Development Of Age-related Diseases Research Articles

SAT046 Canagliflozin Leads To Less Weight Gain, Confers Changes In The Gut Microbiota And Extends Life Span In Male C57BL6 Mice

Abstract Disclosure: E.E. Habeos: None. F. Filippopoulou: None. M. Kanakis: None. G.I. Habeos: None. N. Belmokhtar: None. P. Stathopoulou: None. G. Tsiamis: None. S. Taraviras: None. G. Lagoumintzis: None. D.V. Chartoumpekis: None. Introduction: SGLT2 inhibitors (SGLT2i) are widely prescribed drugs for the treatment of diabetes. Their beneficial health effects appear to be pleiotropic and are not limited to the amelioration of glycemic profile. The SGLT2i-induced glycosuria is suggested to provoke a metabolic shift that mimics the fasting response. Since calorie restriction has been shown to enhance longevity in mice, we hypothesized that treating mice with SGLT2i would also increase their life span. Methods: To this end, 4-months old male C57BL6 mice were fed with a standard chow diet (Control, n=83) or a diet supplemented with 200 mg/kg canagliflozin (Cana, n=92) and were observed up to the natural end of their life. Results: The canagliflozin-treated mice gained less weight over time. For instance, at the age of 10 months, the body weight of control mice was higher (means ± SEM: 33.1 ± 0.26 g) than the body weight of their canagliflozin-treated counterparts (means ± SEM: 31.4± 0.21 g; p<0.01). The development and severity of age-related cataracts were also examined at the age of 14 months, but no statistically significant difference was found in the severity score between the 2 groups. The survival curves of the control and the Cana mice diverged significantly, with the median survival of the control being 107.5 weeks versus 112.5 weeks of the Cana group (p=0.011). As the gut microbiome is known to change with age and be associated with the development of age-related diseases, feces were collected from 17-month-old mice (n=10 per group) and analysis of fecal bacterial 16S rRNA sequences was performed. Differences in beta diversity (diversity of bacterial species across samples) and relative abundance of bacterial species were noted between the Control and the Cana groups. Conclusions-Discussion: Our study highlights the effect of SGLT2i on longevity in a widely used mouse model (C57BL6). The underlying mechanisms leading to the enhancement of longevity are not clear yet. Some microbiota changes associated with the SGLT2i treatment, as described in other mouse models with enhanced longevity, warrant further investigation and analysis. It would be useful to extend these studies employing various SGLT2i with different potencies and selectivity against SGLT so as to determine if the observed effect on longevity is independent of the type of the drug. Presentation: Saturday, June 17, 2023

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease.

Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age-related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood-brain barrier to reach the target areas in the brain or to regulate the function of the blood-brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood-brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Effects of Vitamin E on the Gut Microbiome in Ageing and Its Relationship with Age-Related Diseases: A Review of the Current Literature.

Ageing is inevitable in all living organisms and is associated with physical deterioration, disease and eventually death. Dysbiosis, which is the alteration of the gut microbiome, occurs in individuals during ageing, and plenty of studies support that gut dysbiosis is responsible for the progression of different types of age-related diseases. The economic burden of age-linked health issues increases as ageing populations increase. Hence, an improvement in disease prevention or therapeutic approaches is urgently required. In recent years, vitamin E has garnered significant attention as a promising therapeutic approach for delaying the ageing process and potentially impeding the development of age-related disease. Nevertheless, more research is still required to understand how vitamin E affects the gut microbiome and how it relates to age-related diseases. Therefore, we gathered and summarized recent papers in this review that addressed the impact of the gut microbiome on age-related disease, the effect of vitamin E on age-related disease along with the role of vitamin E on the gut microbiome and the relationship with age-related diseases which are caused by ageing. Based on the studies reported, different bacteria brought on various age-related diseases with either increased or decreased relative abundances. Some studies have also reported the positive effects of vitamin E on the gut microbiome as beneficial bacteria and metabolites increase with vitamin E supplementation. This demonstrates how vitamin E is vital as it affects the gut microbiome positively to delay ageing and the progression of age-related diseases. The findings discussed in this review will provide a simplified yet deeper understanding for researchers studying ageing, the gut microbiome and age-related diseases, allowing them to develop new preclinical and clinical studies.

