Sex Differences In Markers Research Articles

Monocyte-driven inflamm-aging reduces intestinal barrier function in females.

The intestinal barrier encompasses physical and immunological components that act to compartmentalize luminal contents, such as bacteria and endotoxins, from the host. It has been proposed that an age-related decline of intestinal barrier function may allow for the passage of luminal contents into the bloodstream, triggering a low-grade systemic inflammation termed inflamm-aging. Although there is mounting evidence to support this hypothesis in model species, it is unclear if this phenomenon occurs in humans. In addition, despite being well-established that biological sex impacts aging physiology, its influence on intestinal barrier function and inflamm-aging has not been explored. In this study, we observed sex differences in markers of intestinal barrier integrity, where females had increased epithelial permeability throughout life as compared to males. With age, females had an age-associated increase in circulating bacterial products and metabolites such as LPS and kynurenine, suggesting reduced barrier function. Females also had age-associated increases in established markers of inflamm-aging, including peripheral blood monocytes as well as TNF and CRP. To determine if impaired barrier function was driving inflamm-aging, we performed a mediation analysis. The results show that the loss of intestinal barrier integrity was not the mediator of inflamm-aging in humans. Instead, persistent, low-grade inflammation with age preceded the increase in circulating bacterial products, which we confirmed using animal models. We found, as in humans, that sex modified age-associated increases in circulating monocytes in mice, and that inflammation mediates the loss of intestinal barrier function. Taken together, our results suggest that higher basal intestinal permeability in combination with age-associated inflammation, increases circulating LPS in females. Thus, targeting barrier permeability in females may slow the progression of inflamm-aging, but is unlikely to prevent it.

Site-specific tissue lipolysis and fat metabolism differs between men and women during a treadmill-based heat tolerance test without differences in circulating biomarkers

Purpose: To test the hypothesis that measures of lipid metabolism and substrate utilization differ between men and women exposed to extreme exercise-heat stress. Methods: Physically active men (n=6, 30±8 yrs, 78.8±11.0 kg, body fat 19.4±9.8%, VO2max 49.9±2.9 mL -1· kg -1· min -1 ) and women (n=6, 25±3 yrs, 60.6±4.1 kg, 25.2±6.8%, 46.3±4.5mL -1· kg -1· min -1 ) completed a treadmill-based heat tolerance test (HTT) (2 hours, 3.1 mph, 2% grade in extreme environmental conditions (104°F, 40% relative humidity). Differences (pre-, post-, change, percentage change, mean difference (MD)) within and between groups were analyzed with nonparametric inferential statistical tests. Subcutaneous abdominal adipose tissue (SCAAT) interstitial glycerol concentration and adipose tissue blood flow (i.e., ethanol Output: Input (O:I)) pre-exercise, every 30 minutes (min) of exercise, and during recovery was measured with microdialysis and assay of biofluids. Circulating concentrations of non-esterified fatty acids (NEFAs), insulin, insulin-like growth factor (IGF-1), epinephrine (EPI), and norepinephrine (NE), and cortisol were measured with commercially available kits. Resting energy expenditure (REE) was measured pre- and post-exercise using a metabolic cart. Exercising substrate utilization and metabolic heat production (MHP) were collected during 30 and 90 mins of the HTT. Results: Despite no sex differences in markers associated with stress-related metabolic signaling (cortisol, EPI, NE), endocrine response (IGF-1, insulin), or systemic concentrations of NEFAs, fat oxidation (g·min -1 ) was higher in men (vs. women) at 30 min of HTT (men (M), women (W): 0.56±0.03, 0.45±0.05, p=0.005) and at 90 min of HTT (0.61±0.05, 0.48±0.12, p=0.05). SCAAT interstitial glycerol and O:I were similar across all time points between sexes (baseline glycerol ranges (mmol·L -1 ): 92.8-530.7 (W), 321.8-588.8 (M); O:I ratio ranges: 0.42-0.79 (W), 0.55-0.77 (M). However, women had significantly greater percent change in interstitial glycerol concentration from baseline (vs. M) (W vs. M: 275 ± 287.56% vs. -8.69 ± 32.41%, p=0.003). Pre- and post-exercise REE were 16.9% (MD:371.6 kcal·day -1 , p=0.003) and 15.5% (MD:343.5kcal·day -1 , p=0.050) lower in W compared to M. Mean MHP was higher in men (MD 85W). Conclusion: Fat oxidation and SCAAT lipolysis rates were higher in men vs. women after an acute bout of strenuous exercise-heat stress. Ongoing analyses are investigating sex, energy expenditure, and heat production contributions to differences between men and women observed in our study. Our findings suggest potential for sex-specific dietary recommendations during stress exposures. DoD BA200299, HRPO E02882.1a This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex differences in markers of metabolic syndrome and adipose tissue inflammation in obesity-prone, Osborne-Mendel and obesity-resistant, S5B/Pl rats

