Sex and Gender in Ageing and Longevity: Highlights From an International Course.

Gender medicine is a multidisciplinary science and represents an important perspective for pathophysiological and clinical studies in the third millennium. Here, it is provided an overview of the topics discussed in a recent course on the Role of Sex and Gender in Ageing and Longevity. The paper highlights three themes discussed in the course, i.e., the interaction of gender/sex with, i) the pathophysiology of age-related diseases; ii), the role of genetics and epigenetics in ageing and longevity and, iii) the immune responses of older people to pathogens, vaccines, autoantigens, and allergens. Although largely unexplored, it is clear that sex and gender are modulators of disease biology and treatment outcomes. It is becoming evident that men and women should no longer be considered as subgroups, but as biologically distinct groups of patients deserving consideration for specific therapeutic approaches.

Frailty and the risk of infection-related hospitalizations in older age: Differences by sex.

OBJECTIVES: To investigate the extent to which frailty is associated with infection-related hospitalizations in older men and women, and to explore whether, among women, previous exposure to endogenous estrogens in terms of age at menopause and number of pregnancies modify such a relationship. STUDY DESIGN: The sample comprised 2784 participants in the Progetto Veneto Anziani aged ≥65 years. At baseline and after 4.4 years, frailty was identified according to the presence of three or more of the following: weakness, exhaustion, weight loss, low physical activity, and low walking speed. A passive follow-up on infection-related hospitalizations and mortality was performed for 10 years of observation through linkage with regional registers. MAIN OUTCOME MEASURES: The association between frailty and infection-related hospitalizations was assessed through mixed-effects Cox regressions. RESULTS: Frailty was significantly associated with a 78 % higher risk of infection-related hospitalization, with stronger results in men (hazard ratio = 2.32, 95 % confidence interval 1.63-3.30) than in women (hazard ratio = 1.54, 95 % confidence interval 1.18-2.02). Focusing on women, we found a possible modifying effect for the number of pregnancies but not menopausal age. Women who had experienced one or no pregnancy demonstrated a higher hazard of infection-related hospitalization as a function of frailty (hazard ratio = 3.00, 95 % confidence interval 1.58-5.71) than women who had experienced two or more pregnancies (hazard ratio = 1.68, 95 % confidence interval 1.18-2.39). CONCLUSION: Frailty in older age increases the risk of infection-related hospitalizations, especially in men. The "immunologic advantage" of the female sex in younger age seems to persist also after menopause as a function of the number of pregnancies a woman has experienced.

Cardiovascular risk profiles and 20-year mortality in older people: gender differences in the Pro.V.A. study.

The age- and gender-related cardio-metabolic changes may limit the applicability of guidelines for the prevention of cardiovascular diseases (CVD) in older people. We investigated the association of cardiovascular risk profile with 20-year all-cause and CVD-mortality in older adults, focusing on age- and gender-specific differences. This prospective study involved 2895 community-dwelling individuals aged ≥65 years who participated in the Pro.V.A study. The sum of achieved target levels (smoking, diet, physical activity, body weight, blood pressure, lipids, and diabetes) recommended by the European Society of Cardiology 2016 guidelines was assessed in each participant. From this sum, cardiovascular risk profile was categorised as very high (0-2), high (3), medium (4), low (5), and very low (6-7 target levels achieved). All-cause and CV mortality data over 20 years were obtained from health registers. At Cox regression, lower cardiovascular risk profile was associated with reduced 20-year all-cause mortality in both genders, with stronger results for women (HR = 0.42 [95%CI:0.25-0.69] and HR = 0.61 [95%CI:0.42-0.89] for very low vs. very high cardiovascular risk profile in women and men, respectively). This trend was more marked for CVD mortality. Lower cardiovascular risk profile was associated with reduced all-cause and CVD mortality only in men < 75 years, while the associations persisted in the oldest old women. A lower cardiovascular risk profile, as defined by current guidelines, may reduce all-cause and CVD mortality in older people, with stronger and longer benefits in women. These findings suggest that personalised and life-course approaches considering gender and age differences may improve the delivery of preventive actions in older people. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10433-021-00620-y.

Association of physical activity trajectories with major cardiovascular diseases in elderly people.

