An Examination of Mitochondrial Dysfunction in Senescent Cells

Researchers here review what is known of mitochondrial dysfunction in cellular senescence. Senescent cells accumulate with age, and their growing presence is one of the contributing causes of degenerative aging. Some fraction of the damaging behavior of these cells, particularly their ability to generate chronic inflammation, may be driven by failing mitochondria, but there is the question of the ordering of cause and consequence here: does the state of cellular senescence tend to produce cells populated by damaged mitochondria, or is the sort of mitochondrial DNA damage outlined in the SENS view of aging causing cellular senescence? Both cases seem to occur, but knowing that much doesn't tell us which is more important. Further, mitochondria have important roles to play in the normal progression of cellular senescence: this is a state in which most such cells self-destruct via apoptosis, a process of programmed cell death in which mitochondria play a core role. The situation in which senescent cells start down the path to apoptosis but fail to self-destruct is the interesting one, both for the contribution to aging, and for what the mitochondria might be doing in that pathological situation.

Senescent cells accumulate with age in a wide range of tissues. The rate of accumulation of senescent cells in liver and intestinal crypts predicts median and maximum lifespan of mice in cohorts with widely different aging rates. More importantly, interventions that selectively ablate senescent cells by genetic and/or pharmacologic means may improve healthspan and lifespan in mice. Mechanistically, the age-promoting effects of senescence are associated with the restriction of regenerative capacity of stem and progenitor cells as well as the secretion of bioactive molecules (the so-called senescence-associated secretory phenotype, SASP), specifically pro-inflammatory and matrix-modifying peptides. Pro-aging effects of senescent cells are aggravated by SASP and, possibly, other paracrine mediators which can propagate senescence from cell to cell as a bystander effect. In recent years, evidence has been mounting that senescent cells impact on their environment via yet another principal pathway: mitochondrial dysfunction.

Along with cell senescence, mitochondrial dysfunction is another essential 'hallmark of aging', and the two have been independently identified as important drivers of aging. Importantly, they are closely interlinked: mitochondrial dysfunction drives and maintains cell senescence, while at the same time cell senescence, specifically persistent DNA damage response signalling, directly contributes to Senescence-Associated Mitochondrial Dysfunction (SAMD). Despite the close interdependent relationship between senescence and SAMD, the true complexity of these interactions and their role in aging remains to be elucidated. For example, it is currently unclear how much of the mitochondrial dysfunction that has been observed at tissue level during aging is actually associated with senescence at a cellular level. Furthermore, despite its central contribution to the senescent phenotype, it is not clear how mitochondria become dysfunctional in senescence.

An important question is to what extent aging-associated mitochondrial dysfunction and cell senescence/SAMD are interrelated. Does aging-related mitochondrial dysfunction cause senescence in vivo or vice versa? Is mitochondrial dysfunction in aging actually a mosaic phenomenon, occurring preferentially or exclusively in the senescent cells? Given the high prevalence of senescent cells in many tissues, this appears highly possible. Emerging data suggest that it is SAMD rather more than general loss of mitochondrial function in aging that reduces homeostatic capability, causing compromised responses to peak energy demand and driving metabolic insufficiency in aging. For instance, we have found that SAMD in hepatocytes (and other cell types) includes a compromised capacity to metabolize fatty acids, which causes lipid storage in aging liver and thus contributes to fatty liver (steatosis), a common and pathologically significant complication of liver aging. Adipocyte senescence is an essential driver of adipose tissue dysfunction and obesity, and this link is very probably mediated by SAMD. Analysing mitochondrial dysfunction in aging tissues at single-cell resolution in combination with interventions that selectively ablate senescent cells will enable a better understanding of the importance of SAMD in aging.


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