By 2030, the entire baby boomer generation will have reached retirement age, significantly expanding the older adult population. As this demographic grows, the demand for age-related healthcare services will increase substantially
Projections indicate that the number of individuals aged 65 and older will nearly double to 95 million by 2060, while the population aged 85 and older will triple. To effectively address the health needs of an aging population and minimize societal challenges, it is imperative to develop strategies that promote healthy aging and improve the quality of life for older adults.
Aging involves a network of dysregulated mechanisms
Aging is a complex biological process characterized by a progressive decline in physiological function and an increased susceptibility to age-related diseases. Research originally identified nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication.2 This was further expanded to 14 hallmarks, adding compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation.3 These interconnected processes not only contribute to visible signs of aging—such as hair graying, wrinkles, and muscle loss—but also underlie the development of chronic diseases, including neurodegenerative disorders, cardiovascular disease, and metabolic syndrome. Understanding these fundamental mechanisms offers enlightening insights into the aging process, providing pathways for potential therapeutic interventions aimed at promoting healthy aging and mitigating age-related degeneration and disease.
Mitochondrial dysfunction is a central feature of aging
Mitochondria are essential for key cellular processes, including metabolic signaling, cell proliferation, differentiation, immune responses, apoptosis, and buffering of calcium and iron levels. They are the primary energy-producing organelles in cells, generating ATP through the electron transport chain (ETC) in the inner mitochondrial membrane. This process also produces reactive oxygen species (ROS), highly reactive molecules that can cause significant damage to cellular components, including DNA, proteins, and lipids. The mitochondrial free radical theory of aging (MFRTA) suggests that this damage, particularly to mitochondrial DNA (mtDNA), disrupts the ETC, creating a feedback loop of oxidative stress. This ultimately results in mitochondrial dysfunction, impaired oxidative phosphorylation, and reduced energy production. While the MFRTA has evolved over time and numerous other theories have emerged to explain the complexities of aging, mitochondrial dysfunction remains widely accepted as a major contributor to age-related decline.3
Importantly, not all ROS are harmful. While often linked to oxidative damage, ROS also play essential roles in inflammation, signal transduction, and gene expression regulation. Their influence is necessary for supporting cellular function, maintaining organ health, and regulating immune responses. However, when ROS levels are excessively high and/or occur alongside other hallmarks of aging, such as defective quality control mechanisms, they are strongly associated with cellular damage and the progression of age-related diseases.4
Quality control in the mitochondria is less effective with age
The effectiveness of mitochondrial quality control (MQC) mechanisms declines with age, exacerbating dysfunction. MQC is essential for maintaining mitochondrial health and function, involving a range of processes such as protein folding, oxidative stress management, mitochondrial biogenesis and degradation, and dynamic structural changes. Chaperones assist in protein folding, while the ubiquitin-proteasome system removes damaged proteins. The balance between mitochondrial biogenesis and mitophagy helps maintain a healthy mitochondrial population. Mitochondria are highly dynamic organelles, constantly undergoing fusion and fission to maintain cellular health. Fusion helps protect against stress by combining healthy mitochondria, while fission facilitates the removal of damaged mitochondria. Mitophagy, a specialized form of autophagy, helps degrade dysfunctional mitochondria to prevent the accumulation of damaged components. With aging, these quality control mechanisms become less efficient, leading to an increase in dysfunctional mitochondria, oxidative stress, and apoptosis.5
Mitochondrial dysfunction links the hallmarks of aging
Mitochondrial dysfunction intersects with other hallmarks of aging, amplifying cellular decline. Excessive ROS production from dysfunctional mitochondria can damage mtDNA, impair protein function, and disrupt cellular homeostasis. This dysfunction creates a cycle of oxidative stress, inflammation, and genomic instability, accelerating processes like telomere attrition, proteostasis imbalance, and cellular senescence. The depletion of stem cells, essential for tissue regeneration, is also linked to mitochondrial decline through increased ROS production, DNA damage, and metabolic disruptions, ultimately reducing regenerative capacity and increasing cancer risk in older adults. Beyond cellular damage, mitochondrial dysfunction impairs intercellular communication by releasing mtDNA fragments, mitochondrial-derived vesicles, and metabolites, triggering immune responses and disrupting molecular exchange between cells. Additionally, impaired mitochondrial nutrient sensing affects metabolic pathways like AMPK, SIRT1, NAD+, and mTOR, influencing energy regulation and mitophagy.6
Age-related chronic diseases frequently involve mitochondrial dysfunction
Disrupted energy metabolism, excess ROS, and impaired quality control mechanisms underlie many age-related diseases, particularly in tissues with high metabolic demands. Neurons, with their high energy needs, are especially vulnerable to reduced oxidative phosphorylation (OxPhos), contributing to cognitive decline. Aging neurons exhibit lower energy production, decreased OxPhos gene expression, and reduced membrane potential.7 In Alzheimer’s and Parkinson’s diseases, mitochondrial impairments drive plaque buildup and neuronal loss.8
Similarly, muscle loss accelerates with mitochondrial dysfunction, triggering apoptosis, cellular senescence, and impaired regenerative capacity. Oxidative stress disrupts proteostasis, causing protein aggregates to accumulate.9 In cardiovascular tissues, impaired mitochondrial function weakens heart contractility and increases oxidative stress, contributing to hypertension, atherosclerosis, and heart failure.10
In metabolic disorders such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), impaired fatty acid oxidation promotes lipid accumulation, inflammation, and insulin resistance. Chronic inflammation is sustained by ROS and mitochondrial components like mtDNA, which activate immune responses and suppress mitophagy. This feedback loop exacerbates oxidative stress, promoting neurodegeneration, cardiovascular disease, and metabolic disorders.11
Mitochondria-targeted molecules hold significant promise for promoting healthy aging
Given their fundamental role in cellular function and susceptibility to dysfunction, mitochondria present a promising target for therapeutic interventions aimed at healthy aging. Strategies that enhance mitochondrial function and integrity, stimulate biogenesis, and promote mitophagy can mitigate cellular decline associated with aging. Clinical studies have demonstrated the efficacy of supplements targeting these pathways, indicating mitochondrial health may be a key factor in longevity-focused therapies. This section highlights compounds with strong clinical evidence, showcasing their potential to enhance mitochondrial integrity and extend healthspan.
Read the full ebook ‘Keeping the power on: Targeting mitochondrial function for healthy aging’ here.
*See full ebook for references
