Mechanisms underlying the interplay between autophagy and the inflammasome in age-related diseases: Implications for exercise immunology

Abstract

Aging is a multifactorial process characterized by cellular dysfunction and increased susceptibility to age-related diseases. The interplay between autophagy and inflammasome has emerged as a critical factor influencing the aging process. Autophagy, which is responsible for degrading damaged cellular components, declines with age, leading to the accumulation of dysfunctional organelles and misfolded proteins. At the same time, the inflammasome, a key mediator of inflammatory responses, becomes hyperactivated in aging tissues, contributing to chronic low-grade inflammation, commonly referred to as "inflammaging." This dysregulated interaction between autophagy and inflammasome activation plays a significant role in the development and progression of several age-related diseases. In cancer, reduced autophagic activity promotes tumorigenesis, while increased inflammasome activation establishes an inflammatory microenvironment that supports cancer progression. In arthritis, including both osteoarthritis and rheumatoid arthritis, impaired autophagy and inflammasome-driven inflammation contribute to joint degeneration. Neurodegenerative diseases such as Alzheimer's and Parkinson's are marked by defective autophagic clearance of protein aggregates and heightened inflammasome activation, leading to neuronal loss. Cardiovascular diseases, including atherosclerosis and myocardial dysfunction, also involve compromised autophagy and persistent inflammation, which accelerate vascular aging and cardiac damage. Exercise has emerged as a promising intervention for modulating the autophagy NLRP3 inflammasome axis. Moderate-intensity physical activity enhances autophagic flux by upregulating proteins such as BECLIN1, LC3, and ATG12, promoting mitochondrial quality control and reducing protein aggregates. This effect leads to decreased ROS production and suppression of NLRP3 inflammasome activation, lowering IL-1β and IL-18 levels, thereby helping to restore cellular homeostasis and reduce age-associated inflammation. Irisin also showed the importance of inhibiting inflammasome activation by promoting mitophagy after exercise. In both animal and human experiments, exercise has been shown to reduce systemic inflammation, improve cognitive function, attenuate joint degradation, and decrease cardiovascular risk, largely through these molecular pathways. This review explores recent findings that underscore the beneficial role of exercise in mitigating the effects of aging and preventing age-related diseases by regulating autophagy and inflammasome activities.