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Although previous studies have highlighted the association between physical activity and lower extremity function (LEF) in elderly individuals, the mechanisms underlying this relationship remain debated. Our recent work has recognized the utility of nonlinear trimodal regression analysis (NTRA) parameters in characterizing changes in soft tissue radiodensity as a quantitative construct for sarcopenia in the longitudinal, population-based cohort of the AGES-Reykjavík study. For the present work, we assembled a series of prospective multivariate regression models to interrogate whether NTRA parameters mediate the 5-year longitudinal relationship between physical activity and LEF in AGES-Reykjavík participants. Healthy elderly volunteers from the AGES-Reykjavík cohort underwent mid-thigh X-ray CT scans along with a four-part battery of LEF tasks: normal gait speed, fastest-comfortable gait speed, isometric leg strength, and timed up-and-go. These data were recorded at two study timepoints which were separated by approximately 5 years: AGES-I ( n  = 3157) and AGES-II ( n  = 3098). Participants in AGES-I were likewise administered a survey to approximate their weekly frequency of engaging in moderate-to-vigorous physical activity (PA AGES-I ). Using a multivariate mediation analysis framework, linear regression models were assembled to test whether NTRA parameters mediated the longitudinal relationship between PA AGES-I  and LEF AGES-II ; all models were covariate-adjusted for age, sex, BMI, and baseline LEF, and results were corrected for multiple statistical comparisons. Our first series of models confirmed that all four LEF tasks were significantly related to PA AGES-I ; next, modelling the relationship between PA AGES-I  and NTRA AGES-II  identified muscle amplitude ( N   m  ) and location ( μ   m  ) as potential mediators of LEF to test. Finally, adding these two parameters into our PA AGES-I  → LEF AGES-II  models attenuated the prior effect of PA AGES-I ; bootstrapping confirmed  N   m   and  μ   m   as significant partial mediators of the PA AGES-I  → LEF AGES-II  relationship, with the strongest effect found in isometric leg strength. This work describes a novel approach toward clarifying the mechanisms that underly the relationship between physical activity and LEF in aging individuals. Identifying  N   m   and  μ   m   as significant partial mediators of this relationship provides strong evidence that physical activity protects aging mobility through the preservation of both lean tissue quantity and quality.

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Soft tissue radiodensity parameters mediate the relationship between self-reported physical activity and lower extremity function in AGES-Reykjavík participants