Relationships among Development, Growth, Body Size, Reproduction, Aging, and Longevity - Trade-Offs and Pace-Of-Life.

Relationships of growth, metabolism, reproduction, and body size to the biological process of aging and longevity have been studied for decades and various unifying "theories of aging" have been proposed to account for the observed associations. In general, fast development, early sexual maturation leading to early reproductive effort, as well as production of many offspring, have been linked to shorter lifespans. The relationship of adult body size to longevity includes a remarkable contrast between the positive correlation in comparisons between different species and the negative correlation seen in comparisons of individuals within the same species. We now propose that longevity and presumably also the rate of aging are related to the "pace-of-life." A slow pace-of-life including slow growth, late sexual maturation, and a small number of offspring, predicts slow aging and long life. The fast pace of life (rapid growth, early sexual maturation, and major reproductive effort) is associated with faster aging and shorter life, presumably due to underlying trade-offs. The proposed relationships between the pace-of-life and longevity apply to both inter- and intra-species comparisons as well as to dietary, genetic, and pharmacological interventions that extend life and to evidence for early life programming of the trajectory of aging. Although available evidence suggests the causality of at least some of these associations, much further work will be needed to verify this interpretation and to identify mechanisms that are responsible.

Riluzole attenuates glutamatergic tone and cognitive decline in AßPP/PS1 mice.

We have previously demonstrated hippocampal hyperglutamatergic signaling occurs prior to plaque accumulation in AßPP/PS1 mice. Here, we evaluate 2-Amino-6-(trifluoromethoxy) benzothiazole (riluzole) as an early intervention strategy for Alzheimer's disease (AD), aimed at restoring glutamate neurotransmission prior to substantial Beta amyloid (Aß) plaque accumulation and cognitive decline. Male AßPP/PS1 mice, a model of progressive cerebral amyloidosis, were treated with riluzole from 2-6 months of age. Morris water maze, in vivo electrochemistry, and immunofluorescence were performed to assess cognition, glutamatergic neurotransmission, and pathology, respectively, at 12 months. Four months of prodromal riluzole treatment in AßPP/PS1 mice resulted in long-lasting procognitive effects and attenuated glutamatergic tone that was observed six months after discontinuing riluzole treatment. Riluzole-treated AßPP/PS1 mice had significant improvement in long-term memory compared to vehicle-treated AßPP/PS1 mice that was similar to normal aging C57BL/6J control mice. Furthermore, basal glutamate concentration and evoked-glutamate release levels, which were elevated in vehicle-treated AßPP/PS1 mice, were restored to levels observed in age-matched C57BL/6J mice in AßPP/PS1 mice receiving prodromal riluzole treatment. Aß plaque accumulation was not altered with riluzole treatment. This study supports that interventions targeting the glutamatergic system during the early stages of AD progression have long-term effects on disease outcome, and importantly may prevent cognitive decline. Our observations provide preclinical support for targeting glutamate neurotransmission in patients at risk for developing AD. Read the Editorial Highlight for this article on page 399.

Diet-induced insulin resistance elevates hippocampal glutamate as well as VGLUT1 and GFAP expression in AßPP/PS1 mice.

The symptomologies of Alzheimer's disease (AD) develop over decades suggesting modifiable lifestyle factors may contribute to disease pathogenesis. In humans, hyperinsulinemia associated with type 2 diabetes mellitus increases the risk for developing AD and both diseases share similar age-related etiologies including amyloidogenesis. Since we have demonstrated that soluble Aß42 elicits glutamate release, we wanted to understand how diet-induced insulin resistance alters hippocampal glutamate dynamics, which are important for memory formation and consolidation. Eight to twelve-week-old C57BL/6J and AßPP/PS1 mice were placed on either a low-fat diet or high-fat diet (HFD) for 8 months. A HFD led to significant weight increases as well as impaired insulin sensitivity, glucose tolerance, and learning in both C57BL/6J and AßPP/PS1 mice. AßPP/PS1 low-fat diet mice had elevated hippocampal basal as well as stimulus-evoked glutamate release that was further increased with consumption of a HFD. Immunohistochemistry indicated an increase in vesicular glutamate transporter 1 and glial fibrillary acidic protein density in hippocampal subregions corresponding with this elevated extracellular glutamate. While no differences in hippocampal plaque load were observed, the elevated astrogliotic response surrounding the plaques in AßPP/PS1 HFD mice may have been a compensatory mechanism to control plaque accumulation. These data support that AßPP/PS1 mice have chronically elevated extracellular glutamate that is exacerbated by a HFD and that modifiable lifestyle factors such as obesity-induced insulin resistance can contribute to AD pathogenesis. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* and for *Open Data* because it made the data publicly available. The data can be accessed at https://osf.io/5whvu (figures for data) and https://osf.io/gd5vf (materials and methods). The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Cover Image for this issue: doi: 10.1111/jnc.14490.