The Impact of Carvedilol on Organ Index, Inflammatory Mediators, Oxidative Stress Parameters and Skin Markers in D-Galactose-Induced Aging Mice

Background: Aging processes are defined as those that increase the susceptibility of individuals, as they grow older, to the factors that eventually lead to death. It is a complex multi-factorial process where several factors may interact simultaneously and may operate at many levels of functional organization.. Accumulating evidence has suggested that active ingredients that possess antioxidative and anti-inflammatory proprties could decrease the incidence and development of aging-related diseases and promote longevity. Carvedilol is a non-selective third generation β-blocker/α1-blocker with antioxidant and inflammatory activity to evaluate its antiaging effect and to investigate if it is better to given carvedilol with aging induction or after aging induction is established. Aim: To evaluate the effect of carvedilol on organ index, inflammatory mediators, oxidative stress parameters and skin markers in d-galactose-induced aging mice. Method: Male (swiss albino mice) weighing 20 to 30 g and aged 3 to 6 months was randomly divided into six groups , each consisting of 10 animals (60 mice in total). Group I was given normal saline orally only for six weeks, group II was given d-galactose 500 mg/kg orally only for six weeks, group III was given d-galactose 500 mg/kg orally and vitamin C 100 mg/kg orally concomitantly for six weeks, group IV given d-galactose 500 mg/kg orally only for six weeks, then directly next day after ending of aging induction, vitamin c 100 mg/kg started for another six weeks, group V given d-galactose 500 mg/kg orally and carvedilol 10 mg/kg orally concomitantly for six weeks, group VI given d-galactose 500 mg/kg orally only for six weeks, then directly next day after ending of aging induction, carvedilol 10 mg/kg started for another six weeks. After that, animals were weighed, euthanized, and dissected, the heart was removed and the organ index was calculated. Also the heart tissue is divided in to two parts, one homogenated to measure interleukin-Iβ, tumor necrosis factor-alpha, glutathione peroxidase and malondialdehyde, while the other piece for histopathological analysis to determine the presence of hypertrophy. Skin tissue was taken and homogenated for ELISA assay (measurement of collagen I and III levels ). Results: Results showed a significant decrease in heart organ index in animals that received carvedilol orally administered compared to aged group, with a substantial decrease in inflammatory mediators, malondialdehyde level and a marked increase in glutathione peroxidase level, collagen I and collagen III levels. Furthermore, carvedilol reverses the myocardial hypertrophy induced by D-galactose. Conclusion: The present study suggests that carvedilol has a positive antiaging benefit in reducing oxidative stress, decreasing inflammatory and skin aging markers and improving hypertrophic cardiac cells. Regarding the timing of drug administration, although carvedilol shows a benficial continuing impact when given with and after the initiation of aging. It’s better to give at starting of the aging process to control the aging series as soon as possible

The Aging of Cells: Cellular Senescence and Implications for Age-Related Diseases

Cellular senescence, the aging of cells, is a multifaceted process characterized by the progressive accumulation of molecular and cellular changes. Senescent cells, marked by their proinflammatory secretome called the senescence-associated secretory phenotype (SASP), contribute to tissue dysfunction and promote aging processes. In this review, we provide a comprehensive overview of the current understanding of cellular senescence, with a particular focus on the underlying mechanisms driving cell aging and the strategies of targeting senescent cells to extend healthspan and alleviate age-related diseases. We discuss how factors such as telomere shortening, DNA damage, oxidative stress, and oncogene activation contribute to cellular aging and the development of age-related diseases. Furthermore, we explore the potential senotherapeutic interventions, including senolytic and senomorphic therapies, that target senescent cells. Lastly, we highlight the opportunities and challenges of senotherapeutics in the context of aging and aging-associated diseases, underscoring their potential implications for human health and longevity.

