Sex Differences In Health Research Articles

The Processuality of ‘Sex’ in Biomedicine: Exploring Stem Cell Research, Cancer Medicine and Vaccine Safety Research

Incorporating sex into biomedical research is envisioned as key to addressing inequalities in health. However, feminist research suggests that it is a complicated task. This is, we argue, especially the case with research that seeks to mobilise sex across different scales involving bodies, samples and populations to provide a basis for personalised biomedical prevention and treatment. Through case studies from stem cell research, cancer medicine and vaccine safety research, we analyse how sex is enacted, foregrounded and sidelined at different stages of research. We argue that sex becomes suspended between individual bodies, samples and population groups, and that this postpones biomedical analysis of sex differences in health. Yet, research on sex differences in complex embodied processes, such as drug metabolism or immunity, appears as a future potentiality. This potentiality shapes research practices that may open biomedicine towards multi-disciplinary study settings that bring together physiological and social dimensions of bodily difference.

LONG-TERM NMN TREATMENT INCREASES LIFESPAN AND HEALTHSPAN IN MICE IN A SEX DEPENDENT MANNER

Abstract Levels of nicotinamide adenine dinucleotide (NAD+) decline by up to 50% in aging. NAD+ is an essential co-factor for many metabolic processes, including the deacetylase activity of sirtuins, and previous studies have demonstrated that supplementing NAD+ levels has a range of health benefits in both mice and humans. Here we investigate the effect of long-term (from 13 months of age) administration of the NAD+ precursor nicotinamide mononucleotide (NMN) on frailty and lifespan in male and female mice. NMN treatment delayed the onset of frailty in both sexes, improved metabolic health in male mice, and increased median lifespan by 8.5% in female mice. Exploration of the potential mechanisms of this protection showed that NMN treatment prevented age-related gene expression changes in skeletal muscle and led to a large increase in levels of Anaerotruncus colihominis, a microbe associated with reduced inflammation, in the gut. A thorough characterization of NMN metabolism across age, sex and tissues shows context-specific sex differences in metabolic pathways, including greater Preiss-Handler pathway metabolism in females than males, which may contribute to observed sex differences in health and lifespan. Overall, this data provides preclinical evidence that chronic NMN treatment increases lifespan and improves frailty and metabolic health in aging, and highlights the importance of using both sexes for interventional lifespan studies.

Sex matters: the frequently overlooked importance of considering sex in computational models.

Personalised medicine and the development of a virtual human or a digital twin comprises visions of the future of medicine. To realise these innovations, an understanding of the biology and physiology of all people are required if we wish to apply these technologies at a population level. Sex differences in health and biology is one aspect that has frequently been overlooked, with young white males being seen as the "average" human being. This has not been helped by the lack of inclusion of female cells and animals in biomedical research and preclinical studies or the historic exclusion, and still low in proportion, of women in clinical trials. However, there are many known differences in health between the sexes across all scales of biology which can manifest in differences in susceptibility to diseases, symptoms in a given disease, and outcomes to a given treatment. Neglecting these important differences in the development of any health technologies could lead to adverse outcomes for both males and females. Here we highlight just some of the sex differences in the cardio-respiratory systems with the goal of raising awareness that these differences exist. We discuss modelling studies that have considered sex differences and touch on how and when to create sex-specific models. Scientific studies should ensure sex differences are included right from the study planning phase and results reported using sex as a biological variable. Computational models must have sex-specific versions to ensure a movement towards personalised medicine is realised.

Obesity Risk Among West Point Graduates Later in Life.

Szivak, TK, Thomas, MM, Pietrzak, RH, Nguyen, DR, Ryan, DM, and Mazure, CM. Obesity Risk Among West Point Graduates Later in Life. J Strength Cond Res 37(6): 1284-1291, 2023-The purpose of this investigation was to evaluate sex differences in health and fitness outcomes among United States Military Academy (USMA) graduates (class years 1980-2011). Subjects ( n = 701 men, 641 women, age: 45.7 ± 9.3 years) were surveyed as a part of a larger investigation on risk and resiliency factors among USMA graduates. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ) short form and calculation of weekly metabolic equivalents (METs). Overweight and obesity status were assessed by body mass index (BMI). Significance for the study was set at p ≤ 0.05. Obesity rates for men (30.1%) were significantly higher than for women (16.6%). Men reported significantly higher ( p = 0.01) vigorous METs·wk -1 (1,214.6 ± 1,171.6) than women (1,046.8 ± 1,133.2) despite significantly higher ( p = 0.00) BMI values (28.75 ± 4.53 kg·m -2 ) than women (25.90 ± 5.48 kg·m -2 ). Women were 89% more likely to have ever been on a diet and reported higher (15.2%) Army Body Composition Program enrollment rates than men (6.3%). Obesity rates among men reflect trends seen in the broader military, Veteran, and U.S. adult populations, whereas obesity rates among women were lower. Men may be at a greater risk for obesity later in life despite higher self-reported physical activity; however, lean body mass and self-report bias should be considered. Because lifetime obesity may be influenced by factors other than physical activity, health initiatives should use a comprehensive approach early in the career of military officers.

