bims-sediag Biomed News
on Sexual dimorphism in the mechanisms underlying aging
Issue of 2022‒05‒29
thirteen papers selected by
Rahagir Salekeen Susmoy
University of Minnesota
  1. Sex Dimorphism in the Metabolome of Metabolic Syndrome in Morbidly Obese Individuals.
  2. Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases.
  3. Recent Advances in Epigenetics of Age-Related Kidney Diseases.
  4. Sex Differences in the Immune System in Relation to Hypertension and Vascular Disease.
  5. Sex differences in time trends in acute coronary syndrome management and in 12-month lethality: Data from the French MONICA registries.
  6. Se(XY) matters: the importance of incorporating sex in microphysiological models.
  7. Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle.
  8. Are there sex differences in risk for exertional heat stroke? A translational approach.
  9. Aging, sex and NLRP3 inflammasome in cardiac ischaemic disease.
  10. Reproductive tradeoffs govern sexually dimorphic tubular lysosome induction in C. elegans.
  11. Sexual Dimorphism in Renal Heme Oxygenase-1 and Arachidonic Acid Metabolizing Enzymes in Spontaneously Hypertensive Rats versus Normotensive Wistar Kyoto Rats.
  12. Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure.
  13. Significant Sex Differences in the Efficacy of the CSF1R Inhibitor-PLX5622 on Rat Brain Microglia Elimination.
  1. Metabolites. 2022 May 06. pii: 419. [Epub ahead of print]12(5):
    Sex Dimorphism in the Metabolome of Metabolic Syndrome in Morbidly Obese Individuals.
    Serena Pisoni, Vannina G Marrachelli, Jose M Morales, Sabrina Maestrini, Anna M Di Blasio, Daniel Monleón.
      Adult morbid obesity is defined as abnormal or excessive fat accumulation, mostly resulting from a long-term unhealthy lifestyle. Between 10% and 30% of people with obesity exhibit low cardiometabolic risk. The metabolic syndrome has been suggested as an indicator of obesity-related metabolic dysregulation. Although the prevalence of obesity does not seem to be sex-related and metabolic syndrome occurs at all ages, in the last few years, sex-specific differences in the pathophysiology, diagnosis, and treatment of metabolic syndrome have received attention. The aim of this study was to determine the prevalence of metabolic syndrome and its components in different sex and age groups in people with metabolic unhealthy obesity and to compare them with people with metabolic healthy obesity. We analyzed the metabolome in 1350 well-phenotyped morbidly obese individuals and showed that there is a strong sex-dependent association of metabolic syndrome with circulating metabolites. Importantly, we demonstrated that metabolic dysregulation in women and men with severe obesity and metabolic syndrome is age-dependent. The metabolic profiles from our study showed age-dependent sex differences in the impact of MetS which are consistent with the cardiometabolic characterization. Although there is common ground for MetS in the metabolome of severe obesity, men older than 54 are affected in a more extensive and intensive manner. These findings strongly argue for more studies aimed at unraveling the mechanisms that underlie this sex-specific metabolic dysregulation in severe obesity. Moreover, these findings suggest that women and men might benefit from differential sex and age specific interventions to prevent the adverse cardiometabolic effects of severe obesity.
    Keywords:  age dependence; metabolic syndrome; metabolomics; severe obesity; sex dimorphism
    DOI:  https://doi.org/10.3390/metabo12050419
  2. Front Aging Neurosci. 2022 ;14 845330
    Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases.
    Wei Wan, Fuzhou Hua, Pu Fang, Chang Li, Fumou Deng, Shoulin Chen, Jun Ying, Xifeng Wang.
      Sirtuins are protein factors that can delay aging and alleviate age-related diseases through multiple molecular pathways, mainly by promoting DNA damage repair, delaying telomere shortening, and mediating the longevity effect of caloric restriction. In the last decade, sirtuins have also been suggested to exert mitochondrial quality control by mediating mitophagy, which targets damaged mitochondria and delivers them to lysosomes for degradation. This is especially significant for age-related diseases because dysfunctional mitochondria accumulate in aging organisms. Accordingly, it has been suggested that sirtuins and mitophagy have many common and interactive aspects in the aging process. This article reviews the mechanisms and pathways of sirtuin family-mediated mitophagy and further discusses its role in aging and age-related diseases.
