Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging

Abstract

Biological aging research is expected to reveal modifiable molecular mechanisms that can be harnessed to slow or possibly reverse unhealthy trajectories. However, there is first an urgent need to define consensus molecular markers of healthy and unhealthy aging. Established aging hallmarks are all linked to metabolism, and a ‘rewired’ metabolic circuitry has been shown to accelerate or delay biological aging. To identify metabolic signatures distinguishing healthy from unhealthy aging trajectories, we performed nontargeted metabolomics on skeletal muscles from 2-month-old and 21-month-old mice, and after dietary and lifestyle interventions known to impact biological aging. We hypothesized that common metabolic signatures would highlight specific pathways and processes promoting healthy aging, while revealing the molecular underpinnings of unhealthy aging. Here, we report 50 metabolites that commonly distinguished aging trajectories in all cohorts, including 18 commonly reduced under unhealthy aging and 32 increased. We stratified these metabolites according to known relationships with various aging hallmarks and found the greatest associations with oxidative stress and nutrient sensing. Collectively, our data suggest interventions aimed at maintaining skeletal muscle arginine and lysine may be useful therapeutic strategies to minimize biological aging and maintain skeletal muscle health, function, and regenerative capacity in old age.

Metabolomic Profiles of Mouse Tissues Reveal an Interplay between Aging and Energy Metabolism

“…The metabolome of skeletal muscles has also been studied in detail [37,46,54,55]. Our results showed consistent changes in the levels of leucine, lactic acid, alanine, glycine, inosine, and phenylalanine.…”

Metabolomic Profiles of Mice Tissues Reveals an Interplay Between Aging and Energy Metabolism

“…The metabolome of skeletal muscles has also been studied in detail [37,46,54,55]. Our result showed consistent changes in the levels of leucine, lactate, alanine, glycine, inosine, and phenylalanine.…”

Alterations in Peroxisomal-Mitochondrial Interplay in Skeletal Muscle Accelerates Muscle Dysfunction

“…Increased levels of free amino acids such as glutamine, glutamate, asparagine, and aspartate has been linked to increased protein breakdown in conditions characterized by metabolic dysregulation, muscle weakness, and muscle loss 38,39 . Furthermore, the levels of arginine and lysine, whose reduction has been identified as a metabolic signature of unhealthy aging 58 , were decreased in the KO muscle. The changes on lipid and amino acid metabolism parallel the decline in muscle force and exercise performance, occurring prior to the decrease in mitochondrial content and function, as well as muscle atrophy.…”