Sex differences in resting state functional connectivity across the first two years of life

Sex differences in behavior have been reported from infancy through adulthood, but little is known about sex effects on functional circuitry in early infancy. Moreover, the relationship between early sex effects on the functional architecture of the brain and later behavioral performance remains to be elucidated. In this study, we used resting-state fMRI and a novel heatmap analysis to examine sex differences in functional connectivity with cross-sectional and longitudinal mixed models in a large cohort of infants (n = 319 neonates, 1-, and 2-year-olds). An adult dataset (n = 92) was also included for comparison. We investigated the relationship between sex differences in functional circuitry and later measures of language (collected in 1- and 2-year-olds) as well as indices of anxiety, executive function, and intelligence (collected in 4-year-olds). Brain areas showing the most significant sex differences were age-specific across infancy, with two temporal regions demonstrating consistent differences. Measures of functional connectivity showing sex differences in infancy were significantly associated with subsequent behavioral scores of language, executive function, and intelligence. Our findings provide insights into the effects of sex on dynamic neurodevelopmental trajectories during infancy and lay an important foundation for understanding the mechanisms underlying sex differences in health and disease.

Comparing Cohort Survival in Good Health: A Research Note on Decomposing Sex Differentials in the United States.

We introduce a method for decomposing differences in healthy cross-sectional average length of life (HCAL). HCAL provides an alternative to the health expectancy (HE) indicator by including the health and mortality history of all cohorts present at a given time. While decompositions of HE differences account for contributions made by health and mortality, differences in HCAL are further disentangled into cohort-specific contributions. In this research note we illustrate the technique by analyzing the sex gap in health and mortality for the United States. We use the harmonized version of the Health and Retirement Survey data and define the health status in terms of activities of daily living. Our results suggest that the female advantage in cohort survival is partly compensated by women's lower cohort-specific health levels. At older ages, however, the sex differences in health are not large enough to compensate men's disadvantage in cohort survival.

White matter microstructure shows sex differences in late childhood: Evidence from 6797 children.

Sex differences in white matter microstructure have been robustly demonstrated in the adult brain using both conventional and advanced diffusion-weighted magnetic resonance imaging approaches. However, sex differences in white matter microstructure prior to adulthood remain poorly understood; previous developmental work focused on conventional microstructure metrics and yielded mixed results. Here, we rigorously characterized sex differences in white matter microstructure among over 6000 children from the Adolescent Brain Cognitive Development study who were between 9 and 10 years old. Microstructure was quantified using both the conventional model-diffusion tensor imaging (DTI)-and an advanced model, restriction spectrum imaging (RSI). DTI metrics included fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). RSI metrics included normalized isotropic, directional, and total intracellular diffusion (N0, ND, NT). We found significant and replicable sex differences in DTI or RSI microstructure metrics in every white matter region examined across the brain. Sex differences in FA were regionally specific. Across white matter regions, boys exhibited greater MD, AD, and RD than girls, on average. Girls displayed increased N0, ND, and NT compared to boys, on average, suggesting greater cell and neurite density in girls. Together, these robust and replicable findings provide an important foundation for understanding sex differences in health and disease.

Sex differences in activity and health changes following COVID-19 in Europe-results from the SHARE COVID-19 survey.

While a female advantage in the overall survival from the coronavirus disease 2019 (COVID-19) has been demonstrated, potential sex differences in health changes are not investigated. In a sample of 21 395 men and 29 139 women aged 50+ from the SHARE COVID-19 survey, we investigated sex differences in social activities, self-rated health and mental health following the COVID-19 outbreak. We found considerable sex differences in all European regions with women experiencing larger negative changes across all social activities and health measures than men lending support for the male–female health-survival paradox.

Gender norms and the mental health of boys and young men

Over the last half-century, the women's health movement has been a powerful driver in health policy linking gender norms to sex differences in health and wellbeing. Even though gender norms also affect males,1 there has been little emphasis on gender in health policies for males, especially in relation to the mental health of boys and young men.2 Gender norms around masculinity commonly confer power and status to boys and young men, which might in part explain why norms around masculinity are difficult to shift.

