Proteostasis Rebalancing by LET-607 Deficiency Promotes Longevity.

Area of Science:

• Cellular Biology
• Aging Research
• Genetics

Background:

• Proteostasis, the maintenance of protein homeostasis, is crucial for cellular function and declines with age.
• Cellular resources are finite, necessitating trade-offs between different proteostatic pathways.
• The principles governing the coordination of proteostatic subsystems and potential trade-offs remain incompletely understood.

Purpose of the Study:

• To investigate the interplay between the endoplasmic reticulum unfolded protein response (UPR^ER) and the cytosolic unfolded protein response (UPR^cyto) in C. elegans.
• To determine the role of the transcription factor LET-607 in regulating this proteostatic balance.
• To explore the impact of this balance on lifespan and aging.

Main Methods:

• Utilized C. elegans as a model organism.
• Measured UPR^ER and UPR^cyto activity in wild-type and LET-607 deficient animals.
• Investigated the molecular mechanisms linking LET-607, the one-carbon cycle, histone modifications, and UPR activation.
• Assessed lifespan in genetically modified strains.

Main Results:

• Wild-type C. elegans maintain a balance of high UPR^ER and low UPR^cyto activity, enforced by LET-607.
• LET-607 deficiency disrupts this balance, leading to decreased UPR^ER and increased UPR^cyto activity.
• LET-607 deficient animals exhibit extended lifespan, dependent on UPR^cyto activation.
• LET-607 deficiency downregulates the one-carbon cycle, reducing S-adenosylmethionine levels and alleviating H3K9me-mediated repression of UPR^cyto genes.

Conclusions:

• A novel transcriptional mechanism enforces a proteostatic trade-off between UPR^ER and UPR^cyto.
• The evolutionarily conserved UPR balance in wild-type animals is suboptimal for maximizing lifespan.
• This finding supports the antagonistic pleiotropy theory of aging, suggesting that traits beneficial for reproduction may be detrimental to longevity.