Roles of hydrogen peroxide signaling and peroxiredoxin in aging and age-related decline in proteostasis

Research Project, 2021 – 2024

Caloric restriction (CR) slows down aging in most organisms. We identified key roles for peroxiredoxins, conserved H2O2 scavengers, signaling enzymes and gerontogenes, in CR life-span extension. Peroxiredoxins also sustain key roles in suppressing age-related diseases eg cancer. In contrast to what would be expected from current literature, we show that peroxiredoxin does not affect age-related H2O2 levels. In addition, through unique microfluidic monitoring we show that low levels of H2O2 actually extend life-span in a manner dependent on peroxiredoxin. A key role for peroxiredoxin in managing age-induced protein aggregates that we discovered involves a functional switch into a molecular chaperone by H2O2. However, the low levels of H2O2 needed for peroxiredoxin-mediated life-span extension do not induce aggregates. In addition, peroxiredoxins in both yeast and worms control longevity primarily through a distinct mechanism, cysteine-dependent signaling. Through state-of-the-art methods to study protein biogenesis (eg non-invasive ribosome profiling) we found roles for low levels of H2O2 and peroxiredoxin in inhibiting translation as well as extensive functional interaction with specific tRNA modification enzymes. Using a unique combination of genetic, cell biological and biochemical methods I aim to clarify mechanisms by which peroxiredoxins control age-related protein biogenesis. This may increase the comprehension of aging and age-related dysfunction in all organisms.