, 2004, Nijnik et al., 2007 and Rossi et al., 2007). HSCs and primitive hematopoietic progenitors accumulate DNA lesions during aging, marked by γH2AX foci (Figure 2D) (Rossi et al., 2007). DNA damage may accumulate in HSCs because quiescent HSCs have enhanced survival mechanisms compared to differentiated progenitors and rely on error-prone nonhomologous end joining to repair DNA double-strand breaks BMS354825 (Mohrin et al., 2010). The reliance upon nonhomologous end joining to repair DNA double-strand breaks is also observed in epidermal stem cells (Sotiropoulou et al., 2010), but not in all stem cells (Blanpain et al., 2011). Stem cells thus share mechanisms to suppress the

accumulation of DNA damage. Although experimental elimination of DNA repair mechanisms leads to a premature depletion of stem cells, an open question is the extent to which DNA damage in stem cells affects the properties of these cells during physiological aging. Systemic environmental and metabolic changes also contribute to the aging of stem cells (Figure 2D). Aging reduces the selleck compound regenerative capacity of muscle satellite cells through increases in the levels of Wnt and TGF-β and a decrease in the expression of Notch ligands (Brack et al., 2007, Carlson et al., 2008, Conboy et al., 2003, Conboy et al., 2005 and Liu et al., 2007). Declines in mitochondrial

function are also observed during aging (Balaban et al., about 2005 and Chan, 2006) and can be precipitated by premature declines in telomere length as a consequence of telomerase deficiency (Sahin et al., 2011). Given that defects in mitochondrial function can yield phenotypes that resemble premature aging (Balaban et al., 2005 and Chan, 2006), these results suggest that defects in energy metabolism are one mediator of the effects of telomere attrition on aging. Telomere maintenance is also critical for chromosome stability and stem cell maintenance. Stem cells express telomerase to attenuate the decline in telomere length with age or upon tissue regeneration (Morrison et al.,

1996 and Vaziri et al., 1994). Telomerase deficiency leads to reduced stem cell self-renewal, stem cell depletion, and defects in the regeneration of proliferative tissues (Allsopp et al., 2003, Ferrón et al., 2004, Jaskelioff et al., 2011 and Lee et al., 1998). In telomerase-deficient mice, these defects are only observed beginning in the third generation after loss of telomeres or upon serial transplantation of HSCs; however, inbred mice have much longer telomeres and shorter life spans than humans. It therefore remains uncertain whether telomere length is limiting for stem cell function or tissue regeneration in the context of normal human aging. Surprisingly, reactivation of telomerase can elongate telomeres, rescuing epithelial stem cell function (Flores et al.