INTRODUCTION: Cardiovascular benefits deriving from physical activity are well known, but it is unclear whether physical activity trajectories in late life are associated with different risks of cardiovascular diseases. METHODS: Progetto Veneto Anziani (Pro.V.A.) is a cohort study of 3099 Italians aged ≥65 years with baseline assessment in 1995-1997 and follow-up visits at 4 and 7 years. Surveillance was extended to 2018 by linkage with hospital and mortality records. Prevalent and incident cardiovascular diseases (coronary heart disease, heart failure and stroke) were identified through clinical examination, questionnaire, or hospital records. Moderate to vigorous physical activity was considered as a time-varying variable. Physical activity trajectories were categorised as: stable-low, high-decreasing, low-increasing and stable-high. Exposure was also assessed at 70, 75, 80 and 85 years. RESULTS: Overall, physical activity was associated with lower rates of incident cardiovascular diseases. A significant risk reduction was present among men and was stronger earlier in late life (70-75 years). Trajectories of stable-high physical activity were associated with a significantly lower risk of cardiovascular outcomes among men (HR 0.48, 95% CI 0.27 to 0.86) compared with those with stable-low trajectories (p for trend 0.002). No significant association was found with stroke. The greatest cardiovascular risk reduction was observed for >20 min/day of physical activity, and was more marked at 70 years. CONCLUSION: Increasingly active trajectories of physical activity were associated with lower rates of cardiovascular diseases and overall mortality. Promoting at least 20 min/day of physical activity early in late life seems to provide the greatest cardiovascular benefits.

Gender-Related Approach to Kidney Cancer Management: Moving Forward.

Men are more frequently diagnosed with kidney cancer than women, with a more aggressive histology, larger tumors, a higher grade and stage, and worse oncological outcomes. Smoking habits and sex steroid hormones seem to have a possible role in explaining these gender disparities. Moreover, the expression of genes involved in tumor growth and immune response in kidney cancer varies between men and women, having an impact on the gender-related response to oncological therapy, such as anti-angiogenic drugs and immunotherapy. Recent advances have been made in our understanding of the molecular and genetic mechanisms involved in kidney cancer, which could partially explain the gender differences, and they are summarized in this paper. However, other key mechanisms, which fully clarify the striking clinical gender-related differences observed in kidney cancer, are not completely understood at present. We reviewed and summarized the most relevant publications about the relationship between gender and kidney cancer. Efforts should be made to progress in bench and clinical research on gender-related signatures and disparities, and their impact on the clinical management of kidney cancer.

Spotlight on gender-specific disparities in bladder cancer.

Men are at a higher risk of developing bladder cancer, but women present with more advanced disease and have more unfavourable outcomes. Although epidemiologic and genetical studies have underlined the multifactorial aetiology and gender-related differences of bladder cancer, there is lack of evidence-based recommendation for gender-specific management of bladder cancer. We summarize the evidence and most recent findings on gender-specific differences in bladder cancer incidence, diagnosis, treatment and outcome, spotlighting the gender disparities in genetic and hormonal risk factors, pelvic anatomy, diagnostic setting and surgical choices. We reviewed the literature published on PubMed between 1981 and 2018. Males have a threefold to fourfold higher risk of bladder cancer as compared to females; however, women have higher stage-for-stage mortality, being diagnosed with more advanced disease, mostly due to a delay in haematuria evaluation. Numerous studies indicate an increased risk of disease recurrence or progression in women with non-muscle-invasive bladder cancer treated with trans-urethral resection, with or without intravesical chemotherapy or immunotherapy, compared to males. In particular, recent molecular evidence show that there is an excess of female Ta mutant tumours. At the time of radical cystectomy, women have a significantly longer length of hospital stay, operative time, higher blood loss and higher 90-day mortality and perioperative complication rate. Moreover, females are less likely to receive a continent diversion. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of therapies in women, perhaps exploring different therapeutic approaches in men and women. Specific data on functional and oncological outcomes can be analysed to define predictive factors able to guide the surgeon in decisions based on evidence. It is urgently needed to limit gender-related discrepancies in early diagnosis and treatment of bladder cancer. Public awareness and bladder cancer female patients' consciousness on gender inequalities must be similarly uprisen.

