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https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12685
 

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Sirtuins, aging, and stem cells

Sirtuins have long been recognized as regulators of aging – overexpression of sirtuins has been shown to extend lifespan in several organisms (Tissenbaum & Guarente, 2001; Kanfi et al., 2012). Sirtuin function in aging has to date been reported to be related to their roles in regulation of energy metabolism, response to calorie restriction (CR), control of cell death, and circadian rhythms (Araki et al., 2004; Chang & Guarente, 2013; Guarente, 2013). A new mechanism of lifespan modulation by sirtuins has been gaining attention, related to their potential roles in cellular and mitochondrial protein homeostasis networks. Recent developments have highlighted the close relationship between healthy aging and protein homeostasis, or proteostasis (Kaushik & Cuervo, 2015; Walther et al., 2015). A gradual loss of proteostasis is associated with age (Labbadia & Morimoto, 2015) and the longest living organisms are known to have more stable proteasomes and active proteostasis networks (Perez et al., 2009; Treaster et al., 2014). Most importantly, enhancing the functionality of proteostasis networks has been shown to extend both lifespan and healthspan of certain organisms (Morimoto & Cuervo, 2014; Vilchez et al., 2014a; Labbadia & Morimoto, 2015). Given that sirtuins are well‐known lifespan modulators whose deficiencies have been linked to a higher incidence of age‐related diseases, the investigation of their roles in proteostasis networks would appear to be warranted. In fact, a relationship between sirtuins and ER stress appears to be conserved from C. elegans to mammals, indicating a crucial link between sirtuins and proteostasis (Viswanathan et al., 2005).
SIRT1 is a known negative regulator of ER stress responses through deacetylating IRE‐1‐generated active XBP1 and subsequent inhibition of its transcriptional activity to promote ER stress‐induced apoptosis (Wang et al., 2011). SIRT1 also suppresses pERK‐eIF2α‐dependent translational inhibition (Ghosh et al., 2011).

 In breast cancer cells, the unfolded protein response (UPR) triggered by the accumulation of misfolded proteins in the mitochondria (UPR^mt) requires the activation of SIRT3 together with CHOP and estrogen receptor alpha (ERα). By orchestrating both the antioxidant machinery and mitophagy in a CHOP‐ and ERα‐independent manner, SIRT3 contributes to overcoming proteotoxic stress and mitochondrial stress, which may represent an essential mechanism of adaptation of cancer cells (Papa & Germain, 2014).
Looking more closely into stem cells, they seem to have increased mechanisms to protect their proteasomes, and proteostasis networks impact their function (Vilchez et al., 2014b). This would appear to be related to the stem cell theory of aging, which suggests that a progressive decline in the self‐renewal of adult stem cells and their potential to differentiate into specific cell types in order to replenish the tissues of an organism underlie the mechanistic basis for aging. Although the age‐dependent loss of function of different types of adult stem cells has been reported, we are just now starting to understand the molecular mechanisms involved in this process.
 With the focus on sirtuins, SIRT7‐mediated alleviation of mitochondrial protein folding stress plays a critical role in modulating the aging process by regulating HSC quiescence and tissue maintenance (Mohrin et al., 2015). SIRT7 functions as a stress sensor in proliferating, metabolically active HSCs and reduces the expression of the mitochondrial translation machinery through repressing activity of the master regulator of mitochondria, nuclear respiratory factor 1 (NRF1), which is necessary to alleviate mitochondrial protein folding stress. Of note, rescue of the impaired reconstitution capacity in aged HSCs upon SIRT7 overexpression or NRF1 inactivation underscores the significance of sirtuin‐regulated proteostasis in maintaining stemness.
 Interestingly, decreased Sirt3 expression in aged HSCs is associated with a concomitant repression of mitochondrial protective programs (Brown et al., 2013), which might result in compromised function of the previously described SIRT3‐directed UPR^mt pathway. Certainly, further studies need to address whether similar mechanisms are involved in other adult stem cells and tissues. Also, it would be interesting to see whether these mechanisms are crucial for self‐renewal and differentiation of CSCs based on the fact that CSCs resemble a proliferating, metabolically active normal stem cell.
 Furthermore, even though SIRT7 and SIRT3 cross at mitochondrial regulation, they do activate these protective mechanisms through their function in nucleus and mitochondria, respectively. As similar protective programs might be orchestrated by other sirtuins, it remains to be determined whether SIRT2, which is the main cytoplasmic sirtuin strongly downregulated in aged HSCs as well (Chambers et al., 2007), is involved in stem cell maintenance, and possibly, new pathways crucial for stem cell maintenance remain to be identified.