Sex differences in infant health following ART-treated, subfertile, and fertile deliveries

Among infants following ART-treated, subfertile, and fertile deliveries to determine (1) the presence and magnitude of sex differences in health outcomes and (2) whether the presence of sex differences varied among maternal fertility groups. Retrospective cohort analysis of infants born in Massachusetts (MA) in 2004-2013 who were conceived by ART. The Society for Assisted Reproductive Technology Clinic Outcome Reporting System was linked to the Pregnancy to Early Life Longitudinal data system, which links birth certificates to hospital discharge records for MA mothers and infants. Included were singletons born via ART-treated, subfertile, and fertile deliveries. Multivariable logistic regression was used to model the association between infant sex and health outcomes, controlling for maternal demographic and health characteristics. A total of 16,034 ART-treated, 13,277 subfertile, and 620,375 fertile singleton live births were included. For all three groups, males had greater odds of being preterm (AOR range 1.15-1.2), having birth defects (AOR range 1.31-1.71), experiencing respiratory (AOR range 1.33-1.35) and neurologic (AOR range 1.24-1.3) conditions, and prolonged hospital stay (AOR range 1.19-1.25) compared to females. The interaction between maternal fertility group and infant sex for all infant outcomes was nonsignificant, denoting that the presence of sex differences among fertile, subfertile, and ART groups did not vary. Sex differences in birth outcomes of infants following ART-treated, subfertile, and fertile deliveries exist but the magnitude of these differences does not vary among these maternal fertility groups.

Sex differences in health and disease: A review of biological sex differences relevant to cancer with a spotlight on glioma.

The influence of biological sex differences on human health and disease, while being increasingly recognized, has long been underappreciated and underexplored. While humans of all sexes are more alike than different, there is evidence for sex differences in the most basic aspects of human biology and these differences have consequences for the etiology and pathophysiology of many diseases. In a disease like cancer, these consequences manifest in the sex biases in incidence and outcome of many cancer types. The ability to deliver precise, targeted therapies to complex cancer cases is limited by our current understanding of the underlying sex differences. Gaining a better understanding of the implications and interplay of sex differences in diseases like cancer will thus be informative for clinical practice and biological research. Here we review the evidence for a broad array of biological sex differences in humans and discuss how these differences may relate to observed sex differences in various diseases, including many cancers and specifically glioblastoma. We focus on areas of human biology that play vital roles in healthy and disease states, including metabolism, development, hormones, and the immune system, and emphasize that the intersection of sex differences in these areas should not go overlooked. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies.

Greater male than female variability in regional brain structure across the lifespan.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta‐Analysis) Consortium presents the largest‐ever mega‐analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1‐90 years old (47% females). We observed significant patterns of greater male than female between‐subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene‐environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex‐specific vulnerability to disorders.

Sex differences in health and mortality by income and income changes

BackgroundThe adverse association between income, health and survival is well documented, but little is known about how income trajectories influence health and survival for men and women. We aim to...

Widespread sex dimorphism in aging and age-related diseases.

Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex dimorphism in various aspects of aging and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.

X Inactivation and Escape: Epigenetic and Structural Features.

X inactivation represents a complex multi-layer epigenetic mechanism that profoundly modifies chromatin composition and structure of one X chromosome in females. The heterochromatic inactive X chromosome adopts a unique 3D bipartite structure and a location close to the nuclear periphery or the nucleolus. X-linked lncRNA loci and their transcripts play important roles in the recruitment of proteins that catalyze chromatin and DNA modifications for silencing, as well as in the control of chromatin condensation and location of the inactive X chromosome. A subset of genes escapes X inactivation, raising questions about mechanisms that preserve their expression despite being embedded within heterochromatin. Escape gene expression differs between males and females, which can lead to physiological sex differences. We review recent studies that emphasize challenges in understanding the role of lncRNAs in the control of epigenetic modifications, structural features and nuclear positioning of the inactive X chromosome. Second, we highlight new findings about the distribution of genes that escape X inactivation based on single cell studies, and discuss the roles of escape genes in eliciting sex differences in health and disease.

Sex differences in health and aging: a dialog between the brain and gonad?

Women live longer than men in virtually all circumstances. However, a more common pattern among animals is that one sex lives longer under some conditions, the other lives longer under other conditions. In laboratory mice, interventions that extend longevity are surprisingly often sex-specific in their effects. Understanding these conditional sex differences could provide mechanistic insight into how longevity could be modulated in humans. One way that longevity can be consistently enhanced is by inhibiting reproduction or eliminating the capacity to reproduce. Thus, there appears to be a mechanistic link between gonadal activity and longevity. There also appears to be a mechanistic link between some types of neuroendocrine signaling and longevity. Combining these two observations suggest that communication between the brain and gonad is a ripe avenue for further exploring longevity-assurance mechanisms. Also, because the timing and activity of specific brain-gonad endocrine differs between the sexes, neuroendocrine linkages between the brain and gonad, particularly among the less obvious hormones such as activin and inhibin, could provide additional insight into mechanisms of sex differences in aging.

