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Nilsson, M. Mitochondria and Aging. Encyclopedia. Available online: (accessed on 22 June 2024).
Nilsson M. Mitochondria and Aging. Encyclopedia. Available at: Accessed June 22, 2024.
Nilsson, Mats. "Mitochondria and Aging" Encyclopedia, (accessed June 22, 2024).
Nilsson, M. (2021, December 23). Mitochondria and Aging. In Encyclopedia.
Nilsson, Mats. "Mitochondria and Aging." Encyclopedia. Web. 23 December, 2021.
Mitochondria and Aging

Mitochondria orchestrate the life and death of most eukaryotic cells by virtue of their ability to supply adenosine triphosphate from aerobic respiration for growth, development, and maintenance of the ‘physiologic reserve’. Biological aging is characterized by buildup of intracellular debris (e.g., oxidative damage, protein aggregates, and lipofuscin), which fuels a ‘vicious cycle’ of cell/DNA danger response activation (CDR and DDR, respectively), chronic inflammation (‘inflammaging’), and progressive cell deterioration. Therapeutic options that coordinately mitigate age-related declines in mitochondria and organelles involved in quality control, repair, and recycling are therefore highly desirable.

aging mitochondria ROS inflammation senescence lysosome autophagy mitophagy

1. Introduction

Mitochondria are the energy-producing organelles of nearly all eukaryotic cells, which arose ~1.5–2 billion years ago when a phototrophic α-proteobacterium was endocytosed by an ancestral eukaryote [1]. This endosymbiotic relationship is thought to have conferred significant evolutionary advantages to the anaerobic host at a time when Earth was becoming more oxygenated [2]. The increased energy availability allowed for expansion of the eukaryotic genome, enhanced protein expression, and more complex signaling pathways and cellular traits [3], allowing for the rise of complex life [4].
Considering the profound role of mitochondria in the evolution of aerobic life, it is not surprising that they hold a central position in cellular homeostasis and drive many aspects of the biological aging process. Aging is characterized by a progressive impairment of all body organs, including those that regulate VO2max and locomotion (e.g., cardiorespiratory, nervous, and musculoskeletal systems), resulting in a ~10% decline in aerobic capacity per decade in both males and females after ~ 30 years of age [5][6]. Post-mitotic cells are particularly susceptible to the ‘wear and tear’ of aging, as exemplified by the progressive build-up of intracellular debris over a lifetime [7]. Concomitant oxidative damage, protein aggregation, and lipofuscinogenesis are interrelated features of the aging process, neurodegenerative disease, and lysosomal storage disorders [7][8][9]. Collectively, these danger-associated molecular patterns (DAMPs) fuel a ‘vicious cycle’ of cell/DNA danger response activation (CDR and DDR, respectively), senescence, and systemic inflammation (‘inflammaging’) [10]. Organelles that regulate reactive oxygen species (ROS) production (mitochondria), protein quality control/repair (unfolded protein response: endoplasmic reticulum (UPRER) and mitochondria (UPRMT)), and recycling (autophagosomes, lysosomes, and proteasomes) therefore constitute the cell’s major defense systems against aging. Arguably, no other organelle is more important than the mitochondria in this context because they provide the bulk of the energy needed to sustain the ‘physiologic reserve’ and regulate other vital functions for cell survival, including ROS production, inflammation, senescence, and apoptosis (Figure 1) [11][12][13]. Currently, physical activity (PA) and caloric restriction represent the only non-pharmacologic means to enhance health-span and life expectancy by their ability to coordinately rejuvenate the systems that drive the biological aging process [14][15]; however, exercise is the only factor confirmed to lower morbidity and all-cause mortality in epidemiological studies.
Figure 1. Major eukaryotic cell functions regulated by mitochondria. ATP: adenosine triphosphate; ROS: reactive oxygen species; Ca2+: calcium ion.

