Metabolic kinetics and muscle and brain health markers in older adults, and the role of age and presence of chronic morbidities: A large cross-sectional cohort study.

Background & Aims: Older adults are at risk for muscle and cognitive function decline during advanced aging, but the underlying metabolic mechanisms and the role of aging-associated chronic morbidities remain unclear. In the present study, we examined whether protein and amino acid kinetics in older adults with and without chronic morbidities are different when 50-70 and 70-90 of age and related to markers of muscle and brain health declines.

Methods: In a large cross-sectional observational study, 575 older adults from 12 trials (2014-2022) were stratified based on their age (50-70y vs. 70-95y) and the presence of chronic morbidities. The main outcomes were whole-body production (WBP) and interconversions of amino acids by stable amino acid tracers, body composition, and muscle and cognitive performance. Additionally, the association between metabolic markers and muscle and brain health was assessed.

Results: Overall lower muscle strength, muscle and fat mass, and cognitive function (p < 0.03), but no mood disturbances, were found in 70-95y compared to 50-70y older adults. Presence of morbidities was associated with lower muscle strength and mass, and cognitive function, but higher visceral adipose tissue, and mood disturbances (p < 0.05). Aging was associated with suppressed WBP of most amino acids, de novo arginine production, and net protein breakdown, but higher myofibrillar protein breakdown (p < 0.007). Presence of morbidities was associated with lower WBP of glutamine, glutamate, histidine, isoleucine, phenylalanine, tyrosine, and net protein breakdown, and higher WBP of valine and taurine (p < 0.04). Age showed significant negative correlations with WBP of nearly all amino acids, de novo arginine production and net protein breakdown (r: [-0.407, -0.136], p < 0.01) but a positive correlation with WBP of myofibrillar protein breakdown (r = 0.133, p = 0.009). Lean mass showed positive correlations with de novo arginine production and net protein breakdown and WBP of all amino acids except for isoleucine (r: [0.16, 0.799], p < 0.005). MoCA showed a positive correlation with WBP of leucine and valine (r: [0.163, 0.2], p < 0.03). Worse cognitive performance was positively associated with WBP of tau-methylhistidine and taurine (r: [0.13, 0.141], p < 0.04), but negatively associated with WBP of glycine and valine, de novo arginine production, and net protein breakdown (r: [-0.222, -0.115], p < 0.05).

Conclusion: Comprehensive phenotyping of a large group of older adults revealed differences in metabolic health in response to advanced aging and chronic morbidities. Poor muscle health accompanied by advanced aging was associated with overall metabolic downregulation, except for enhanced myofibrillar (muscle) protein breakdown. Presence of chronic morbidities was further associated with disturbed muscle health, mood, arginine, and taurine pathways, and higher visceral adipose tissue. Therefore, different phenotypes among older adults need to be considered when evaluating therapeutic approaches to improve muscle and brain health.