Iron dysregulation and mitochondrial dysfunction in aging: A longitudinal study on mobility decline in low- and high-functioning older adults

Background: Mobility loss in older adults reduces quality of life and increases risks of falls, hospitalizations, and mortality. Low-functioning (LF) older adults experience faster mobility decline than their high-functioning (HF) peers, but the underlying biological mechanisms remain unclear. Although iron accumulation in aging muscle mitochondria has recently been linked to lower physical function, its longitudinal impact on physical function remains understudied. Methods: Muscle Iron Flow is a prospective, observational study which enrolled LF and HF older adults (N = 114; age 75.8 ± 3.2 years, 64.9% female) to examine links between iron dysregulation, mitochondrial function, and physical performance. Assessments include blood biomarkers, physical function tests, and behavioral measures (diet, activity, sleep, medication use), collected at baseline and annually, and muscle biopsies obtained at baseline and year three. This manuscript reports baseline characteristics and measurement procedures only; longitudinal portion is ongoing. Results: At baseline, HF older adults demonstrated significantly better physical performance than LF adults across all functional tests, including Short Physical Performance Battery (SPPB), 6-minute walk distance, handgrip strength, and knee extensor torque (ps < 0.05). LF participants also had lower hemoglobin levels and higher red cell distribution width (RDW; ps < 0.05). Discussion: This study is among the first to investigate how biomarkers of iron dysregulation, mitochondrial function, and related ferroptosis and senescence pathways may contribute to changes in physical function in LF and HF older adults. By integrating molecular and functional assessments, the study will inform how disrupted iron handling and mitochondrial health influence mobility trajectories in aging populations.