2. Integrated Systems Hypothesis of Aging

Although over 300 hypotheses of aging have been proposed to date, with the vast majority focused on observable age effects (‘wear and tear’) or presumed root causes of age-associated pathology (‘primary damage’) [16], the common denominator across species has not yet been identified. The works of Schrödinger [17], Bortz [18], and Hayflick [19][20] collectively point to biological aging being a stochastic process occurring after reproductive maturity that is driven by entropy and results in progressive accumulation of random, irreparable losses in molecular fidelity. In line with the second law of thermodynamics, entropy is the tendency of a system to spontaneously disperse energy and evolve toward thermodynamic equilibrium, which is exemplified by a molecule’s altered energy state following breakage of its intra- and/or inter-molecular bonds. According to Hayflick [20], entropic changes are circumvented by the cell’s high-fidelity repair and replacement mechanisms until reproductive maturity, at which the rate of damage accumulation exceeds the rate of self-renewal.
One of the most prominent hypotheses in the category of ‘primary damage’ is Denham Harman’s free radical theory of aging [21], originally conceptualized in 1954 but still garnering interest in the research community [22]. The original hypothesis posits that oxygen free radicals are the driving factors of aging, but has evolved to include all forms of reactive oxygen species (ROS) and mitochondria as the main source of ROS (oxidative stress and mitochondrial theories of aging, respectively) [21][23][24]. Subsequent observations of buildup of indigestible material in the lysosomes of post-mitotic cells (e.g., ferritin, mitochondrial fragments, and lipofuscin/‘age-pigment’) connected the aging process with an impairment in autolysosomal clearance (the mitochondrial–lysosomal axis theory of aging) [7]. Franceschi et al. further expanded on this integrated hypothesis by arguing that chronic, systemic inflammation at old age (inflammaging) is fueled by intracellular DAMPs originating from this ‘garbage catastrophe’ [25].
In summary, aging may be driven by entropy and manifests as a progressive accumulation of molecules with altered energy states, rendering them inactive or malfunctioning, prone to posttranslational modifications (e.g., oxidation, acetylation, methylation, glycation, etc.), cross-linking, and aggregation, and ultimately resistant to normal recycling mechanisms (for example, advanced glycation end products (AGEs) and lipofuscin). While mitochondria still remain central to the biological aging process in this view (by virtue of altered ROS and energy production), other organelles involved in recycling and quality control/repair also age, thus contributing to the ‘vicious cycle’ of debris accumulation, DAMP-activation of CDR/DDR, inflammation, and induction of cell-death (Figure 2).
Figure 2. Integrated Systems Hypothesis of Aging (see text for details). DAMPs: danger-associated molecular patterns; ER: endoplasmic reticulum; CDR: cell danger response; DDR: DNA danger response; Inflammaging: chronic, low-grade inflammation with aging; SASP: senescence-associated secretory phenotype; Gerokines: cytokines, chemokines, growth factors, and proteases increased with aging; Vicious cycle: self-reinforcing feedback loop with detrimental outcome(s); NLRP3: inflammasome; P16: tumor suppressor protein P16INK4A/CDKN2A; P21: tumor suppressor protein P21Cip1/CDKN1A; IL: interleukin; TNF: tumor necrosis factor; CXCL-1: chemokine (C-X-C motif) ligand 1 (also KC and GROα); GM-CSF: granulocyte-macrophage colony-stimulating factor.