Calorie restriction (CR) and stem cells

CR is one of the most potent dietary interventions for increasing lifespan and delays the onset of age‐related diseases including cancer (Wanagat et al., 1999; Longo & Fontana, 2010; Colman et al., 2014). It is accepted that its beneficial effects might relate, at least in some significant part, to epigenetically reprogramming stemness while prolonging the capacity of stem‐like cell states to proliferate, differentiate, and replace mature cells in adult aging tissues. This is based on studies showing that CR may maintain stem cell function of HSCs (Ertl et al., 2008), enhance stem cell availability and activity in the muscle of young and old animals (Cerletti et al., 2012), and increase hippocampal neural stem and progenitor cell proliferation in aging mice (Park et al., 2013b). Considering that sirtuins are NAD‐dependent protein deacetylases directly activated by CR, it could be proposed that they may mediate some of the beneficial effects of CR on normal stem cells in adult somatic tissues. However, this is a relatively unexplored area of research and there is lack of experimental evidence to either support or counter this hypothesis.
 Only very recently, it was reported that SIRT1 is necessary for the expansion of intestinal stem cells (ISCs) upon CR. More specifically, CR results in deacetylation of p70 ribosomal S6 kinase due to SIRT1 activation, which consequently promotes its phosphorylation by mammalian target of rapamycin complex 1 (mTORC1). This signal‐response mechanism mediates the increase in both protein synthesis and number of ISCs, even as mTOR signaling is turned down by CR in more differentiated cells (Igarashi & Guarente, 2016). Similarly, little is known about the role of sirtuins as mediators of the CR‐induced effect on tumorigenesis. As previously mentioned, cancer was among the age‐related diseases which exhibited a delayed onset in response to CR in several early studies (Hursting et al., 1994; Berrigan et al., 2002; Mai et al., 2003). Thus, it is rather surprising that there is a lack of experimental data to address the contribution of sirtuins in the inhibitory effect of CR on tumorigenesis. Regarding SIRT1, which is the only sirtuin studied so far, its overexpression failed to influence the anticancer effects of every‐other‐day fasting (a variation in CR), suggesting that SIRT1 may play a limited role in the effects of CR on cancer (Herranz et al., 2011). Undoubtedly, future studies are necessary to check more thoroughly the role of sirtuins under this setting. However, it seems a very intriguing question to ask whether sirtuin‐directed functions may regulate either CSCs or non‐CSCs, given that cancer is now viewed as a stem cell disease. This is further supported by recent evidence highlighting the effect of CR on unique characteristics of CSCs such as EMT (Dunlap et al., 2012), protein synthesis (Lamb et al., 2015), metabolic plasticity (Peiris‐Pages et al., 2016), as well as the importance of the HIF pathway in regulating metabolism, cellular responses to hypoxia and stemness (Lim et al., 2010; Zhong et al., 2010; Yun & Lin, 2014), which are all processes previously shown to be regulated by sirtuins. It is hoped that future research will shed light on mechanisms underlying the interplay between CR, sirtuins, and stem cells.

Conclusion/Future directions

Emerging evidence suggests that sirtuins could be placed at the crossroads of stemness,  and cancer. This is based on the plethora of functions they regulate both in normal stem cells and in CSCs. However, it is clear that we are just starting to appreciate the importance of identifying specific processes regulated by the different members of the sirtuin family in a tissue‐, cell type‐, and genetic‐specific context. This might be necessary in order to gain a better understanding of their role and fill current knowledge gaps in the field. With this in mind, it is worth mentioning that most of the previous studies, including the published papers presented in this review article, have followed a targeted approach regarding elucidation of mechanisms regulated by sirtuins. To do so, they were focused on either unraveling how sirtuins regulate signaling pathways/processes already implicated in stemness or exploring whether previously well‐established functions of sirtuins play a significant role in stem cells. Toward this direction, it could be proposed that implementation of unbiased high‐throughput experimental approaches would provide more mechanistic insights. Proteomics have been employed in the past to identify sirtuin‐specific interacting proteins and substrates. The regulatory role of SIRT2 on anaphase‐promoting complex (APC/C) during mitosis was identified based on a proteomics approach that revealed its interaction with proteins of the complex including the APC activator proteins Cdc20 and Cdh1 (Kim et al., 2011). Recently, proteomics were used to elucidate the mitochondrial sirtuin protein interaction landscape showing that this experimental approach can uncover novel functions and/or substrates (Yang et al., 2016). Thus, it could be suggested that similar approaches on stem and progenitor cells or CSCs would identify novel functions of sirtuins. Furthermore, recent advances in high‐resolution mass spectrometry‐based proteomics have enabled the study of the acetylome under different experimental conditions establishing acetylation as an equally widespread PTM as phosphorylation (Kim et al., 2006; Choudhary et al., 2009, 2014). Given that similar approaches have enabled the identification of sirtuin‐specific deacetylation targets (Hebert et al., 2013; Vassilopoulos et al., 2014), it would be reasonable to suggest that studying the acetylome in the context of stem cells/progenitors or CSCs would reveal novel functions/substrates regulated at the post‐translational level. In a similar way, a detailed characterization of target genes epigenetically regulated by sirtuins in specific subcellular populations could help shape new directions in this field and complement previous comprehensive studies focused on the analysis of the transcriptome, DNA methylome, and histone modifications (Sun et al., 2014) in stem cells. Collectively, such studies will provide novel insights into both aging and cancer.