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The many different types of damage accumulated in mitochondria over time probably underlie the decline of mitochondrial mass and function observed with aging in skeletal muscle. Noteworthy, the rate of damage accumulation is blunted by several resilience mechanisms, but unfortunately the efficiency of this resilience declines with aging.

A primary mechanism aimed at maintaining mitochondrial integrity is the alternation of constant cycles of fission and fusion. Fission is the mechanism by which mitochondria divide and duplicate, while through fusion two or more smaller mitochondria form a unique larger structure. The conceptualization of fission and fusion is usually referred to mitochondria as single organelles, but how mitochondrial fission and fusion occur in skeletal muscle mitochondria that form a highly connected network is not understood. Thus, our knowledge of these mechanisms in humans is scant, although it is evident that the functionality of fission and fusion is essential to the preservation of mitochondrial health and energetic metabolism [66]. Mitochondria exert a tight quality control on protein integrity, they can repair misfolded proteins or eliminate them through chaperon‐mediated autophagy and proteasome proteolysis, without the need of activating other mechanisms [67]. However, when the severity of damage is overt, damaged mitochondria may fuse with other mitochondria in the same myofiber, share undamaged components and, as long as the mtDNA mutation load remains below a certain threshold, maintain a good level of function [68]. If mitochondrial functionality cannot be restored through these mechanisms, damaged and dysfunctional mitochondria can be eliminated though mitophagy (mitochondrial autophagy, see later). In particular, distressed mitochondria undergo fission and segregate most of the damaged components into small mitochondrial vesicles with partially depolarized membranes. These smaller vesicles can either be targeted for autophagy or fuse with other healthy mitochondria. However, if the level of damage is overt and above a certain threshold, both fission and fusion are inhibited to avoid the transfer of damaged material to healthy mitochondria. Under these conditions, the whole mitochondrial membrane would become depolarized and ATP production declines below a critical threshold, activating autophagy (mitophagy), a process that consists in the sequestration of a mitochondrion in an autophagic vacuole (autophagosome) and the hydrolytic degradation of its cargo by fusion with lysosomes (autolysosome) [69].

Profound alterations in mitochondrial fusion and fission proteins have been associated with many age‐related conditions, including obesity, neurodegenerative diseases, cardiovascular diseases, type 2 diabetes, and age‐related sarcopenia. Although most of these studies were conducted in animal models, they suggest that a dysregulation of mitochondrial dynamics may play an important role in age‐related sarcopenia and other age‐related chronic conditions in humans [70]. Supporting evidence for this theory comes from the fact that “in vivo;” genetic manipulations of proteins involved in fission accelerated muscle mass decline with aging in mice, while the inhibition of fission prevented sarcopenia. Moreover, overexpression of dynamin‐like 120‐kDa protein (OPA1), an essential protein for mitochondrial fusion, is protective against denervation‐induced muscle atrophy [71]. The expression of mitochondrial fusion and fission proteins is reduced during aging in human skeletal muscle [72, 73]. Reduced levels of Mitofusin‐2 (MFN‐2), an outer membrane mitochondrial protein essential for mitochondrial fusion, have been found in sarcopenic older individuals, as compared to age‐matched controls [74]. In addition, several lines of research suggest that autophagy becomes defective with aging, including some evidence regarding human skeletal muscle.

The persistence of severely damaged mitochondria jeopardizes attempts to replace them with new, healthy mitochondria. Stressed mitochondria also release non‐methylated mtDNA and formyl peptides, that are viewed by the immune system as damage‐associated molecular patterns (DAMPs) and detected by Toll Like Receptor 9 (TLR9) and the NLRP3 Inflammasome [75]. The latter triggers caspase‐1 activation and the production of interleukin (IL)‐1β and IL‐18 [76]. A third recently identified pro‐inflammatory pathway triggered by released mtDNA involves recognition by the cytosolic sensor cGAS, which activates the adaptor protein STING and the kinase TKB1 leading to the production of type 1 interferons (IFN) [77]. Based on these mechanisms, it is not surprising that the slow, continuous release of mtDNA has been proposed as one of the potential causes of the pro‐inflammatory state that is often recognized in older individuals and that has been associated with cardiovascular diseases and other chronic diseases [78]. Interestingly, a pro‐inflammatory state witnessed by high levels of pro‐inflammatory markers, such as C‐Reactive protein and, less consistently, IL‐6, has been associated with age‐related sarcopenia and recognized as a risk factor for sarcopenia development [79]. It has been suggested that this association is caused by inflammatory mediators that enhance protein catabolism and inhibit protein synthesis, both directly and through interference with the production and biological activity of Insulin‐like growth factor‐1 [75]. However, the specific mechanism by which inflammation affects muscle protein metabolism has not been fully elucidated. Attempts to prevent or reverse sarcopenia by reducing inflammation in humans have had limited success [79].