Age and Sex Are Critical Factors in Ischemic Stroke Pathology

Abstract

Ischemic stroke is a devastating brain injury resulting in high mortality and substantial loss of function. Understanding the pathophysiology of ischemic stroke risk, mortality, and functional loss is critical to the development of new therapies. Age and sex have a complex and interactive effect on ischemic stroke risk and pathophysiology. Aging is the strongest nonmodifiable risk factor for ischemic stroke, and aged stroke patients have higher mortality and morbidity and poorer functional recovery than their young counterparts. Importantly, patient age modifies the influence of patient sex in ischemic stroke. Early in life, the burden of ischemic stroke is higher in men, but stroke becomes more common and debilitating for women in elderly populations. The profound effects of sex and age on clinical ischemic stroke are mirrored in the results of experimental in vivo and in vitro studies. Here, we review current knowledge on the influence of age and sex in the incidence, mortality, and functional outcome of ischemic stroke in clinical populations. We also discuss the experimental evidence for sex and age differences in stroke pathophysiology and how a better understanding of these biological variables can improve clinical care and enhance development of novel therapies.

Figure 1.

Schematic illustration of the relationship between age- and sex-related risk factors across the lifespan. An approximation of the overall increase in stroke incidence with aging is given, in addition to sex-specific or sexually dimorphic stroke risk factors at each stage of life. Sex differences in stroke incidence throughout the lifespan are also depicted. AF, atrial fibrillation; MetS, metabolic syndrome; OCP, oral contraceptive pill.

Figure 2.

Schematic representation of sex differences in stroke pathology and therapeutic efficacy. Sex differences in mitochondrial disruption exist; experimental stroke models in both mice and rats have shown that female animals experience less oxidative stress and dysregulated respiration after ischemia than males, an advantage that is eliminated by ovariectomy or aging. Sex differences in vasodilation have also been described, in which experimental mouse models have shown that females experience enhanced vasodilation at baseline compared with males, and male animals show benefit only when vasodilation is enhanced [inhibition of soluble epoxide hydrolase (sEH), selection of angiotensin II type 2 receptor (Agtr2)]. Studies in mice have shown enhanced reactive astrocytosis in females after ischemic, which can be ameliorated by the deletion of the proinflammatory protein Pannexin 1. Conversely, female mice show reduced microglial activation compared with male animals in experimental mouse models of ischemic stroke. In vivo and in vitro studies in mice and mouse-derived neuronal cells have demonstrated that the PARP-1/nitric oxide (NO) pathway of cell death predominates in males, whereas the caspase pathway of cell death is dominant in females. In line with this, inhibition of each of these pathways benefits only males, or only females, respectively.