Immunomodulatory Effects of SGLT2 Inhibitors-Targeting Inflammation and Oxidative Stress in Aging.

Given that the increase in the aging population has grown into one of the largest public health issues, inflammation and oxidative stress, which are closely associated with the aging process, became a focus of recent research. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a group of drugs initially developed as oral antidiabetics, have shown many beneficial effects over time, including improvement in renal function and cardioprotective effects. It has been shown that SGLT2 inhibitors, as a drug class, have an immunomodulatory and antioxidative effect, affecting endothelial function as well as metabolic parameters. Therefore, it is not surprising that various studies have investigated the potential mechanisms of action of SGLT2 inhibitors in age-related diseases. The proposed mechanisms by which SGLT2 inhibitors can achieve their anti-inflammatory effects include influence on AMPK/SIRT1/PGC-1α signaling, various cytokines, and the NLRP3 inflammasome. The antioxidative effect is related to their action on mitochondria and their influence on the signaling pathways of transforming growth factor β and nuclear erythroid 2-related factor 2/antioxidant response element. Also, SGLT2 inhibitors achieve their anti-inflammatory and antioxidative effects by affecting metabolic parameters, such as uric acid reduction, stimulation of ketogenesis, reduction of body weight, lipolysis, and epicardial fat tissue. Finally, SGLT2 inhibitors display anti-atherosclerotic effects that modulate inflammatory reactions, potentially resulting in improvement in endothelial function. This narrative review offers a complete and comprehensive overview of the possible pathophysiologic mechanisms of the SGLT2 inhibitors involved in the aging process and development of age-related disease. However, in order to use SGLT2 inhibitor drugs as an anti-aging therapy, further basic and clinical research is needed to elucidate the potential effects and complex mechanisms they have on inflammation processes.

Retinal microvascular complexity as a putative biomarker of biological age: a pilot study.

Physiological changes associated with aging increase the risk for the development of age-related diseases. This increase is non-specific to the type of age-related disease, although each disease develops through a unique pathophysiologic mechanism. People who age at a faster rate develop age-related diseases earlier in their life. They have an older "biological age" compared to their "chronological age". Early detection of individuals with accelerated aging would allow timely intervention to postpone the onset of age-related diseases. This would increase their life expectancy and their length of good quality life. The goal of this study was to investigate whether retinal microvascular complexity could be used as a biomarker of biological age. Retinal images of 68 participants ages ranging from 19 to 82years were collected in an observational cross-sectional study. Twenty of the old participants had age-related diseases such as hypertension, type 2 diabetes, and/or Alzheimer's dementia. The rest of the participants were healthy. Retinal images were captured by a hand-held, non-mydriatic fundus camera and quantification of the microvascular complexity was performed by using Sholl's, box-counting fractal, and lacunarity analysis. In the healthy subjects, increasing chronological age was associated with lower retinal microvascular complexity measured by Sholl's analysis. Decreased box-counting fractal dimension was present in old patients, and this decrease was 2.1 times faster in participants who had age-related diseases (p = 0.047). Retinal microvascular complexity could be a promising new biomarker of biological age. The data from this study is the first of this kind collected in Montenegro. It is freely available for use.

Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review.

The aging of an organism is hallmarked by systemic loss of functional tissue, resulting in increased fragility and eventual development of age-related neurodegenerative, musculoskeletal, cardiovascular, and neoplastic diseases. Growing scientific evidence points to mitochondrial dysfunction as a key contributor in the aging process and subsequent development of age-related pathologies. Under normal physiologic conditions, the body removes dysfunctional mitochondria via an autophagic process known as mitophagy. Urolithin A (UA), a metabolite produced when gut microflora digests the polyphenol compounds ellagitannin and ellagic acid, is a known inducer of mitophagy via several identified mechanisms of action. The primary objective of this scoping review is to identify and summarize the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases. A computer-assisted literature review was performed using PubMed and EMBASE for primary source research articles examining UA supplementation and aging-related pathologies. A total of 293 articles were initially identified from a database search, and 15 articles remained for inclusion in this review, based on predetermined criteria. Analysis of the 15 identified publications demonstrated that UA holds potential as a dietary intervention for slowing the progression of aging and preventing the development of age-related disease. This review also illustrates the potential role that mitochondrial health and inflammation play in the progression of age-related pathology. Identifying the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases will help further the focus of research on treatments that may improve the longevity and quality of life in patientsat risk for these comorbidities.

