EDITORIAL Special Issue: The influence of biological sex in ageing

ZÁRATE, SANDRA; GREDILLA, RICARDO

MECHANISMS OF AGEING AND DEVELOPMENT

ELSEVIER IRELAND LTD

Año: 2022 vol. 202

0047-6374

One of the most robust certainties within biological processes is ageing and death of the individuals. Ageing is an inevitable process that is characterized by the decline in most physiological functions. However, not all species age at the same rate and within a particular species, remarkable individual differences are observed in the ageing process. Also, the variation in several parameters is quite significant when biological sex is taken into account. A high number of studies have reported that male and female animals from all species, including humans differ in several aspects regarding ageing. For example, it is now well accepted that females have longer lifespans than their male counterparts (Promislow, 1991; Schroots et al., 1999). The female higher life expectancy is not limited to humans, revealing specific biological characteristics of sexes rather than differences in socio-behavioral factors between men and women (Zárate et al., 2017). Also, detrimental effects of brain ageing as well as many age-related neurodegenerative diseases exhibit a sex-dependent incidence. In this regard, men over the age of 40 show worse memory performance than age-matched women (Jack et al., 2015). While men are at higher risk for Parkinson’s disease, post-menopausal women are more likely to develop Alzheimer´s as well as to show faster cognition decline after disease onset (Gillies et al., 2014; Li and Singh, 2014; Zagni et al., 2016). Moreover, there is increasing evidence in different organs and tissues for sex dimorphism in molecular hallmarks of ageing, such as DNA damage and mutation rates, mitochondrial dysfunction, telomere attrition, epigenetics and nuclear architecture among others (Fischer and Riddle, 2018). Those differences clearly indicate that biological sex should be taken into account as a critical variable when designing therapies to treat different diseases or to delay the ageing process (Young and Pfaff, 2014; May, 2016).Despite the vast evidence on sex dimorphism in different aspects of ageing, the main object of research in this field has been males during several decades. Thus, in order to fully understand the ageing process, and not only how it affects only approximately half of the population, it is necessary to approach it with a broader view and analyze not only the molecular changes that lead to ageing and associated diseases in male models, but also to compare and investigate how those changes occur in females. The aim of this special issue of Mechanisms of Ageing and Development is to cover some of the most relevant aspects of the influence of biological sex in ageing. Contributions include both reviews and original articles by major experts in the field. Thus, the importance of considering sex as a key factor in ageing research is covered by Navarro Pardo et al. Considering the exceptional increase in life expectancy, Navarro-Pardo et al discuss in their review the significance of approaching a healthy ageing taking into account the differences existing between both sexes. As life expectancy increases, ageing greatly affects gonadal function and reproduction. Both males and females are affected by physiological decline in gonadal function. Although in humans such decline is normally more associated with women due to an easy detection, a significant age-related gonadal impairment also occurs in men, sometimes undetected though. Gonadal dysfunction leads to reproduction impairment and it affects quality of life, which has been correlated with an increased risk in age-related diseases. In this special issue, two contributions highlight the relevance of gonadal ageing. The review by Frunguieri et al summarizes how ovarian and testicular ageing are affected by pro-inflammatory, oxidative and apoptotic events, stressing the relevance of the crosstalk among them. Moreover, they describe the clinical implications and some potential interventions in order to improve gonadal health leading to a better quality of life. On the other hand, Chico-Sordo et al explore the molecular pathways involved in reproductive ageing both in men and women, and the potential effects in fertility, paying special attention to telomere shortening. Increased inflammation is another hallmark of ageing, and it has been described to play a critical role not only in gonadal decline, but also in several biological processes associated with age. The role of inflammation in ageing is covered by the review by Varghese et al. In their review, the authors summarize how alterations in adipose tissue metabolism are related to inflammation and the influence of sex differences and ageing in this process. The impact of sex differences has been widely investigated with regard to cognitive function. The influence of gonadal hormones and neuroactive steroid metabolites has been investigated under physiological and pathological conditions, such as brain injury, type 2 diabetes and some of the most remarkable age-related neurodegenerative processes. Two reviews and one original article focus on this particular topic. Chowen and García-Segura discuss how glial cells participate in the differential adaptation of the nervous system to pathological conditions between females and males, and the potential mechanisms involved. Moreover, Lennol et al report differences in the response of hippocampal male and female astrocytes to Aβ oligomers regarding cell survival and death, oxidative stress and inflammation pathways. Their results suggest sex-dependent astroglial susceptibility to Aβ toxic stimuli, which may be involved in the diferential progression of Alzheimer’s disease between males and females. On the other hand, the article by Borrás et al, deals with the effect of phytoestrogens present in soya on lifespan in two animal models, i. e. male healthy mice and type 2 diabetic male rats. Their results show that soya consumption have beneficial effects on healthspan only in metabolically-stressed animals, through a mechanism not involving antioxidant gene expression. The long established clinical expression of frailty has traditionally been associated to concern over an older person´s vulnerability and prognosis. This clinical condition develops as a result of age-related decline in multiple physiological systems and implies increased susceptibility to adverse health consequences. In recent years, frailty has also emerged as a major mechanism to understand ageing. However, the effect of sex on frailty and associated outcomes remains poorly understood. The review by Kane and Howlett deals with this topic and highlights the paradox of women being frailer but also living longer than men. Remarkably, similar results are found in most preclinical models of frailty, suggesting that fundamental biological mechanisms underlie sex differences rather than socio-behavioral factors.Overall, the articles composing this Special Issue reveal a clear influence of biological sex in different aspects of ageing and highlight the urgent need for explicitly taking this variable into account when designing studies and drawing conclusions in this research field.