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Mitochondrial decline and chronic conditions of older adults 

Mitochondrial decline and chronic conditions of older adults
Mitochondrial decline and chronic conditions of older adults

Emanuele Marzetti

, Francesco Landi

, Francesca Martini

, Christiaan Leeuwenburgh

, and Riccardo Calvani

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In recent years, mitochondrial pathophysiology has been the subject of intense investigation in the attempt of deciphering the intimate processes responsible for organismal ageing and the development of several disease conditions. Indeed, mitochondria stand at the crossroad of signalling pathways that regulate cell function and viability, including bioenergetics, redox homeostasis, quality control systems, and cell death/survival pathways. As such, mitochondrial dysfunction is attributed a central role in the process of ageing and the pathogenesis of a wide range of health conditions, such as cardiovascular disease (CVD), neurodegeneration, sarcopenia, cancer, diabetes mellitus, and obesity (Bratic & Larsson, 2013; Swerdlow, 2014). Nevertheless, the complexity of mitochondrial pathophysiology in the context of ageing and diseases has only partly been disentangled.

According to the mitochondrial-free radical theory of ageing (Miquel et al., 1980), the accumulation of somatic mutations in the mitochondrial DNA (mtDNA) would result in reduced energy production through oxidative phosphorylation (OXPHOS), and redirection of OXPHOS electrons into reactive oxygen species (ROS) generation. The combination of defective bioenergetics and oxidative stress eventually triggers the opening of the mitochondrial permeability transition pore (mtPTP) to initiate apoptosis (Wallace, 2005). In postmitotic tissues, such as the heart, skeletal muscle, and nervous system, cell loss, in turn, would be primarily responsible for the appearance of age- and disease-associated phenotypes (Fig. 46.1). Based on this paradigm, organ-specific manifestations of ageing and diseases depend on the varying energetic needs and renewal capacity of the different tissues (Wallace, 2005). It needs however to be considered that the phenotypic effects of mtDNA mutations show a large degree of intra and interindividual variation, which is difficult to reconcile with OXPHOS dysfunction as the only pathogenic factor. A possible explanation to this discrepancy is offered by the recently formulated bioenergetic-epigenomic hypothesis, according to which mitochondrial metabolism is supposed to impact the epigenetic landscape and stability of nuclear genome (Wallace & Fan, 2010). In turn, epigenetic changes, resulting in alterations of gene expression and disturbances in broad genome architecture, contribute to the ageing process and the pathogenesis of major age-related diseases (Brunet & Berger, 2014). Epigenetic modifications have also been discovered in mtDNA (D’Aquila et al., 2015), which further extends the environment/genome interface. It is noteworthy that, similar to nuclear DNA, mtDNA epigenetic modifications may be involved in ageing and disease development (Iacobazzi et al., 2013).

Fig. 46.1 Progression of mitochondrial dysfunction during the development of sarcopenia, cardiovascular disease, and neurodegeneration. Over the life course, mitochondrial function and integrity experience a progressive decline. Accumulation of mtDNA mutations, altered mitochondriogenesis and dynamics, and abnormal regulation of mitophagy result in diminished bioenergetic efficiency, enhanced oxidative stress, and eventually loss of cell viability. The onset of mitochondrial dysfunction precedes the appearance of disease conditions associated with mitochondrial dysfunction, suggesting possible windows for interventions.

Fig. 46.1 Progression of mitochondrial dysfunction during the development of sarcopenia, cardiovascular disease, and neurodegeneration. Over the life course, mitochondrial function and integrity experience a progressive decline. Accumulation of mtDNA mutations, altered mitochondriogenesis and dynamics, and abnormal regulation of mitophagy result in diminished bioenergetic efficiency, enhanced oxidative stress, and eventually loss of cell viability. The onset of mitochondrial dysfunction precedes the appearance of disease conditions associated with mitochondrial dysfunction, suggesting possible windows for interventions.

Reproduced with kind permission of Francesco Antognarelli.

Another level of complexity is added by the observation that different mtDNA lineages are qualitatively different from each other. These lineages are indeed characterized by mutations that can impact mitochondrial energy metabolism and consequently influence complex processes, including ageing, longevity and, probably, the susceptibility to developing diseases (Mishmar et al., 2003; D’Aquila et al., 2015).