Towards disease-oriented dosing of rapamycin for longevity: does aging exist or only age-related diseases?

Both individuals taking rapamycin, an anti-aging drug, and those not taking it will ultimately succumb to age-related diseases. However, the former, if administered disease-oriented dosages for a long time, may experience a delayed onset of such diseases and live longer. The goal is to delay a particular disease that is expected to be life-limiting in a particular person. Age-related diseases, quasi-programmed during development, progress at varying rates in different individuals. Rapamycin is a prophylactic anti-aging drug that decelerates early development of age-related diseases. I further discuss hyperfunction theory of quasi-programmed diseases, which challenges the need for the traditional concept of aging itself.

Dasatinib and quercetin increase testosterone andsperm concentration in mice.

Cellular senescence is a defense mechanism to arrest proliferation of damaged cells. The number of senescentcells increases with age in different tissues and contributes to the development of age-related diseases. Old mice treated with senolytics drugs, dasatinib and quercetin (D+Q), have reduced senescent cells burden. The aim of this study was to evaluate the effects of D+Q on testicular function and fertility of male mice. Mice (n = 9/group) received D (5 mg kg-1) and Q (50 mg kg-1) via gavage every moth for three consecutive days from 3 to 8 months of age. At 8 months mice were breed with young non-treated females and euthanized. The treatment of male mice with D+Q increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology. Sperm motility, seminiferous tubule morphometry, testicular gene expression and fertility were not affected by treatment. There was no effect of D+Q treatment in β-galactosidase activity and in lipofuscin staining in testes. D+Q treatment also did not affect body mass gain and testes mass. In conclusion, D+Q treatment increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology, however did not affect fertility. Further studies with older mice and different senolytics are necessary to elucidate the effects in the decline of sperm output (quality and quantity) associated with aging.

A Role for Advanced Glycation End Products in Molecular Ageing.

Ageing is a composite process that involves numerous changes at the cellular, tissue, organ and whole-body levels. These changes result in decreased functioning of the organism and the development of certain conditions, which ultimately lead to an increased risk of death. Advanced glycation end products (AGEs) are a family of compounds with a diverse chemical nature. They are the products of non-enzymatic reactions between reducing sugars and proteins, lipids or nucleic acids and are synthesised in high amounts in both physiological and pathological conditions. Accumulation of these molecules increases the level of damage to tissue/organs structures (immune elements, connective tissue, brain, pancreatic beta cells, nephrons, and muscles), which consequently triggers the development of age-related diseases, such as diabetes mellitus, neurodegeneration, and cardiovascular and kidney disorders. Irrespective of the role of AGEs in the initiation or progression of chronic disorders, a reduction in their levels would certainly provide health benefits. In this review, we provide an overview of the role of AGEs in these areas. Moreover, we provide examples of lifestyle interventions, such as caloric restriction or physical activities, that may modulate AGE formation and accumulation and help to promote healthy ageing.

