Evolution of sexual dimorphism in human lifespan (4)

Part 4. Androgens and the health of older men

The beginning of the article is here.

Understanding the biological basis of sex differences in life expectancy will help in the development of interventions that can extend the period of healthy life of men for several years. It is obvious that most men will not agree to orchiectomy (castration), especially considering the fact that this will entail the loss of attributes of belonging to the male sex, including hypotrophy of the genitals, loss of libido, the development of gynecomastia and the appearance of female-type fat deposits [40]. However, the results discussed in the previous part of the article, obtained when studying the life of Korean eunuchs, will give food for thought to transsexuals who change gender from male to female, as some of them undergo orchiectomy. (The effect of sex change on aging is currently unclear, since these operations began to be actively carried out only in the 1970s, however, existing data indicate that there are no changes in the structure of mortality [44]).

Antiandrogenic therapy and health in the later stages of lifeMost likely, the seminal glands affect the state of health in old age through the production of testosterone, the secretion of which by Leydig cells is stimulated by the luteinizing hormone of the pituitary gland.

In the prostate gland, under the action of enzymes of class 5a-reductases, testosterone is converted into a more active derivative – dihydrotestosterone. Apparently, these androgenic hormones have a negative effect on health, including suppressing immunity [45] and contributing to the formation of unhealthy lipoprotein profiles [46, 47]. Androgens have a particularly pronounced detrimental effect on the prostate gland, contributing to the development of its benign hyperplasia (adenoma) and, in rare cases, cancer [35, 48]. By the age of 80, at least 75% of men develop adenoma, mainly affecting the glandular and stromal tissue of the transitional zone of the prostate gland [49].

The development of benign hyperplasia and prostate cancer depends on the presence of seminal glands, the removal of which before the age of 40 eliminates the risk of developing these diseases [44, 50]. The role of the seminal glands in the development of prostate adenoma is due, at least in part, to androgenic hormones, since blocking the conversion of testosterone to dihydrotestosterone with drugs such as the 5a-reductase inhibitor finasteride suppresses the development of hyperplasia [48]. However, it is possible that the role of the seminal glands in the development of prostate adenoma may not be limited to these factors [35].

The use of 5a-reductase inhibitors as antiandrogenic therapy is currently widely practiced for the treatment of late-stage prostate cancer [48]. Antiandrogenic therapy is a form of chemical castration and its widespread use has led to the emergence of a population of modern eunuchs. The ability of this therapeutic approach to slow down the aging of men is the subject of discussion [35], fueled by the results of the study of Korean eunuchs. Could it be that, like Korean eunuchs, modern men undergoing antiandrogenic therapy will live longer? If you do not take into account prostate adenoma, will this therapeutic intervention be able to protect them from other manifestations of the aging process?

Androgenic hormones and diseases of the cardiovascular systemOne of the reasons for the existence of a sex difference in life expectancy is the increased predisposition of men to diseases of the cardiovascular system [51].

Contrary to the assumption that androgen hormones contribute to this [52], a large amount of data denies this relationship [51]. For example, a recent meta-analysis of the results of 70 studies revealed an association between low testosterone levels and an increased risk of developing cardiovascular diseases [53]. This pattern is most clearly visible when conducting simultaneous (cross-sectional) studies, in which the state of health and androgen levels in older men are compared. In this case, the distortion of the results may be due to the fact that poor health may be accompanied by suppression of androgen synthesis [38, 53]. Therefore, the data obtained when studying the long-term effects of antiandrogenic therapy are more informative. However, in this case, there is an increase in the frequency of cardiovascular diseases [53, 54, 55]. Moreover, a meta-analysis of the results of 30 placebo-controlled studies on the effects of testosterone replacement therapy did not reveal an increased risk of cardiovascular diseases [56]. Accordingly, the incidence of the corresponding pathologies was not reduced in 297 eunuchs in the USA [37]. However, its decrease was registered in 989 eunuchs held in closed institutions in Denmark [57]. Antiandogenic therapy can also increase insulin resistance, hyperinsulinemia and hyperglycemia [58].

Thus, testosterone contributes to the aging of at least one organ (prostate gland), but not a number of others (for example, the cardiovascular system, musculature). At the same time, there is evidence that the removal of seminal glands can increase life expectancy, at least in certain conditions (at the court of the Korean emperor).

