, 2010). Deletion of HIF1α from neural stem cells depletes neurogenic progenitors in the subgranular zone of the dentate gyrus ( Mazumdar et al., 2010). HIF1α deletion also leads to a progressive decline in HSC function during bone marrow transplantation or aging ( Takubo et al., 2010). Deletion of von Hippel Lindau, which

encodes a ubiquitin ligase involved in the degradation of HIF1α, also leads to HSC defects, even though this increases HIF1α levels ( Takubo et al., 2010). This suggests that HIF1α levels must be tightly regulated. Stem cells likely depend on a variety of mechanisms to maintain homeostasis in the face of hypoxia or changes in oxygen tension. Caloric restriction increases longevity Selleck PF-06463922 and reduces age-related disease in an evolutionarily conserved manner Smad inhibitor (Bishop and Guarente, 2007), partly by influencing the function of stem and progenitor cells. Caloric restriction in rodents enhances neurogenesis in the dentate gyrus by promoting the survival of newborn neurons and astrocytes (Bondolfi et al., 2004 and Lee et al., 2002) and potentially by increasing

progenitor proliferation (Kumar et al., 2009). In the hematopoietic system, short-lived mouse strains exhibit a decline in HSC frequency and function during aging, through whereas long-lived mouse strains do not (de Haan et al., 1997). Caloric restriction attenuates the age-related decline in HSC frequency in at least one short-lived mouse strain (Ertl et al., 2008). Feeding adult Drosophila a low-nutrient

diet alleviates the age-related reduction in the number and proliferation of male germline stem cells ( Mair et al., 2010). Caloric restriction can therefore attenuate the reduction in stem cell function during aging in multiple tissues and species. Nutritional changes can alter the expression of systemic factors that regulate stem cells (Figure 4). Protein starvation in Drosophila leads to a reversible loss of male germline stem cells and intestinal stem cells due to reduced expression of insulin-like peptides, possibly by insulin-producing cells in the brain ( McLeod et al., 2010). Expression of constitutively active insulin receptor is able to suppress the starvation-induced loss of germline stem cells, suggesting that insulin directly regulates germline stem cell maintenance. This allows stem cell function in multiple tissues to be modulated by changes in nutritional status. Changes in the nutritional status of the organism can also indirectly affect stem cell function by modulating the environment (Figure 4).