Longevity determined by developmental arrest genes in Caenorhabditis elegans

Abstract

SummaryThe antagonistic pleiotropy theory of aging proposes that aging takes place because natural selection favors genes that confer benefit early on life at the cost of deterioration later in life. This theory predicts that genes that impact development would play a key role in shaping adult lifespan. To better understand the link between development and adult lifespan, we examined the genes previously known to be essential for development. From a pool of 57 genes that cause developmental arrest after inhibition using RNA interference, we have identified 24 genes that extend lifespan in Caenorhabditis elegans when inactivated during adulthood. Many of these genes are involved in regulation of mRNA translation and mitochondrial functions. Genetic epistasis experiments indicate that the mechanisms of lifespan extension by inactivating the identified genes may be different from those of the insulin/insulin-like growth factor 1 (IGF-1) and dietary restriction pathways. Inhibition of many of these genes also results in increased stress resistance and decreased fecundity, suggesting that they may mediate the trade-offs between somatic maintenance and reproduction. We have isolated novel lifespanextension genes, which may help understand the intrinsic link between organism development and adult lifespan.

Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

“…The enrichment of lifespan-extending mutants is consistent with the antagonistic pleiotropy hypothesis that genes beneficial to early development may become detrimental later in life (41). This hypothesis has been explored in other species (e.g., in worms), where a strong overlap between longevity genes and genes important for development was observed (42). For potential rejuvenating factors, we expect that the deletion will shorten lifespan.…”

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

“…S4H; Table S7, Supporting information) with a less penetrant developmental arrest, suggesting that KYNU‐1 is required for normal development at 15 °C. This is consistent with past studies that find enrichment for lifespan extension in response to RNAi knockdown of genes required for development (Chen et al ., 2007; Curran & Ruvkun, 2007). …”

“…The percentage of candidate genes that directly affected lifespan at 25 °C (43.9%) was substantially higher than RNAi screens in C. elegans without a preselection criteria (<2%) (Lee et al ., 2003b; Hamilton et al ., 2005; Hansen et al ., 2005; Samuelson et al ., 2007) and within the range for screens that preselected candidates based on secondary C. elegans phenotypes, including developmental arrest (2–42%) (Chen et al ., 2007; Curran & Ruvkun, 2007), reproductive senescence (16%) (Wang et al ., 2014), thermal stress resistance (78%) (Munoz & Riddle, 2003), oxidative stress resistance (13–67%) (de Castro et al ., 2004; Kim & Sun, 2007), and activation of the mitochondrial unfolded‐protein response (53%) (Bennett et al ., 2014) (reviewed by Yanos et al ., 2012 and Sutphin & Korstanje, 2016). Tacutu et al .…”

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

“…'s use of a higher dose at 2.4 m m , which showed no significant increase in lifespan. Mutations of age‐1 and daf‐2 , which acts upstream of age‐1 , result in lifespan extension in N2 worms, but daf‐2 mutations and RNAi also increases the lifespan of eat‐2 worms, which suggests that age‐1 would do so also (Chen et al ., 2007). This is the opposite of what we have found.…”