapeutic targets for aging and disease by identifying stressors that are necessary and sufficient to drive the aging process. ## Key facts - **NIH application ID:** 10744784 - **Project number:** 5F32AG074655-03 - **Recipient organization:** UNIVERSITY OF WASHINGTON - **Principal Investigator:** Ethan Lambert Ostrom - **Activity code:** F32 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $74,284 - **Award type:** 5 - **Project period:** 2021-12-01 → 2024-11-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10744784 ## Citation > US National Institutes of Health, RePORTER application 10744784, The role of mitochondrial redox stress in the impaired Nrf2 response to contraction in aged muscle (5F32AG074655-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10744784. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*