The Mitochondrial Basis of Aging and Age-Related Disorders

Abstract

Aging is a natural phenomenon characterized by progressive decline in tissue and organ function leading to increased risk of disease and mortality. Among diverse factors that contribute to human aging, the mitochondrial dysfunction has emerged as one of the key hallmarks of aging process and is linked to the development of numerous age-related pathologies including metabolic syndrome, neurodegenerative disorders, cardiovascular diseases and cancer. Mitochondria are central in the regulation of energy and metabolic homeostasis, and harbor a complex quality control system that limits mitochondrial damage to ensure mitochondrial integrity and function. The intricate regulatory network that balances the generation of new and removal of damaged mitochondria forms the basis of aging and longevity. Here, I will review our current understanding on how mitochondrial functional decline contributes to aging, including the role of somatic mitochondrial DNA (mtDNA) mutations, reactive oxygen species (ROS), mitochondrial dynamics and quality control pathways. I will further discuss the emerging evidence on how dysregulated mitochondrial dynamics, mitochondrial biogenesis and turnover mechanisms contribute to the pathogenesis of age-related disorders. Strategies aimed to enhance mitochondrial function by targeting mitochondrial dynamics, quality control, and mitohormesis pathways might promote healthy aging, protect against age-related diseases, and mediate longevity.

Keywords: age-related disorders; aging; mitochondria; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; reactive oxygen species.

Figure 1

Mitochondrial dysfunction during aging and age-related disorders. Aging is associated with progressive mitochondrial dysfunction that occurs due to accumulation of mitochondrial DNA (mtDNA) mutations and increased reactive oxygen species (ROS) production that causes oxidative damage to cellular macromolecules, thereby leading to reduced respiratory chain activity and adenosine triphosphate (ATP) generation. Mitochondrial fission and fusion play a vital role in the regulation of mitochondrial function, metabolism and quality control. Altered mitochondrial dynamics with chronological age can inhibit mitophagy leading to accumulation of damaged or dysfunctional mitochondria in cells. Moreover, decline in mitophagy with increasing age prevents clearance of dysfunctional mitochondria leading to further mitochondrial damage accrual and deterioration of cellular function. Genetic mutations or functional declines in mitochondrial dynamics and quality control are thus linked to pathogenesis of numerous age-related disorders including metabolic syndrome, neurodegenerative and cardiovascular diseases as well as cancer.

Figure 2

Crosstalk between mitochondrial biogenesis and mitophagy. The crosstalk or coordination between the two opposing processes i.e., selective elimination of damaged or dysfunctional mitochondria by mitophagy and generation of newly synthesized mitochondria by mitochondrial biogenesis is pivotal for the maintenance of mitochondrial energy and cellular homeostasis in response to various physiological and environmental cues.