Reconsidering the Role of Mitochondria in Aging

Abstract

Background: Mitochondrial dysfunction has long been considered a major contributor to aging and age-related diseases. Harman's Mitochondrial Free Radical Theory of Aging postulated that somatic mitochondrial DNA mutations that accumulate over the life span cause excessive production of reactive oxygen species that damage macromolecules and impair cell and tissue function. Indeed, studies have shown that maximal oxidative capacity declines with age while reactive oxygen species production increases. Harman's hypothesis has been seriously challenged by recent studies showing that reactive oxygen species evoke metabolic health and longevity, perhaps through hormetic mechanisms that include autophagy. The purpose of this review is to scan the ever-growing literature on mitochondria from the perspective of aging research and try to identify priority questions that should be addressed in future research.

Methods: A systematic search of peer-reviewed studies was performed using PubMed. Search terms included (i) mitochondria or mitochondrial; (ii) aging, ageing, older adults or elderly; and (iii) reactive oxygen species, mitochondria dynamics, mitochondrial proteostasis, cytosol, mitochondrial-associated membranes, redox homeostasis, electron transport chain, electron transport chain efficiency, epigenetic regulation, DNA heteroplasmy.

Results: The importance of mitochondrial biology as a trait d'union between the basic biology of aging and the pathogenesis of age-related diseases is stronger than ever, although the emphasis has moved from reactive oxygen species production to other aspects of mitochondrial physiology, including mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics.

Conclusions: Mitochondria could play a key role in the pathophysiology of aging or in the earlier stages of some events that lead to the aging phenotype. Therefore, mitochondria will increasingly be targeted to prevent and treat chronic diseases and to promote healthy aging.

Keywords: Aging; Lifespan; Mitochondria.

Figure 1.

Tissue-specific oxygen consumption rate. Impaired mitochondrial function may cause an accelerated aging phenotype mainly in high energy demanding tissues such as brain, heart, and skeletal muscle, and in kidney and liver, two organs with essential metabolic roles.

Figure 2.

Signaling pathways implicated in metabolism and mitochondrial dysfunction during aging. A well-controlled balance between mitochondrial biogenesis and mitophagy ensures successful aging. Caloric restriction (CR), CR mimetics and exercise generate mild stress that result in elevated production of adenosine monophosphate (AMP), nicotinamide adenine dinucleotide, and/or ROS levels with subsequent activation of metabolic sensors, such as AMP kinase (AMPK) and the protein deacetylase SIRT1. Activated AMPK inhibits the insulin/IGF-1/mTOR signaling and triggers, along with SIRT1, the biogenesis of new mitochondria via PGC-1α-mediated transcriptional regulation. Modulation of tumor suppressor p53 promotes mitophagy by replacing defective mitochondria with new functionally competent mitochondria. Hence, the burden of disability in older persons may be dramatically reduce through preservation and improvement of mitochondrial quality.

Figure 3.

Factors affecting aged mitochondria. Numerous biological processes modulate mitochondrial function. Defects in mitochondria maintenance and turnover because of impaired biogenesis and/or defective removal are thought to contribute to the pathogenesis of complex diseases and aging. The assembly and maintenance of respiratory complexes that can sustain a high energetic flux without generating excessive ROS, and the quantity and quality of energetic fuel are essential to health and successful aging.

Figure 4.

Mitochondria as a key regulator in the pathophysiology of aging or in the earlier stages of some events that may lead to the aging phenotype. Even minor mitochondrial dysfunction when coupled with specific organ susceptibility may cause diseases, such as atherosclerosis, and also conditions that we still do not recognize as diseases, such as arterial stiffness or sarcopenia. The difference between the so-called “diseases” and these age-related conditions resides in our ignorance. What is clear is that some disease may sometime accelerate mitochondrial function decline and create a vicious cycle that leads to frailty and disability. For example, atherosclerosis of the femoral arteries may cause irreversible mitochondrial dysfunction in the leg muscle, further accelerating sarcopenia. If this hypothesis is correct, for example, early revascularization or treatment that protect mitocondrial integrity may substantial change the prognosis and clinical evolution of peripheral arterial disease. Indeed, integrating traditional pathophysiology and mitochondrial biology may increase our understanding of disease and help identify new therapeutic targets.