Mitochondrial Respiration in Peripheral Blood Cells Links to Metabolic Flexibility and Physical Performance in Ageing

Age-related declines in energy metabolism, muscle strength and physical performance have been linked to lower mitochondrial respiratory capacity. Peripheral blood mononuclear cell (PBMC) respiration offers a minimally invasive marker of systemic bioenergetics, yet its relationship to whole-body metabolic flexibility remains unclear. This study examined whether PBMC respiratory capacity is associated with substrate utilization during submaximal exercise, muscle strength and physical function in healthy older adults.

PBMC mitochondrial respiratory capacity was quantified by high-resolution respirometry assessing ROUTINE, LEAK and MAX states. Postprandial substrate oxidation during steady-state treadmill walking at 60% of VO₂max (oxygen uptake) was quantified by indirect calorimetry, and fat and carbohydrate oxidation rates were calculated using standard stoichiometric equations. Metabolic flexibility was defined as lower respiratory exchange ratio (RER) and higher relative fat oxidation at a fixed workload. Muscle strength was determined by handgrip dynamometry and one-repetition maximum leg extension. Physical function was evaluated by gait speed and five-repetition chair rise time. Associations were tested with linear and logistic regression adjusted for age, sex, skeletal muscle index, physical activity and high-sensitive C-reactive protein concentrations. Exploratory K-means clustering identified mitochondrial respiration phenotypes.

Fifty community-dwelling older adults (22 men, 28 women; age 70 ± 4 years) were examined. Higher ROUTINE respiration was correlated with RER (rho = -0.335, p = 0.020), fat utilization (rho = -0.334, p = 0.019), grip strength (rho = 0.302, p = 0.033) and gait speed (rho = 0.324, p = 0.022). Adjusted regression analyses confirmed the association of ROUTINE respiration with greater fat oxidation (β = 0.212, 95% CI 0.049; 0.375), lower RER (β = -0.160, 95% CI -0.300; -0.020) and higher gait speed (β = 0.153, 95% CI 0.028; 0.277). Similar associations were found for ATP-linked respiration. Cluster analysis identified high- and low-respiration phenotypes. Compared with the high-respiration group the low-respiration group showed lower CMJ height (OR: 0.204, 95% CI 0.055; 0.763) and quadriceps strength (OR: 0.373, 95% CI 0.155; 0.897).

In healthy older adults, higher PBMC ROUTINE respiration was associated with a more fat-dominant substrate utilization profile during submaximal exercise, greater muscle strength and faster gait speed. PBMC respiratory capacity may reflect systemic bioenergetic status relevant to exercise substrate utilization and physical performance in ageing.