Importantly the interconnections between SAMD SASP

Importantly, the interconnections between SAMD, SASP and cell senescence do not form a simple linear cause-effect relationship. There is ample evidence for the existence of multiple positive feedback loops between the major components of the senescent phenotype (Fig. 3). Positive feedback loops between SASP factors and DDR (Acosta et al., 2008; Kuilman et al., 2008) or between SAMD and DDR (Passos et al., 2010) are well documented. It has also been shown that chronic activation of NF-κB not only enhances the SASP but also aggravates ROS production and the DDR in senescence (Jurk et al., 2014) possibly at least in part via a ‘non-canonical’ function of NLRP3. There is also evidence for intriguing interactions between SASP, SAMD and the extracellular matrix (ECM) (Fig. 3): Senescent cells are known to negatively impact their surrounding environment, including both bystander cells and composition and structure of the ECM via secretion of matrix metalloproteinases, especially MMP-1, and decreased expression of its endogenous inhibitor TIMP-1 as part of the SASP, resulting in ECM degradation with aging (Brennan et al., 2003). SAMD may play an important role for these degenerative changes, as they can be triggered by retrograde signalling in response to mtDNA mutations and electron transport chain dysfunction (Krutmann and Schroeder, 2009; Wiley et al., 2016). ECM collagenolysis autonomously inhibits further pro-collagen synthesis and down-regulates hyaluronic buy zip synthase 2 (Rock et al., 2011), further contributing to ECM degeneration. Hyaluronic acid is a linear polysaccharide with pro- or anti-proliferative properties depending on its molecular weight; the extremely high molecular weight hyaluronic acid produced by naked mole rats is a major determinant of their remarkable tumour resistance because of its strong anti-proliferative effect (Tian et al., 2013). It is thus probable that ECM remodelling by senescent cells feeds back into aggravation of the senescent phenotype and mitochondrial dysfunction in the matrix-embedded cells. Together, these data show that mitochondrial dysfunction is both a cause and a consequence of senescence. Thus, mitochondrial turnover and especially mitophagy might be the central regulator of cell senescence (Fig. 3).
Outstanding questions Mitochondrial dysfunction is well accepted as a driver of tissue and organism aging with potential to modulate aging either positively or negatively depending on a set of insufficiently understood conditions (Wang and Hekimi, 2015). 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 (see above), 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 cell-autonomous lipid storage in aging liver and thus contributes to fatty liver (steatosis), a common and pathologically significant complication of liver aging (Ogrodnik et al. unpublished). Adipocyte senescence is an essential driver of adipose tissue dysfunction and obesity (Stout et al., 2017), 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 (senolytics) will enable a better understanding of the importance of SAMD in aging.