The effect of childcare activities on cognitive status and depression in older adults: gender differences in a 4.4-year longitudinal study.

OBJECTIVES: Although involvement in childcare activities seems to promote better physical and mental health in older adults, its impact on cognitive status and depression has not yet been fully elucidated. We aimed to analyze the association between engagement in childcare activities and cognitive and psychological status over a 4.4-year period in community-dwelling older adults. METHODS: Two thousand one hundred four subjects older than 65 years without severe cognitive impairment at baseline were categorized according to the frequency of their involvement in childcare activities (everyday, occasionally, never). The participants' cognitive status and depressive symptoms were evaluated at baseline and after 4.4 years. RESULTS: During the follow-up, 269 (12.8%) new cases of cognitive impairment and 229 (10.9%) new cases of depression were registered. Men engaged in childcare showed an almost 20% lower risk of cognitive impairment and cognitive decline. Women demonstrated similar results, except for those occasionally involved in childcare, who had a higher risk of cognitive decline compared with women who never engaged in it. The risk of developing depression was reduced in men involved daily (OR = 0.44, 95% CI: 0.30-0.62, p < 0.0001) and occasionally in childcare, who also demonstrated a lower risk of exacerbating depressive symptoms compared with subjects who never involved in it. The onset of depression was reduced in women occasionally engaged in childcare (OR = 0.68, 95% CI: 0.56-0.82, p < 0.0001), but not significantly in those daily involved in it. CONCLUSIONS: Involvement of older adults in childcare activities seems to lower the risk of cognitive impairment in both genders and to prevent onset or worsening of depression particularly in older men. Copyright © 2017 John Wiley & Sons, Ltd.

Poor Physical Performance Predicts Future Onset of Depression in Elderly People: Progetto Veneto Anziani Longitudinal Study.

BACKGROUND: Reduced physical performance is predictive of deleterious outcomes in older adults. Data considering objective physical performance and incident depression are sparse. OBJECTIVE: The objective of this study was to investigate during a 4-year study whether objective physical performance can predict incident depression among older adults who do not have depression at the baseline. DESIGN: This was a longitudinal study. METHODS: From 3,099 older people initially enrolled in the Progetto Veneto Anziani study, 970 participants without depression at the baseline were included (mean age = 72.5 years; 54.6% women). Physical performance measures included the Short Physical Performance Battery, 4-m gait speed, Five-Times Sit-to-Stand test, leg extension and flexion, handgrip strength, and 6-minute walk test, categorized in sex-specific tertiles. Depression was classified on the basis of the Geriatric Depression Scale and a diagnosis from a geriatric psychiatrist. Area under the curve and logistic regression analyses were conducted. RESULTS: At the baseline, participants developing depression during the follow-up (n = 207) scored significantly worse across all physical performance measures than those who did not develop depression. The area under the curve and predictive power were similar for all of the physical performance tests assessed. In the logistic regression analysis, after adjustment for 14 potential confounders, worse physical performance across all tests increased the risk of depression. Participants in the lowest tertile of the Short Physical Performance Battery were at notable odds of developing depression (odds ratio = 1.79; 95% CI = 1.18-2.71). The association between poor physical performance and depression was typically stronger in women than in men, except for 4-m gait speed. LIMITATIONS: No gold standard was used for a depression diagnosis; oxidative stress and inflammatory markers were not included; and there was a high rate of missing data at the follow-up. CONCLUSIONS: Low physical performance appeared to be an independent predictor of depression over a 4-year follow-up in a sample of elderly people.

Hyperuricemia, Cardiovascular Profile, and Comorbidity in Older Men and Women: The Pro.V.A. Study.

