Age-related dysfunction of SCs is caused by both cell-intrinsic and cell-extrinsic mechanisms. While the germline stem cell lineage is in principle immortal, and should therefore have acquired mechanisms to prevent age-related decline, their proliferative activity is affected by changes in local and systemic support processes that decay in aging animals, leading to reproductive senescence. Somatic SCs, in turn, while being affected by systemic changes, also seem to age due to intrinsic mechanisms that limit their replicative lifespan. These include telomere dysfunction, DNA damage-induced cellular senescence, and age-related increases in the expression of cell cycle inhibitors (Gunes and Rudolph 2013; Jones and Rando 2011; Rando 2006; Sharpless and DePinho 2007). It has been proposed that these age-related changes in somatic stem cells are part of anticancer mechanisms that prevent deregulation of SC proliferation. The inability of somatic SCs to sustain efficient tissue regeneration in aging organisms would thus be a trade-off of processes required for cancer prevention (Campisi 2013; Sharpless and DePinho 2007). Supporting this view, recent studies confirm that deregulation of stem cell proliferation can contribute to tumor formation (Barker et al. 2009; Lapouge et al. 2011; White et al. 2011; Youssef et al. 2010). Furthermore, the identification of molecular similarities between cancer stem cells and tissue-specific stem cells highlights the importance of preventing deregulation of these cells to ensure long-term tissue homeostasis (Merlos-Suarez et al. 2011). This insight suggests that to promote tissue health and ultimately organismal lifespan, it is key to find strategies to modulate somatic SC function and increase their regenerative capacity without promoting excessive and deregulated proliferation.

While stereotypical age-related processes that limit regeneration can thus be defined, somatic SCs exhibit a large proliferative diversity, reflecting the specific requirement of individual tissues. Specific modes of SC proliferation include (i) continuously cycling stem cells of high-turnover tissues, such as intestinal stem cells (Li and Clevers 2010; Simons and Clevers 2011; van der Flier and Clevers 2009) and short-term hematopoietic stem cells (HSCs) (Fuchs 2009); (ii) SCs whose proliferation is induced by injury, including airway basal epithelial stem cells and muscle satellite cells (Abou-Khalil and Brack 2010; Dhawan and Rando 2005; Rock et al. 2011); and (iii) stem cells with alternate quiescent and proliferative periods, such as hair follicle stem cells (Fuchs 2009). This diversity results in distinct age-associated deficiencies that contribute to regenerative decline of individual tissues and highlights the need to study aging of distinct SC systems separately to achieve a comprehensive understanding of the regenerative decline in aging organisms. Here, we take account of this diversity of aging processes in different stem cell populations by focusing on the age-associated dysfunction of individual stem cell populations separately in individual chapters.

While cell-intrinsic age-related changes in somatic stem cells often specifically impact cell cycle regulation (and can thus be defined as anticancer “programs” that contribute to tissue aging), somatic SCs are also impacted by the random age-related accumulation of molecular damage, as well as by changes in local and systemic conditions in the aging organism. This includes inflammatory conditions and oxidative stress, as described in the hematopoietic system of the mouse and in the posterior midgut of flies (Biteau et al. 2011; Tothova and Gilliland 2007). The resulting accumulation of damage to DNA and other macromolecules is thus likely an important accelerator of SC aging (Biteau et al. 2011; Jones and Rando 2011; Rudolph et al. 2009; Tothova and Gilliland 2007). Mechanisms that allow cells to cope with these challenges and processes that contribute to the development of proliferative dysfunction in aging SCs are likely to be conserved from yeast to humans, and studies exploring the regulation of replicative lifespan in yeast are thus expected to provide important insight into somatic SC aging. One interesting example is the observation that budding yeast ensures rejuvenation of newly formed cells by asymmetrically segregating damaged and old macromolecules, providing a new “young copy” of such molecules to daughter cells (Aguilaniu et al. 2003; Shcheprova et al. 2008). Recent studies suggest that similar processes occur in human embryonic stem cells and in germline and somatic stem cells of flies (Bufalino et al. 2013; Fuentealba et al. 2008).

The complexity of somatic stem cell lineages in vertebrates often causes difficulties in definitively characterizing age-associated dysfunctions at the stem cell level in vivo. Characterization of stem cell aging in simpler model organisms in which lineage relationships are clearly defined, and which allow lineage tracing with relative ease to study stem cell proliferation and pluripotency, is thus necessary to provide a conceptual framework of stem cell aging and the loss of regenerative capacity. Work in flies and worms has provided such insight in recent years. This work initially focused on the effects of aging on germline stem cells (GSCs), and a large body of literature has examined mechanisms of stem cell aging in the worm and fly germline, as well as identified endocrine mechanisms by which GSCs influence metabolism and longevity of the animal (Arantes-Oliveira et al. 2002; Crawford et al. 2007; Drummond-Barbosa and Spradling 2001; Hsin and Kenyon 1999; Hsu et al. 2008; Jones and Rando 2011; LaFever and Drummond-Barbosa 2005; Mair et al. 2010; Pan et al. 2007; Pinkston et al. 2006; Toledano et al. 2012; Ueishi et al. 2009; Wang et al. 2008). These studies have established that in the aging animal, GSC maintenance is affected by a decline in specific niche factors, by metabolic imbalances, as well as by oxidative stress.

