RPN-6 determines C. elegans longevity under proteotoxic stress conditions

Abstract

Organisms that protect their germ-cell lineages from damage often do so at considerable cost: limited metabolic resources become partitioned away from maintenance of the soma, leaving the ageing somatic tissues to navigate survival amid an environment containing damaged and poorly functioning proteins. Historically, experimental paradigms that limit reproductive investment result in lifespan extension. We proposed that germline-deficient animals might exhibit heightened protection from proteotoxic stressors in somatic tissues. We find that the forced re-investment of resources from the germ line to the soma in Caenorhabditis elegans results in elevated somatic proteasome activity, clearance of damaged proteins and increased longevity. This activity is associated with increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders.

Quantifying compartment‐associated variations of protein abundance in proteomics data

“…The CNV approach highlighted an age‐dependent decrease in members of the cytosolic ribosome and an increase in the proteasome, relative to their respective cell compartment (Mann–Whitney test P  <   0.01; Fig EV5 and Dataset EV6). Indeed, the same age‐related variations were observed by the authors of the original publication, and they are corroborated by other independent studies (Hsu et al , 2003; Golden & Melov, 2004; Vilchez et al , 2012; Kirstein‐miles et al , 2013). …”

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

“…One such conserved pathway shown to play a role in aging is maintaining an appropriate balance between protein synthesis and protein degradation pathways in order to maintain a normal proteome, a process known as protein homeostasis (Powers & Balch, 2013; Labbadia & Morimoto, 2015). Maintaining protein homeostasis via upregulation of protein quality control systems, such as the ubiquitin‐proteasome system (UPS), has been shown to extend lifespan from yeast to rodents (Mehta et al ., 2009; Kruegel et al ., 2011; Rodriguez et al ., 2012; Vilchez et al ., 2012; Kaeberlein, 2013; Kevei & Hoppe, 2014). Inducing protein quality control systems is thought to extend lifespan by counteracting the age‐associated accumulation of damaged and aggregated proteins (Kevei & Hoppe, 2014); however, this age‐associated decline in proteostasis may be more finely regulated than currently appreciated (Labbadia & Morimoto, 2014).…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Fibroblasts treated with proteasome inhibitors have a shortened replicative lifespan and a senescent-like phenotype 52 . Knockdown of 19S and 20S subunits during adulthood shortens lifespan in Caenohabditis elegans 53,54 . Strikingly, a transgenic mouse with reduced chymotrypsin-like activity by replacement of the b5 subunit with b5t exhibits a shortened lifespan, premature agerelated phenotypes and aggravation of age-related metabolic disorders 55 .…”

“…Enhancement of the proteasome machinery has been proven beneficial in HD models. Increased levels of Rpn6 in C. elegans or Rpn11 in D. melanogaster reduce toxic aggregates and suppress expanded PolyQ-induced neurodegeneration in HD models 54,141 . Increased expression of PA28g improves cell survival in a cellular model of HD 152 .…”