Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age‐Related Disease

Exercise-induced mitochondrial remodeling in energy-demanding organs during aging

Summary Age-associated organ dysfunction markedly impairs quality of life and increases mortality in older adults. Aging frequently results in compromised mitochondrial function in organs with high energy demands, such as skeletal muscle, the brain, heart, kidneys, and liver. This impairment leads to excessive production of reactive oxygen species, increased inflammation, energy deficits, and aberrant cellular signaling, collectively fostering cellular senescence, and chronic diseases. Empirical research has demonstrated that regular physical exercise preserves mitochondrial integrity. This review summarizes common and specific responses to exercise in mitochondrial regulation across various organs and provides a comprehensive cross-organ analysis. The objective was to elucidate the molecular mechanisms through which exercise confers anti-aging effects and mitigates degenerative functional decline by restoring mitochondrial homeostasis. This review provides a theoretical foundation for developing targeted anti-aging interventions and for attenuating aging in multiple organs through lifestyle modifications.

The organellar biology of aging: A mitochondrial vantage

Mitochondria in health and disease: cellular powerhouses, signaling centers, and drivers of dysfunction

Although the mitochondria are known as the cellular powerhouse, their function is beyond energy generation. These organelles regulate cellular metabolism, yet maintains a tightly regulated reactive oxygen species (ROS) generation and optimal redox state. In addition, mitochondria serve as mediators of physiological and pathological processes, such as maintenance of calcium balance, and control of apoptosis and mitophagy. All these make the mitochondria a major factor in both cellular and organismal regulation. However, mitochondria dysfunction may occur through many processes, including genetic mutations, increased production of ROS, metabolic failure from impaired electron transport chain activity, and dysregulated dynamics or mitophagy. Several self-perpetuating damages accumulate from these processes and influence clinical pathologies, such as aging, metabolic syndrome, cancer, neurodegeneration, and reproductive disorders. Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction. Examples include targeted antioxidants, such as MitoQ and SkQ1, to selectively neutralize mitochondrial ROS, pharmacological modulators to enhance mitochondrial biogenesis and to restore NAD + homeostasis via PGC-1α activation, gene-editing technologies, such as mitoTALENs and mtZFNs to selectively eliminate pathogenic mitochondrial DNA mutations, and mitochondrial transplantation as a new technique to replace damaged organelles. Together, these novel approaches highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.

Meloxicam protects against muscle and metabolic decline in ageing through Cdon restoration and oxidative stress modulation.

Sarcopenia is characterized by progressive decline in skeletal muscle mass and function, driven in part by impaired mitochondrial homeostasis and redox imbalance. However, the upstream regulators that integrate metabolic resilience with muscle integrity during ageing remain poorly defined. Here, we identify the cell adhesion molecule Cdon as a conserved determinant of adult muscle maintenance whose expression declines with human aging, sarcopenia and muscle-wasting disease. Reduced Cdon expression was associated with transcriptional atrophy signatures, metabolic insufficiency and reduced myofibre size. Using a Cdon promoter-based screen, we identified meloxicam (Mcam) as a small molecule inducer of Cdon that enhances myogenic differentiation, increases muscle mass and function in young mice and mitigates age-related muscle atrophy. Mcam treatment also improved neuromuscular conduction and systemic metabolic parameters, including blood glucose regulation and hepatic lipid accumulation. In aged muscle, Mcam normalized cysteine accumulation, restored redox balance, improved mitochondrial metabolism and reduced oxidative stress. Mechanistically, Mcam activated Ampk signalling to preserve Cdon expression under oxidative challenge and support antioxidant and mitochondrial quality control pathways. Together, these findings identify Cdon decline as a hallmark of muscle ageing and demonstrate that Mcam preserves muscle integrity by reestablishing redox and metabolic homeostasis through Ampk-dependent maintenance of Cdon. Age-related decline of Cdon is a key molecular feature of skeletal muscle dysfunction. In this study, meloxicam restored Cdon expression through Ampk activation, thereby preserving muscle integrity and functional capacity in aged muscle. Mechanistically, meloxicam normalized cysteine metabolism and elevates Gpx4 expression, improving glutathione buffering and suppressing excessive reactive oxygen species accumulation. Activation of the Ampk-Cdon axis was associated with maintenance of mitochondrial homeostasis and redox balance. Together, these findings identify Cdon as a potential therapeutic target for age-associated skeletal muscle degeneration.

Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.

Beyond their canonical role in bioenergetics, mitochondria are now recognized as critical signaling platforms that orchestrate innate immune responses. Central to this function is mitochondrial dynamics-the controlled equilibrium between fission and fusion-which serves as a critical structural and thermodynamic checkpoint for cellular fate and immunological status. A substantial body of evidence indicates that pathological mitochondrial fission, frequently driven by Dynamin-related protein 1 (Drp1), is a hallmark of numerous inflammatory conditions. Mechanistically, fragmented mitochondria release damage-associated molecular patterns (DAMPs) and induce acute ATP suppression, metabolically "licensing" NLRP3 activation by collapsing the ATP hydrolysis potential (ΔGATP). Recent breakthroughs have redefined this axis, distinguishing between physical damage and metabolic triggers, such as pyrimidine imbalance via the YME1L-SLC25A33 axis. Furthermore, the immunogenicity of DAMPs is strictly context-dependent; oxidized or "fragile" mtDNA containing ribonucleotides act as hyper-immunogenic ligands for cytosolic sensors like cGAS-STING. Emerging evidence further highlights that endosomal-mitochondrial crosstalk, intercellular mitochondrial transfer, and lipid-driven metabolic rewiring profoundly govern macrophage polarization and tissue homeostasis. Conversely, promoting mitochondrial fusion and robust quality control preserves organellar integrity and attenuates inflammatory cascades. This review critically synthesizes current literature, deconstructing the molecular linkages between organelle structure and metabolic signaling. By exploring the consequences in sepsis, neuroinflammation, osteoarthritis, and cancer, this treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.

Mitochondrial respiratory supercomplexes associated with longevity in mammals

Because of population aging and morbidity expansion, extending healthspan has become a global challenge and it is required to elucidate molecular mechanisms underlying aging and age-related diseases. Mitochondrial dysfunction is a hallmark of aging, characterized by impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and metabolic imbalance. Therefore, maintaining mitochondrial homeostasis is essential for healthspan. Mitochondrial respiratory chain complexes organize into higher-order assemblies known as supercomplexes (SCs), which enable to efficient energy or ATP production with repressed ROS generation. Notably, the assembly and stability of these SCs likely decline in aged mammals. In addition, factors such as COX7RP/SCAF1 and mitochondrial lipid cardiolipin have emerged as key regulators of SC assembly. In this review, we summarize the molecular assembly, physiological roles, and longevity implications of SC in healthy mammals. We further discuss emerging evidence supporting SC modulation as a potential strategy for promoting healthy aging.