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.
Highlights
Aging is broadly defined as a time-dependent gradual and progressive decline in living organisms cellular and organ functions leading to increased vulnerability to chronic diseases and death [1,2].Nine candidate hallmarks of mammalian aging have recently been identified and classified under three categories i.e., the primary hallmarks, the antagonistic hallmarks, and the integrative hallmarks [2]
The damaged or dysfunctional mitochondria are selectively degraded by a mitochondria-specific autophagy clearance process known as mitophagy, whereas new mitochondria are synthesized by mitochondrial biogenesis
This study demonstrated that impaired mitophagy in C. elegans compromises stress resistance and elegans compromises stress resistance and activates the mitochondrial retrograde signaling to induce activates the mitochondrial retrograde signaling to induce SKN-1 expression, which in turn stimulates
Summary
Aging is broadly defined as a time-dependent gradual and progressive decline in living organisms cellular and organ functions leading to increased vulnerability to chronic diseases and death [1,2]. Mitochondrial dysfunction is linked to various aspects of aging including impaired oxidative phosphorylation (OXPHOS) activity, increased oxidative damage, decline in mitochondrial quality control, reduced activity of metabolic enzymes, as well as changes in mitochondrial morphology, dynamics and biogenesis [10,11]. Therapeutic strategies that improve mitochondrial dysfunction by targeting mitochondrial dynamics, quality control and stress response-mediated mitohormesis pathways may benefit humans in terms of healthy aging, protection against age-related diseases, and longevity. A growing body of evidence has shown that mitochondrial dysfunction contributes to aging in multiple model organisms and that several factors cause increased mitochondrial dysfunction with chronological age including accumulation of somatic mtDNA mutations, enhanced oxidative damage, decreased abundance and quality of mitochondria, as well as dysregulation of mitochondrial dynamics as discussed below
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