Hyperuricemia (HU) is growing worldwide and associates with several medical conditions in the elderly. However, data about older people and possible gender differences are sparse. The aim of this study was to compare HU prevalence rates and association with relevant medical disorders in elderly subjects of both sexes. Pro.V.A. is a survey of 3099 individuals aged 65+, focusing on chronic diseases and disability. Uric acid (UA) levels were dichotomized using 6.0 mg/dL (females) and 7.0 mg/dL (males), and multivariate logistic regression models were used to estimate odds ratios (ORs) between HU and single comorbidity. HU prevalence was 21.5% in females and 15.8% in males. HU was associated with most anthropometric and laboratory variables in women, but not in men. After adjustment for age, body mass index, and renal function, HU was independently associated with the presence of cardiovascular diseases in both sexes. In women, HU was associated with hand osteoarthritis (OR = 1.52; 95%CI: 1.12-2.08) and edentulism (OR = 1.31; 95%CI: 1.01-1.71), while resulted protective for osteoporosis (OR = 0.69; 95%CI: 0.53-0.91). In men, HU was significantly related with knee osteoarthritis (OR = 1.72; 95%CI: 1.06-2.79) and chronic obstructive pulmonary disease (OR = 1.60; 95%CI: 1.04-2.45). The presence of ≥4 comorbidities was a stronger determinant of HU in men (OR = 2.54; 95%CI: 1.21-5.37) than in women (ns). Patterns of age-dependent UA increase are markedly different in men and women. HU prevalence is substantial and its association with other diseases is gender specific, connoting a peculiar clinical profile.

Estrogen and thyroid cancer is a stem affair: A preliminary study.

Gender influences Papillary Thyroid Cancer (PTC) with an incidence of 3:1 when comparing women to men with different aggressiveness. This gender discrepancy suggests some role of sex hormones in favoring the malignant progression of thyroid tissue to cancer. Estrogens are known to promote Stem Cell self-renewal and, therefore, may be involved in tumor initiation. The goals of these studies are to investigate the underlying causes of gender differences in PTC by studying the specific role of estrogens on tumor cells and their involvement within the Cancer Stem Cell (CSC) compartment. Exposure to 1nmoll-1 Estradiol for 24h promotes growth and maintenance of PTC Stem Cells, while inducing dose-dependent cellular proliferation and differentiation following Estradiol administration. Whereas mimicking a condition of hormonal imbalance led to an opposite phenotype compared to a continuous treatment. In vivo we find that Estradiol promotes motility and tumorigenicity of CSCs. Estradiol-treated mice inoculated with Thyroid Cancer Stem Cell-enriched cells developed larger tumor masses than control mice. Furthermore, Estradiol-pretreated Cancer Stem cells migrated to distant organs, while untreated cells remained circumscribed. We also find that the biological response elicited by estrogens on Papillary Thyroid Cancer in women differed from men in pathways mediated. This could explain the gender imbalance in tumor incidence and development and could be useful to develop gender specific treatment of (PTC).

Changes in Frailty Status and Risk of Depression: Results From the Progetto Veneto Anziani Longitudinal Study.

OBJECTIVE: To evaluate whether prefrailty was associated with the risk of developing depression and if longitudinal changes in frailty status corresponded to changes in incident depression during follow up. METHODS: A population-based, prospective cohort study was conducted for 4.4 years in two separate geographic areas near the city of Padua in the Veneto Region of Northern Italy. In 891 nondepressed, nonfrail, community-dwelling Italian subjects aged ≥ 65 (46.6% men) belonging to the Progetto Veneto Anziani study, depression was defined according to the Geriatric Depression Scale and was confirmed by geriatricians skilled in psychogeriatric medicine. Prefrailty was defined by the presence of one or two criteria among the Fried criteria. RESULTS: The incidence rate of depression was 13.3% among subjects improving their frailty status at follow-up (N = 15), 15.0% in those who remained stable (N = 79), and 26.7% among worsening participants (N = 67) (p = 0.001). Prefrailty at baseline did not predict the onset of depression (HR: 0.82; 95% CI: 0.55-1.21; Wald χ2 = 0.73; df = 1; p = 0.43), but a deterioration during follow-up in at least one additional frailty criteria was associated with a significantly higher risk (HR: 1.95; 95% CI: 1.32-2.89; Wald χ2 = 5.78; df = 2; p = 0.01). Improvement in frailty status was not associated with the risk of incident depression (HR: 0.71; 95% CI: 0.35-1.42; Wald χ2 = 0.47; df = 2; p = 0.28). CONCLUSION: Our data did not offer evidence that prefrailty per se predisposes to the onset of depression, but worsening in frailty status is associated with an almost twofold increased risk of incident depression, irrespective from the initial level of impairment.

[Gender medicine: a interdisciplinary approach to medicine.] / La Medicina di Genere: un approccio interdisciplinare alla medicina.