The loss of mitochondrial metabolic flexibility and integrity, due to the varying combination of alterations in mitochondriogenesis, dynamics and removal, is presently believed to underlie many aspects of the ageing process as well as several age-related disorders (Riera & Dillin, 2015). According to this view, the ‘metabolic inflexibility’ observed in old age corresponds to a progressive, irreversible transition from carbohydrate to lipid metabolism (Galgani et al., 2008). The inability to adapt substrate oxidation to fuel availability impairs the metabolic homeostasis and the capacity to properly respond to metabolic demands. This series of events, coupled with inefficient mitochondrial biogenesis, is eventually followed by impaired degradation of dysfunctional mitochondria and accumulation of abnormal, ROS-producing organelles (Riera & Dillin, 2015). The latter phenomenon, in turn, would play a major role in the appearance and progression of age- and disease-related phenotypes, especially in postmitotic tissues (Fig. 46.1) (Marzetti et al., 2013).

The following sections provide a concise overview of the current state of knowledge about the mechanisms whereby mitochondrial dysfunction intervenes in major age-related conditions affecting the heart, the skeletal muscle, and the central nervous system.

Mechanisms of mitochondrial dysfunction in cardiac ageing and cardiovascular disease

The prevalence and incidence of CVD increase steadily with advancing age, with highest rates observed among persons aged 75 years or older (Lloyd-Jones et al., 2009). While long-term exposure to risk factors plays a major role in the age-related CVD epidemics, intrinsic cardiac ageing renders the heart more vulnerable to internal and external stressors, thereby facilitating the development of cardiac diseases late in life (Lakatta, 2001). The intimate mechanisms involved in heart ageing and CVD are not fully understood. However, alterations in mitochondrial function are thought to be a major contributing factor (Dutta et al., 2012). ROS generation by dysfunctional myocardial mitochondria is approximately 10-fold greater than that measured under physiologic conditions (Grivennikova et al., 2010). Abnormal mitochondria, characterized by matrix derangement, loss of cristae, and bioenergetic inefficiency, accumulate in the aged myocardium (Karbowski et al., 1999). Furthermore, the frequency of the common 4,977-bp mtDNA deletion, a typical consequence of oxidative stress, is increased in the old human heart (Mohamed et al., 2006). This deletion affects genes encoding 7 polypeptide components of the electron transport chain (ETC) and 5 tRNAs required for mitochondrial protein synthesis, thereby impinging OXPHOS efficiency (Porteous et al., 1998). Notably, mice genetically engineered to accumulate mtDNA mutation are characterized by reduced activity of ETC complexes and accumulation of swollen, irregularly shaped, and bioenergetically inefficient mitochondria in the myocardium (Trifunovic et al., 2004).

It is noteworthy that mitochondrial dysfunction and oxidative stress are also deeply involved in the pathogenesis of major cardiac diseases, including heart failure, pathological left ventricular hypertrophy, ischaemia/reperfusion (I/R) injury, and diabetic cardiomyopathy (Dutta et al., 2012). Under such circumstances, the loss of bioenergetic efficiency occurs as a consequence of ETC dysfunction independent of mtDNA damage (Gottlieb & Mentzer, 2010). It is therefore legitimate to hypothesize that the decline in mitochondrial function that accompanies ageing might amplify myocardial dysfunction during the development of CVD and especially congestive heart failure (CHF).

The maintenance of a healthy and functional mitochondrial pool is essential for preserving heart tissue homeostasis. In this regard, mitochondrial quality control is presently considered to be a major target for interventions aimed at delaying cardiac ageing and treating CVD (Wohlgemuth et al., 2014). The morphology and function of mitochondria are regulated by highly coordinated fusion and fission cycles. These processes are crucial not only for determining organelle shape, but also for transmitting redox-sensitive signals, redistributing metabolites and proteins, maintaining mtDNA integrity, and regulating cell death pathways (Ikeda et al., 2014). For instance, the functionality of damaged mitochondria can be complemented and possibly restored by their fusion with neighbouring intact mitochondria. On the other hand, irreversibly damaged mitochondria are segregated from the mitochondrial network through fission and subsequently eliminated by mitophagy (Twig et al., 2008).

