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Despite the many associations (Fig. 2), also in the MR analyses we observed no clear evidence for T being directly causal for metabolic traits. The MR Egger value in the x-axis corresponds to 1 SD increase in risk per 1 SD increase in T/free T. Finally, we distinguished between the effects of T and SHBG by including the latter as a covariate in multivariable MR Egger analyses56.
Yet, through the emergence of genetic and biomarker data from large biobanks, currently more than a hundred, mostly autosomal, loci for serum total T, SHBG and free T have been identified, with evidence for sex-specific genetic effects23–25. Genetic, i.e. inherited, differences in testosterone levels contribute to many traits specific to men or women, such as women’s reproductive health, hormonal cancers, and hair growth typical in males. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also review the relationship of reproductive genetics to related health and behavioral traits, aging and longevity and the effect of parental age on offspring outcomes as well as reflecting on limitations, open questions and challenges in this fast-moving field.
Sixth, canalization, i.e., compensation for genetic effects might exist. Exercise and weight loss reduce testosterone in women51,52,53, but possibly less so in men54,55, although severe caloric restriction (50% energy requirements) reduces testosterone in men56. Experimental studies suggest testosterone increases coronary plaque volume39 and coagulation40 while impairing endothelial function41,42,43. Testosterone in men falls with aging and ill-health18,19,20, likely generating residual confounding, as health status is difficult to adjust for comprehensively. Promising observational evidence exists for survival benefits of endogenous testosterone in women10,11,12 and men13,14, although some inconsistencies exist15,16,17.
For example, did you know that testosterone is a key player in prostate cancer? Testosterone's role in bad behavior is largely a myth. When you think of testosterone, what comes to mind? Provided insightful comments on the study and text improving the manuscript.
Table 1 summarizes the latest sirtuin modulators with effects on selected model species. In recent years, (until 2022), there has been a noticeable increase in interest in synthetic activators and inhibitors of sirtuins that can support natural modulators in action. Studies on the use of sirtuin activators focus on resveratrol (RV), which is found as a flavonoid in food and beverages 150,151,152. Mechanisms of interaction between sirtuins and forkhead box proteins are complicated. In addition, it has been proven that Sir2 can increase the lifespan of individuals by inhibiting homologous recombination of ribosomal DNA 1,126. Studies have shown that, in a sirtuin-dependent manner, a chronic stressor can prolong the life of S. The proteins belonging to the FoxO family (forkhead boxO) are transcription factors that play a significant role in the organism at many levels.
Nuclear receptors are also known to play an important role in the aging process. In case of TORC1 induces longevity of life, SKN-1/Nrf are required and presence of DAF-16/FOXO is not obligatory (Figure 4). Genetic interference to inhibit the translation process has been linked with the longevity of life in C. Longevity of lifespan regulated by IIS pathway via DAF-16/FOXO, TOR pathway vis SKN1/Nrf and FOXO regulation, and by JNK under oxidative stress by phosphorylation and inactivation of IRS1 and activation of AKT. The main consequences of this cascade include the promotion of glucose transport, protein synthesis, cell proliferation, cell differentiation, and inhibition of apoptosis that enhance the longevity. The circadian desynchrony may lead to the neurodegenerative disorders and metabolic pathologies that ultimately impact the lifespan . DNA damage triggers aging process by blocking transcription, activating the signal transduction processes, regulating the DNA metabolism, altering the epigenome and finally by inducing apoptosis 310,311,312.
The figure includes traits from the endocrine, metabolic, circulatory and sex-specific categories shown in Fig. B Shows hazard ratios per one SD increase in PGS for 20 traits from endocrine, metabolic, circulatory and sex-specific categories. To this end we used the FinnGen data, consisting of 217,464 (94,478 men, 122,986 women) Finnish participants, representing roughly 5% of the Finnish adult population, with genotypes linked to up to 46 years of follow-up within nationwide healthcare registries41. Notably, the sex-specific PGSs for T and free T had no predictive value in the opposite sex, as expected based on serum T being determined by distinct genetic variants in both sexes (Supplementary Data 6 and Supplementary Fig. 5). Co-localization analyses between male and female GWASs confirmed the widespread sex-specificity of the genetic loci for T (Supplementary Fig. 4, Supplementary Data 4 and Supplementary Data 5)24.