3. Mitochondrial Respiration: Yin and Yang of Aerobic Life

From an aging perspective, thermodynamically unfavorable/endergonic processes, such as biosynthesis and repair, are essential to counteract inevitable energy dispersal by entropy. A consistent supply of energy in the form of adenosine triphosphate (ATP) is integral to maintain tissue order and function; a task that is governed by the mitochondria [26]. Mammalian mitochondria generate >80% of cellular ATP under normal conditions and are composed of ~1158 proteins encoded by the nuclear genome and to a lesser extent by mitochondrial DNA (mtDNA) (MitoCarta2.0 [27]). The 37 gene products transcribed by mtDNA (e.g., 2 ribosomal ribonucleic acids (rRNAs), 22 transfer ribonucleic acids (tRNAs), 13 protein sub-units (7 complex I, 1 complex III, 3 complex IV, and 2 complex V)) are synthesized within the organelle itself, while the vast majority of mitochondrial proteins are encoded by the nuclear genome, synthesized in the cytoplasm, and imported by the mitochondrial translocation machinery. Mitochondrial biogenesis, and by extension energy supply, cell homeostasis, and human longevity, rely on the synchronous and concerted action of these processes.
Aerobic energy production by mitochondria, referred to as oxidative phosphorylation (OXPHOS), consumes the vast majority of cellular oxygen and is driven by a series of redox reactions/electron transfers in the inner mitochondrial membrane (mitochondrial respiratory chain (MRC)) [28]. In this process, electrons are successively transferred from electron donors (reducing agents) generated by macronutrient oxidation (glucose, fatty acids, and amino acids) to successively more electronegative electron-acceptors (oxidizing agents) in order to establish a proton gradient to drive ATP synthesis. Ironically, molecular oxygen is not only essential for ATP synthesis, but also represents a major source of reactive oxygen species (ROS) in mammalian cells, making oxidative metabolism a double-edged sword requiring careful cellular coordination.
As a natural by-product of respiration, ~0.2–2% of molecular oxygen undergoes a one-electron reduction into superoxide radicals in complexes I and III (O2−•), which may be further converted into membrane-permeable singlet oxygen (1ΔgO2 and 2∑gO2) or hydrogen peroxide (H2O2) [29][30][31][32]. Although mainly generated by complexes I and III, H2O2 and O2−• are also produced by the monoamine oxidases and NADPH oxidases in mitochondria [32][33]. Transition metals in iron–sulfur clusters in the MRC and lysosomes may react with H2O2 to generate hydroxyl radicals (OH; via Fenton-type reactions), which are short-lived but indiscriminate oxidants that are highly dangerous to biological organisms [13]. Superoxide may also become protonated into perhydroxyl radicals (HO2) and have been proposed to play a central role in mediating the toxic side effects of aerobic respiration because of their high reactivity and membrane permeability [34]. Other potentially damaging molecules are also produced by the mitochondria, such as nitric oxide (NO) and peroxynitrite (ONOO), but are technically considered reactive nitrogen species (RNS).
Chronic overproduction of ROS can lead to oxidative damage, cell toxicity, and apoptosis, and is linked to neurodegenerative diseases, cancer, and aging [35][36]. Paradoxically, ROS are also integral for regulation of cell signaling pathways, gene expression, and exercise adaptations [13]. Consequently, the complete amelioration of pro-oxidants is not advantageous for cell viability or health [36][37]. ROS levels are thereby exquisitely fine-tuned by the cell’s principal enzymatic (EA) and non-enzymatic (NEA) antioxidant defense systems (EA: superoxide dismutases 1 and 2 (Cu/Zn-SOD and Mn-SOD, respectively), catalase, glutathione reductase, and glutathione peroxidases (GPx 1-4); NEA: reduced vs. oxidized glutathione (GSH: GSSG ratio), vitamin E, and vitamin C). Perturbations in the ‘redox state’ of the cell, generally defined as an imbalance between (pro-oxidants)/(anti-oxidants), predisposes towards oxidative damage [13]. Biological targets include lipids and proteins of cell membranes and nucleic acids of either genome being the most vulnerable in post-mitotic tissues. Oxidative modifications may lead to inactivation, fragmentation, and degradation of proteins, decomposition of membrane lipids, and significant RNA/DNA damage, including strand breaks, cross-links, and mutations, which predispose for senescence and cell-death [36].

4. Mitochondrial Aging

4.1. Oxidative Stress, mtDNA Mutagenesis, Apoptosis, and Respiration

Although direct evidence from human trials is lacking, mitochondrial O2−• and H2O2 production increases with advancing age and is inversely correlated to lifespan in multiple mammalian species and flies [38][39][40][41]. Excessive mitochondrial ROS production (and/or reduced antioxidant capacity) is associated with oxidative damage, MRC dysfunction, loss of mitochondrial membrane potential (ΔΨm), and induction of cell-death pathways in post-mitotic tissues of both prematurely (progeroid) and physiologically aged animal models. For example, mtDNA polymerase gamma-deficient mice (PolG; ↑ mtDNA mutagenesis) exhibit an accelerated aging phenotype (shorter lifespan, muscle atrophy, cardiomyopathy, anemia, thin dermis, gray fur, and kyphosis), deficits in OXPHOS function and ATP synthesis, and increased ROS-induced damage to mitochondrial proteins and nucleic acids [42]. Consistent with observations made in old Fisher 344 Brown Norway rats [41], reduced ΔΨm in PolG mice is associated with the release of pro-apoptotic factors and induction of apoptosis, which likely contributes to organ dysfunction and muscle wasting in this model [43][44][45]. As cogently summarized by others [46][47], ROS imbalance, Ca2+ dysregulation, and/or loss of ΔΨm may mediate mitochondrial outer membrane permeabilization and activation of intrinsic apoptotic pathways by opening of the mitochondrial permeability transition pore (mPTP) and the Bax/Bcl2-controlled mitochondrial apoptosis channel. ROS also contribute to telomere shortening and nuclear DNA instability (mainly in stem cells [48]), and genotoxic damage is a known activator of p53-mediated mPTP opening and apoptosis [49], which is the basis of the telomere-p53-mitochondrion model of aging [50]. In other words, several intrinsic (mitochondrial, ER, and lysosomal) and extrinsic (death receptor-induction by TNF-α and FasL) pathways may cooperate in myonuclear and satellite cell apoptosis, while mitochondria-driven cell death is believed to play the most important role in sarcopenia of aging [46][47][51][52].

