Reactive oxygen species as early-in-life modulators of lifespan

Why do we age and why do some of us stay healthy longer than others? Thanks to the development of shorter-lived aging model organisms, much has been learnt about the processes that contribute to our inevitable demise, and the tight connection between these processes and the development of age-associated diseases, including Alzheimer’s and Parkinson’s Disease. Our recent genetic and biochemical studies in C. elegans have revealed a novel longevity paradigm, triggered by early-in-life oxidative stress and mediated by the redox sensitivity of the histone 3 lysine 4 trimethylating (H3K4me3) COMPASS complex. We discovered that modulation of the H3K4me3 landscape in C. elegans led to the activation of at least two highly conserved longevity factors, heat shock factor-1 (HSF-1) and the starvation response regulator HLH-30 (TFEB in mammals), both of which essential for the lifespan-extending effects. Mechanistic follow-up studies revealed that the observed increase in lifespan depends on a non-canonical role of HSF-1 in modulating lipid homeostasis and fatty acid oxidation and involves a hitherto unknown regulatory interaction between HSF-1 and HLH-30. We found this interplay between transient ROS accumulation, changes in H3K4me3 levels and transcription factor activation to be conserved from C. elegans to mammalian cells and, most recently, to select tissues of post-weaned mice, which were exposed to oxidants for the first three weeks of their life. Based on these exciting data, and recent reports that in a range of different model organisms, including mice, early-in-life time windows exist in which lifespan can be set, we now propose that mild oxidative stress, when experienced at the right time in life, triggers a hormetic response that manifests itself through stable changes in the epigenetic landscape, gene expression and physiology. In this proposal, we will take a multipronged approach to determine the molecular mechanism by which ROS-mediated changes in developmental H3K4me3 levels promote lifespan extension in C. elegans (Aim 1), explore the long-term epigenetic and transcriptional changes that are elicited by short-term oxidative stress treatment in C. elegans as well as mitotic and postmitotic mammalian cells (Aim 2), and evaluate the molecular and physiological consequences of early-in-life oxidative stress treatment in mice (Aim 3). These studies have the clear potential to provide us with previously unknown mechanistic insights into how ROS-sensitive epigenetic circuits transform transient events in early life into long-lasting, and potentially universal, health- and lifespan extending processes. Our studies in C. elegans and cell culture models will furthermore serve us to guide parallel explorations in mice and provide new leads useful in the search for drugs that slow aging in mammals.