Some examples of candidate genes and their orthologs reported for their association with longevity of lifespan have been tabulated in Table 1. During past three- or four-decades, genetic researchers have identified many genes that promote lifespan in different species 22,23,24. Further studies on Drosophila melanogaster have shown up to 7% increase in lifespan after moderate red wine applications . While the data is promising, it’s important to note that TRT is not a miracle cure or a guaranteed path to longevity. Clinical trials have shown that TRT can significantly increase lean muscle mass and improve physical performance in older men with clinically low testosterone. Sarcopenia—the age-related loss of muscle mass and strength—is a major factor in frailty, falls, and loss of independence in older adults. Several studies have linked low testosterone with insulin resistance, increased visceral fat, and higher rates of metabolic syndrome—all key drivers of type 2 diabetes. Since low Testosterone is a life-long condition and there is no cure, which only gets worse with age, treatment is the only course to remain symptom free. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. MR-Egger detects pleiotropic effects acting on the outcome other than via the exposure, but assumes that the genetic instruments do not act via confounders of exposure on outcome66. Estrogens also play a key role in regulation of bone mass and strength by controllingactivity of bone-forming osteoblasts and inhibiting activity and vitality ofbone-resorbing osteoclasts (100). Also Vina and colleagues (73) showed that estrogens play a protective role against oxidativestress. They exhibit an accelerated decline inmuscle mass and strength around the time of the menopause (2,4,90–95), which isrelated to this loss of estrogens (4,96) and causes subsequent decreases in function(76,97). This may be regulated byalteration the protein content of medium-chain acyl-CoA (MCAD), possibly throughperoxisome proliferator-activated receptor γ coactivator 1-α(PGC-1α)–mediated transcription and decrease of miR-29b, leading to increasedmitochondrial gene expression (MCAD and hippuric acid HA) and thus lipid utilization(89). The meta-analysis of Greising and colleagues (87) showed that postmenopausal women on estrogen hormone therapy hadgreater physical strength than those without treatment. Out of the metabolic traits, our T2D results that are in line with clinical trials but contrast recent genetic findings23,33,76 merit an extended discussion. In addition, all these traits correlate with obesity32, that in turn correlates with PCOS and T levels (Supplementary Fig. 10 and Supplementary Data 8), and we may have not been able to fully account for such confounding. We further estimate that normal heritable variation in T levels—contrary to popular beliefs—has only modest effects on many phenotypes. Accordingly, we stress the complex relationship of T levels with many metabolic and endocrine traits. Whereas our analyses supported causality of genetically determined T, e.g., to hormone-sensitive cancers and hirsutism, this did not apply for traits such as obesity, T2D or hypothyroidism. We observed significant genetic correlations to hormonal cancers in both sexes, as expected23,26. The comparison between the survival of the siblings of centenarians and that of their brothers-in-law, who likely shared the same lifestyle for most of their lives, showed that "the survival advantage" of siblings of long-lived subjects was not fully shared from their brothers-in-law. Aging depends on stochastic events and the aging phenotype is the result of the accumulation of cellular damage that cannot be repaired by the cellular maintenance systems that are running out . Therefore, it is necessary to fully understand the mechanisms of successful aging and longevity to prevent the harmful aspects of aging. The somatic mutation rate per year varied greatly across species and showed a strong inverse relationship with species lifespan. Although none of these methods are ideal and all have non–hormone-related side effects, we have come a long way in improving T replacement methods. It may be, for example, that most older men who are candidates for T therapy have baseline T levels already above the prostate threshold, so that administering additional T will have little effect. It is estimated that a T replacement clinical trial would need to enroll a minimum of 6000 men, who would need to be followed for at least 5 years, to have adequate power to appropriately assess prostate risk. 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).
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