# Dynamic Oxidative States: Interplay of Aging, Metabolic Stress, and Circadian Rhythms in Modulating Stroke Severity

## TL;DR

This review explains how aging, metabolic issues, and disrupted body clocks dynamically affect oxidative stress during strokes, influencing brain damage and recovery.

## Contribution

The paper introduces a dynamic view of oxidative stress in stroke, emphasizing the interplay of aging, metabolism, and circadian rhythms.

## Key findings

- Aging weakens antioxidant defenses and increases vulnerability to oxidative damage during stroke.
- Metabolic disorders like obesity and diabetes worsen oxidative stress and inflammation after stroke.
- Circadian disruption reduces the brain's resilience by altering antioxidant enzyme rhythms.

## Abstract

Oxidative stress is a defining feature of stroke pathology, but the magnitude, timing and impact of redox imbalance are not static. Emerging evidence indicates that physiological contexts, such as aging, metabolic stress, and circadian disruption, continuously reshape oxidative status and determine the brain’s vulnerability to ischemic and reperfusion injury. This review integrates recent insights into how these intrinsic modulators govern the transition from adaptive physiological redox signaling to pathological oxidative stress during stroke. Aging compromises mitochondrial quality control and blunts NRF2-driven antioxidant responses, heightening susceptibility to ROS-driven damage. Metabolic dysfunction, as seen in obesity and diabetes, amplifies oxidative burden through NADPH oxidase activation, lipid peroxidation, and impaired glutathione recycling, further aggravating post-ischemic inflammation. Circadian misalignment, meanwhile, disrupts the rhythmic expression of antioxidant enzymes and metabolic regulators such as BMAL1, REV-ERBα, and SIRT1, constricting the brain’s temporal window of resilience. We highlight convergent signaling hubs, NRF2/KEAP1, SIRT–PGC1α, and AMPK pathways, as integrators of these physiological inputs that collectively calibrate redox homeostasis. Recognizing oxidative stress as a dynamic, context-dependent process reframes it from a static pathological state to a dynamic outcome of systemic and temporal imbalance, offering new opportunities for time-sensitive and metabolism-informed redox interventions in stroke.