A Illustrates the distribution of association p-values by disease category for each biomarker PGS separately for both sexes. We tested the predictive ability of the PGSs in the YFS where the phenotypic variance explained by a genome-wide PGS (R2) ranged between 1.1% (male free T) to 9.2% (male SHBG), indicating the PGSs predict T and SHBG levels in an independent cohort (Supplementary Data 6). Reflecting the high heritability, T measurements from two different time points were highly correlated in both sexes (Supplementary Fig. 3). Using an external dataset (Young Finns Study; YFS), we validated the performance of the PGSs. These causality analyses on the FinnGen traits included both autosomal and X-chromosomal SNPs. Therefore, it is conceivable to speculate that hyper or hypo activation of this signaling pathway, due to genetic variants that lead to different expressions of homeostatic genes. FOXO3A, which is part of the nutrient sensing pathway linked to insulin and insulin growth factor(IGF)-1, has an important role as "gatekeeper" by balancing the cell response to oxidative stress and nutrient availability. The results are consistent with previous findings showing that the MedDiet reduces the risk of AD . In Sicilian LLIs, we did not observe the positive association of APOEε2 nor the negative one of APOε4 with longevity although this might be due to the small size of the sample . In this way, the persistence of genes favoring the onset of type 2 diabetes (T2D) was explained since they would have been advantageous for hunter–gatherer populations . We used published sex-specific genetic predictors of testosterone (125 variants for men and 254 for women)28. Fourth, our study gives lifetime effects of endogenous testosterone up to age ~ 57 years rather than the effect of an intervention. Explicitly, searching sex-specifically for interventions based on this insight might facilitate the search for new means of promoting healthy aging by identifying at an early stage any potential interventions that are likely to be unsuccessful, and where interventions should be sex-specific. Our findings differ from previous observational studies which suggest that endogenous testosterone might improve health and lifespan10–14. As such, longevity studies, take advantage of the changing structure of risk factors with age to obtain estimates of effects on mortality free from selection bias34. A marker of vitamin C metabolism, absorbate, was used as a negative control outcome because vitamin C is no longer thought to affect health36. Smoking initiation was used as a positive control outcome because smoking is very well-known to be addictive and to substantially reduce survival to old age35. In addition, as this is a hypothesis driven study, we also included positive and negative control exposures. Despite that no age cut off was adopted and all ages were included, it is reasonable that the ages of individuals used in these studies reflect the average population lifespan, which includes only a small percentage of centenarians (less than 1 in 5000). These mechanisms are positively or negatively modulated by various factors, i.e., genetics, epigenetics, sex and gender, socioeconomic and educational status, chance and circumstances of life, nutrition and physical activity, stress management and social support, and pathogenic load. A number of well-designed longitudinal studies have shown that in most men there is a slow decline in serum total testosterone (T) levels with aging, even in the absence of disease (Figure) (Harman et al, 2001; Mohr et al, 2005). Parkinson’s disease progresses with age, and the proper function and biological activity of mitochondrial proteins are attributed to SIRT3, SIRT4, and SIRT5 (mitochondrial sirtuins). In addition, NAD+, as a metabolite consumed by sirtuins, plays an essential role in pain regulation and peripheral neuropathic pain . Kumari et al. (2015) pointed out that it may cause thrombocytopenia as a side effect in research on anticancer therapy, suggesting while sirtuins are involved in platelet aging and the general aging processes . The mutually antagonistic mechanisms of sirtuins initiated by proper modulators can prevent many different diseases and thus become a valuable therapeutic agent. Due to the participation of sirtuins in the aging process, determining which compounds have the most effective effect on the modulation of their activity is an urgent issue . Thus, sirtuins may regulate the activity of FOXO factors through deacetylation and involvement in DNA damage repair. Forkhead box proteins present in mitochondria may interact with sirtuins and affect the processes responsible for aging . JVZ and CMS had full access to the data and take full responsibility for the results. J.V.Z. contributed to the conceptualization, extracted data, checked the analysis and reviewed the interpretation. C.M.S. conceptualized the study, conducted the initial analysis and wrote the first draft. Estimates of genetic associations were taken from publicly available UK Biobank summary statistics, except for the unavailable associations which were based on individual level genetic associations from the UK Biobank obtained under application #42468. The MendelianRandomization R package was used for the MR estimates and the metafor R package for meta-analysis.