Responses to Many Anti-Aging Interventions Are Sexually Dimorphic.

There is increasing appreciation that sex differences are not limited to reproductive organs or traits related to reproduction and that sex is an important biological variable in most characteristics of a living organism. The biological process of aging and aging-related traits are no exception and exhibit numerous, often major, sex differences. This article explores one aspect of these differences, namely sex differences in the responses to anti-aging interventions. Aging can be slowed down and/or postponed by a variety of environmental ("lifestyle"), genetic or pharmacological interventions. Although many, particularly older studies utilized only one sex of experimental animals, there is considerable evidence that responses to these interventions can be very different in females and males. Calorie restriction (CR), that is reducing food intake without malnutrition can extend longevity in both sexes, but specific metabolic alterations and health benefits induced by CR are not the same in women and men. In laboratory mice, several of the genetic alterations that reduce insulin-like growth factor I (IGF-1) signaling extend longevity more effectively in females or in females only. Beneficial effects of rapamycin, an inhibitor of mTOR signaling, on mouse longevity are greater in females. In contrast, several anti-aging compounds, including a weak estrogen, 17 alpha estradiol, extend longevity of male, but not female, mice. Apparently, fundamental mechanisms of aging are not identical in females and males and it is essential to use both sexes in studies aimed at identifying novel anti-aging interventions. Recommendations for lifestyle modifications, drugs, and dietary supplements to maintain good health and functionality into advanced age and to live longer will likely need to be tailored to the sex of the user.

Microglial Piezo1 mechanosensitive channel as a therapeutic target in Alzheimer's disease.

Microglia are the resident macrophages of the central nervous system (CNS) that control brain development, maintain neural environments, respond to injuries, and regulate neuroinflammation. Despite their significant impact on various physiological and pathological processes across mammalian biology, there remains a notable gap in our understanding of how microglia perceive and transmit mechanical signals in both normal and diseased states. Recent studies have revealed that microglia possess the ability to detect changes in the mechanical properties of their environment, such as alterations in stiffness or pressure. These changes may occur during development, aging, or in pathological conditions such as trauma or neurodegenerative diseases. This review will discuss microglial Piezo1 mechanosensitive channels as potential therapeutic targets for Alzheimer's disease (AD). The structure, function, and modulation of Piezo1 will be discussed, as well as its role in facilitating microglial clearance of misfolded amyloid-ß (Aß) proteins implicated in the pathology of AD.

Sex-Dependent Effects of Chronic Circadian Disruption in AßPP/PS1 Mice.

BACKGROUND: Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects. OBJECTIVE: The current study examined how chronic circadian disruption (CD) could contribute to pathology and rate of progression in the AßPP/PS1 mouse model of Alzheimer's disease (AD). METHODS: A chronic CD was imposed until animals reached 6 or 12 months of age in AßPP/PS1 and C57BL/6J control mice. Home cage activity was monitored for a period of 3-4 weeks prior to the endpoint along with a single timepoint measure of glucose sensitivity. To assess long term effects of CD on the AD phenotype, animals were re-entrained to a no disruption (ND) schedule just prior to the endpoint, after which a Morris water maze (MWM) was used to assess spatial learning and memory. RESULTS: Dampening of nighttime activity levels occurred in disrupted animals, and female animals demonstrated a greater adaptability to CD. Diminished arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) levels in the suprachiasmatic nucleus (SCN) of 12-month male AßPP/PS1 exposed to the CD paradigm were observed, potentially accounting for the diminished re-entrainment response. Similarly, CD worsened performance in the MWM in 12-month male AßPP/PS1 animals, whereas no effect was seen in females. CONCLUSIONS: Collectively, these findings show that exposure to chronic CD impairs circadian behavioral patterns and cognitive phenotypes of AßPP/PS1 mouse model in a sex-dependent manner.

Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice.

Background: It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer's disease (AD) progression, contributing to negative cognitive outcomes. Objective: In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL-F). Methods: At 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Results: Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. Conclusions: These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer's disease (AD). The APP NL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APP NL-F/NL-F mice. Thus, four month old male and female APP NL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasatinib + 50 mg/kg Quercetin, or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + Quercetin treatment in female APP NL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-ß (Aß) 42 and senescence associated-ß-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APP NL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL-F/NL-F mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer's disease (AD). The APPNL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-F mice. Thus, 4-month-old male and female APPNL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APPNL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-ß (Aß)42 and senescence-associated-ß-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-ß (Aß)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.