It's all about balance: p53 and aging

suppressor influences lifespan in flies highlight the complexities inherent in modulating the activity of this potent and versatile transcriptional regulator. Promoting efficient regeneration while preventing cancer is critical for tissue homeostasis. Genes and processes that influence the balance between regenera-tion and cancer are thus likely to affect lifespan of metazoans. Supporting this view, the tumor suppressor p53 has been found to strongly influence aging in mice. Interestingly, the lifespan consequences of increasing or decreasing p53 activity in mice are complex [1-5]. It is no surprise that loss of p53 leads to increased cancer incidence, and thus shorter lifespan [2]. Yet increasing p53 activity can have pleiotropic consequences: such interventions generally prevent cancer, increasing lifespan in some cases, but can also cause accelerated aging in others [6-11]. The discrepancy between lifespan shortening and lifespan extending consequences of p53 gain-of-function conditions has been attributed to differences in regulation of the corresponding transgenes, and highlights the complex and dose-dependent effects that such a versatile regulator of cell proliferation, repair and death can have on health span and aging [2]. The exact reasons for the pleiotropic effects of p53 on aging, however, remain elusive. Aging studies in less complex model organisms might be expected to contribute important insights into this puzzle. New studies by the Tower and Helfand labs assess the consequences of modulating p53 activity for the lifespan of flies, and shed light on the complexities of p53 function in even such relatively simple organisms [12-15]. In an exhaustive analysis of the lifespan effects of p53 gain-and loss-of-function conditions, Waskar and colleagues find strikingly pleiotropic effects resulting from ubiquitous increase or decrease of wild type p53 function [12]. Importantly, the consequences of modulating p53 are found to be tissue-, stage-and sex-specific: ubiquitous over-expression of p53 in adults shortens lifespan in females but slightly increases lifespan in males [12], whereas neuronal expression of the same construct extends lifespan in females and decreases life span in males [13]. Over-expressing p53 in larval stages, on the other hand, is sufficient to extend adult lifespan in both sexes, but in a dose-dependent manner, where strong expression is deleterious for lifespan, while moderate to weak over-expression increases lifespan [12]. The authors further examine the lifespan of a battery of mutants in which the endogenous p53 gene is disrupted, and find robust increase of lifespan in females, but context-dependent effects in males [12]. Confirming earlier studies by the Helfand …