Remarkable longevity and stress resistance of nematode PI3K‐null mutants

Abstract

SummaryThe great majority of lifespan-augmenting mutations were discovered in the nematode Caenorhabditis elegans . In particular, genetic disruption of insulin-like signaling extends longevity 1.5-to 3-fold in the nematode, and to lesser degrees in other taxa, including fruit flies and mice. C. elegans strains bearing homozygous nonsense mutations in the age-1 gene, which encodes the class-I phosphatidylinositol 3-kinase catalytic subunit (PI3K CS ), produce progeny that were thought to undergo obligatory developmental arrest. We now find that, after prolonged developmental times at 15-20 °°°° C, they mature into extremely long-lived adults with near-normal feeding rates and motility. They survive to a median of 145 -190 days at 20 °°°° C, with nearly 10-fold extension of both median and maximum adult lifespan relative to N2DRM, a long-lived wild-type stock into which the null mutant was outcrossed. PI3K-null adults, although a little less thermotolerant, are considerably more resistant to oxidative and electrophilic stresses than worms bearing normal or less long-lived alleles. Their unprecedented factorial gains in survival, under both normal and toxic environments, are attributed to elimination of residual and maternally contributed PI3K CS or its products, and consequent modification of kinase signaling cascades.

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

“…This, nonetheless, may explain why we find an additive effect on lifespan of insulin/IGF signaling in combination with other treatments. In fact null mutants of PI3K, a downstream kinase of the insulin/IGF signaling pathway, have extreme longevity beyond that of daf-2 mutants (Ayyadevara et al 2008). The optimization of DR protocol used in this study, for technical reasons, was not possible with this method of DR.…”

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

“…A positive impact on lifespan rarely exceeds 40% in invertebrates and is often less in mammals (Spindler, 2012; Lucanic et al ., 2013). In contrast, much larger effects have been observed with genetic interventions, for instance a 10‐fold enhancement induced by mutations in a PI3K subunit gene (Ayyadevara et al ., 2008). It is possible that the most promising path to increase the efficiency of geroprotectors lies in the increase in their specificity to molecular targets.…”

Universal transcriptomic signature of age reveals temporal scaling ofCaenorhabditis elegansaging trajectories

“…Several mutations leading to exceptional longevity of C.elegans have been identified [21][22][23][24] and studied extensively for their remarkable elevations of both lifespan and stress-resistance traits [1,2] (see also Table Ia). To model the effects of anti-aging interventions we have tested five RNAi treatments targeting genes with the largest reported life-span extending effects (see Figure 1a and Table Ib for the summary of our confirmatory survival experiment and the lifespans reported in the original publications).…”

“…To date, the strongest lifespan extension effect is achieved in C.elegans and corresponds to almost 10-fold increase of lifespan by the mg44 nonsense mutation of age-1 gene [1,2]. That extreme hyperlongevity, however, requires two generations of homozygosity for a mutation, and thus total pre-embryonal genetic disruption.…”

“…We started by studying isogenic strains carrying the most long-lived C.elegans mutations: daf-2 (e1370 ) [strain SR806], age-1 (mg44 ) [SR808, at the first and second generations of homozygosity], and the longest-lived daf-2; daf-12 double mutant [strain DR1694] [1,2]. The average lifespans in the series range from twofold to tenfold longer than that of the wild type.…”