How to reconcile these data with each other? On the one hand, a certain role in the regulation of the aging process may be played not by androgens, but by other factors synthesized by the seminal glands. On the other hand, the elimination of the influence of androgens in childhood or adolescence has a positive effect, whereas at a later age it is generally detrimental to the body. It should be noted here that eunuchs at the court of the Josun dynasty, as a rule, were castrated at an early age, before reaching puberty [43]. This does not contradict the observations of Hamilton and Mestler, according to which the most pronounced increase in life expectancy is observed with early castration [37]. These observations confirm the hypothesis that it is during puberty and youth that androgens of the seminal glands trigger changes that ensure the development of the body, but are involved in the development of pathological conditions at a later age [15].

Prostatic hyperplasia as a model of aging evolutionThe appearance of age-related benign prostatic hyperplasia in the course of evolution can be explained by the principle of antagonistic pleiotropy, in which elevated levels of androgens and/or altered prostate response to them increases survival in the early stages of life, but later leads to the development of hyperplasia [7, 35, 59].

Thus, benign prostatic hyperplasia is a good model for studying generalized biological mechanisms of aging evolution. In this case, the key question is the following: what are the selection advantages provided by changes in the functioning of the prostate gland that ultimately lead to the development of its hyperplasia?

The main function of the prostate gland is the production of sperm: in humans, it produces 50-75% of the volume of sperm. Based on this, it can be assumed that in this case an important role belongs to the advantage in sperm competition. Considering that sperm competition is not an important factor in polygynous families, it can be assumed that predisposition to prostate hyperplasia is a hereditary trait that arose before the appearance of polygyny. This is confirmed by the fact that, according to available data, one of the few mammals prone to the development of benign prostatic hyperplasia is our close relative chimpanzee [60]. It is also important to note that the relatively large size of human seminal glands in relation to body size indicates the existence of a certain propensity inherited from distant ancestors to have sexual relations with multiple partners practiced by chimpanzees, unlike gorillas who have small seminal glands and live exclusively in polygynous families [61].

Antagonistic selection affecting the mechanisms of sperm competition and life expectancy has been studied in detail on Drosophila melanogaster flies [62]. In these insects, complex effects are provided by seminal fluid peptides secreted by accessory glands, which are the equivalent of the mammalian prostate gland [63]. For example, sex peptides in the seminal fluid of drosophila stimulate the production of eggs in females, but reduce their lifespan [64]. Similarly, the secret of the prostate gland contains hundreds of proteins, including immunosuppressants (prostaglandins, transforming growth factor beta-1) and antibacterial peptides. For example, transforming growth factor beta-1 (TGF-beta1) performs the function of protecting spermatozoa in the female body by suppressing immunity, but in the later stages of men's life it leads to transdifferentiation of prostate fibroblasts into myofibroblasts, causing epithelial cell hypertrophy [49]. This demonstrates how, at the molecular and cellular levels, androgens can make a "deal" between sexual advantages in the early stages of life and pathologies developing later in life.

ConclusionsAccording to the issues covered in the article, schematically presented in Figure 2, the modern model of human aging is the result of the interaction of three key factors.

An increase in male reproductive function in old age increased human life expectancy compared to other higher primates (patriarchal hypothesis) [18]; the structure of the ovaries prevented the evolution of a longer reproductive period in women [65]; and antagonistic pleiotropy, by influencing the function of the seminal glands, reduced the life expectancy of men [35].

Figure 2. Evolution of the modern model of human aging. A hypothetical scheme demonstrating the evolutionary origin of human longevity (compared to other primates), the sexual difference in life expectancy and menopause. Figures and curves reflect only general trends and do not provide accurate values.Conducted in 2012 by Min et al.

a study that demonstrated the longevity of eunuchs who lived at the court of the Korean imperial dynasty [43] provided new data in support of the idea that the functioning of the seminal glands contributes to the development of pathological changes later in life and mortality among men. According to one possible explanation, castration brings to the surface the longevity originally inherent in the male body [66], that is, the effects of autosomal determinants of human longevity, which are the result of male selection, but are usually more strongly expressed in women [17]. Perhaps for this reason, maturity in men comes later than in women [67]. At the same time, despite the fact that androgens stimulate the development of a number of age-related pathologies (for example, prostate cancer), they protect against many other problems (for example, cardiovascular diseases, sarcopenia, osteoporosis) [53]. Perhaps during puberty and youth androgens have an effect on the body, adversely affecting health in old age. At this stage, it is most important to conduct additional research on the aging of eunuchs.

The list of references is given on a separate page.

Portal "Eternal youth" http://vechnayamolodost.ru10.10.2014