The role of IGF-1/GH in the aging process and the development of age-related diseases

One of the most important trends in geroscience is the search for the biomechanisms of aging and geroprotective methods. In recent years, more and more attention has been paid to the role of age-related decline in IGF-1 levels; processes that start with a decrease in the activity of the GH/IGF-1 axis. IGF-1 levels correlate differently with many age-associated diseases: diabetes mellitus, cancer, cardiovascular disease. A decrease in the level of IGF-1 and growth hormone in the elderly can contribute to the deterioration of the course of some pathologies, and also have a protective effect in the occurrence of different nosologies. The possibility of slowing down aging with the help of IGF-1 in basic research led to research aimed at studying the possibility of using IGF-1 preparations and growth hormone in clinical practice to slow down aging. We have studied the literature on the Pubmed platform, Scopus for the past 10 years in order to find some new information regarding influence of IGF-1 on aging, about the association between IGF-1 levels and major age-related diseases. We analyzed data of publications on the role of IGF-1 in aging and the development of age-related diseases. The search was carried out using key words: IGF-1, growth hormone, aging, the review included data from more than 60 publications.

Zbp1 gene: a modulator of multiple aging hallmarks as potential therapeutic target for age-related diseases.

The Zbp1 gene has recently emerged as a potential therapeutic target for age-related diseases. Multiple studies have reported that Zbp1 plays a key role in regulating several aging hallmarks, including cellular senescence, chronic inflammation, DNA damage response, and mitochondrial dysfunction. Regarding cellular senescence, Zbp1 appears to regulate the onset and progression of senescence by controlling the expression of key markers such as p16INK4a and p21CIP1/WAF1. Similarly, evidence suggests that Zbp1 plays a role in regulating inflammation by promoting the production of pro-inflammatory cytokines, such as IL-6 and IL-1β, through activation of the NLRP3 inflammasome. Furthermore, Zbp1 seems to be involved in the DNA damage response, coordinating the cellular response to DNA damage by regulating the expression of genes such as p53 and ATM. Additionally, Zbp1 appears to regulate mitochondrial function, which is crucial for energy production and cellular homeostasis. Given the involvement of Zbp1 in multiple aging hallmarks, targeting this gene represents a potential strategy to prevent or treat age-related diseases. For example, inhibiting Zbp1 activity could be a promising approach to reduce cellular senescence and chronic inflammation, two critical hallmarks of aging associated with various age-related diseases. Similarly, modulating Zbp1 expression or activity could also improve DNA damage response and mitochondrial function, thus delaying or preventing the development of age-related diseases. Overall, the Zbp1 gene appears to be a promising therapeutic target for age-related diseases. In the current review, we have discussed the molecular mechanisms underlying the involvement of Zbp1 in aging hallmarks and proposed to develop effective strategies to target this gene for therapeutic purposes.

Fas (CD95)/FasL (CD178) system during ageing.

The Fas/FasL system plays a central role in the physiological regulation of apoptosis and has been implicated in the pathogenesis of several neoplasms and diseases of the immune system. Until now, it has received little attention in the context of ageing, but there is sufficient evidence that it plays an important role in this process and its deregulation favours the development of age-related diseases such as osteoarthritis, diabetes, eye diseases, ischaemic processes, anaemia, Alzheimer's disease and cancer. With this in mind, the aim of this work was to describe the main changes that occur in the Fas/FasL system during ageing and their association with the development of age-related diseases. Furthermore, it discusses how exercise and diet, considered the cornerstone of almost all healthy ageing programmes, produce beneficial effects through the regulation of the Fas/FasL system.

Redox-Mechanisms of Molecular Hydrogen Promote Healthful Longevity.

Age-related diseases represent the largest threat to public health. Aging is a degenerative, systemic, multifactorial and progressive process, coupled with progressive loss of function and eventually leading to high mortality rates. Excessive levels of both pro- and anti-oxidant species qualify as oxidative stress (OS) and result in damage to molecules and cells. OS plays a crucial role in the development of age-related diseases. In fact, damage due to oxidation depends strongly on the inherited or acquired defects of the redox-mediated enzymes. Molecular hydrogen (H2) has recently been reported to function as an anti-oxidant and anti-inflammatory agent for the treatment of several oxidative stress and aging-related diseases, including Alzheimer's, Parkinson's, cancer and osteoporosis. Additionally, H2 promotes healthy aging, increases the number of good germs in the intestine that produce more intestinal hydrogen and reduces oxidative stress through its anti-oxidant and anti-inflammatory activities. This review focuses on the therapeutic role of H2 in the treatment of neurological diseases. This review manuscript would be useful in knowing the role of H2 in the redox mechanisms for promoting healthful longevity.

