Abstract
Diet profoundly affects metabolism and incidences of age-related diseases. Animals adapt their physiology to different food-types, modulating complex life-history traits like aging. The molecular mechanisms linking adaptive capacity to diet with aging are less known. We identify FLR-4 kinase as a novel modulator of aging in C. elegans, depending on bacterial diet. FLR-4 functions to prevent differential activation of the p38MAPK pathway in response to diverse food-types, thereby maintaining normal life span. In a kinase-dead flr-4 mutant, E. coli HT115 (K12 strain), but not the standard diet OP50 (B strain), is able to activate p38MAPK, elevate expression of cytoprotective genes through the nuclear hormone receptor NHR-8 and enhance life span. Interestingly, flr-4 and dietary restriction utilize similar pathways for longevity assurance, suggesting cross-talks between cellular modules that respond to diet quality and quantity. Together, our study discovers a new C. elegans gene-diet pair that controls the plasticity of aging.
Highlights
Animals dwell in a complex ecosystem where they interact with a host of other organisms; some of them may alter their life history traits
C. elegans as a model, we show that the adaptive capacity to different diet is maintained by a kinase gene
We show that knocking down flr-4 leads to increased cytoprotective xenobiotic detoxification pathway (XDP) gene expression, through the nuclear hormone receptor NHR-8, that plays a causal role in its increased life span
Summary
C. elegans strains used in this study were obtained from the Caenorhabditis Genetics Center and maintained on NGM agar plates at 20 ̊C, unless otherwise stated, on Escherichia coli OP50 lawns. [pSAK2 (myo-3::NGFP-LacZ)], tir-1(tm3036)III, unc-43(e408)IV, nsy-1(ag3)II, nsy-1(ok593)II, sek-1(km4)X, pmk-1(km25)IV, pmk-3(ok169)IV, flr-4(n2259)X; sek-1(km4)X, nhr-8(ok186) IV, daf-2(e1370)III, bvIs5 [cyp-35B1p::GFP + gcy-7p::GFP] referred to as cyp-35B1p::gfpin this manuscript, nhr-8(ok186) IV;bvIs5, flr-4(n2259)X;bvIs5, rrf-3(pk1426)II;eat-2(ad1116)II, rrf-3. Initially grown on E. coli OP50, were bleached and the eggs were L1 synchronized in M9 buffer for 16 hours before placing them on the respective RNAi plates Once worms reached L4 stage, they were transferred to intermediate RNAi plates (seeded with the same ‘X’ gene RNAi) for 12 hours. The worms were picked onto fresh ‘X’ gene RNAi plates overlaid with 5-fluorodeoxyuridine (FUDR, final concentration 0.1 mg/ml of media). For statistical analyses of survival, OASIS software (http://sbi.postech.ac.kr/oasis) was used and P-values were calculated by using a log rank (Mantel-Cox method) test
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