Gender Differences in Circulating TFAM Levels Are Associated with Functional Impairment and Sarcopenia

Background/Objectives: Mitochondrial dysfunction contributes to age-related muscle decline. Mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial biogenesis, may serve as a marker of chronic inflammation and cellular stress when released into circulation following mitochondrial damage. However, its association with functional impairment and sarcopenia, particularly across sexes, remains poorly addressed. The objective was to examine the association between circulating TFAM levels, physical function, and sarcopenia in older adults, considering sex-specific differences. Methods: This study included 989 community-dwelling older adults (mean age 75.4 years; 45.6% men) from the Toledo Study for Healthy Aging. Plasma TFAM was measured by ELISA. Functional status was assessed with the frailty trait scale-5 (FTS-5). Sarcopenia was defined by established criteria. Associations between TFAM and functional outcomes were analyzed using multivariate linear and logistic regressions adjusted for age, sex, comorbidity, and sedentary time. Results: Participants in the (Q2–Q4) TFAM quartiles showed a 1.15-point increase in FTS-5 scores (95% CI: 0.23–2.06; p = 0.014), indicating poorer physical performance compared to Q1. Weaker balance, slower gait speed, and reduced grip strength were also found. In women, higher TFAM concentrations were strongly related to worse physical function (β = 2.16; 95% CI: 0.89–3.44; p = 0.001) and greater impairment across strength-related subcomponents. No significant associations were identified in men. Elevated TFAM was also associated with greater sarcopenia risk in the total sample (OR = 1.56; 95% CI: 1.05–2.31; p = 0.028), although sex-stratified analyses were not significant. Conclusions: Higher circulating TFAM is associated with poorer functional status, especially in women, and with greater sarcopenia risk, suggesting TFAM as a potential biomarker of age-related musculoskeletal impairment.