A multi-system approach to ameliorate the age-dependent loss of the Nrf2-mediated cellular stress response: implications on stress adaptation and longevity.

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Project Summary One major hallmark of aging and age-associated diseases is the inability to activate cellular quality control mechanisms after exposure to endogenous and exogenous oxidative damage, which if not removed, can wreak havoc upon cellular DNA, lipids, and proteins. The accumulation of cellular damage can accelerate the aging phenotype. Therefore, the characterization of regulatory mechanisms of the adaptive stress response (ASR) remains an important goal of aging research. Cells rely upon the ASR for the transient and reversible response to mild oxidative stress (resulting from metabolic and environmental conditions) to activate stress responsive genes, thereby enabling cells and organisms to cope with a wide array of cytotoxic conditions. The ASR consists of two components: the immediate activation of stress responsive genes for damage removal, followed by the time-delayed inactivation of the response, when no longer necessary. A master transcriptional regulator is Nrf2, which upon oxidative stress transcriptionally activates protective pathways and enzymes to counteract cytotoxic conditions. Bach1 acts as a time-delayed transcriptional suppressor of Nrf2 signaling to inactivate the ASR. However, with increasing age Nrf2-target gene expression declines, contributing to cellular dysfunction, damage and senescence. Historically, the primary approach to reduce the age-dependent Nrf2 decline was focused on Nrf2 overexpression or the suppression of its cytosolic inhibitor Keap1. Unfortunately, these approaches have failed to restore the ASR and, in some instances, proven detrimental. Instead, Bach1 may play a crucial role in restoring the ASR, as supported by its age-dependent increase. I hypothesize that reducing/removal of Bach1 signaling in later life will allow for Nrf2 signal amplification and the restoration of the Nrf2- mediated adaptive stress response. I propose to investigate the age-dependent change in Nrf2/Bach1 signaling upon oxidative stress in 3 model systems (human primary cells, D. melanogaster, and mice) (Aims 1- 3). Additionally, I will seek to restore the age-dependent decline in the Nrf2-mediated ASR by Bach1 inhibition (direct) and caloric restriction (indirect), as caloric restriction has been previously reported to reduce the age- associated increase in oxidative stress (Aims 2 & 3). Together, this exploration will offer an alternative approach for restoration of the ASR with age, with the potential for slowing the aging process and/or disease progression.