Neuronal Expression of p53 Dominant-Negative Proteins in Adult Drosophila melanogaster Extends Life Span

Abstract

Hyperactivation of p53 leads to a reduction in tumor formation and an unexpected shortening of life span in two different model systems . The decreased life span occurs with signs of accelerated aging, such as osteoporosis, reduction in body weight, atrophy of organs, decreased stress resistance, and depletion of hematopoietic stem cells. These observations suggest a role for p53 in the determination of life span and the speculation that decreasing p53 activity may result in positive effects on some aging phenotypes . In this report, we show that expression of dominant-negative versions of Drosophila melanogaster p53 in adult neurons extends life span and increases genotoxic stress resistance in the fly. Consistent with this, a naturally occurring allele with decreased p53 activity has been associated with extended survival in humans . Expression of the dominant-negative Drosophila melanogaster p53 constructs does not further increase the extended life span of flies that are calorie restricted, suggesting that a decrease in p53 activity may mediate a component of the calorie-restriction life span-extending pathway in flies.

Expression of dominant-negative Dmp53 in the adult fly brain inhibits insulin signaling

“…This lifespan extension is not additive to CR (12), suggesting that Dmp53 may be part of the CR pathway of lifespan extension. To understand more about the mechanisms by which neuronal reduction of Dmp53 extends lifespan, we examined the expression of DN-Dmp53 in subsets of neuronal cells.…”

“…We showed (12) that lifespan extension by pan-neuronal DNDmp53 expression is not additive with CR lifespan extension, suggesting that a decrease in neuronal Dmp53 activity may be part of the CR lifespan-extending pathway. We therefore tested whether lifespan extension by DN-Dmp53 expression only in IPCs may also be related to CR.…”

“…Interestingly, the lifespan-extending effects of downregulated IIS appear to be active in the fat body, Drosophila's major metabolic organ, because dFoxO or dPTEN can extend lifespan only when over-expressed in the fat body, but not in neurons (10). This is in contrast to what is seen with other regulators of Drosophila lifespan, like dSir2 (11) or dominantnegative (DN) Dmp53 (12), where lifespan is extended when over-expressed in neurons, but not in the fat body. The picture to date suggests that in flies lifespan is regulated by discreet, tissue-specific pathways.…”

“…However, it remains unclear how DN-Dmp53 expression extends lifespan. Inhibition of caspase-dependent apoptosis in the adult brain does not extend lifespan, and can therefore be ruled out as a mechanism for DN-Dmp53-dependent lifespan extension (12). Other effector pathways have thus to be explored that may explain the lifespan-extending effects of DN-Dmp53.…”

The effects of p53 on whole organism longevity are mediated by autophagy

“…In Drosophila, dominant-negative (DN) p53 can enhance life span if it is only expressed in the brain (but not in the fat body or muscle) 32 or even only in the insulin-producing brain cells (as opposed to dopaminergic or serotoninergic neurons), thus impairing the release of insulin-like peptides and interfering with PI3K activity in peripheral organs. 10 These results point to the possibility that p53 may (also) affect aging by endocrine signaling, a possibility that has not been investigated in mammals or nematodes thus far.…”