E-mail: JCampisi@ lbl. gov www. impactaging. com AGING, July 2010, Vol. 2. No 7 www. impactaging. com 377 AGING, July2010, Vol. 2 No. 7 determinant, it might reduce IIS. So, what is the status of IIS in mice with elevated p53 activity? Inconsistently, higher levels of circulating IGF-1 and tissue-associated IIS are present in both a short-[9] and long-lived [17] transgenic mouse with elevated p53 activity. Moreover, a second short-lived hyper-p53 mouse model showed reduced IIS, at least in the mammary gland [18]. Further, IGFBP-3, a secreted IGF-1 binding protein that inhibits IGF-1 signaling, is a classic target of p53 transactivation activity [19]. Clearly, whether and to what extent the effects of p53 on aging and longevity are mediated by IIS must be determined in each of the mouse models, taking into account the multiple ways in which IIS activity can be modulated.

A second potentially important p53 target is the senescence-associated secretory phenotype (SASP). As discussed above, p53 is an important regulator of cellular senescence [20], the essentially irreversible arrest of cell proliferation that occurs in response to potentially oncogenic stresses [21]. We recently showed that senescent cells secrete a plethora of biologically active molecules that can alter the systemic or local tissue milieu [22, 23]. Of particular significance, p53 restrained the SASP [22]. That is, compared to wild-type cells, cells that lacked p53 function secreted markedly higher levels of most of the SASP components.