The Physical Health of Men and Boys: Integrating Biomedical and Psychological Science.

Rigid adherence to traditional male norms has been found to be associated with many health outcomes. This special issue aims to bring together biomedical and psychological researchers as a means to generate interest in integrating scientific approaches so as to advance the health of men and boys. In this guest editorial, the authors first provide a brief review of some key biological factors that contribute to sex differences in health. The editorial then introduces the ten articles included in this special issue, which focus on paternal influence on health-related behaviors; cancer; reproductive and sexual health; eating disorders; and health-related beliefs. Ultimately, by continuing to work across disciplines, those interested in the psychological study of men and masculinities can assist biomedical researchers in promoting better health outcomes.

Gender Inequality and Sex Differences in Physical Fighting, Physical Activity, and Injury Among Adolescents Across 36 Countries

PurposeSex differences in adolescent health are widely documented, but social explanations for these sex differences are scarce. This study examines whether societal gender inequality (i.e., men's and women's unequal share in political participation, decision-making power, economic participation, and command over resources) relates to sex differences in adolescent physical fighting, physical activity, and injuries. MethodsNational-level data on gender inequality (i.e., the United Nations Development Program's Gender Inequality Index) were linked to health data from 71,255 15-year-olds from 36 countries in the 2009–2010 Health Behaviour in School-Aged Children study. Using multilevel logistic regression analyses, we tested the association between gender inequality and sex differences in health while controlling for country wealth (gross domestic product per capita). ResultsIn all countries, boys reported more physical fighting, physical activity, and injuries than girls, but the magnitude of these sex differences varied greatly between countries. Societal gender inequality positively related to sex differences in all three outcomes. In more gender unequal countries, boys reported higher levels of fighting and physical activity compared with boys in more gender equal countries. In girls, scores were consistently low for these outcomes; however, injury was more common in countries with less gender inequality. ConclusionsSocietal gender inequality appears to relate to sex differences in some adolescent health behaviors and may contribute to the establishment of sex differences in morbidity and mortality. To reduce inequalities in the health of future generations, public health policy should target social and cultural factors that shape perceived gender norms in young people.

Prohibitin: A hypothetical target for sex-based new therapeutics for metabolic and immune diseases.

Traditional sex-related biases in research are now obsolete, and it is important to identify the sex of humans, animals, and even cells in research protocols, due to the role of sex as a fundamental facet of biology, predisposition to disease, and response to therapy. Genetic sex, epigenetics and hormonal regulations, generate sex-dimorphisms. Recent investigations acknowledge sex differences in metabolic and immune health as well as chronic diseases. Prohibitin, an evolutionarily conserved molecule, has pleotropic functions in mitochondrial housekeeping, plasma membrane signaling, and nuclear genetic transcription. Studies in adipocytes, macrophages, and transgenic mice indicate that prohibitin interacts with sex steroids and plays a role in mediating sex differences in adipose tissues and immune cell types. Prohibitin may, depending on context, modulate predisposition to chronic metabolic diseases and malignancy and, because of these attributes, could be a target for sex-based therapies of metabolic and immune-related diseases as well as cancer.

Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities.

In chronic obstructive pulmonary disease (COPD), lower limb dysfunction is associated with reduced exercise capacity, increased hospitalizations and mortality. We investigated sex differences in the prevalence of quadriceps dysfunction and fibre abnormalities in a large COPD cohort, controlling for the normal sex differences in health. We compared existing data from 76 male and 38 female COPD patients where each variable was expressed as a function of gender-specific normal values (obtained from 16 male and 14 female controls). Female COPD patients had lower quadriceps muscle strength and peak workload on a maximal incremental cycle ergometry protocol compared to male patients. Female patients had a smaller type II fibre cross-sectional area (CSA) compared to male patients, suggesting a greater female preponderance to fibre atrophy, although this result was largely driven by a few male patients with a large type II fibre CSA. Female patients had significantly higher concentrations of a number of plasma pro-inflammatory cytokines including tumour necrosis factor alpha and interleukin 8 (IL8), but not lower levels of physical activity or arterial oxygenation, compared to males. Our data confirm results from a previous small study and suggest that female COPD patients have a greater prevalence of muscle wasting and weakness. Larger studies investigating sex differences in COPD-related muscle atrophy and weakness are needed, as the results will have implications for monitoring in clinical practice and for design of clinical trials evaluating novel muscle anabolic agents.