Evidence is accumulating in support of dysfunctional mitochondrial dynamics and autophagy as a mechanism in cardiac ageing and CVD (Fig. 46.2). Indeed, reduced fission and impaired mitophagy have been shown in the myocardium of old rodents (Das et al., 2014). In addition, excessive fission (and/or decreased fusion) is involved in ischaemia/reperfusion (I/R) injury (Ong et al., 2010), left ventricular remodelling (Piquereau et al., 2012), and heart failure (Chen et al., 2009). Similar to mitochondrial dynamics, mitochondrial autophagy is altered in the aged heart and in the setting of CVD. Autophagy is indeed downregulated during cardiac ageing (Inuzuka et al., 2009), which may favour the accumulation of dysfunctional and bioenergetically inefficient mitochondria. In addition to the persistence of damaged mitochondria, the myocardium of aged rodents is also characterized by the buildup of a non-degradable, yellow-brown pigment called lipofuscin (Terman & Brunk, 2005). Lipofuscin is generated within lysosomes through oxidative modifications of proteins and lipids. Lipofuscin-loaded lysosomes consume a major part of newly produced lysosomal hydrolases that, however, cannot digest their cargo. At the same time, a smaller amount of lysosomal enzymes remains available for autophagic degradation, including mitophagy. The progressive accumulation of lipofuscin eventual overburdens the autophagy-lysosomal system, thereby impeding the efficient removal of dysfunctional mitochondria and other damaged cellular components (Fig. 46.2) (Terman & Brunk, 2005).

Fig. 46.2 Possible scenarios resulting from mitochondrial quality control failure during the development of cardiovascular disease, neurodegeneration, and sarcopenia. Age-related mitochondrial dysfunction is associated with the appearance of giant mitochondria, characterized by aberrant morphology, reduced bioenergetic efficiency, and increased ROS production. Enlarged mitochondria cannot be efficiently cleared due to their size. The accumulation of lipofuscin within lysosomes further contributes to impairing the autophagosomal-lysosomal axis. Oxidants generated by dysfunctional mitochondria eventually promote cell death through apoptosis, with disruption tissue integrity.

Fig. 46.2 Possible scenarios resulting from mitochondrial quality control failure during the development of cardiovascular disease, neurodegeneration, and sarcopenia. Age-related mitochondrial dysfunction is associated with the appearance of giant mitochondria, characterized by aberrant morphology, reduced bioenergetic efficiency, and increased ROS production. Enlarged mitochondria cannot be efficiently cleared due to their size. The accumulation of lipofuscin within lysosomes further contributes to impairing the autophagosomal-lysosomal axis. Oxidants generated by dysfunctional mitochondria eventually promote cell death through apoptosis, with disruption tissue integrity.

Reproduced with kind permission of Francesco Antognarelli.

Defective autophagy has been implicated in cardiomyocyte apoptosis and myocardial dysfunction during I/R (Hamacher-Brady et al., 2006). Similarly, the accumulation of dysfunctional mitochondria, secondary to inefficient autophagy, has been proposed as a mechanism responsible for the development of diabetic cardiomyopathy (Xie et al., 2011). Finally, the induction of autophagy has shown to ameliorate myocardial remodelling, improve mitochondrial morphology and reduce mortality in transgenic rats expressing human renin and angiotensin genes (Finckenberg et al., 2012). In contrast to the above studies showing a cardioprotective function of autophagy, sustained activation of this self-digestion process aggravates cardiomyocyte apoptosis and increases infarct size during reperfusion (Matsui et al., 2007). These seemingly contrasting findings indicate that, depending on the context under which it is induced and the extent and duration of activation, autophagy can serve either beneficial or detrimental functions in the setting of cardiac ageing and CVD. Hence, interventions that fine tune the autophagic process, without inducing too low or excessive activation of this pathway, may offer substantial therapeutic gain in the context of heart ageing and several cardiac diseases (Marzetti et al., 2013).