OBJECTIVES: From1995 (Beijing Conference) the World Health Organization strongly did call the attention on the need of great attention to women health and on the lack of studies on the differences in medicine between men and women. From the women health attention we arrived to gender medicine that is a transversal dimension of medicine which describes the differences within the same disease of symptoms, clinical evolution, drug therapy as well as prevention between men and women. METHODS: From some real life examples in this article we wish to make it clear that gender medicine is not a separated medical specialty but a dimension which pass through all specialties. RESULTS: Thus we should speak about gender-specific medicine since all medical specialties have to do a medical training on the basis of gender differences. CONCLUSIONS: Lastly it is underlined also the need of a social approach to gender health in order to pick up all social weight factors that influence diseases in the two genders.

Factors Influencing Transitions Between Frailty States in Elderly Adults: The Progetto Veneto Anziani Longitudinal Study.

OBJECTIVES: To investigate frailty state transitions in a cohort of older Italian adults to identify factors exacerbating or improving frailty conditions. DESIGN: Population-based longitudinal study with mean follow-up of 4.4 years. SETTING: Community. PARTICIPANTS: Individuals enrolled in the Progetto Veneto Anziani (Pro.V.A.) (N = 2,925; n = 1,179 male, n = 1,746 female; mean age 74.4 ± 7.3). MEASUREMENTS: Frailty was identified at baseline and follow-up based on the presence of at least three Fried criteria; prefrailty was defined as the presence of one or two Fried criteria. Anthropometric, socioeconomic, and clinical characteristics were assessed at baseline in a personal interview and clinical examination using validated scales and medical history. RESULTS: During the study period, 1,114 (38.1%) subjects retained their baseline frailty status, 1,066 (36.4%) had a transition in frailty status, and the remainder of the sample died. Older age, female sex, obesity, cardiovascular disease, osteoarthritis, smoking, loss of vision, low levels of self-sufficiency and physical performance, cognitive impairment, hypovitaminosis D, hyperuricemia, and polypharmacy were associated with increasing frailty and greater mortality. Conversely, overweight, low to moderate drinking, high educational level, and living alone were associated with decreasing frailty. CONCLUSIONS: Frailty was confirmed as a dynamic syndrome, with socioeconomic and clinical factors that could be targets of preventive actions influencing transitions to better or worse frailty status.

Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine.

Data showing a remarkable gender difference in life expectancy and mortality, including survival to extreme age, are reviewed starting from clinical and demographic data and stressing the importance of a comprehensive historical perspective and a gene-environment/lifestyle interaction. Gender difference regarding prevalence and incidence of the most important age-related diseases, such as cardiovascular and neurodegenerative diseases, cancer, Type 2 diabetes, disability, autoimmunity and infections, are reviewed and updated with particular attention to the role of the immune system and immunosenescence. On the whole, gender differences appear to be pervasive and still poorly considered and investigated despite their biomedical relevance. The basic biological mechanisms responsible for gender differences in aging and longevity are quite complex and still poorly understood. The present review focuses on centenarians and their offspring as a model of healthy aging and summarizes available knowledge on three basic biological phenomena, i.e. age-related X chromosome inactivation skewing, gut microbiome changes and maternally inherited mitochondrial DNA genetic variants. In conclusion, an appropriate gender-specific medicine approach is urgently needed and should be systematically pursued in studies on healthy aging, longevity and age-related diseases, in a globalized world characterized by great gender differences which have a high impact on health and diseases.

Serum Dehydroepiandrosterone Sulfate and Risk for Type 2 Diabetes in Older Men and Women: The Pro.V.A Study.

