At replacement doses in the normal range, muscle of older men responds similarly to that of young men (Bhasin et al, 2005). Some of the clinical outcomes that are being targeted by T replacement studies in older men also are ones in which multiple factors other than T are implicated. This needs to be taken into account when studies of T replacement therapy are designed or interpreted. None of the current screening questionnaires for hypogonadism in older men (eg, ADAM, Massachusetts Male Aging Study, Aging Males Survey scales) has high enough specificity to help either with clinical diagnosis or monitoring response to therapy. Unfortunately, using other hormonal evaluations, such as gonadotropin levels, to help make that decision is rarely helpful; as noted previously, the majority of older men, even those with quite low T levels, do not have significantly elevated LH levels. These clinical T assays have significant deficiencies, particularly in the low range, just where one would want them to work best for assisting with appropriate diagnoses and clinical management. Considering the 7–15× differences in T levels between an average male and female, that should lead to vast differences in disease incidence between the sexes if adult T levels were a major determinant for health, this is only to be expected. Finally, we report that genetic differences affecting T levels seemed to affect disease risk especially in women, including PCOS-related endpoints like hirsutism, PMB and infertility. First, we detected causality between higher T levels and several sex-biased phenotypes with biological links to T, but less contribution to most other phenotypes, echoing experimental data and findings from recent MR studies23,26. Here, using genetic data is an alternative means to estimate how population variability in baseline T levels connects with human health, leading to causal insights beyond the reported epidemiological relationships. Owing to the unique genetic architecture, the sex-specific PGS for T and free T do not predict the corresponding hormone levels in the opposite sex (Supplementary Data 6). For the traits from public GWAS included in genetic correlation analyses, in 16 out 44 instances we could perform two sample MR (phenotype data not including UK Biobank samples) and in 19/44 instances the studies included X-chromosomal data (Supplementary Data 11). Resistance exercise caninduce acute subtle increases in serum testosterone; however, a high relative intensityand a high total volume of resistance exercise must be performed to acutely inducephysiologically significant increases in concentrations of testosterone necessary toincrease muscle anabolism (128). Testosterone stimulates skeletal muscle protein synthesis (anabolic effect) andinhibits protein degradation (anticatabolic effect) in the skeletal muscle of humans,regardless of age. The balance of GHand IGF-1 seems to be a well-recognized target of intervention that extends longevity.However, the role of the GH/IGF-1 pathway in the modulation of human longevity continues tobe hotly debated. Recent data indicate that reduced somatotropic signaling provides protection from cancerand other age-related diseases and may promote old age survival (124,125). High levels of IGF-1 are a risk factor for many types of cancers (115–117), whereas lowIGF-1 has been implicated in the pathogenesis of a wide range of conditions, such as type 2diabetes (118), osteoporosis (119), and coronary heart disease (120). GH has direct effects on tissues such asbrain and muscle as well as indirect paracrine and autocrine effects, via stimulation of thelocal production of IGF-1 in target tissues. Life expectancy in the developed West is currently stagnated and remains shorter in men than women. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. DAF-16/FOXO is translocated to the nucleus, this action is mediated by HLH-30 under longevity promoting conditions. Circadian rhythms also play important role in the mammalian cell biochemistry and physiology. Genomic instability may lead to changes in the gene expression, enhance the changes of apoptosis, and it is known as a hall-mark of cancer initiation, age related neurodegenerative diseases 327,328,329. Oxidative stress typically caused by reactive oxygen species (ROS), ultra-violet and ionizing radiations can damage cellular components, especially the lipids, proteins and DNA . Successful DNA repair leads to the continuation of life activity/cell division, contrary to that failure in the DNA repair promotes programmed cell death (apoptosis). P53 is required for cellular degeneration by genomic DNA damage not required for mitochondrial DNA damage response .
