Complicating the role of p53 in aging

Recently, we described a p53 mutant mouse model (p53+/m mouse model) that presented a paradox, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan (Tyner et al ., 2002). The p53+/m mice expressed a truncated p53 transcript attached to a leader sequence and showed a moderate increase in p53 activity. Based on this data we hypothesized that enhanced levels of p53 caused the early aging and cancer resistance phenotypes. This hypothesis was attractive as it indirectly implied a ‘fine tuning’ mechanism of tumor suppressor gene expression to maintain homeostasis at the organismal level (Campisi, 2002; Kirkwood, 2002). Our results also lent support to the evolutionary theory of antagonistic pleiotropy that predicts the deleterious effects of tumor‐suppressor genes later in life (Williams, 1957). These observations notwithstanding, the p53+/m mouse model presented a caveat, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan. Studies in model organisms have shown that enhanced resistance to oxidative stress correlates with increased longevity (Johnson et al ., 2002; Murakami et al ., 2003). The tumor suppressor functions of p53 overwhelmingly categorize it as a longevity assurance gene and suggest a synergistic effect on lifespan via tumor free survival of the organism. We show that there are 24 genes deleted in the p53+/m mouse model, complicating the role of p53 in aging and raising the possibility that the phenotypes while resembling ‘premature aging‐like’ symptoms, may not be related to the physiological changes seen during normal aging processes.