Mammalian aging is associated with reduced tissue regeneration increased degenerative disease and cancer. effects on stem cells. Introduction Damage accumulates in biological macromolecules during aging impairing cellular processes tissue homeostasis and organ function. This contributes to the onset of age-related diseases including cognitive (Yankner et al. 2008 neoplastic (Hoeijmakers 2009 immunologic (Dorshkind et al. 2009 and metabolic (Wallace 2005 disorders. Age-related morbidity is determined partly by changes in nondividing differentiated cells such as neurons (Lu et al. 2004 and partly by changes in mitotic cells including stem cells restricted progenitors and differentiated cells (Sharpless and DePinho 2007 Stem cells persist throughout life in numerous mammalian tissues replacing cells lost to homeostatic turnover injury and disease. However stem cell function declines with age in a number of tissues including the blood (Morrison et al. 1996 de Haan et al. 1997 Chen et al. 2000 forebrain (Kuhn et al. 1996 Maslov et al. 2004 Molofsky et AZD5363 al. 2006 skeletal muscle (Conboy et al. 2003 2005 and skin (Nishimura et al. 2005 (Table 1). These declines in stem cell function may contribute to degeneration and dysfunction in aging regenerative tissues (Sharpless and DePinho 2007 Thus age-related changes in the function of stem cells and other progenitors may contribute to some diseases of aging particularly in regenerative tissues even while other diseases of aging may not be influenced by stem cell aging at all. Table 1 Summary of Age-Related Changes in Various Mammalian Stem Cell Populations It is unknown whether stem cell aging influences mammalian life span. However in genetic changes that improve homeostasis in the intestinal epithelium by blocking stem cell overproliferation and differentiation defects during aging do extend life span (Biteau et al. 2010 This raises the possibility that some age-related changes in mammalian stem cells promote homeostasis in aging tissues despite declines in stem cell function. It is important to emphasize that stem AZD5363 cells are not the only mitotic cells that persist throughout life and whose aging might influence age-related diseases. Like stem cells some restricted progenitors and differentiated cells are also perpetuated throughout life by intermittent self-renewing divisions. Such cells include pancreatic β cells and memory B and T cells. During aging declines in the number or function of pancreatic β cells (Teta et al. 2005 and memory T cells (Liu et al. 2011 contribute to the development of type 2 diabetes (Butler et al. 2003 and reduced immune function (Dorshkind et al. 2009 There is at least some overlap in self-renewal mechanisms AZD5363 between these differentiated cells and stem cells (Luckey et al. 2006 This suggests that some of the mechanisms that regulate stem cell aging may also regulate the aging of mitotic differentiated cells and both classes of progenitors may contribute to age-related morbidity. Stem cells must change their properties throughout life to match the changing growth and regeneration demands of tissues. Stem cells divide rapidly during fetal development to support rapid growth. By young adulthood growth has slowed or ceased in mammalian tissues and most stem cells are quiescent most of the time intermittently dividing to maintain tissue homeostasis. In old adults stem cells increase gate-keeping tumor suppressor expression. This may reduce the incidence of AZD5363 cancer in aging tissues but also reduces regenerative capacity (Janzen AZD5363 et al. 2006 Krishnamurthy et al. 2006 Molofsky et al. 2006 These changes in stem cells likely reflect regulation by heterochronic genes-genes whose expression changes over time in a way that causes temporal changes in stem cell function (Nishino et al. 2008 Keratin 18 (phospho-Ser33) antibody Toledano et al. 2012 Heterochronic AZD5363 genes were originally identified as regulating the timing of developmental transitions in (Ambros and Horvitz 1984 This raises the question of whether the increase in tumor suppressor expression and the temporal changes in stem cell function in aging mammalian tissues are partly developmentally programmed. Mitochondrial activity tissue growth and metabolic rates during development can also influence life span and the rates of cellular aging.