The current study examined the role of sex differences in the development of risk factors associated with obesity and its comorbidities using models that differ in their susceptibility to develop obesity, obesity-resistant S5B/Pl (S5B) and obesity-prone Osborne-Mendel (OM) rats. Male and female rats were fed a low fat or high fat diet (HFD) and markers of metabolic syndrome (MetSyn) and expression of inflammatory cytokines/chemokines in visceral and subcutaneous adipose depots were measured. We hypothesized that male and female OM and S5B rats would exhibit differential responses to the consumption of HFD and that females, regardless of susceptibility to develop obesity, would display decreased obesity-related risk factors. Results suggested that consumption of HFD increased adiposity and fasting glucose levels in male OM and S5B rats, decreased circulating adiponectin levels in male S5B rats, and increased body weight and triglyceride levels in male OM rats. The consumption of HFD increased body weight and adiposity in female OM rats, not female S5B rats. Overall, female rats did not meet criteria for MetSyn, while male rats consuming HFD met criteria for MetSyn. Visceral and subcutaneous adipose tissue inflammation was higher in male rats. In visceral adipose tissue, HFD consumption differentially altered expression of cytokines in male and female S5B and OM rats. These findings suggest that resistance to obesity in males may be overridden by chronic consumption of HFD and lead to increased risk for development of obesity-related comorbidities, while female rats appear to be protected from the adverse effects of HFD consumption.

Examining Sex Differences in Markers of Cognition and Neurodegeneration in Autosomal Dominant Alzheimer's Disease: Preliminary Findings from the Colombian Alzheimer's Prevention Initiative Biomarker Study.

Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer's disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy). Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD. We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20-44; 11 females), 11 symptomatic carriers (age range 42-56; 8 females), and 23 matched non-carriers family members (age range 20-50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted. There were no differential associations between age, CERAD Total Score, CERAD Word List-Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups. Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, and as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers.

Sexual selection and sex differences in the prevalence of childhood externalizing and adolescent internalizing disorders.

Despite the well-established sex difference in prevalence of many childhood and adolescent psychopathological conditions, no integrative metatheory of sex differences in psychopathology exists. This review attempts to provide a metatheoretical framework to guide empirical examination of sex differences in prevalence of childhood-onset "externalizing" and adolescent-onset "internalizing" disorders, based on sexual selection evolutionary theory. Sexual selection theory suggests important between-sex differences in markers, mechanisms, etiology, and developmental timing of risk and resilience relevant to psychopathology. Namely, sexual selection theory hypothesizes that disinhibition and sensation-seeking may be important proximate risk markers for childhood-onset externalizing disorders in males. The theory suggests that these male-biased markers may be a product of their higher exposure to prenatal testosterone, which makes them more susceptible to prenatal stressors with downstream effects on dopaminergic neurotransmission, especially for those with genetic alleles associated with lower dopaminergic function. In contrast, sexual selection theory hypothesizes that negative emotionality, empathy, and cognitive rumination may be important proximate risk markers for adolescent-onset internalizing disorders in females. The theory suggests that these markers are propagated by rapidly rising levels of estradiol at puberty that interact with cortisol and oxytocin. These hormones exert downstream effects on the serotonergic system in such a way as to increase females' sensitivity to interpersonal stressors particularly at puberty and especially for those with lower functional serotonergic activity. Such a metatheory can help integrate prior ideas about sex differences and can also generate new predictions of sex differences in markers, etiology, mechanisms, and developmental timing of common forms of psychopathology.

Is Serum-Glutamylatransferase a Biomarker of Xenobiotics Which Are Conjugated by Glutathione?

In Response: GGT has long been used as a marker of alcohol consumption. However, we have shown that an association between GGT and cardiovascular disease exists even among nondrinkers.1 What then explains these findings? In their letter, Lee and colleagues explore the evidence supporting their suggestion that GGT is a marker of environmental exposure to xenobiotics. Lee et al present a comprehensive case in support of their hypothesis that GGT levels are determined by exposure to environmental pollutants. We would like to highlight several points that do not contradict the …

Prevalence of Elevated Alanine Aminotransferase Among US Adolescents and Associated Factors: NHANES 1999–2004

Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver disease in children and adolescents. The majority of studies of NAFLD in children have been in select populations of the clinically obese. Study aims were to estimate the prevalence of elevated alanine aminotransferase (ALT, as a marker of NAFLD) in a general contemporary adolescent population and to identify leading risk factors for ALT elevation (>30 U/L). We analyzed data of adolescent participants (aged 12-19 years; N = 5586) in the National Health and Nutrition Examination Survey 1999-2004, a representative sample of the civilian noninstitutionalized US population. The prevalence of elevated ALT levels (>30 U/L) was 7.4% among white adolescents, 11.5% among Mexican American adolescents, and 6.0% among black adolescents. Elevated ALT levels were prevalent in 12.4% of male subjects compared with 3.5% of female subjects. Multivariable associations with elevated ALT levels were found for sex (odds ratio [OR] male vs female, 7.7; 95% confidence interval [CI], 3.9-15.1), ethnicity (OR black vs white, 0.6; 95% CI, 0.3-1.3; OR Mexican American vs white, 1.6; 95% CI, 1.0-2.6), waist circumference (OR per 1 SD, 1.4; 95% CI, 1.0-2.0), and fasting insulin level (OR per 1 SD, 1.6; 95% CI, 1.2-2.1). Age, C-reactive protein levels, and triglyceride levels were also positively and socioeconomic position inversely associated with elevated ALT levels. The magnitude of associations were similar across ethnic groups. ALT level is associated with waist circumference and insulin resistance even in a young population. These characteristics could be utilized to identify adolescents who may benefit from screening for NAFLD, offering an opportunity to prevent disease progression at an early age.

Heritability and genetic loci of fatty liver in familial combined hyperlipidemia

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20-36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.