In 1957, George C. Williams published the antagonistic pleiotropy hypothesis of aging, which was later mathematically supported by Brian Charlesworth. This theory predicts that some genes mediate beneficial effects early in life when natural selection is strong, but are detrimental late in life when natural selection is weak. Natural selection favors these beneficial effects on fitness early in life at the expense of enriching harmful effects late in life; hence leading to the evolution of aging.We screened 800 chromatin regulators and transcription factors in order to identify novel genes that exhibit antagonistic pleiotropy. Genes were inactivated in the post-reproductive phase by the use of RNAi from day nine of adulthood onwards. The screen led to the identification of several genes that significantly extend lifespan upon late-life inactivation, while shortening lifespan when inactivated early in life.The forkhead box (FOX) A transcription factor
pha-4 represents a top candidate of our screen. Late-life inactivation of
pha-4 resulted in a strong lifespan extension of 33%. In contrast, inactivation of
pha-4 from the first day of adulthood reduced C.elegans lifespan. This is of particular interest, as
pha-4 has been shown to mediate diet-restriction and germline-less induced longevity. Our findings indicate that, depending on the age,
pha-4 is either needed for normal lifespan and longevity or exhibits detrimental effects. We are currently aiming to identify and to characterize the biological processes underlying the observed negative effects of
pha-4 late in life.Generally, genes that behave according to the antagonistic pleiotropy hypothesis may represent promising drug targets to fight age-associated diseases. Our findings emphasize that timing needs to be addressed to fully understand how genes and gene networks impinge on the aging process.