Positive Feedback between Transcriptional and Kinase Suppression in Nematodes with Extraordinary Longevity and Stress Resistance

Abstract

Insulin/IGF-1 signaling (IIS) regulates development and metabolism, and modulates aging, of Caenorhabditis elegans. In nematodes, as in mammals, IIS is understood to operate through a kinase-phosphorylation cascade that inactivates the DAF-16/FOXO transcription factor. Situated at the center of this pathway, phosphatidylinositol 3-kinase (PI3K) phosphorylates PIP2 to form PIP3, a phospholipid required for membrane tethering and activation of many signaling molecules. Nonsense mutants of age-1, the nematode gene encoding the class-I catalytic subunit of PI3K, produce only a truncated protein lacking the kinase domain, and yet confer 10-fold greater longevity on second-generation (F2) homozygotes, and comparable gains in stress resistance. Their F1 parents, like weaker age-1 mutants, are far less robust—implying that maternally contributed trace amounts of PI3K activity or of PIP3 block the extreme age-1 phenotypes. We find that F2-mutant adults have <10% of wild-type kinase activity in vitro and <60% of normal phosphoprotein levels in vivo. Inactivation of PI3K not only disrupts PIP3-dependent kinase signaling, but surprisingly also attenuates transcripts of numerous IIS components, even upstream of PI3K, and those of signaling molecules that cross-talk with IIS. The age-1(mg44) nonsense mutation results, in F2 adults, in changes to kinase profiles and to expression levels of multiple transcripts that distinguish this mutant from F1 age-1 homozygotes, a weaker age-1 mutant, or wild-type adults. Most but not all of those changes are reversed by a second mutation to daf-16, implicating both DAF-16/ FOXO–dependent and –independent mechanisms. RNAi, silencing genes that are downregulated in long-lived worms, improves oxidative-stress resistance of wild-type adults. It is therefore plausible that attenuation of those genes in age-1(mg44)-F2 adults contributes to their exceptional survival. IIS in nematodes (and presumably in other species) thus involves transcriptional as well as kinase regulation in a positive-feedback circuit, favoring either survival or reproduction. Hyperlongevity of strong age-1(mg44) mutants may result from their inability to reset this molecular switch to the reproductive mode.

Genetics and epigenetics of aging and longevity

“…Mutations in genes encoding kinases PI3K, AKT/PKB, and PDK are associated with a prolonged life in animals 41 - 43 . Activity of phosphatases such as PTEN, SHIP1, and SHIP2, counteracting the function of PI3K, also promote longevity 36 . Insulin-like signaling inhibits the mechanisms of stress response regulated by FOXO transcription factor.…”

Genetics and Epigenetics of Aging and Longevity

“…Активность инсулиноподоб-ного сигналинга и уровень экспрессии инсулиноподоб- ОбразОвание в Области экОлОгическОй генетики ных пептидов снижены у долгоживущих нематод, мы-шей и людей (Bartke, 2008;Suh et al, 2008;Tazearslan et al, 2009;Parrella, Longo, 2010). Мыши-гетерозиготы и люди с мутацией гена рецептора IGF-1 имеют большую продолжительность жизни (Holzenberger et al, 2003;Suh et al, 2008).…”

“…Мутации в генах киназ PI3K, AKT/PKB, PDK сопровождаются увеличе-нием продолжительности жизни животных (Puig, Tjian, 2005;Ayyadevara et al, 2008;Narasimhan et al, 2009). Напротив, активность фосфатаз PTEN, SHIP1 и SHIP2, противостоящих действию PI3K, способствует долголе-тию (Tazearslan et al, 2009). Инсулиноподобный сигна-линг подавляет активность механизмов стресс-ответа, связанных с транскрипционным фактором FOXO.…”

“…TGF-β сигналинг снижен у долго-живущих червей (Tazearslan et al, 2009). При старении мышц наблюдается патологическая активизация Wnt-сигналинга (Brack et al, 2007).…”

Neuronal Inputs and Outputs of Aging and Longevity

“…Feedback loops are critically important in regulating physiology and metabolism, particularly with respect to homeostasis, and are often controlled by hormones (reviewed in Baker and Thummel, 2007;Leopold and Perrimon, 2007;Fielenbach and Antebi, 2008;Rajan and Perrimon, 2011;Hill et al, 2012). Notably, many such endocrine feedback mechanisms are thought to modulate aging and lifespan (Tatar et al, 2003;Murphy et al, 2007;Fielenbach and Antebi, 2008;Broughton and Partridge, 2009;Tazearslan et al, 2009;Landis and Murphy, 2010), and the nervous system has been implicated in several of them (Hwangbo et al, 2004;Broughton et al, 2008;Flatt et al, 2008;Grönke et al, 2010;Alic et al, 2011;Boulias and Horvitz, 2012). Here, we focus on a few examples of feedback mechanisms that involve IIS and the nervous system.…”