AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.

The increased risk of stroke observed in the Women's Health Initiative (WHI) trial in connection with combined estrogen/progestin hormone therapy was one reason for ending the study early. The present authors analyzed theeffects of combined hormone therapy (CHT) on ischemic and hemorrhagic stroke in the 16,608 postmenopausal women, 50 to 79 years of age, who participated in the multicenter, double-blind, placebo-controlled WHI trial and were followed up for 5.6 years on average. All women were followed for at least 3.7 years. The women were randomly assigned to receive either CHT (0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate) or a placebo each day. The rate of stroke was 1.8% in women given CHT and 1.3% in the placebo group. Four of 5 strokes were ischemic. Hemorrhagic stroke accounted for 11.9% of events in the CHT group and 18.6% in the placebo group. There were 23 deaths resulting from stroke, 12 in the CHT group and 11 in placebo recipients. The combined hazard ratio (hour) for all subtypes of stroke combined was 1.31 (nominal 95% confidence interval [CI], 1.02-1.68). Women who had never taken hormones had a 37% excess risk of stroke when given CHT, for a hazard ratio of 1.37 (95% CI, 1.03-1.82). On multivariate analysis, controlling for race/ethnicity and baseline systolic blood pressure did not influence stroke risk for women taking CHT. An excess risk was noted in all age groups; in women with all levels of baseline stroke risk; and in participants with and without hypertension, a history of cardiovascular disease, and statin or aspirin treatment. A number or risk factors for stroke failed to modify the effect of CHT on stroke risk. They included smoking, diabetes, biomarkers of inflammation, and a higher white blood cell count or hematocrit. These findings indicate that, independently of blood pressure, estrogen/progestin therapy augments the risk of stroke in postmenopausal women who are in good general health. Considering the increased risk of invasive breast cancer, myocardial infarction, and venous thrombosis in women participating in the WHI trial, the findings reinforce the view that the overall risk from CHT outweighs its possible benefits.

Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health initiative: A randomized trial

Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke

Inflammaging refers to a low-grade pro-inflammatory phenotype which accompanies aging in mammals. The aging process is associated with a decline in autophagic capacity which impairs cellular housekeeping, leading to protein aggregation and accumulation of dysfunctional mitochondria which provoke reactive oxygen species (ROS) production and oxidative stress. Recent studies have clearly indicated that the ROS production induced by damaged mitochondria can stimulate intracellular danger-sensing multiprotein platforms called inflammasomes. Nod-like receptor 3 (NLRP3) can be activated by many danger signals, e.g. ROS, cathepsin B released from destabilized lysosomes and aggregated proteins, all of which evoke cellular stress and are involved in the aging process. NLRP3 activation is also enhanced in many age-related diseases, e.g. atherosclerosis, obesity and type 2 diabetes. NLRP3 activates inflammatory caspases, mostly caspase-1, which cleave the inactive precursors of IL-1β and IL-18 and stimulate their secretion. Consequently, these cytokines provoke inflammatory responses and accelerate the aging process by inhibiting autophagy. In conclusion, inhibition of autophagic capacity with aging generates the inflammaging condition via the activation of inflammasomes, in particular NLRP3. We will provide here a perspective on the current research of the ROS-dependent activation of inflammasomes triggered by the decline in autophagic cleansing of dysfunctional mitochondria.

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Inflammaging: disturbed interplay between autophagy and inflammasomes

Recent discoveries have shown that both hormonal and brain-derived oestradiol have neuroprotective effects. This Review provides a comprehensive review of the multiple cell types, receptors and signalling cascades that underlie oestradiol-mediated neuroprotection.

