**3. The evidence for stem cell aging**

A growing body of evidence shows that the capacity of stem cells to maintain tissue homeostasis declines with age, and suggests that this decline may account for many agerelated phenotypes and diseases (Kirkwood and Austad, 2000). Significantly, engraftment of HSCs are capable of serial passages through a succession of mouse recipients, outliving the donor mouse (Ross et al., 1982; Siminovitch et al., 1964), though it is not possible to exceed up to five successful passages, and the recipients do not restore the hematopoietic system to the normal state (Gordon and Blackett, 1998). On the other hand, telomere length in blood cells of the transplanted recipient are 1-2 kb shorter than those in the donor, when evaluated several years following transplantation (Allsopp et al., 2003), which indicates that the level of telomerase is insufficient to prevent progressive telomere shortening in HSC. On the other hand, immunophenotypic characterization of hematopoietic stem- and progenitor-cell subsets diverges from function in old animals. The engraftment efficiency of immunophenotypically selected long-term HSCs from old mice approximately is threefold lower than that of the equivalent population from young mice (Morrison et al., 1997; Yilmaz et al., 2006). Also, age-related changes in stem-cell function include myeloid-biased differentiation and decreased homing ability (Liang et al., 2005). In conclusion, it has been extensively proved that the properties of HSCs change in several ways as they age, but still is poorly known which are the changes in the intrinsic and extrinsic factors involved that regulate the self-renewal and multilineage differentiation capacities of these regenerative cells (Huang et al., 2007).

Although the stem- and progenitor-cell proliferation guarantees tissue repair, and thereby regeneration, it can also develop hyperproliferative diseases, like cancer, risk that is moderated by tumor-suppressors mechanisms. For example, while the increased expression of tumor suppressors with age (p53, p16INK4a) inhibits the development of cancer (inducing apoptosis or/and senescence) (Krishnamurthy et al., 2004; Ressler et al., 2006), over time it may have a negative effect on stem cell functionality, reducing capacity for self-renewal or differentiation, and ultimately leading to aging phenotypes (Beausejour and Campisi, 2006; Rodier et al., 2007). Thus, it is thought that many of the same mechanisms that contribute to cellular aging also act as suppressors of neoplastic growth (Campisi, 2005) (Figure 2). We will therefore need a better understanding of age-related changes in stem cell function by altering genetically the expression of tumor suppressors, which may improve effective longevity-promoting therapies.
