Age-related decline in total testosterone levels among young men: insights from a large single-center observational study
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Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging
Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer’s, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.
The impact of biological sex on diseases of the urinary tract
Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.
Age-dependent differences in breast tumor microenvironment: challenges and opportunities for efficacy studies in preclinical models
Immunity suffers a function deficit during aging, and the incidence of cancer is increased in the elderly. However, most cancer models employ young mice, which are poorly representative of adult cancer patients. We have previously reported that Triple-Therapy (TT), involving antigen-presenting-cell activation by vinorelbine and generation of TCF1+-stem-cell-like T cells (scTs) by cyclophosphamide significantly improved anti-PD-1 efficacy in anti-PD1-resistant models like Triple-Negative Breast Cancer (TNBC) and Non-Hodgkin’s Lymphoma (NHL), due to T-cell-mediated tumor killing. Here, we describe the effect of TT on TNBC growth and on tumor-microenvironment (TME) of young (6–8w, representative of human puberty) versus adult (12 m, representative of 40y-humans) mice. TT-efficacy was similar in young and adults, as CD8+ scTs were only marginally reduced in adults. However, single-cell analyses revealed major differences in the TME: adults had fewer CD4+ scTs, B-naïve and NK-cells, and more memory-B-cells. Cancer-associated-fibroblasts (CAF) with an Extracellular Matrix (ECM) deposition-signature (Matrix-CAFs) were more common in young mice, while pro-inflammatory stromal populations and myofibroblasts were more represented in adults. Matrix-CAFs in adult mice displayed decreased ECM-remodeling abilities, reduced collagen deposition, and a different pattern of interactions with the other cells of the TME. Taken together, our results suggest that age-dependent differences in the TME should be considered when designing preclinical studies.
What makes a man unmanly? The global concept of ‘unmanliness’
This paper presents the findings of a multi-national study that led to the development of a new analytical framework in masculinity research—the Global Concept of ‘Unmanliness’ (GCU). Drawing on three key theories—hegemonic masculinity, precarious manhood and masculinity threat, and emasculation—we conducted an innovative study across 15 countries (selected from an initial pool of 62) to examine cultural perceptions of ‘unmanliness.’ Participants provided open-ended responses to identify traits and behaviors considered unmanly within their cultural contexts. By analyzing common themes expressed by young men, we propose the Global Concept of ‘Unmanliness’ as a framework for understanding how societies define and enforce masculinity norms. Furthermore, comparing these findings with the Global Gender Gap Index (GGGI) revealed a key distinction in how ‘unmanliness’ is characterized across different levels of gender emancipation. In countries with high GGGI rankings (e.g., Norway, Ireland, Germany), ‘unmanliness’ is more often associated with physical traits and behaviors linked to femininity (e.g., clothing, makeup). Conversely, in countries with low GGGI rankings (e.g., Pakistan, Morocco, Nigeria), it is more commonly defined by acts such as violence against women. Our study highlights how cultural and structural gender dynamics shape the boundaries of masculinity and offers a new lens for cross-cultural research on gender norms.
Risk prediction score and equation for progression of arterial stiffness using Japanese longitudinal health examination data
The brachial-ankle pulse wave velocity (baPWV) is useful for evaluating arterial stiffness. No longitudinal studies have examined the association between multiple arterial stiffness risk factors and increased baPWV. We sought to identify factors associated with baPWV ≥1400 cm/s within 5 years and create an equation and simple risk score to predict its occurrence, using data from a large-scale Japanese health examination database. Of 10,284 participants aged 30–69 years for whom follow-up data were available over a 5-year period, 3394 men and 2710 women with baseline baPWV<1400 cm/s were analyzed. We used age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), fasting blood sugar (FBS), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), estimated glomerular filtration rate (eGFR), habitual exercise, habitual drinking, and smoking history as variables. In the multivariate logistic regression analysis, baPWV≥1400 cm/s was associated significantly with age, BMI, SBP, DBP, HR, FBS, and TG in men and age, SBP, DBP, HR, and smoking history in women. A prediction score based on these factors yielded an area under the curve (AUC) for the 5-year incidence of baPWV≥1400 cm/s of 0.68 for men and 0.71 for women. Furthermore, a risk prediction equation for the 5-year incidence of baPWV≥1400 cm/s showed an AUC = 0.71 for men and 0.77 for women. The prediction equation and a simple prediction score are easy to implement clinically. The predictive ability of these scores and equations for arterial stiffness should be validated in prospective studies.
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