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Previous studies of East Asian welfare regimes focus on similarities between social security schemes. In contrast, this paper explores cross-national variations in public–private pension mixes in six welfare states: China, Hong Kong, Japan, Singapore, South Korea and Taiwan. Our research echoes the pension policy analysis of international organisations but takes a step forward with emphasis on the historical and institutional characteristics of the respective pension systems. The analysis identifies three institutional patterns. First, the statist pension system (Taiwan and China) primarily relies on public pensions to provide old-age security, with private pensions playing a rather minor role. Second, in the dualist pension system (Japan and Korea) both public and private pensions work in parallel to ensure retirement income, though a clear security gap exists between workers in the formal and informal economies. Finally, the individualist pension system (Hong Kong and Singapore) is characterised by genuine fully funded individual accounts, emphasising citizens’ own responsibilities for ensuring old-age security. These three types of pension systems demonstrate distinct institutional characteristics and policy outcomes, illustrated by the juxtaposition of their institutional structures as well as by the comparison of key indicators collected from government reports and Organisation for Economic Co-operation and Development statistics. The paper concludes with a theoretical reflection of East Asian pension policies and a diagnosis of the distinct challenges confronted by each of the various pension patterns.

Achieving neuroprotection in ischemic stroke patients has been a multidecade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently, however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In this review, we describe the clinical studies that significantly expanded the time window of eligibility for patients to receive mechanical endovascular thrombectomy. We further summarize the results available thus far for nerinetide, a promising neuroprotective agent for stroke treatment. Lastly, we reflect upon aspects of these impactful trials in our own studies targeting the Kv2.1-mediated cell death pathway in neurons for neuroprotection. We argue that recent changes in the clinical landscape should be adapted by preclinical research in order to continue progressing toward the development of efficacious neuroprotective therapies for ischemic stroke.

Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR‐treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole‐body ablation of Hmgcs2, the rate‐limiting enzyme producing the main ketone body β‐hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR‐driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex‐specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long‐term CR are not mediated by ketogenesis. In this study, we demonstrated that metabolic responses to a daily‐fed caloric restriction (CR) protocol remain robust in mice that cannot engage in canonical ketogenesis. This surprising finding is due to mice physiologically adapting to the daily bouts of fasting during CR by downregulating ketone production.

Caloric restriction slows or prevents Alzheimer’s disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer’s disease by placing male and female 3xTg and non-transgenic control mice on a series of diet regimens enabling us to dissect the effects of calories and fasting. We find that reducing calories alone improves body weight and glucose tolerance. However, a prolonged fast between meals is necessary for many of the benefits of calorie restriction, including improved insulin sensitivity, reduced Alzheimer’s pathology, improved neuroprotective signaling, and improved cognition. Overall, our results suggest that both when and how much we eat may influence the development and progression of Alzheimer’s disease. Caloric restriction improves Alzheimer’s Disease outcomes in mice, but this diet not only reduces calories, but imposes a prolonged fast between meals. Here, the authors show this fast is essential to improve Alzheimer’s pathology and cognition.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer’s disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD. There is growing need for ways to slow or prevent Alzheimer’s disease (AD). Here, the authors demonstrate that a low protein diet can protect against metabolic dysfunction, slow AD progression, and preserve cognitive function in a mouse model of AD.

Low-protein (LP) diets extend the lifespan of diverse species and are associated with improved metabolic health in both rodents and humans. Paradoxically, many athletes and bodybuilders consume high-protein (HP) diets and protein supplements, yet are both fit and metabolically healthy. Here, we examine this paradox using weight pulling, a validated progressive resistance exercise training regimen, in mice fed either an LP diet or an isocaloric HP diet. We find that despite having lower food consumption than the LP group, HP-fed mice gain significantly more fat mass than LP-fed mice when not exercising, while weight pulling protected HP-fed mice from this excess fat accretion. The HP diet augmented exercise-induced hypertrophy of the forearm flexor complex, and weight pulling ability increased more rapidly in the exercised HP-fed mice. Surprisingly, exercise did not protect from HP-induced changes in glycemic control. Our results confirm that HP diets can augment muscle hypertrophy and accelerate strength gain induced by resistance exercise without negative effects on fat mass, and also demonstrate that LP diets may be advantageous in the sedentary. Our results highlight the need to consider both dietary composition and activity, not simply calories, when taking a precision nutrition approach to health.

Stress is often associated with binge eating. A critical component of the control of stress is the central norepinephrine system. We investigated how dietary-induced binge eating alters central norepinephrine and related behaviors. Young male Sprague Dawley rats received calorie deprivation (24 h) and /or intermittent sweetened fat (vegetable shortening with sucrose; 30 min) twice a week for 10 weeks. The groups were Restrict Binge (calorie deprivation/sweetened fat), Binge (sweetened fat), Restrict (calorie deprivation), and Naive (no calorie deprivation/no sweetened fat). Dietary-induced binge eating was demonstrated by Restrict Binge and Binge, which showed an escalation in 30-min intake over time. Feeding suppression following nisoxetine (3 mg/kg; IP), a selective norepinephrine reuptake inhibitor, was not evident in Restrict Binge (Restrict Binge: 107±13, Binge: 52±9, Restrict: 80±8, Naive: 59±13% of saline injection at 1 h). In subsequent experiments with Restrict Binge and Naive, Restrict Binge had reduced corticosterone (Restrict Binge: 266±25; Naive: 494±36 ng/ml) and less feeding suppression (Restrict Binge: 81±12, Naive: 50±11% of non-restraint intake at 30 min) following restraint stress (1 h). Dietary-induced binge eating in Restrict Binge was not altered by a dorsal noradrenergic bundle lesion caused by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), but frontal cortex norepinephrine was positively correlated with the average 30-min intake post-lesion (0.69; p<0.01). In a separate set of animals, single-unit in vivo electrophysiological recording of locus coeruleus-norepinephrine neural activity demonstrated reduced sensory-evoked response as a consequence of the Restrict Binge schedule (Restrict Binge: 8.1±0.67, Naive: 11.9±1.09 Hz). These results, which suggest that a consequence of dietary-induced binge eating is to attenuate the responsiveness of the brain norepinephrine system, will further our understanding of how highly palatable foods dampen the stress neuraxis.

The neuronal cell death-promoting loss of cytoplasmic K⁺ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1–syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1–syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection.

Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. Both dietary regimens effectively promote overall metabolic health without reducing calorie intake. Both low AA and low Ile diets improve aspects of frailty and slow multiple molecular indicators of aging rate; however, the low Ile diet reduces grip strength in both sexes and has mixed, sexually dimorphic effects on the heart. These results demonstrate that low AA and low Ile diets can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults. Yeh et al. explore the effects of restricting dietary protein, or isoleucine specifically, in aged mice. They uncover benefits to metabolic health and certain indicators of aging and a sexually dimorphic effect on the heart.