Cross-National and Cross-Generational Evidence That Educational Attainment May Slow the Pace of Aging in European-Descent Individuals.

Individuals with more education are at lower risk of developing multiple, different age-related diseases than their less-educated peers. A reason for this might be that individuals with more education age slower. There are 2 complications in testing this hypothesis. First, there exists no definitive measure of biological aging. Second, shared genetic factors contribute toward both lower educational attainment and the development of age-related diseases. Here, we tested whether the protective effect of educational attainment was associated with the pace of aging after accounting for genetic factors. We examined data from 5 studies together totaling almost 17,000 individuals with European ancestry born in different countries during different historical periods, ranging in age from 16 to 98 years old. To assess the pace of aging, we used DunedinPACE, a DNA methylation algorithm that reflects an individual's rate of aging and predicts age-related decline and Alzheimer's disease and related disorders. To assess genetic factors related to education, we created a polygenic score based on the results of a genome-wide association study of educational attainment. Across the 5 studies, and across the life span, higher educational attainment was associated with a slower pace of aging even after accounting for genetic factors (meta-analysis effect size = -0.20; 95% confidence interval [CI]: -0.30 to -0.10; p = .006). Further, this effect persisted after taking into account tobacco smoking (meta-analysis effect size = -0.13; 95% CI: -0.21 to -0.05; p = .01). These results indicate that higher levels of education have positive effects on the pace of aging, and that the benefits can be realized irrespective of individuals' genetics.

Humanin and Its Pathophysiological Roles in Aging: A Systematic Review.

Senescence is a cellular aging process in all multicellular organisms. It is characterized by a decline in cellular functions and proliferation, resulting in increased cellular damage and death. These conditions play an essential role in aging and significantly contribute to the development of age-related complications. Humanin is a mitochondrial-derived peptide (MDP), encoded by mitochondrial DNA, playing a cytoprotective role to preserve mitochondrial function and cell viability under stressful and senescence conditions. For these reasons, humanin can be exploited in strategies aiming to counteract several processes involved in aging, including cardiovascular disease, neurodegeneration, and cancer. Relevance of these conditions to aging and disease: Senescence appears to be involved in the decay in organ and tissue function, it has also been related to the development of age-related diseases, such as cardiovascular conditions, cancer, and diabetes. In particular, senescent cells produce inflammatory cytokines and other pro-inflammatory molecules that can participate to the development of such diseases. Humanin, on the other hand, seems to contrast the development of such conditions, and it is also known to play a role in these diseases by promoting the death of damaged or malfunctioning cells and contributing to the inflammation often associated with them. Both senescence and humanin-related mechanisms are complex processes that have not been fully clarified yet. Further research is needed to thoroughly understand the role of such processes in aging and disease and identify potential interventions to target them in order to prevent or treat age-related conditions. This systematic review aims to assess the potential mechanisms underlying the link connecting senescence, humanin, aging, and disease.

Development of new non-viral systems for genetic modification of senescent cells

Senescence is a process characterized by a prolonged irreversible cell-cycle arrest. The accumulation of senescent cells in tissues is related to aging and to the development of age-related diseases. Recently, gene therapy has emerged as a powerful tool for treating age-associated diseases by the transference of specific genes into the target cell population. However, thehigh sensitivity of senescent cells significantly precludes their genetic modification via classical viral and non-viral systems. Niosomes are self-assembled non-viral nanocarriers that exhibit important advantages due to their elevated cytocompatibility, versatility, and cost-efficiency, arising as a new alternative for genetic modification of senescent cells. In this work, we explore for the first time the use of niosomes for genetic modification of senescent umbilical cord-derived mesenchymal stem cells. We report that niosome composition greatly affected transfection efficiency; those formulations prepared in medium with sucrose and containing cholesterol as helper lipid being the most suitable to transfect senescent cells. Moreover, resulting niosome formulations exhibited a superior transfection efficiency with a markedly less cytotoxicity than the commercial reagent Lipofectamine. These findings highlight the potentiality of niosomes as effective vectors for genetic modification of senescent cells, providing new tools for the prevention and/or treatment of age-related diseases.

