Abstract
Metazoans respond to harmful challenges by mounting anti-stress responses. This adaptation along with the evolvement of metabolic networks, were fundamental forces during evolution. Central to anti-stress responses are a number of short-lived transcription factors that by functioning as stress sensors mobilize genomic responses aiming to eliminate stressors and restore tissue homeodynamics. We have found that increased expression of nuclear factor erythroid 2-related factor (Nrf2) in Drosophila flies activated cytoprotective modules and enhanced stress tolerance. However, while mild Nrf2 activation extended lifespan, high Nrf2 expression levels resulted in larvae lethality or, after inducible activation in adult flies, in altered mitochondrial bioenergetics; the appearance of diabetic phenotypes and reduced longevity. Genetic or dietary suppression of Insulin/IGF-like signaling (IIS) alleviated these effects and extended flies’ lifespan. Our observations indicate that prolonged stress signaling by otherwise cytoprotective short-lived stress sensors re-allocates resources from growth and longevity to somatic preservation and stress tolerance. They also suggest a role for potential dietary-restriction-like therapeutic interventions in various diseases of chronic stress including progeroid genome instability syndromes and/or neurodegeneration. Finally, as our in vivo insights indicate that long-term mild Nrf2 activation exerts benign effects we screen marine natural products (derived from the mesophotic zone) libraries for the discovery of (among others) novel bioactive Nrf2-activating small molecules.
Highlights
The viability of metazoans largely depends on their ability to regulate metabolic processes in order to produce energetic molecules, as well as on their capacity to mount anti‐stress responses
While mild nuclear factor erythroid 2‐related factor (Nrf2) upregulation extended lifespan, high Nrf2 expression levels reduced longevity due to reprogramming of cellular bioenergetics that resulted in the appearance of Diabetes Type 1‐like (DT1) phenotypes; these toxic effects were alleviated by downregulating IGF‐like signaling (IIS)
By analyzing the expression levels of genes involved in IIS, we found a late downregulation of insulin‐like peptide 2, along with dilp6 and impL2 upregulation
Summary
The viability of metazoans largely depends on their ability to regulate metabolic processes in order to produce energetic molecules, as well as on their capacity to mount anti‐stress responses These processes are mostly regulated by short‐lived sensors (mainly transcription factors) which in cases of disturbing departures from the optimal levels. At the whole organism level, these responses require complex co‐regulation and wiring of cell‐autonomous and non‐autonomous mechanisms (Kaushik & Cuervo, 2015) The efficiency of these processes declines during aging leading to increased morbidity and mortality (López‐Otín et al, 2013). The functionality of both the anti‐stress responses module and the PN declines during in vivo aging contributing to age‐related diseases (Kaushik & Cuervo, 2015); in support, disruption of proteostasis in young Drosophila flies accelerated aging (Tsakiri, Sykiotis, Papassideri, Terpos, et al, 2013). While mild Nrf upregulation extended lifespan, high Nrf expression levels reduced longevity due to reprogramming of cellular bioenergetics that resulted in the appearance of Diabetes Type 1‐like (DT1) phenotypes; these toxic effects were alleviated by downregulating IIS
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