4.2. Garbage Catastrophe—The Role of Mitochondria

Recycling of biologic waste provides the cell with new building-blocks and substrates for energy metabolism; an integral housekeeping process predominately executed by the proteasome and lysosomes. Clearance of damaged organelles and macromolecules is critically important to maintain tissue homeostasis, particularly in post-mitotic cells that are unable to undergo waste dilution by cell division. Mitochondrial proteostasis is governed by an integrated network of pathways that include the organelles specialized in recycling and protein quality control (e.g., 26S proteasome, autolysosomal system, and PERK-mediated UPRER) and mitochondria-specific QC mechanisms (fusion/fission, mitophagy, various proteases, and the GCN2-mediated UPRMT) [53][54]. Failure to maintain cellular clearance causes clumping of oxidatively damaged and misfolded proteins, formation of insoluble aggregates, and cell death by apoptosis or necrosis. The importance of efficient waste disposal is demonstrated by the fact that its disruption leads to neurodegenerative disease and lysosomal storage disorders; conditions linked to accelerated aging of neurons and muscle cells. Ablation of genes coding for lysosomal hydrolases or proteins that regulate intracellular waste delivery to lysosomes (e.g., autophagy) is associated with autophagic blockage, mitochondrial dysfunction, and tissue deterioration. In the case of acid α-glucosidase deficiency (Pompe disease), failure to clear lysosomal glycogen leads to cardiorespiratory insufficiency, muscle wasting, and premature death [55]. Conversely, pharmacological or genetic manipulations that prolong lifespan in model organisms typically activate cellular clearance pathways, and their inhibition may negate the life-extending effects, as in the case of caloric restriction [56].
A unifying feature in the pathogenesis of mammalian aging and accelerated aging conditions is the progressive deposition of cytotoxic debris impervious to lysosomal and proteasomal degradation. Age-related functional declines in autophagy, including macroautophagy and microautophagy (and likely aggrephagy), are linked to impaired mitochondrial turnover, protein aggregation, and accumulation of lipofuscin [7][9][56][57][58][59][60]. Lipofuscin, or ‘aging pigment’, is a degradation-resistant, redox-active biomolecule composed of oxidized proteins (30–70%), lipids (20–50%), and transition metals (iron, copper etc.) and increases with advancing age in lysosomes of post-mitotic cells [57][61][62][63]. In humans, lipofuscin has been demonstrated in heart, liver, kidney, and skin, but is believed to play the most fundamental role in the aging process of neurons and muscle cells [57]. Motor neurons in the anterior horn of the spinal cord, which innervate muscles necessary for voluntary movement of the limbs and trunk, appear particularly susceptible to lipofuscin deposition [61]. In addition, lipofuscin in skeletal muscle has been proposed to be a more robust marker of age-induced pathology compared to oxidative stress/damage [64].

4.3. Inflammaging—The Role of Mitochondria

Inflammation is a basic biological response to prevent, limit, and repair damage by invading pathogens or endogenous biomolecules. Cell stress and infectious agents trigger transmembrane (Toll-like (TLR) and C-type lectin) and cytosolic (NOD-like (NLR), RIG-I-like (RLR), and PYHIN protein family) signaling receptors in immune and non-immune cells, which activate intracellular and humoral components of the innate and acquired immune systems [65]. While the transient inflammatory response is beneficial (removal of pathogens, mitigation of injury, and clearance of dying cells), persistent inflammation is associated with tissue dysfunction and pathology (obesity, type 2 diabetes, atherosclerosis, asthma, and neurodegenerative diseases) [66]. Chronic low-grade inflammation (inflammaging) is a hallmark of biological aging and is characterized by a 2 to 4-fold increase in circulating cytokines, chemokines, growth factors, and proteases, collectively termed ‘gerokines’, which may be broadly classified into pro- (TNF-α, IL-1α/β, IL-8, IFNγ, VEGF, etc.) and anti-inflammatory (IL-2, IL-4, IL-10, IL-13, TGF-β, etc.) factors [10][25]. Inflammaging is attributed to DAMP-activation of the innate immune response, cell senescence (e.g., SASP; senescence-associated secretory phenotype), and immunosenescence, and has been linked to an elevation in all-cause mortality and sarcopenia [67][68][69][70][71][72][73].


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