    Keywords:  age-related disease; aging; mitochondria; mitophagy; neurodegenerative diseases; sirtuins
    DOI:  https://doi.org/10.3389/fnagi.2022.845330
  3. Genes (Basel). 2022 Apr 29. pii: 796. [Epub ahead of print]13(5):
    Recent Advances in Epigenetics of Age-Related Kidney Diseases.
    Feng Liu, Jiefang Chen, Zhenqiong Li, Xianfang Meng.
      Renal aging has attracted increasing attention in today's aging society, as elderly people with advanced age are more susceptible to various kidney disorders such as acute kidney injury (AKI) and chronic kidney disease (CKD). There is no clear-cut universal mechanism for identifying age-related kidney diseases, and therefore, they pose a considerable medical and public health challenge. Epigenetics refers to the study of heritable modifications in the regulation of gene expression that do not require changes in the underlying genomic DNA sequence. A variety of epigenetic modifiers such as histone deacetylases (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have been proposed as potential biomarkers and therapeutic targets in numerous fields including cardiovascular diseases, immune system disease, nervous system diseases, and neoplasms. Accumulating evidence in recent years indicates that epigenetic modifications have been implicated in renal aging. However, no previous systematic review has been performed to systematically generalize the relationship between epigenetics and age-related kidney diseases. In this review, we aim to summarize the recent advances in epigenetic mechanisms of age-related kidney diseases as well as discuss the application of epigenetic modifiers as potential biomarkers and therapeutic targets in the field of age-related kidney diseases. In summary, the main types of epigenetic processes including DNA methylation, histone modifications, non-coding RNA (ncRNA) modulation have all been implicated in the progression of age-related kidney diseases, and therapeutic targeting of these processes will yield novel therapeutic strategies for the prevention and/or treatment of age-related kidney diseases.
    Keywords:  DNA methylation; age-related kidney diseases; epigenetics; histone modification; non-coding RNA regulation
    DOI:  https://doi.org/10.3390/genes13050796
  4. Can J Cardiol. 2022 May 18. pii: S0828-282X(22)00318-X. [Epub ahead of print]
    Sex Differences in the Immune System in Relation to Hypertension and Vascular Disease.
    Kevin D Comeau, Brandon G Shokoples, Ernesto L Schiffrin.
      Hypertension is the leading risk factor for cardiovascular disease and mortality worldwide. Despite intensive research into the mechanisms underlying the development of hypertension, it remains difficult to control blood pressure in a large proportion of patients. Young men have a higher prevalence of hypertension compared to age-matched women, and this holds true until approximately the fifth decade of life. Following the onset of menopause, the incidence of hypertension among women begins to surpass that of men. The immune system has been demonstrated to play a role in the pathophysiology of hypertension, and biological sex and sex hormones can affect the function of innate and adaptive immune cell populations. Recent studies in male and female animal models of hypertension have begun to unravel the relationship between sex, immunity, and hypertension. Hypertensive male animals show a bias towards proinflammatory T cell subsets, including IL-17-producing Th17 cells, and increased renal infiltration of T cells and inflammatory macrophages. Conversely, premenopausal female animals are largely protected from hypertension, and have a predilection for anti-inflammatory T regulatory cells and production of anti-inflammatory cytokines, such as IL-10. Menopause abrogates female protection from hypertension, which may be due to changes among anti-inflammatory T regulatory cell populations. Since development of novel treatments for hypertension has plateaued, determining the role of sex in the pathophysiology of hypertension may open new therapeutic avenues for both men and women.
    DOI:  https://doi.org/10.1016/j.cjca.2022.05.010
  5. Int J Cardiol. 2022 May 18. pii: S0167-5273(22)00752-5. [Epub ahead of print]
    Sex differences in time trends in acute coronary syndrome management and in 12-month lethality: Data from the French MONICA registries.
    Victoria Gauthier, Michèle Montaye, Jean Ferrières, Samantha Huo Yung Kai, Katia Biasch, Marie Moitry, Philippe Amouyel, Jean Dallongeville, Aline Meirhaeghe.