Zingiber officinale Roscoe Rhizome Extract Exerts Senomorphic and Anti-Inflammatory Activities on Human Endothelial Cells

Aging is related to a low-grade and sterile inflammation called inflammaging, recognized as the main risk factor for age-related disease (ARD) development. Inflammaging is fostered by the repeated activation of immune cells, as well as by the accumulation of senescent cells. Recently, a number of natural compounds have gained attention to be tested as anti-aging therapies, based on their anti-inflammatory activity and/or ability to reduce the pro-inflammatory secretome of senescent cells (senomorphyc activity). Here, we investigated the anti-inflammatory and senomorphic properties of an Asian-native Zingiber officinale Roscoe extract (ZOE), commonly consumed as a food spice and herbal medicine. We employed two models of primary endothelial cells (HUVECs), such as the replicative-senescence and LPS-induced response, to investigate the anti-inflammatory/senomorphic effect of ZOE, and one cellular model of neuroinflammation, i.e., immortalized murine microglial cells (BV2). First, we found that the ZOE treatment induced the inhibition of NF-kB activation in BV2 cells. Among the constituents of ZOE, we showed that the terpenoid-enriched fraction (ZTE) was the component able to counteract the phosphorylation of NF-kB(p65), while 6-gingerol (GIN) and 6-shogaol (SHO) did not produce any significant effect. Further, we observed that the treatment with 10 µg/mL of ZOE exerted anti-inflammatory activity on LPS-stimulated young (y)HUVEC and senomorphyc activity on replicative senescent (s)HUVEC, significantly reducing the expression levels of IL-1β, TNF -α, IL-8, MCP-1, and ICAM-1. Moreover, the ZTE treatment was able to significantly reduce the IL-8 levels secreted in the medium of both LPS-stimulated yHUVEC and sHUVEC. Overall, our data suggest a potential protective role of ZOE on neuroinflammation and endothelial inflammation/activation, thus suggesting its potential relevance in delaying/postponing ARD development and progression, characterized by endothelial dysfunction.

Neuronal SIRT3 Deletion Predisposes to Female-Specific Alterations in Cellular Metabolism, Memory, and Network Excitability.

Mitochondrial dysfunction is an early event in the pathogenesis of neurologic disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass spectrometry-based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons in the cortex and hippocampus produces altered neuronal excitability and metabolic dysfunction in female mice. Targeted deletion of SIRT3 from neuronal helix-loop-helix 1 (NEX)-expressing neurons resulted in mitochondrial hyperacetylation, female-specific superoxide dismutase-2 (SOD2) modification, increased steady-state superoxide levels, metabolic reprogramming, altered neuronal excitability, and working spatial memory deficits. Inducible neuronal deletion of SIRT3 likewise produced female-specific deficits in spatial working memory. Together, the data demonstrate that deletion of SIRT3 from forebrain neurons selectively predisposes female mice to deficits in mitochondrial and cognitive function.SIGNIFICANCE STATEMENT Mitochondrial SIRT3 is an enzyme shown to regulate energy metabolism and antioxidant function, by direct deacetylation of proteins. In this study, we show that neuronal SIRT3 deficiency renders female mice selectively vulnerable to impairment in redox and metabolic function, spatial memory, and neuronal excitability. The observed sex-specific effects on cognition and neuronal excitability in female SIRT3-deficient mice suggest that mitochondrial dysfunction may be one factor underlying comorbid neuronal diseases, such as Alzheimer's disease and epilepsy. Furthermore, the data suggest that SIRT3 dysfunction may predispose females to age-related metabolic and cognitive impairment.