The neuroprotective actions of oestradiol and oestrogen receptors

Stroke is the leading cause of disability in the United States and affects 15 million people worldwide Studies performed in various parts of the world have found differences between sexes in stroke incidence, prevalence, mortality, and outcomes Although men are at higher risk of stroke for most age groups below age 85 years, after this age the incidence reverses dramatically, with women being much more at risk Furthermore, recent studies suggest that women have worse recovery than men post-stroke Many aspects of recovery may influence this outcome, including sex-specific comorbidities, aggressiveness of acute treatment, prevention therapies, and varying degrees of social support and rates of depression It is important to further define and investigate sex differences in stroke incidence, care, treatment, and outcomes to improve functional recovery in women

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Stroke in Women: Disparities and Outcomes

Stroke is a leading cause of permanent disability and death It is well accepted that the principal mammalian estrogen (E2), 17-β estradiol, provides robust neuroprotection in a variety of brain injury models in animals of both sexes E2 enhances neurogenesis after stroke in the subventricular zone; however, it is unknown if these cells survive long-term or enhance functional recovery In this study, we examined stroke-induced neurogenesis in male, gonadally intact female, and ovariectomized female mice 2 and 6 weeks after stroke Treatment with 17-β estradiol increased 5-bromo-2′-deoxyuridine-labeled cells at both time points in both the dentate gyrus and subventricular zone; the majority were colabeled with doublecortin at 2 weeks and with NeuN at 6 weeks Stroke-induced neurogenesis was reduced in estrogen receptor knockout mice, as well as in mice lacking the gene for aromatase, which converts testosterone into E2 Improved behavioral deficits were seen in E2-treated mice, suggesting that E2-induced increases in poststroke neurogenesis contribute to poststroke recovery

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2010.181

Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke

Aging is a non-modifiable risk factor for stroke. Since not all strokes can be prevented, a major emerging area of research is the development of effective strategies to enhance functional recovery after stroke. However, in the vast majority of pre-clinical stroke studies, the behavioral tests used to assess functional recovery have only been validated for use in young animals, or are designed for rats. Mice are increasingly utilized in stroke models but well validated behavioral tests designed for rats are not necessarily reproducible in mice. We examined a battery of behavioral tests to evaluate functional recovery in an aging murine model of stroke. We found that the vertical pole, hanging wire and open field can accurately assess acute behavioral impairments after stroke in both young and aging male mice, but animals recover rapidly on these tasks. The corner test can accurately and repeatedly differentiate stroke from sham animals up to 30 days post stroke and can be performed reliably in aging mice. Aging male mice had significantly worse behavioral impairment compared to young male mice in the first two weeks after stroke but eventually recovered to the same degree as young mice. In contrast, chronic infarct size, as measured by ipsilateral cerebral atrophy, was significantly lower in aging male mice compared to young male mice. Reactive gliosis, formation of glial scar, and an enhanced innate immune response was seen in the aging brain and may contribute to the delayed behavioral recovery seen in the aging animals.

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Functional recovery in aging mice after experimental stroke.

Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved energy sensor sensitive to changes in cellular AMP/ATP ratio which is activated by phosphorylation (pAMPK). pAMPK levels decrease in peripheral tissues with age, but whether this also occurs in the aged brain, and how this contributes to the ability of the aged brain to cope with ischemic stress is unknown. This study investigated the activation of AMPK and the response to AMPK inhibition after induced stroke in both young and aged male mice. Baseline levels of phosphorylated AMPK were higher in aged brains compared to young mice. Stroke-induced a robust activation of AMPK in young mice, yet this response was muted in the aged brain. Young mice had larger infarct volumes compared with aged animals; however, more severe behavioral deficits and higher mortality were seen in aged mice after stroke. Inhibition of AMPK with Compound C decreased infarct size in young animals, but had no effect in aged mice. Compound C administration led to a reduction in brain ATP levels and induced hypothermia, which led to enhanced neuroprotection in young but not aged mice. This work demonstrates that aging increases baseline brain pAMPK levels; aged mice have a muted stroke-induced pAMPK response; and that AMPK inhibition and hypothermia are less efficacious neuroprotective agents in the aged brain. This has important translational relevance for the development of neuroprotective agents in preclinical models and our understanding of the enhanced metabolic stress experienced by the aged brain.

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Rebecca Persky

Papers

Stroke in Women: Disparities and Outcomes

Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke

Functional recovery in aging mice after experimental stroke.

Age-related changes in AMP-activated protein kinase after stroke

Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice.