Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging

Abstract

DNA damage is presumed to be one type of stochastic macromolecular damage that contributes to aging, yet little is known about the precise mechanism by which DNA damage drives aging. Here, we attempt to address this gap in knowledge using DNA repair-deficient C. elegans and mice. ERCC1-XPF is a nuclear endonuclease required for genomic stability and loss of ERCC1 in humans and mice accelerates the incidence of age-related pathologies. Like mice, ercc-1 worms are UV sensitive, shorter lived, display premature functional decline and they accumulate spontaneous oxidative DNA lesions (cyclopurines) more rapidly than wild-type worms. We found that ercc-1 worms displayed early activation of DAF-16 relative to wild-type worms, which conferred resistance to multiple stressors and was important for maximal longevity of the mutant worms. However, DAF-16 activity was not maintained over the lifespan of ercc-1 animals and this decline in DAF-16 activation corresponded with a loss of stress resistance, a rise in oxidant levels and increased morbidity, all of which were cep-1/ p53 dependent. A similar early activation of FOXO3A (the mammalian homolog of DAF-16), with increased resistance to oxidative stress, followed by a decline in FOXO3A activity and an increase in oxidant abundance was observed in Ercc1-/- primary mouse embryonic fibroblasts. Likewise, in vivo, ERCC1-deficient mice had transient activation of FOXO3A in early adulthood as did middle-aged wild-type mice, followed by a late life decline. The healthspan and mean lifespan of ERCC1 deficient mice was rescued by inactivation of p53. These data indicate that activation of DAF-16/FOXO3A is a highly conserved response to genotoxic stress that is important for suppressing consequent oxidative stress. Correspondingly, dysregulation of DAF-16/FOXO3A appears to underpin shortened healthspan and lifespan, rather than the increased DNA damage burden itself.

Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner

“…In addition, FOXO3a activity has been shown to reduce the effects of reactive oxygen species (ROS) production in multiple ways. For example, its expression improves the fidelity of DNA damage repair by arresting the cell cycle to allow the repair of damaged DNA (Fluteau et al, 2015;Gurkar et al, 2018;Tran et al, 2002;Tsai et al, 2008). In addition FOXO3a activation results in the repression of a large number of nuclear-encoded genes with mitochondrial function (Ferber et al, 2012), (Ferber et al, 2012).…”

FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

“…A recent study carried out in C. elegans showed that in younger worms, transcription factor cep 1, CEP-1 promotes nuclear DAF-16 activation to induce protective stress response to DNA damage, while CEP-1/p53-dependent loss of DAF-16 nuclear retention was observed upon chronic genotoxic stress in older worms. This change in DAF-16 subcellular localization suggests a potential extra-nuclear role for DAF-16 in chronic genotoxic stress resistance [151].…”

Downregulated FOXO3a Associates With Poor Prognosis and Promotes Cell Invasion and Migration via WNT/β-catenin Signaling in Cervical Carcinoma

“…Forkhead box O 3a (FOXO3a) is a key transcriptional regulator of proteins that regulates a wide spectrum of biological processes, including proliferation (4), cell cycle regulation (5), survival (6), apoptosis (7), and autophagy (8). FOXO3a is also associated with oxidative stress (9), DNA damage (10), and longevity (11). FOXO3a is a key downstream transcription factor of the PI3K/AKT pathway.…”