Adult somatic stem cells have been identified in the fly gonad, the intestine, and the Malpighian tubules (Decotto and Spradling 2005; Fox and Spradling 2009; Gonczy and DiNardo 1996; Margolis and Spradling 1995; Micchelli and Perrimon 2006; Ohlstein and Spradling 2006; Singh et al. 2007; Takashima et al. 2008). Among these stem cell populations, intestinal stem cells (ISCs) have served as a model to characterize processes and signaling mechanisms that regulate regenerative responses and whose deregulation contributes to the age-related decline in regenerative capacity (Biteau et al. 2011; Casali and Batlle 2009). These include signaling pathways required for homeostatic epithelial renewal (such as EGF and insulin signaling), stem cell maintenance (such as Wnt and Tor signaling), as well as stem cell stress responses (JNK, Jak/Stat, and Hippo signaling). Characterizing these signaling mechanisms is likely to not only provide insight into basic mechanisms of stem cell regulation but also elucidate the molecular etiology of tissue dysfunction, including age-related degeneration and cancer (Radtke and Clevers 2005; Rossi et al. 2008; Sharpless and DePinho 2007). It is important to note that the processes driving stem cell aging appear to be conserved from flies to mammals. FoxO transcription factors, for example, promote stem cell maintenance and function in both mice and flies (Biteau et al. 2010, 2011; Tothova and Gilliland 2007).

A central cause of stem cell and regenerative dysfunction in aging organisms appears to be the loss of support from the local microenvironment, the “niche” (Jones and Rando 2011). Age-related niche dysfunction has been characterized primarily in the male and female germline of Drosophila, but studies in mice support the notion that similar processes are conserved in vertebrates. The interaction between GSCs and their niche is disrupted in aging females due to increased oxidative stress (Pan et al. 2007), while a decline in trophic support from the niche drives GSC decline in males (Jones and Rando 2011; Toledano et al. 2012). Interestingly, this decline is caused by an increase in the expression of the microRNA let-7, which negatively regulates the RNA-binding protein Imp (IGFII mRNA-binding protein), which in turn is required to stabilize the mRNA of the IL-6 like ligand Upd in the niche. Highlighting the potential conservation of processes driving age-related stem cell dysfunction, the let-7 microRNA has been implicated in stem cell self-renewal and differentiation in vertebrates, and deregulation of IL-6 expression by inhibition of let-7 promotes cell transformation into cancer stem cells in a breast cancer paradigm (Iliopoulos et al. 2009; Melton et al. 2010).

The influence of the local and systemic environment on somatic SC function has been explored extensively in mice. Studies using heterochronic parabiosis and assessing the regenerative capacity of satellite cells (muscle stem cells) suggest that changes in the exposure to growth and differentiation factors, including Wnt ligands, play a critical role in age-related stem cell dysfunction (Brack et al. 2007, 2008; Conboy et al. 2005; Conboy and Rando 2005; Jones and Rando 2011; Wagers and Conboy 2005).

A recent study further shows the importance of niche-derived factors for long-term maintenance of intestinal stem cells in mice and for the effects of nutritional status on stem cell maintenance: Paneth cells express the ligands Wnt3, Wnt11, and EGF to promote stem cell function in vitro and in vivo and can be considered “niche” cells for these SCs (Sato et al. 2011). Nutrient-responsive Tor signaling in Paneth cells influences their ability to promote SC maintenance, most likely by regulating the expression of bone stromal antigen 1 (Bst1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (Yilmaz et al. 2012).

While it is clear that improved regenerative capacity of stem cells promotes tissue health, the effects of stem cell function on overall lifespan of the organism have only recently begun to be understood. Studies in worms and flies have uncovered significant effects of germline stem cells on lifespan, primarily through endocrine effects on metabolism. But also somatic stem cell function in the fly intestine has recently been shown to affect lifespan, primarily by influencing the integrity of this critical tissue (Biteau et al. 2010; Rera et al. 2011, 2012). Strikingly, these studies revealed that stem cell activity has to be maintained within a critical window to improve tissue function and extend lifespan, highlighting the delicate balance between maintaining regenerative capacity and promoting dysplasia or cancer when stem cell proliferation is enhanced. Interestingly, IIS activity influences ISC function, suggesting that the lifespan effects of modulating IIS activity are mediated, at least in part, by its effects on ISC maintenance and activity. Similar effects may be conserved in vertebrates: Similar to flies, where dysplasia in the intestine is triggered by hyper-activation of IIS (Biteau et al. 2010), loss of FoxO negatively impacts NSC and HSC behavior in mammals (Renault et al. 2009; Tothova and Gilliland 2007; Tothova et al. 2007). It is likely that an optimal level of IIS is achieved during DR and contributes to SC maintenance (Mair et al. 2010).

The relationship between stem cell deregulation and tumor formation suggests that modulating somatic stem cell function in vertebrates should have significant effects on lifespan (Radtke and Clevers 2005). In the intestinal epithelium of mice, for example, intestinal stem cell proliferation and intestinal cancer have been linked: stress signaling can induce cell proliferation in the intestinal crypt and increases tumor incidence and growth in an inflammation-induced colon cancer model (Sancho et al. 2009). The precise role of stem cell-specific stress signaling in the development of tumors remains unclear, however, and the detailed analysis of stem cell activity in the Drosophila

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