OBJECTIVE: A large body of clinical data suggests the importance of endogenous sex hormones in the pathogenesis of diabetes, but very little is known about the possible relationship between dehydroepiandrosterone sulfate (DHEAS) and diabetes, particularly in the elderly. We aimed, therefore, to examine whether high serum levels of DHEAS have any protective effects on the incidence of type 2 diabetes and to elucidate the possible role of gender in a cohort of older subjects. METHODS: We followed 1258 community-dwelling subjects aged ≥65 years without type 2 diabetes who belonged to the Progetto Veneto Anziani (Pro.V.A.) for 4.4±1.2 years. DHEAS were measured at baseline and categorized into gender-specific tertiles. The incidence of type 2 diabetes was diagnosed in cases of fasting plasma glucose above 7.0 nmol/L, glycated hemoglobin ≥6.5%, use of glucose-lowering drugs or a 2-hour postload blood sugar level ≥11.1 nmol/L during the follow-up period. RESULTS: Although no significant differences in potential risk factors for diabetes were apparent across DHEAS tertiles at the baseline in either gender, when those with lower DHEAS were taken for reference, Cox regression analysis showed that males in the highest DHEAS tertile had lower risks for being diagnosed with diabetes during the follow up (HR=0.23; 95% CI: 0.11-0.51; p<0.0001), whereas no significant differences emerged across DHEAS tertiles for females or for the sample as a whole. CONCLUSIONS: Higher serum DHEAS levels revealed a significant protective effect against the onset of type 2 diabetes in older men but not in older women, confirming different sensitivities of type 2 diabetes to DHEAS between genders.

Marital Status and Frailty in Older People: Gender Differences in the Progetto Veneto Anziani Longitudinal Study.

OBJECTIVES: Marital status has been associated with disability and mortality, but its potential role as a factor influencing frailty has yet to be thoroughly investigated. The analysis of gender-related differences in the relationship between marital status and frailty is another interesting matter that remains to be fully elucidated. The aim of our study was to examine the association between marital status and the incidence of frailty in a cohort of older men and women over a 4.4-year follow-up. MATERIALS AND METHODS: A sample of 1887 subjects older than 65 years, enrolled under the Progetto Veneto Anziani (Pro.V.A.) and with no evidence of frailty at baseline, were grouped by marital status. The incidence of frailty after 4.4 years was measured as the presence of at least three of the Fried criteria. RESULTS: After the follow-up period, 414 (21.9%) new cases of frailty were identified. Multivariate logistic regression models demonstrated that male gender carried a higher risk of developing frailty among men who had never married (odds ratio [OR] = 3.84, 95% confidence interval [95% CI] = 2.76-5.35; p < 0.0001) and were widowed (OR = 1.43, 95% CI = 1.06-1.95, p = 0.02) than among married participants. For female gender, widows had significantly lower odds of becoming frail than married women (OR = 0.77, 95% CI = 0.66-0.91, p = 0.002). The determinants of frailty more influenced by marital status were unintentional weight loss, low daily energy expenditure, and exhaustion. CONCLUSIONS: Marital status seems to significantly influence the onset of frailty, with some gender-specific differences. Unmarried men were at higher risk of frailty, while widowed women carried a lower risk of becoming frail than married women.

Serum 25-Hydroxyvitamin D and Osteoarthritis in Older People: The Progetto Veneto Anziani Study.

Recent work has shown that low 25-hydroxyvitamin D (25OHD) levels are associated with the presence of osteoarthritis (OA), but these studies focused on radiographical changes of OA, investigated only one joint, and did not consider the association with OA-related pain. In this study, we aimed to examine the relationship between 25OHD levels and any presence of OA and pain in a cohort of older people. This study was part of the Progetto Veneto Anziani (Pro.V.A), a population-based cohort study in older people. In this cross-sectional work, we considered 2756 subjects (1102 males and 1654 females) with a mean age of 74.2 ± 7.1 years. OA and OA-related pain were defined using a standardized algorithm investigating disease history, medical documentation, symptoms, and physical examination of the joints. On logistic regression analysis, taking those in the highest 25OHD quartile for reference, those in the lowest quartile had significantly higher odds of OA involving the hands (odds ratio [OR] = 1.26, 95% confidence interval [CI] 1.15-1.38 in the sample as whole; 1.36, 95% CI 1.15-1.60 in men and 1.22, 95% CI 1.09-1.37 in women), and pain (OR = 1.18, 95% CI 1.06-1.32 in the sample as whole; 1.52, 95% CI 1.21-1.90 in men and 1.15, 95% CI 1.03-1.29 in women). Similar results were found for the hip. For the knee, low 25OHD levels were associated with the presence of OA in the sample as a whole, and in women, and with the presence of pain in the sample as a whole. In conclusion, low 25OHD levels are associated with the presence of OA and with OA-related pain, particularly when the hand and hip are involved.