Mechanisms of mitochondrial dysfunction in muscle ageing and sarcopenia

The loss of muscle mass and function is one of the most pervasive changes that accompany ageing (Rosenberg, 1989). After the age of 35 years, a healthy person loses muscle mass at a rate of 1–2% per year in conjunction with a 1.5% annual decline in strength, which accelerates to approximately 3% per year after the age of 60 (Hughes et al., 2002). Debate is ongoing with regard to the definition of clear thresholds that distinguish physiological muscle ageing from pathological declines in muscle mass and strength. On the other hand, large consensus exists in the recognition of sarcopenia as a major risk factor for major negative health-related events, independent of the operational definition considered. Sarcopenia is indeed a powerful predictor of frailty, disability, poor quality of life, institutionalization and mortality (Visser & Schaap, 2011).

Numerous pathways are implicated in the pathogenesis of sarcopenia, with mitochondrial dysfunction being proposed as a major determinant (Marzetti et al., 2013). Both resting and maximal oxygen consumption decreases with advancing age, independent of declines in fat-free mass (Short et al., 2005). Furthermore, in vivo OXPHOS activity is reduced by 50% in older individuals relative to younger subjects as determined by 31P nuclear magnetic resonance spectroscopy (Conley et al., 2000). The age-related decline in muscle mitochondrial bioenergetic has an impact on functional capacity, as evidenced by the recently reported correlation between myocyte ATP synthesis and preferred walking speed in healthy older people (Coen et al., 2013).

Similar to cardiac senescence, mtDNA damage is proposed to be a major factor underlying OXPHOS dysfunction in the ageing muscle. Indeed, both the abundance of mtDNA deletion-mutations and the occurrence of ETC abnormalities increase dramatically with advancing age in human muscle (Bua et al., 2006). Notably, ETC alterations colocalized with clonal expansions of somatically derived mtDNA deletion-mutations are more frequent in fibre segments with morphological aberrations. Furthermore, sarcopenia develops prematurely in mice that express an error-prone mtDNA polymerase-γ‎ (Kujoth et al., 2005). Similar findings were obtained in mice with double-strand mtDNA breaks caused by the transient expression of a mitochondrial-targeted endonuclease (Wang et al., 2013).

The accumulation of mitochondria harbouring mtDNA mutations and OXPHOS defects is thought to originate from an altered regulation of quality control processes (Calvani et al., 2013). Indeed, disruption of fusion through mitofusin (Mfn) 1 deletion was found to increase mitochondrial dysfunction and lethality in mtDNA-mutator mice (Chen et al., 2010). In addition, during the development of sarcopenia, excessive mitochondrial fragmentation through fission may lead to bioenergetic inefficiency and triggering of apoptosis (Lee et al., 2004; Iqbal et al., 2013; Joseph et al., 2013). The latter, in turn, is believed to be the final common pathway responsible for muscle fibre atrophy (Marzetti et al., 2010b). It is worth mentioning that mitochondria are deeply involved in the regulation of cell death, being the major centre for the integration and execution of apoptotic signalling (Marzetti et al., 2010a).

Accumulating evidence indicates that mitochondrial turnover is altered during muscle ageing (Johnson et al., 2013). For instance, protein expression levels of peroxisome proliferator-activated receptor-γ‎ coactivator-1α‎ (PGC-1α‎), the master regulator of mitochondrial biogenesis, are reduced in muscle of older subjects relative to younger persons, indicative of decreased mitochondriogenesis (Joseph et al., 2012). Remarkably, PGC-1α‎ expression was found to be positively correlated with four-metre walk speed (Joseph et al., 2012), a major physical performance parameter in old age (Cesari, 2011). It is interesting to note that, in the same study sample, the expression of mitochondrion-derived apoptotic mediators was correlated with indices of muscle mass and function (Marzetti et al., 2012).

