Overexpression of the DNA Repair Gene PRP19 is Shown to Modestly Extend Life in Female Flies
Genetic and other interventions that extend life span in only one gender of a laboratory species seem not to involve large effects, judging from those discovered to date. In this example, a gene known to be involved in DNA repair is found to decline with age in a more pronounced way in female flies. In turn, enhanced levels of the protein produced from this gene extend only female median life span in flies, by something like 10-25% according to the data presented in this paper. This isn't all that large an effect in the grand scheme of things; short-lived species have a far greater plasticity of life span in response to environment and genetic alterations, and researchers have produced far larger gains than this in flies using methods that are known to produce very little effect on life expectancy in humans.
This is the way things tend to work: members of longer lived species have life spans that are relatively unresponsive to environmental influences and single gene alterations that produce quite large changes in the life spans of flies, worms, and mice. These interventions are are all based on producing altered states of metabolism capable of slowing down the pace of aging in some way, however. They are a slowing of the accumulation of damage, without any attempt to repair that damage. There is as yet no data on how the other approach to the problem, actually repairing that cell and tissue damage in order to produce rejuvenation, will differ between short-lived and long-lived species. This will arrive in the years ahead; there is life span data now for senescent cell clearance in mice, and something like a five year study of efficient senolytic treatments in old humans should provide enough data to estimate the effects on human life span.
According to the disposability hypothesis of aging, functional decline results from the accumulation of stochastic damage, for example, due to somatic mutations, and is counteracted by investment into somatic maintenance and repair. Accumulation of DNA damage due to decreased repair can accelerate aging, as is observed in progeroid syndromes in humans and mouse models. Similarly, increased exposure to DNA damaging agents, for instance during chemotherapy, can lead to a phenotype of acquired premature progeroid syndrome. Accelerated accumulation of DNA damage and premature aging phenotypes are typically well correlated, but whether improved DNA damage repair (DDR) can extend organismal life span remains largely unclear.
In the fruit fly (Drosophila melanogaster), a well-studied model for dissecting the mechanisms of aging, spontaneous somatic mutations accumulate with age, and defective DNA repair is associated with reduced life span. However, overexpression of DNA repair factors in the fly seems to have highly variable, sometimes contradictory effects that depend on sex, developmental stage, and the tissue of intervention. For instance, PARP-1 modifies histones, transcription factors and repair enzymes in response to DNA breaks, and its endogenous activity is well correlated with life span in several mammalian species. In Drosophila, overexpression of PARP-1 prolongs life span in both sexes, yet only when restricted to the adult nervous system. Similarly, overexpression of Gadd45, a regulator of DNA repair and cellular stress responses, in the nervous system increases fly life span but ubiquitous expression is lethal. Thus DNA repair factors can affect Drosophila life span and stress resistance either positively or negatively, depending on the sex and on whether overexpression is ubiquitous or limited to the nervous system. Interestingly, all repair factors that were expressed throughout the adult fly body were found to shorten life span.
Here, we examine the role of adult-specific overexpression of the DNA repair factor Prp19 in affecting life span, stress resistance, and DNA damage in Drosophila. Biochemically, PRP19 interacts with multiple players in the DNA repair pathways. Apart from its role in the DNA damage response, an intriguing aspect of PRP19 function is its concomitant and essential involvement in co-transcriptional splicing, where the PRP19 complex regulates the rearrangement of the spliceosome.
In support of a role for PRP19 in the aging process, it has previously been shown that decreased levels of PRP19 accelerate the induction of cellular senescence in mouse embryonic fibroblasts, reduce self renewal of mouse hematopoietic stem cells, increase UV-A-induced skin aging in mice and decrease differentiation of human adipose-derived stromal cells. Conversely, increased levels of PRP19 extend the replicative potential and total life span of cultured human endothelial cells. However, the role of PRP19 in organismal life span is unknown. Here, we show that ubiquitous overexpression of the Drosophila ortholog of PRP19, dPrp19, reduces DNA damage and extends organismal life span of adult female flies. Our results suggest that PRP19 plays an evolutionarily conserved role in the DNA damage response, aging, and stress resistance.