Breen Good (feetchard3)

The enormous mammal's lifespan variation is the result of each species' adaptations to their own biological trade-offs and ecological conditions. Comparative genomics have demonstrated that genomic factors underlying both, species lifespans and longevity of individuals, are in part shared across the tree of life. Here, we compared protein-coding regions across the mammalian phylogeny to detect individual amino-acid (AA) changes shared by the most long-lived mammals and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 AA in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (p = 0.003). These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by Genome-Wide Association Studies (GWAS). Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human GWAS. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan. In a recent study a pattern of 27 metabolites, including serum glycine, associated with bone mineral density (BMD). To investigate associations for serum and urinary glycine levels with BMD, bone microstructure and fracture risk in men. In the population based MrOS Sweden study (men, 69-81 years) serum glycine and BMD were measured at baseline (n=965) and 5-year follow up (n=546). Cortical and trabecular bone parameters of the distal tibia were measured at follow-up using high resolution peripheral quantitative computed tomography. Urinary (n=2,682) glycine was analyzed at baseline. X-ray validated fractures (n=594) were ascertained during a median follow-up of 9.6 years. Associations were evaluated using linear regression (bone parameters) or Cox regression (fractures). Circulating glycine levels were inversely associated with femoral neck (FN)-BMD. A meta-analysis (n=7,543) combining MrOS Sweden data with data from three other cohorts confirmed a robust inverse association between serum glycine levels and FN-BMD (p=7.7 x 10 -9). Serum glycine was inversely associated with the bone strength parameter failure load in the distal tibia (p=0.002), mainly as a consequence of an inverse association with cortical cross-sectional area and a direct association with cortical porosity. Both serum and urinary glycine levels predicted major osteoporotic fractures (serum, HR per SD increase = 1.20, 95% CI 1.03-1.40; urine HR=1.13, 95% CI 1.02-1.24). These fracture associations were only marginally reduced in models adjusted for FRAX with BMD. Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men. Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men.In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not