      BACKGROUND: Sex differences in clinical presentation, patient care and fatal outcomes after an acute coronary syndrome (ACS) have been reported. However, recent improvements in the care and treatment of ACSs have not been assessed with regard to possible sex differences.AIM: To assess sex differences in trends between 2006 and 2016 in the characteristics of ACSs, their management, and the associated mortality.
    METHODS: We assessed all men and women (aged 35-74) covered by the MONICA registries in north, east and south-west France and having been hospitalized for an incident (first) ACS during a 12-month period in 2006 or a 6-month period in 2016. We analyzed the patients' clinical, biochemical, electrocardiographic and care-related data, and their vital status 28 days and 12 months after the ACS.
    RESULTS: In 2006, women were older (<0.0001) and had more atypical symptoms than men (p < 0.01). These differences were no longer statistically significant in 2016. Medical care improved in both men and women. However, revascularization treatment, prescriptions of platelet aggregation inhibitors, statins, and functional rehabilitation were still more frequently provided to men than to women (p < 0.01) in 2016, independently of confounders. The 28-day or 12-month case fatality was not different between men and women in both 2006 and 2016.
    CONCLUSIONS: The results of the present study evidenced an improvement over time in the management of ACS. However, although there were no longer sex differences in the patients' age and clinical presentation, women with ACS were still less likely than men to receive revascularization and pharmacological treatments in 2016.
    Keywords:  Acute coronary event; Lethality; Medical care; Morbidity; Mortality; Register
    DOI:  https://doi.org/10.1016/j.ijcard.2022.05.040
  6. Trends Biotechnol. 2022 May 18. pii: S0167-7799(22)00103-2. [Epub ahead of print]
    Se(XY) matters: the importance of incorporating sex in microphysiological models.
    Sonya Kouthouridis, Eleanor Robson, Alicia Hartung, Sandeep Raha, Boyang Zhang.
      The development of microphysiological models is currently at the forefront of preclinical research. Although these 3D tissue models are being developed to mimic physiological organ function and diseases, which are often sexually dimorphic, sex is usually neglected as a biological variable. For decades, national research agencies have required government-funded clinical trials to include both male and female participants as a means of eliminating male bias. However, this is not the case in preclinical trials, which have been shown to favor male rodents in animal studies and male cell types in in vitro studies. In this Opinion, we highlight the importance of considering sex as a biological variable and outline five approaches for incorporating sex-specific features into current microphysiological models.
    Keywords:  organ-on-a-chip; organoids; preclinical research; sex bias; sexual dimorphism
    DOI:  https://doi.org/10.1016/j.tibtech.2022.04.005
  7. Exp Gerontol. 2022 May 24. pii: S0531-5565(22)00149-8. [Epub ahead of print] 111841
    Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle.
    Melissa C Orenduff, Michael F Coleman, Elaine M Glenny, Kim M Huffman, Erika T Rezeli, Akshay Bareja, Carl F Pieper, Virginia B Kraus, Stephen D Hursting.
      Aging is a multifactorial process associated with progressive degradation of physiological integrity and function. One of the greatest factors contributing to the deleterious effects of aging is the decline of functional ability due to loss of muscle mass, strength, and function, a condition termed sarcopenia. Calorie restriction (CR) has consistently been shown to extend lifespan and delay the onset and progression of various age-related diseases, including sarcopenia. Additional anti-aging interventions that are receiving scientific attention are CR mimetics. Of these pharmacological compounds, rapamycin has shown similar CR-related longevity benefits without the need for diet restrictions. To investigate the potential role of rapamycin as an anti-sarcopenic alternative to CR, we conducted a study in male and female C57BL/6 J mice to assess the effects of rapamycin on age-related gene expression changes in skeletal muscle associated with loss of muscle mass, strength, and function, relative to control. We hypothesize that the effects of rapamycin will closely align with CR with respect to physical function and molecular indices associated with muscle quality. Our results indicate CR and rapamycin provide partial protection against age-related decline in muscle, while engaging uniquely different molecular pathways in skeletal muscle. Our preclinical findings of the therapeutic potential of rapamycin or a CR regimen on geroprotective benefits in muscle should be extended to translational studies towards the development of effective strategies for the prevention and management of sarcopenia.
    Keywords:  Calorie restriction; Rapamycin; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2022.111841
  8. Exp Physiol. 2022 May 22.
    Are there sex differences in risk for exertional heat stroke? A translational approach.
