Linking Histone Modifications, HSF-1 activity and Lifespan

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One of the most fascinating questions in the aging field is: Why do some organisms live longer than others? That lifespan variations are not solely based on the genetic makeup or the environment becomes clear when one studies isogenic organisms, such as Caenorhabditis elegans. Even when carefully age-synchronized and cultivated under uniform environmental conditions, the lifespan of individuals within a population of C. elegans varies several-fold. What causes this lifespan variation and when is the clock set? Our previous work demonstrated that individuals of a synchronized C. elegans population show high inter-individual differences in their levels of endogenous reactive oxygen species (ROS) during early development. Sorting of larval worms according to their endogenous redox states (i.e., oxidized vs. reduced) followed by longitudinal physiological and cell-biological assays revealed that larval worms that are more oxidized have significantly increased stress resistance, a more reduced redox state during adulthood and a longer lifespan. We found that this increase in stress resistance and lifespan is due to the ROS-dependent transient inactivation of Set2, a conserved member of the COMPASS complex, the complex which is responsible for the trimethylation of H3K4 (i.e., H3K4me3) in eukaryotes. To our knowledge, these studies not only provide the first demonstration of a redox- regulated histone methylation event in biology, but are the first to give mechanistic insights into how early life events can increase longevity. We will now investigate the mechanisms by which a decrease in H3K4me3 levels during development leads to increased stress resistance and extended lifespan. Our proposed studies are guided by preliminary results, which demonstrate a hitherto unknown link between the global reduction in H3K4me3 marks, and the increase in the levels and activity of the heat shock factor HSF1, one of the most conserved longevity factors known. We will exploit genetic tools in C. elegans to directly monitor the effects of H3K4me3 depletion on HSF1 synthesis, stability and turnover, and deplete H3K4me3 levels at defined time points and in specific tissues to reveal when, how and in what tissues the individuality in lifespan arises. To determine where developmental ROS variations come from, we will follow up on exciting preliminary data suggesting that the redox states in developing C. elegans larvae (and hence their lifespan) are inversely related to the age and redox state of the mother. These studies are likely to shed new mechanistic insights into the Lansing Effect, a long recognized but so far mostly descriptive phenomenon that describes the negative relationship between the maternal age and the lifespan of the offspring. The results of these studies will provide fundamentally new insights into the underlying mechanisms that lead to early life redox variations, and the subsequent events that delay aging.