• 2018-07
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  • 2020-01
  • 2020-02
  • SAMD appears to be a central mediator for interventions that


    SAMD appears to be a central mediator for interventions that extend healthy lifespan. Dietary restriction induces autophagy, improves mitochondrial function, specifically in complex I (Miwa et al., 2014) and reduces frequencies of senescent oxyntomodulin in many tissues (Wang et al., 2010). Similarly the dietary restriction mimetic rapamycin, which also prolongs healthy lifespan in many species by activating autophagy (Kennedy and Lamming, 2016) and improving mitochondrial complex I function (Miwa et al., 2014), acts as a senostatic, i.e. it inhibits multiple aspects of the senescent phenotype including SAMD (Demidenko and Blagosklonny, 2008; Correia-Melo et al., 2016). Recently, metformin gained increasing attention as a drug that can enhance lifespan and healthspan not only in rodents but also in man (Bannister et al., 2014). Metformin improves mitochondrial complex I function (Foretz et al., 2014), inhibits mTORC1 signalling by activating AMPK (Howell et al., 2016) and blocks pro-inflammatory NF-κB signalling (Saisho, 2015). While metformin may sensitize some cell types to stress-induced senescence in vitro, it inhibits the SASP, thus blocking senescent cell-induced bystander effects (Moiseeva et al., 2013) and may act as a senostatic drug in vivo similar to rapamycin. Senescent cells typically upregulate anti-apoptotic pathways, and are preferentially susceptible to inhibition of these pro-survival mechanisms. This has been dubbed the ‘Achilles heel’ of senescent cells and used as a rationale for the development of senostatic drugs (Kirkland & Tchkonia, in this volume). It is tempting to speculate that the low mitochondrial membrane potential found in many senescent cells lies at the heart of this preferential sensitivity by easing the release of apoptosis-stimulating factors from mitochondria. Interestingly in this respect, a recent screen of compounds that modify autophagy (and possibly mitophagy) identified a large number of these as potential senolytics (Fuhrmann-Stroissig et al., unpublished). It seems probable that for drugs to effectively extend such a multifaceted phenotype as healthy lifespan they need to target not just a singular molecular node but a complex network of aging-determining pathways and mechanisms like the one defined by the interactions between mitophagy, SAMD and SASP in cell senescence (see Fig. 3). We believe that improved understanding of this network will offer an exciting avenue in the development of novel interventions that can prolong healthy lifespan including senolytic and senostatic agents.
    Author contributions
    Conflict of interests
    Cellular Senescence and Telomeres Cellular senescence was first described by Hayflick and Moorhead as the progressive and irreversible loss of proliferative potential of human somatic cells (Hayflick and Moorhead, 1961). This phenomenon is characterized not only by a loss in replicative capacity, but also by a series of dramatic changes in cell morphology, gene expression, metabolism, epigenetics and others (van Deursen, 2014). It is a stable phenotype, with senescent cells being able to be kept in culture for several years following the initial arrest. So far, the best explanation for replicative senescence is the shortening of telomeres, regions composed of DNA repeats associated with proteins, found at the ends of chromosomes. In the 1990s, it was shown that telomere regions gradually shorten with cell division and that this correlates with the induction of cellular senescence (Harley et al., 1990). Importantly, it was demonstrated that ectopic expression of the enzyme telomerase, which is capable of elongating telomeres, counteracts telomere shortening driven by cell division and bypasses the senescence arrest (Bodnar et al., 1998). This experiment, demonstrated that telomere length was the limiting factor in the senescence arrest and therefore played a causal role in the process. Since then, great advances have been made in the understanding of how telomeres are able to signal the senescence arrest. These mechanisms are of particular importance in the field of ageing, since cellular senescence, driven by telomere dysfunction, has been shown to be a causal driver of ageing and age-related pathology (van Deursen, 2014).