MicroRNA modulation of caenorhadbitis elegans dietary restriction and longevity

Aging is a universal biological phenomenon involving a complex decline in the ability of the organism to respond adequately to intrinsic and extrinsic stresses, leading to age-related diseases and pathologies. All organisms age, but the larger questions of how and why aging occurs are still being deciphered despite decades of research and experimentation . We present evidence identifying microRNAs, small non-coding RNAs that regulate gene expression by repressing target mRNAs through partially complementary binding, significantly impact Caenorhabditis elegans longevity. We have identified several mir mutants that impact not only lifespan but also specific aspects of aging like metabolic aging vs muscle aging. Excitingly we have also identified that the mir-80 mutant animal is under chronic dietary restriction – a conserved pathway that extends life- and healthspan in many diverse organisms. The mir-80(Δ) mutant exhibits multiple parameters of healthy aging, reduced fecundity and expression of molecular reporters associated with dietary restriction. Using a targeted RNAi approach we have identified several stress response transcription factors (daf-16, hsf-1 and skn-1), the metabolic energy sensor (AMPK) and the transcriptional co-factor cbp-1 as important requirements for mir-80(Δ) longevity and the DR-state. Finally we show that mir-80 longevity is also partially regulated by the conserved insulin/IGF-1 signaling pathway. In summary, we identify the first metazoan microRNA that regulates longevity through conserved dietary restriction and suggest a model whereby mir-80 may regulate a network of stress response and metabolic genes to impact C. elegans longevity. In conclusion, we identify novel miRNAs that modulate C. elegans longevity and the first microRNA that modulates longevity through dietary restriction.Ph. D.Includes bibliographical referencesby Mehul M Vor