Genetically and chronologically identical animals show surprisingly large variations in lifespan and random patterns of aging-related pathologies. This apparent randomness, a phenomenon known as stochasticity of aging, is thought to either result from stochastic accumulation of damage over the entire lifespan and/or from developmentally set regulatory signals, which affect lifespan early in life. Based on previous results from our lab, we will now test the hypothesis that large fluctuations in peroxide levels observed during the larval development of C. elegans trigger a chain of redox-controlled events that individualize lifespan, thereby contributing to the observed lifespan variability. Reactive oxygen species, such as peroxide, have long been postulated to contribute to the age-associated physiological decline in organisms. More recent studies, however, also revealed regulatory roles of reactive oxygen species as intracellular signaling molecules, positively affecting metabolism, growth and development. We have generated transgenic C. elegans, which express ratiometric peroxide sensor proteins. These sensor proteins allow us to determine and monitor in real- time and in live organisms the relative amount of endogenous peroxide produced at any defined point in their life. We have discovered that C. elegans accumulate high levels of peroxide early in life, that the ability to restore a reducing environmen upon entering adulthood appears to predict longevity, and that individuals with lower than average developmental peroxide levels show an extended lifespan. We will now use these peroxide sensor-expressing worms to correlate endogenous peroxide levels in individual C. elegans with their age-related phenotypes, stress resistance and lifespan. We will sort C. elegans according to their ROS levels in early development, investigate the gene expression profile associated with variable early-life peroxide levels and apply targeted redox-proteomic techniques to identify physiologically important redox sensitive target proteins. Our studies have therefore the clear potential to reveal when individuality arises and uncover the mechanism(s) by which developmentally produced reactive oxygen species determine lifespan.
Our recent discovery that transient accumulation of reactive oxygen species during development correlates with lifespan suggests that lifespan is affected by very early events in life. We will now reveal the pathways that are affected by early oxidant production, and the mechanisms by which they affect lifespan. These studies will reveal not only potential targets but should also indicate the most appropriate time window for the successful application of genetic and pharmacological interventions.
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