Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging

Aging is a major risk factor for both cardiovascular and neurodegenerative diseases, and accumulating evidence indicates that impaired mitochondrial FAO contributes to dysfunction in both systems. In the heart, FAO provides 60–90% of ATP under physiological conditions, and aging-associated reductions in FAO capacity result in metabolic inflexibility, lipid accumulation, and contractile dysfunction, features observed in cardiac aging and heart failure [96,97]. Decreased expression of key FAO enzymes, including CPT1B and ACADs, has been reported in aged myocardium, while restoration of FAO through PPARα or AMPK activation improves cardiac energetics and attenuates pathological remodeling [98,99].

Similarly, aged brain exhibits a marked decline in mitochondrial metabolic flexibility, and recent studies have highlighted altered acylcarnitine profiles and reduced FAO capacity in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease [100,101,102]. FAO-derived ketone bodies serve as critical alternative fuels during aging, and impaired ketone utilization has been associated with neuronal energy deficits and cognitive decline [103,104]. Moreover, FAO dysregulation can exacerbate neuroinflammation, oxidative stress, and mitochondrial fragmentation, key drivers of neurodegeneration [105,106]. Together, these findings underscore the importance of maintaining FAO capacity to preserve cardiac and neuronal resilience during aging.

There have been tremendous advances in our understanding of the diverse functions of mitochondrial FAO in various cellular processes. Growing evidence indicates that mitochondrial FAO is intimately involved in maintaining cellular homeostasis and coordinating stress responses. Nevertheless, the metabolic aspects of stress response remain incompletely explored, and the roles of FAO in coordinating nutrient and energy homeostasis, as well as cellular stress and adaptation pathways, are complex. Thus, further study should clarify how FAO not only supplies the energy required to operate stress response pathways but also scavenges ROS and modulates protein acetylation to facilitate cellular adaptation to stress. Moreover, although our knowledge of FAO’s roles in stress response and senescence at a cellular level is expanding, its contribution to organismal stress adaptation and aging remains to be elucidated. Since the elderly population is rapidly increasing, defining the physiological functions and regulatory mechanisms of mitochondrial FAO in stress and aging could open new avenues for treating age-associated disease and developing targeted therapeutics.