Elucidating intra- and inter- individual variability in proteostasis network capacity during aging

Proteome integrity is maintained by a cellular network that consists of interconnected systems governing protein synthesis, folding, transport, and degradation. It comprises constitutive and inducible machineries that continuously work to promote protein homeostasis (proteostasis) and prevent off-pathway events that lead to the formation of damaged, misfolded, or aggregated species. The functionality of the proteostasis network declines during aging and, as a result, cells progressively lose the capacity to buffer against damage to the proteome and accumulate non-native protein conformations. Reversing this process holds promise for prolonging cellular health and treating age-related disease, however, the sequence of events, the molecules involved, and the underlying mechanisms are at present largely unknown. In multicellular organisms, the proteostasis network is tailored to the specific proteomes expressed in different cell types and tissues. The existence of such sub-networks and tissue-specific circuitries of regulatory pathways strongly suggests that local fluctuations in proteostasis network functionality could have a profound influence on organismal decline and disease susceptibility in aging. Here, we propose to uncover spatio-temporal dynamics of the proteostasis network in different tissues in stress and aging, and to establish molecular signatures of optimal network capacity that promote a long and healthy life. To address this, we will make use of nematode Caenorhabditis elegans which is ideal for this purpose due to its small size, short lifespan, transparency, and ease of genetic manipulation. The proposed work may help to discover biomarkers of human aging, and could also reveal new strategies to treat or prevent age-related disease.