    Gabrielle Giersch, Christian Garcia, Nina Stachenfeld, Nisha Charkoudian.
      NEW FINDINGS: What is the topic of this review? This review discusses the current status of the literature in sex differences in exertional heat stroke. What advances does this review highlight? We utilize a translational model to explore possible physical and physiological differences with respect risk and treatment of exertional heat stroke.ABSTRACT: Exertional heat stroke (EHS) is a potentially fatal condition brought about by a combination of physical activity and heat stress and resulting in central nervous system dysfunction and organ damage. EHS impacts several hundred individuals each year ranging from military personnel, athletes, to occupational workers. Understanding the pathophysiology and risk factors can aid in reducing EHS across the globe. While we know there are differences between sexes in mechanisms of thermoregulation, there is currently not a clear understanding if/how those differences impact EHS risk. The purpose of this review is to assess the current status of the literature surrounding EHS from risk factors to treatment using both animal and human models. We use a translational approach, considering both animal and human research to elucidate the possible influence of female sex hormones on temperature regulation and performance in the heat and highlight the specific areas with limited research. While more work is necessary to comprehensively understand these differences, the current research presented provides a good framework for future investigations. This article is protected by copyright. All rights reserved.
    Keywords:  female sex hormones; heat illness; thermoregulation
    DOI:  https://doi.org/10.1113/EP090402
  9. Vascul Pharmacol. 2022 May 24. pii: S1537-1891(22)00050-7. [Epub ahead of print] 107001
    Aging, sex and NLRP3 inflammasome in cardiac ischaemic disease.
    Giuseppe Alloatti, Claudia Penna, Stefano Comità, Francesca Tullio, Manuela Aragno, Fiorella Biasi, Pasquale Pagliaro.
      Experimentally, many strong cardioprotective treatments have been identified in different animal models of acute ischaemia/reperfusion injury (IRI) and coronary artery disease (CAD). However, the translation of these cardioprotective therapies for the benefit of the patients into the clinical scenario has been very disappointing. The reasons for this lack are certainly multiple. Indeed, many confounding factors we must deal in clinical reality, such as aging, sex and inflammatory processes are neglected in many experiments. Due to the pivotal role of aging, sex and inflammation in determining cardiac ischaemic disease, in this review, we take into account age as a modifier of tolerance to IRI in the two sexes, dissecting aging and myocardial reperfusion injury mechanisms and the sex differences in tolerance to IRI. Then we focus on the role of the gut microbiota and the NLRP3 inflammasome in myocardial IRI and on the possibility to consider NLRP3 inflammasome as a potential target in the treatment of CAD in relationship with age and sex. Finally, we consider the cardioprotective mechanisms and cardioprotective treatments during aging in the two sexes.
    Keywords:  Cardioprotection; Comorbidities; Diabetes; Inflammasome; Ischaemia/reperfusion; Microbiota
    DOI:  https://doi.org/10.1016/j.vph.2022.107001
  10. J Exp Biol. 2022 May 27. pii: jeb.244282. [Epub ahead of print]
    Reproductive tradeoffs govern sexually dimorphic tubular lysosome induction in C. elegans.
    Cara D Ramos, K Adam Bohnert, Alyssa E Johnson.
      Sex-specific differences in animal behavior commonly reflect unique reproductive interests. In the nematode Caenorhabditis elegans, hermaphrodites can reproduce without a mate and thus prioritize feeding to satisfy the high energetic costs of reproduction. However, males, which must mate to reproduce, sacrifice feeding to prioritize mate-searching behavior. Here, we demonstrate that these behavioral differences influence sexual dimorphism at the organelle level; young males raised on a rich food source show constitutive induction of gut tubular lysosomes, a non-canonical lysosome morphology that forms in the gut of hermaphrodites when food is limited or as animals age. We find that constitutive induction of gut tubular lysosomes in males results from self-imposed dietary restriction through daf-7/TGFβ, which promotes exploratory behavior. In contrast, age-dependent induction of gut tubular lysosomes in hermaphrodites is stimulated by self-fertilization activity. Thus, separate reproductive tradeoffs influence tubular lysosome induction in each sex, potentially supporting different requirements for reproductive success.
