Ischemic stroke remains a leading cause of global mortality and disability, exhibiting marked sexual dimorphism in incidence, severity, and functional outcomes. While epidemiological disparities are well-documented, emerging evidence indicates that these differences are rooted in sex-specific molecular and cellular programs that evolve across the lifespan. This review synthesizes the complex interplay between biological sex and aging in stroke pathophysiology, emphasizing how chromosomal complement and hormonal status dictate the brain's differential response to ischemia. Within the salvageable penumbra, programmed cell death pathways diverge sharply, with male-specific PARP-1-mediated parthanatos contrasting against a caspase-dependent apoptotic bias in premenopausal females. Mitochondrial bioenergetics, Drp1 dynamics, and the NAD⁺-sirtuin axis act as central hubs for this sex-dependent vulnerability. This framework leads into the catastrophic transition following reproductive senescence, marked by Esr1 promoter hypermethylation, eNOS uncoupling, mitochondrial decay, microglial priming, and neurovascular unit breakdown, effectively abolishing the earlier neuroprotective female phenotype. Crucially, we move beyond a neurocentric view to integrate systemic modulators, including cGAS-STING-mediated astrocytic inflammation, age-associated B cells (ABCs), and the gut-brain axis governed by the estrobolome, which exacerbate central injury in a sex-informed manner. By addressing the inherent limitations of uniform neuroprotective strategies and the timing window paradox of hormonal therapies, this manuscript highlights the necessity of shifting toward stratified precision medicine. To overcome translational hurdles, we evaluate targeted therapeutics, including pathway-selective ERα modulators like PaPE-1, NAD⁺ precursors, and estrobolome-targeted probiotics. Furthermore, we highlight combinatorial niche-clearing strategies, such as Dasatinib plus Quercetin senolytics, STAT3 inhibitors, and bioengineered intranasal extracellular vesicles. Ultimately, tailoring these targeted therapies to biological sex and reproductive age is imperative to secure superior clinical stroke recovery.
