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Background: The impact of aging on skeletal muscle mitochondrial function, as assessed by maximal mitochondrial respiration (OXPHOS), is a developing field of research with no clear consensus. Older individuals often display a greater range of OXPHOS, compared to younger individuals, possibly reflecting heterogeneity in the aging process. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a role in the transcription of genes involved in many pathways including the regulation of metabolism, inflammation, oxidative stress, and mitochondrial physiology. Since Nrf2 is downregulated with aging and significantly inactivated with sedentary behaviors, we hypothesized that activating this pathway with the nutraceutical PB125 would improve OXPHOS in older individuals with lower OXPHOS starting values. Methods: OXPHOS (CI&II, State 3) was assessed in permeabilized muscle fibers via high-resolution respirometry (Oroboros, O2k) on samples biopsied from the vastus lateralis in 19 young (26 ± 5 years; 13 female) and 18 older (67 ± 7 years; 11 female) volunteers. Sixteen of the older individuals were then randomized to receive a two-week supplementation of either PB125 (n = 10) or Placebo (n = 6) and OXPHOS was reassessed post-supplementation. Results: Baseline OXPHOS was not different between the young (32 ± 8 pmol/s/mg; Range: 18-44) and old (35 ± 12 pmol/s/mg; Range: 14-60; P = 0.49). The supplement-induced change in OXPHOS was not different between the older groups (PB125: 3 ± 9 vs Placebo: -0 ± 10 pmol/s/mg; P = 0.56) and neither was different from baseline (both, P > 0.05). However, a “threshold-like” relationship between the baseline OXPHOS and the PB125-induced change was identified within the PB125-treated group, whereby older individuals with a relatively lower baseline OXPHOS ( 0.05). Conclusion: These findings support previous reports that mitochondrial function, as measured by OXPHOS, is not impaired in older individuals compared to their younger counterparts. However, older individuals with low mitochondrial function exhibited improved OXPHOS following Nrf2 activation via PB125 supplementation. These findings highlight the importance of heterogeneity in aging and provide novel evidence that activating Nrf2 may prove beneficial to improve maximal mitochondrial respiration. NIH: T32HL007576, T32HL139451, R01HL142603; VA: I01CX001999 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.