Female (left) and male (right) flies lacking (black lines) neuronal p53 live significantly longer.

HELFAND/ELSEVIER

New findings from Johannes Bauer, Stephen Helfand (Brown University, Providence, RI), and colleagues show that flies lacking neuronal p53 activity live longer.

Hyperactivation of p53, which kills DNA-damaged cells, reduces tumor incidence in mammals but also shortens their life span. These earlier findings suggested that reducing p53 activity might increase life span. Helfand's group found that this did not pan out for flies lacking all p53—they died earlier than normal, probably because of the requirement for p53 in developmental apoptosis. But if the authors blocked p53 activity only in neurons, the flies lived longer healthy lives and were also more resistant to DNA-damaging agents.

Loss of p53 only in the fat body or muscle tissue did not extend life span. “Maybe,” says Helfand, “the nervous system is the weak link. If it goes [via p53-mediated apoptosis, for example], the rest of the body goes.” The group does not yet know whether neurons survive longer in the p53 mutants due to less apoptosis, but they provide evidence that traditional caspase-dependent apoptosis is probably not affected. The involvement of caspase-independent apoptosis has not been ruled out.

Another possibility is that the neuronal tinkering causes systemic effects, perhaps via the neuroendocrine system. Indeed, calorie restriction also increases life span in flies, and p53 inhibition seems to lie in this pathway, since both together did not have an additive effect. Calorie restriction has unwanted side effects, however, including reduced fertility and activity levels. Since p53-inhibited flies did not suffer from these problems, the authors have shown that the downstream effects of calorie restriction can be teased apart.The p53-inhibited flies might also be expected to have many tumors, but since adult flies are primarily post-mitotic, they are not cancer prone. If only mature human neurons, which are also post-mitotic, were smart enough to rid themselves of p53, perhaps we could all live longer. Says the cautious Helfand, “a judicious decrease in p53 activity might be advantageous.”

Reference:

Bauer, J.H., et al.
2005
.
Curr. Biol.
15
:
2063
–2068.