Preserving transcriptional stress responses as an anti‐aging strategy. Issue 2 (20th January 2021)

• Record Type: Journal Article
• Authors: Cheng, Yang; Pitoniak, Andrew; Wang, Julia; Bohmann, Dirk
• Is Part Of: Aging cell. Volume 20:Issue 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-20
• Subjects: aging -- chromatin -- drosophila -- Nrf2 -- oxidative stress -- transcription; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13297
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: The progressively increasing frailty, morbidity and mortality of aging organisms coincides with, and may be causally related to, their waning ability to adapt to environmental perturbations. Transcriptional responses to challenges, such as oxidative stress or pathogens, diminish with age. This effect is manifest in the declining function of the stress responsive transcription factor Nrf2. Protective gene expression programs that are controlled by the Drosophila Nrf2 homolog, CncC, support homeostasis and longevity. Age‐associated chromatin changes make these genes inaccessible to CncC binding and render them inert to signal‐dependent transcriptional activation in old animals. In a previous paper, we have reported that overexpression of the CncC dimerization partner Maf‐S counteracts this degenerative effect and preserves organism fitness. Building on this work, we show here that Maf‐S overexpression prevents loss of chromatin accessibility and maintains gene responsiveness. Moreover, the same outcome, along with an extension of lifespan, can be achieved by inducing CncC target gene expression pharmacologically throughout adult life. Thus, pharmacological or dietary interventions that can preserve stress responsive gene expression may be feasible anti‐aging strategies. Abstract : Nrf2‐dependent transcriptional activity declines with age due to epigenetic degeneration at the target promoters in Drosophila. Here, we describe genetic and pharmacological startegies to delay the epigenetic decline and to preserve Nrf2‐target antioxidant gene responsiveness. These findings support the notion that hormetic mechanisms that serve to maintain the function and accessible chromatin structure of signal responsive genes can evoke long‐lasting, anti‐aging effects.