    Keywords:  C. elegans; Dietary restriction; Sexual dimorphism; Spinster; Tubular lysosomes; daf-7
    DOI:  https://doi.org/10.1242/jeb.244282
  11. Prostaglandins Other Lipid Mediat. 2022 May 23. pii: S1098-8823(22)00040-5. [Epub ahead of print] 106650
    Sexual Dimorphism in Renal Heme Oxygenase-1 and Arachidonic Acid Metabolizing Enzymes in Spontaneously Hypertensive Rats versus Normotensive Wistar Kyoto Rats.
    Abdulmohsin Alhashim, Mahmoud Abdelbary, Jennifer C Sullivan, Sahar Emami Naeini, Ahmed A Elmarakby.
      Numerous studies have demonstrated a sexual dimorphism in blood pressure (BP) control in spontaneously hypertensive rats (SHR), however the mechanisms remain to be further elucidated. Based on the established role of arachidonic acid metabolites and heme oxygenase (HO) in BP control, we hypothesize that higher BP in male SHR is associated with differential expression in renal HO and arachidonic acid metabolizing enzymes vs. female SHR. Higher BP in male SHR coincided with significant increases in renal cortical superoxide production and thiobarbituric acid reactive substances (TBARs) levels as measures of oxidative stress compared to normotensive female WKY and female SHR. The elevations in BP and oxidative stress in male SHR were also associated with a decrease in cortical heme oxygenase-1 (HO-1) expression when compared to normotensive female WKY. Although there was no sex or strain differences in cortical expression of the epoxyeicosatrienoic acids (EETs) producing enzyme, cytochrome P450 epoxygenase (CYP2C23), in male and female SHR and WKY, SHR had greater expression of the EETs metabolizing enzyme, soluble epoxide hydrolase (sEH) vs. WKY. Cortical expression of the 20-hydroxyeicosatetraenoic acid (20-HETE) producing enzyme, cytochrome P450 hydroxylase (CYP4A), was less in female WKY and SHR compared to strain-matched males and cortical 20-HETE levels were also less in female SHR vs. male SHR. Cortical cyclooxygenase-2 (COX-2) expression was significantly greater in female SHR and WKY vs. males and cortical prostaglandin E2 (PGE2) levels in female SHR was significantly greater than male WKY. In conclusion, our data suggest that sex differences in renal oxidative stress, HO-1 and arachidonic acid metabolizing enzymes could contribute to sexual dimorphism in hypertension in young SHR.
    Keywords:  HO-1; SHR; WKY; arachidonic acid enzymes; kidney cortex; oxidative stress; sex differences
    DOI:  https://doi.org/10.1016/j.prostaglandins.2022.106650
  12. Environ Toxicol. 2022 May 21.
    Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure.
    Omamuyovwi M Ijomone, Joy D Iroegbu, Patricia Morcillo, Akinyemi J Ayodele, Olayemi K Ijomone, Julia Bornhorst, Tanja Schwerdtle, Michael Aschner.
      Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions.
    Keywords:  brain; female; male; manganese; oxidative stress
    DOI:  https://doi.org/10.1002/tox.23583
  13. Pharmaceuticals (Basel). 2022 May 02. pii: 569. [Epub ahead of print]15(5):
    Significant Sex Differences in the Efficacy of the CSF1R Inhibitor-PLX5622 on Rat Brain Microglia Elimination.
    Aviv Sharon, Hadas Erez, Micha E Spira.
      Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R). The inhibition of CSF1R by brain-permeant PLX5622 in the chow eliminates, within 5-10 days, ~90% of the microglia in female and male mice, thereby enabling the investigation of the roles of the microglia in health and pathological mice models. Because of a prevailing "impression" that PLX5622 is ineffective in rats, it has hardly been used in studies of adult rats. Here, we report that effective microglia elimination by PLX5622-chow in rats is highly sex-dependent. Our observations provide missing information for the limited use and interpretation of PLX5622 in biomedical studies of the microglia in rat models. The sex differences that are too often overlooked must be carefully considered and clearly emphasized.
    Keywords:  CSF1R; PLX5622; immunohistology; microglia; rat; sex differences
    DOI:  https://doi.org/10.3390/ph15050569
This page is being maintained by Thomas Krichel. It was last updated on 2022‒05‒29 at 17:29:52.