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    • Mechanistically the age promoting effects

    2018-11-07

    Mechanistically, the age-promoting effects of senescence are associated with the restriction of regenerative capacity of stem and progenitor thrombin inhibitors (Choudhury et al., 2007; Jurk et al., 2014) as well as the secretion of bioactive molecules (the so-called SASP (Coppe et al., 2008)), 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 (Nelson et al., 2012). 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’ (Lopez-Otin et al., 2013), and the two have been independently identified as important drivers of aging (Finkel, 2015). Importantly, they are closely interlinked: mitochondrial dysfunction drives and maintains cell senescence (Correia-Melo et al., 2016; Passos et al., 2007; Wiley et al., 2016), while at the same time cell senescence, specifically persistent DNA damage response signalling, directly contributes to Senescence-Associated Mitochondrial Dysfunction (SAMD) (Passos et al., 2010). 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 (Correia-Melo et al., 2016), it is not clear how mitochondria become dysfunctional in senescence. Importantly, an understanding of the potential consequences of SAMD in the context of tissue aging is only beginning to emerge. In this review, we will explore the following hypotheses:
    Dysfunctional mitochondria accumulate in senescent cells It is well established that not only cell size but also mitochondrial mass increases significantly in senescent cells (Table 1). Kinetic studies in stress-induced senescence showed that the increase in mitochondrial mass is a fast but not immediate process, occurring with a delay of 2–3days after the peak in DNA damage but before a robust SASP is established (Passos et al., 2010). As with most other senescence phenotypes, mitochondrial accumulation has preferentially been studied in fibroblasts, but occurs also in senescent epithelial cells (Hara et al., 2013), hepatocytes (Correia-Melo et al., 2016), enterocytes (Jurk et al., 2014) or neurons that develop a senescence-like phenotype in response to persistent DNA damage (Jurk et al., 2012). In oncogene-induced senescence, the activity of the mitochondrial ‘gatekeeper’ protein pyruvate dehydrogenase is increased by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress (Kaplon et al., 2013). In senescent cells, the expression of fission mediators Drp1 and Fis1 (Mai et al., 2010) and frequencies of both fusion and fission events (Dalle Pezze et al., 2014) are reduced, resulting in enhanced connectivity of the mitochondrial network. In functional mitochondria, oxygen uptake, ATP production, membrane potential and generation of ROS are tightly regulated to maintain the redox balance (Brand, 2016). While there is no simple correlation between membrane potential and superoxide production by the electron transport chain, mitochondria that accumulate in senescence often show a decreased membrane potential and at the same time produce increased levels of ROS (Table 1), suggesting dysfunctionality. In accordance with this notion, the capacity of senescent cells to regulate [Ca]i is decreased and a retrograde response is initiated (Passos et al., 2007). In mitochondria from senescent cells, the Respiratory Control Ratio (RCR, the ratio of oxygen uptake in state 3 (presence of ATP) to state 4 (presence of oligomycin)), is much lower than in young cells (Table 1), specifically if respiration is fuelled by complex I-linked substrates. Together, these data show that the mitochondria that accumulate during cell senescence are dysfunctional. We propose the notion of Senescence-Associated Mitochondrial Dysfunction (SAMD) for this phenotype.