Heterogeneity in heat shock response dynamics caused by translation fidelity decline and proteostasis collapse

Abstract

Genetics, environment, and stochasticity influence the rate of ageing in living organisms. Individual Caenorhabditis elegans that are genetically identical and cultured in the same environment have different lifespans, suggesting a significant role of stochasticity in ageing. We have developed a novel microfluidic methodology to measure heat-shock response as a surrogate marker for heterogeneity associated with lifespan and have quantified the heatshock response of C. elegans at the population, single individual, and tissue levels. We have further mathematically modelled our data to identify the major drivers determining such heterogeneity. This approach demonstrates that protein translation and degradation rate constants explain the individuality of the heat-shock time-course dynamic. We observed a decline of protein turnover capacity in early adulthood, co-incidentally occurring as the predicted proteostasis collapse. We identified a decline of intestinal response as the tissue that underlies the individual heterogeneity. Additionally, we verified that individuals with enhanced translation fidelity in early adulthood live longer. Altogether, our results reveal that the stochastic onset of proteostasis collapse of somatic tissues during early adulthood reflects individual protein translation capacity underlying heterogenic ageing of isogenic C. elegans.

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

“…We observed tissue-specific gene ontology (GO) enrichment of the best longevity correlated genes (Figure 3 and Supplementary Table 3). These include several processes known to be vital to promote healthy aging, such as immune responses, neuronal signaling, heat shock proteins, epigenetic reprogramming, extracellular matrix, and mitochondrial energy metabolism (Figure 3; Greer et al, 2011;Houtkooper et al, 2013;López-Otín et al, 2013;Ewald et al, 2015;Denzel et al, 2019;Ewald, 2019;Hess et al, 2019;Vertti-Quintero et al, 2019;Gallotta et al, 2020). For instance, the adrenal gland showed enrichment for immune responses, whereas in the liver, oxidative phosphorylation and mitochondrial components were enriched (Figure 3).…”