Stochastic and Age‐Dependent Proteostasis Decline Underlies Heterogeneity in Heat‐Shock Response Dynamics

Significant non-genetic stochastic factors affect aging, causing lifespan differences among individuals, even those sharing the same genetic and environmental background. In Caenorhabditis elegans, in heat-shock response (HSR) are predictive of lifespan. However, contributing to heterogeneity HSR still not fully elucidated. Here, authors characterized dynamics isogenic C. elegans expressing GFP reporter for hsp-16.2 identifying key contributors heterogeneity. Specifically, microfluidic devices that enable cross-sectional longitudinal measurements at different scales developed: populations, within embryos. The adapted a mathematical model single identified parameters associated with proteostasis—maintenance protein homeostasis—more specifically, turnover, as major drivers dynamics. It is verified individuals enhanced proteostasis fidelity early adulthood live longer. model-based comparative analysis turnover day-1 day-2 adult revealed stochastic-onset age-related decline increases capacity. Finally, embryos showed higher capacity than young adults established transgenerational contribution depends on maternal age.