The longevity response to warm temperature is neurally controlled via the regulation of collagen genes

Abstract

Studies in diverse species have associated higher temperatures with shorter lifespan and lower temperatures with longer lifespan. These inverse effects of temperature on longevity are traditionally explained using the rate of living theory, which posits that higher temperatures increase chemical reaction rates, thus speeding up the aging process. Recent studies have identified specific molecules and cells that affect the longevity response to temperature, indicating that this response is regulated, not simply thermodynamic. Here, we demonstrate that in Caenorhabditis elegans, functional loss of NPR‐8, a G protein‐coupled receptor related to mammalian neuropeptide Y receptors, increases worm lifespan at 25°C but not at 20°C or 15°C, and that the lifespan extension at 25°C is regulated by the NPR‐8‐expressing AWB and AWC chemosensory neurons as well as AFD thermosensory neurons. Integrative transcriptomic analyses revealed that both warm temperature and old age profoundly alter gene expression and that genes involved in the metabolic and biosynthetic processes increase expression at 25°C relative to 20°C, indicating elevated metabolism at warm temperature. These data demonstrate that the temperature‐induced longevity response is neurally regulated and also provide a partial molecular basis for the rate of living theory, suggesting that these two views are not mutually exclusive. Genetic manipulation and functional assays further uncovered that the NPR‐8‐dependent longevity response to warm temperature is achieved by regulating the expression of a subset of collagen genes. As increased collagen expression is a common feature of many lifespan‐extending interventions and enhanced stress resistance, collagen expression could be critical for healthy aging.

Loss of age-accumulatedcrh-1circRNAs ameliorate amyloid β-induced toxicity in aC. elegansmodel for Alzheimer’s disease

“…We selected 6 upregulated collagen genes in circ- crh-1 (-) mutants (Knupp et al, 2022) and tested them in circ- crh-1 (-) mutants expressing Aβ 1-42 in muscle. We found that expression levels of the predicted cuticular collagen, col-49 , with a known role in lifespan regulation (Palani et al, 2023) and cuticular integrity (Jackson et al, 2014) was significantly increased, while the other tested collagen genes were not different from the GMC101 control. We do not yet know how loss of circ- crh-1 expression results in increased col-49 mRNA levels in the presence of muscle expressing Aβ 1-42 .…”

“…We hypothesized that the upregulation of cuticular collagen gene expression contributes to the amelioration of Aβ-induced toxicity in circ- crh-1 (-) mutants carrying the unc-54::A β 1-42 transgene. To test this hypothesis, from the 21 upregulated collagen genes previously identified in crh-1(syb385) mutants (Knupp et al, 2022), we selected six cuticular collagen genes of interest, including collagens that have a known association with lifespan such as col-49 and col-179 (Palani et al, 2023).…”

Genome-wide temporal gene expression reveals a post-reproductive shift in the nematodeC. briggsae

“…Our analysis of collagens in C. elegans revealed a similar expression trend as in C. briggsae . Intertwined with the progression from reproductive to post-reproductive stage are also age-related effects on expression of certain collagen and cuticle-related genes that were reported to decline in older adults (Budovskaya et al, 2008; Ewald et al, 2015; Palani et al, 2023). Cuticular collagens have been found to confer resistance to pathogen infection and oxidative stress (Ewald et al, 2015; Sellegounder et al, 2019), which wane as animals age (Lopez-Otin et al, 2013).…”

ADARs regulate cuticle collagen expression and promote survival to pathogen infection

“…It has been proposed that although the epidermis plays a major role in synthesizing the cuticle, neurons can sense both the environment and tension to influence collagen dynamics [59]. In this regard, it was recently demonstrated that a neural G-protein coupled receptor, NPR-8, dynamically regulates collagen expression and cuticle structure in response to temperature changes and infection [48,60]. Furthermore, loss of npr-8 leads to increased resistance to pathogen infection [48].…”