Dietary-Induced Signals That Activate the Gonadal Longevity Pathway during Development Regulate a Proteostasis Switch in Caenorhabditis elegans Adulthood

Abstract

Cell-non-autonomous signals dictate the functional state of cellular quality control systems, remodeling the ability of cells to cope with stress and maintain protein homeostasis (proteostasis). One highly regulated cell-non-autonomous switch controls proteostatic capacity in Caenorhabditis elegans adulthood. Signals from the reproductive system down-regulate cyto-protective pathways, unless countered by signals reporting on germline proliferation disruption. Here, we utilized dihomo-γ-linolenic acid (DGLA) that depletes the C. elegans germline to ask when cell-non-autonomous signals from the reproductive system determine somatic proteostasis and whether such regulation is reversible. We found that diet supplementation of DGLA resulted in the maintenance of somatic proteostasis after the onset of reproduction. DGLA-dependent proteostasis remodeling was only effective if animals were exposed to DGLA during larval development. A short exposure of 16 h during the second to fourth larval stages was sufficient and required to maintain somatic proteostasis in adulthood but not to extend lifespan. The reproductive system was required for DGLA-dependent remodeling of proteostasis in adulthood, likely via DGLA-dependent disruption of germline stem cells. However, arachidonic acid (AA), a somatic regulator of this pathway that does not require the reproductive system, presented similar regulatory timing. Finally, we showed that DGLA- and AA-supplementation led to activation of the gonadal longevity pathway but presented differential regulatory timing. Proteostasis and stress response regulators, including hsf-1 and daf-16, were only activated if exposed to DGLA and AA during development, while other gonadal longevity factors did not show this regulatory timing. We propose that C. elegans determines its proteostatic fate during development and is committed to either reproduction, and thus present restricted proteostasis, or survival, and thus present robust proteostasis. Given the critical role of proteostatic networks in the onset and progression of many aging-related diseases, such a choice could impact susceptibility to protein misfolding diseases later in life.

Dietary restriction and gonadal signaling differentially regulate post‐development quality control functions in Caenorhabditis elegans

“…By day 6 of adulthood, Q35 animal motility was strongly reduced (12 ± 9%), while 79 ± 7% the Q35; eat‐2 animals remained motile (Figure d). Q40n‐dependent decline in motility (Shemesh et al, ) was also abrogated by DR. By day 6 of adulthood, Q40n animals showed severely reduced motility (27% ± 4%). In contrast, Q40n ;eat‐2 animals, as well as 24 hr BD‐treated Q40n animals, remained completely motile (99 ± 1% and 90 ± 4%, respectively), similar to wt animals (90 ± 4%; Figure e).…”

“…Our observations indicate that DR and the gonadal longevity pathway enhanced quality control networks independently, at least in part. Indeed, the commitment to network remodeling by gonadal signaling occurs during larval development (Shemesh et al, ). At the same time, DR‐dependent network remodeling was induced by BD treatment post‐development and even late in adulthood.…”

“…RNA extraction from synchronized animals, cDNA synthesis, and quantitative real‐time PCR was performed as previously described (Shemesh et al, ). Samples were normalized (using the 2‐ΔΔCT method) to act‐1 or 18S levels.…”

“…These signals are mediated by differential regulation of a wide range of transcription factors, some of which control the expression of various quality control machineries. For example, germline stem cell (GSC) arrest modulates the transcriptional reprogramming of HSF‐1, DAF‐16, PHA‐4, and SKN‐1 and thus counters the decline in folding capacity and stress activation (Berman & Kenyon, ; Chang et al, ; Labbadia & Morimoto, ; Shemesh, Meshnik, Shpigel, & Ben‐Zvi, ; Shemesh et al, ; Steinbaugh et al, ). Given how the remodeling of quality control networks converges on a similar set of transcription factors, we asked whether different endocrine or environmental signals result in equivalent or distinctive quality control networks.…”

Linking Lipid Metabolism to Chromatin Regulation in Aging

“…Activating autophagy by supplementation of PUFAs is conserved in human epithelial cells [104]. In addition, supplementation of PUFAs (AA and DGLA) during development in C. elegans improves protein quality control mechanisms that are normally decreased during aging, resulting in fewer toxic protein aggregates [105]. These observations highlight a crosstalk between different hallmarks of aging, namely lipid metabolism and protein homeostasis.…”