Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity

Kaitlyn N. Lewis, James Mele, John D. Hayes, Rochelle Buffenstein

    Research output: Contribution to journalArticle

    157 Citations (Scopus)

    Abstract

    Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-kappa B) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.

    Original languageEnglish
    Pages (from-to)829-843
    Number of pages15
    JournalIntegrative and Comparative Biology
    Volume50
    Issue number5
    DOIs
    Publication statusPublished - Nov 2010

    Keywords

    • TRANSCRIPTION FACTOR NRF2
    • NAKED MOLE-RAT
    • ANTIOXIDANT-RESPONSE ELEMENT
    • LONGEST-LIVING RODENT
    • GLUTAMATE-CYSTEINE LIGASE
    • FREE-RADICAL THEORY
    • OXIDATIVE STRESS
    • LIFE-SPAN
    • CAENORHABDITIS-ELEGANS
    • GENE-EXPRESSION

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