Similar to mitochondriogenesis, mitochondrial removal through autophagy is impaired during the development of sarcopenia. Indeed, Russ et al. (2012) showed that the ratio between microtubule-associated protein 1 light chain 3 (LC3)-II and LC3-I, an index of ongoing autophagy, was reduced in the gastrocnemius muscle of old rats, which was partially restored by voluntary wheel running. This finding is in agreement with the observation that a six-month weight loss programme combined with moderate intensity exercise increased the transcript levels of LC3, autophagy-related (Atg) protein 7 and lysosome-associated membrane protein 2 (LAMP-2) in the vastus lateralis muscle of overweight older women (Wohlgemuth et al., 2011). Moreover, the mRNA abundance of the mitophagy-related factors, Beclin1, Atg7, Bcl2/adenovirus E1B 19 kDa interacting protein 3 (Bnip3), and Parkinson protein 2 (Parkin), were found to be lower in inactive frail older women compared with physically active, robust peers (Drummond et al., 2014). Importantly, mitophagy markers were positively correlated with physical performance and muscle mass, reinforcing the involvement of defective mitochondrial autophagy in sarcopenia and functional impairment (Fig. 46.2).

Mitochondrial dysfunction in brain ageing and neurodegenerative diseases

With advancing age, impairments in energy metabolism, perturbations in the level of excitation or inhibition, and altered release of neurotrophic factors lead to neuronal dysfunction and derangement of brain networks (Kapogiannis & Mattson, 2011). Disruptions in brain metabolism and bioenergetics are also implicated in age-related neurodegeneration (Yin et al., 2014). A major determinant of altered energy metabolism in brain ageing and neurodegeneration resides in decreased brain insulin signalling, which, in turn, might arise from neuronal mitochondrial dysfunction (Cholerton et al., 2011). Neurons have an absolute dependence on mitochondrial OXPHOS for ATP supply, with very limited capacity for glycolysis. It is therefore no surprise that mitochondrial dysfunction is proposed to be a central unifying mechanism responsible for degenerative disorders affecting distinct populations of central and peripheral neurons (Mattson et al., 2008). Mitochondrion-derived ATP is necessary not only for the excitability and survival of neurons, but also for synaptic signalling and neuroplasticity (Mattson et al., 2008). In addition, neuronal mitochondria are involved in critical processes, such as modulation of calcium homeostasis, redox signalling, synaptic plasticity, and regulation of cell survival/death pathways (Mattson et al., 2008).

The relevance of mitochondrial function to neuronal function and viability is evidenced by the wide range of neurological abnormalities (e.g. stroke-like episodes, epilepsy, movement disorders, cerebellar ataxia, visual impairment, encephalopathy, cognitive impairment, dementia, psychosis, neuropathies) occurring as part of rare inherited mitochondrial disorders (Finsterer, 2012). Notably, mitochondrion-mediated oxidative stress, perturbations in calcium homeostasis, and triggering of apoptosis also contribute to the pathogenesis of prominent age-related neurodegenerative conditions, including mild cognitive impairment, Alzheimer’s disease (AD), Parkinson’s diseases (PD), vascular dementia, amyotrophic lateral sclerosis, stroke, and psychiatric disorders (Martin, 2012).

AD is the most common cause of dementia in middle and late life, accounting for 60–80% of cases. AD affects 7–10% of individuals older than 65 years and, possibly, 50–60% of those over 85 years (Murray et al., 2013). Strikingly, one new case of AD is expected to develop every 33 seconds worldwide (Alzheimer’s Association, 2014). From a pathophysiological perspective, AD involves progressive synaptic dysfunction and neuronal loss in brain regions critical for learning and memory processes (hippocampus, entorhinal and frontal cortices, and associated structures). Histopathologically, the condition is characterized by the accumulation of extracellular plaques of amyloid-β‎ peptide (Aβ‎) and intracellular neurofibrillary tangles, consisting of aggregates of microtubule-associated protein tau (Goedert & Spillantini, 2006). Neuronal degeneration downstream of Aβ‎ accumulation occurs as a result of mitochondrial dysfunction, which involves impaired energy metabolism, oxidative stress, calcium dyshomeostasis, and apoptosis (Bubber et al., 2005; Mattson et al., 2008). Notably, findings in animal models of brain ageing and AD indicate that mitochondrial dysfunction is both necessary and sufficient for impairing cognition (Kapogiannis & Mattson, 2011). Aβ‎-independent mitochondrial dysfunction has also been described. For instance, mutations of presenilin (one of the subunits of γ‎-secretase, responsible for Aβ‎ generation) may promote mitochondrial dysfunction and/or impair axonal movement of mitochondria (Mattson et al., 2008).

Neuroimaging studies using positron emission tomography have shown reduced energy metabolism in affected brain regions of AD patients (Nordberg et al., 2010). Interestingly, a prospective imaging study found that hippocampal energy deficit predicts AD development and precedes cognitive symptoms (Fig. 46.1) (Mosconi et al., 2008). In further support of the bioenergetic origin of AD, the activity of cytochrome c oxidase, the forth complex of the ETC, is decreased in the brain of AD patients (Maurer et al., 2000). It is also noteworthy that the autophagic degradation of mitochondria is enhanced in the brain of AD patients (Moreira et al., 2007). Whether this phenomenon serves to eliminate damaged mitochondria or if these organelles are more susceptible to autophagy in AD remains to be clarified.

PD is the second most common neurodegenerative disorder after AD. The incidence of PD ranges between 8 and 18 cases per 100,000 person-years, with a prevalence of 0.3% of the entire population (de Lau & Breteler, 2006). The prevalence of PD increases with age, rising from 1% in persons older than 60 years to 4% in those over 80 years. The degeneration of dopaminergic neurons in the substantia nigra is primarily responsible for motor dysfunction in PD. The disease also involves neuronal loss in brain regions that control autonomic functions, mood, and cognition (Braak et al., 2003).

Mitochondrial dysfunction is attributed a major role in the pathogenesis of PD (Celardo et al., 2014). The link between mitochondrial dysfunction and PD was originally established by the discovery of complex I deficiency in the substantia nigra (Schapira et al., 1989). This connection was subsequently reinforced by the observation that several of the genes that are mutated in familial PD (e.g. PTEN-induced putative kinase 1, DJ-1, α‎-synuclein, leucine-rich repeat kinase 2, parkin), code for proteins that are either mitochondrial or associated with mitochondria (Schapira, 2008).

From a pathophysiological standpoint, PD is characterized by a vicious circle involving mitochondrial dysfunction/oxidative stress/proteasomal inhibition (Dias et al., 2013). Mitochondrial dysfunction, in particular complex I defects, enhances ROS generation, which, in turn, impairs ETC function. Mutations and multiplications of the gene encoding α‎-synuclein favour the aggregation of the protein, in a process amplified by free radicals. Interestingly, α‎-synuclein is itself involved in oxidant generation and neuronal loss through apoptosis (Schapira, 2008). In addition, mitochondrial abnormalities impair UPS activity, which is further compromised by the accumulation of oxidatively damaged protein aggregates (Dias et al., 2013). Eventually, UPS dysfunction interferes with mitochondrial dynamics and the autophagic degradation of damaged mitochondria, thereby compromising neuronal bioenergetics and increasing the susceptibility to triggering apoptosis (Büeler, 2009).


While there is very little doubt that declines in mitochondrial bioenergetic efficiency and enhanced ROS generation are implicated in ageing and disease development, mitochondrial quality control failure has emerged as a major contributing factor to these processes. In particular, disruption of mitochondrial functional integrity and cell loss via mitochondrion-mediated apoptosis are deeply involved in ageing and diseases affecting the heart, the skeletal muscle, and the central nervous system (Fig. 46.1). Mitochondrial pathology affects several pathways concomitantly (ATP production, calcium homeostasis, ROS generation, mitochondrial dynamics and biogenesis, mitophagy, apoptosis). However, the primary events responsible for mitochondrial dysfunction and the sequence of events that lead to cell death are still poorly understood. This lack of knowledge is largely due to the complex interconnection of the pathways outlined above and difficulties inherent to their study. Indeed, it is very unlikely that experimental alterations in one single pathway may recapitulate the complexity of ageing and related diseases. This is especially true if one considers that virtually all of the molecules involved in mitochondrial quality control and apoptosis possess pleiotropic functions. This obviously limits the possibility of manipulating one pathway without simultaneously affecting other cellular processes.

Future studies should explore how these isolated pathways work in concert under physiologic conditions and how they orchestrate cell death during ageing and under pathological conditions. The knowledge gained through such investigations may eventually allow the development of novel therapeutics that target mitochondrial dysfunction to counteract ageing and treating highly prevalent, disabling age-related conditions.


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