Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 Caucasian individuals from 20 population-based studies to identify new susceptibility loci for reduced renal function, estimated by serum creatinine (eGFRcrea), cystatin C (eGFRcys), and CKD (eGFRcrea <60 ml/min/1.73m2; n = 5,807 CKD cases). Follow-up of the 23 genome-wide significant loci (p<5×10−8) in 22,982 replication samples identified 13 novel loci for renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2, and SLC7A9) and 7 creatinine production and secretion loci (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72, BCAS3). These results further our understanding of biologic mechanisms of kidney function by identifying loci potentially influencing nephrogenesis, podocyte function, angiogenesis, solute transport, and metabolic functions of the kidney.

In a population-based, cross-sectional study, we assessed age-and sex-specific changes in bone structure by QCT. Over life, the cross-sectional area of the vertebrae and proximal femur increased by ϳ15% in both sexes, whereas vBMD at these sites decreased by 39 -55% and 34 -46%, respectively, with greater decreases in women than in men.Introduction: The changes in bone structure and density with aging that lead to fragility fractures are still unclear. Materials and Methods: In an age-and sex-stratified population sample of 373 women and 323 men (age, 20 -97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia. Results: In young adulthood, men had 35-42% larger bone areas than women (p Ͻ 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by ϳ15% (p Ͻ 0.001) at central sites and by ϳ16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p Ͻ 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (Ϫ55%) than in men (Ϫ46%, p Ͻ 0.001) at central sites, but were similar (Ϫ24% and Ϫ26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women (ϳ25%) than in men (ϳ18%, p Ͻ 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity. Conclusions: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.

Vertebral fractures are the most frequent of the fractures associated with osteoporosis, yet little is known of their impact on health in the United States. To aid in this understanding, the authors examined the survival rate of 335 residents of Rochester, Minnesota, who had an initial radiologic diagnosis of vertebral fracture between 1985 and 1989. Seventy-six died during 809 person-years of follow-up. The overall survival rate was worse than expected, and diverged steadily from expected values throughout the course of the study. At 5 years after diagnosis, the estimated survival was 61% compared with an expected value of 76% (relative survival = 0.81, 95% confidence interval (CI) 0.70-0.92). The 5-year relative survival after a hip fracture in Rochester was a comparable 0.82 (95% CI 0.77-0.87), but there was a much greater excess of deaths within the first 6 months as compared with patients with vertebral fractures. The 5-year relative survival rate after a distal forearm fracture was 1.00 (95% CI 0.95-1.05). Clinically diagnosed vertebral fractures are rarely fatal, and the reduced survival seen subsequently could related to comorbid conditions. Nonetheless, the excess mortality should be accounted for in assessing the public health impact of osteoporosis.

Vertebral fractures are the classic hallmark of osteoporosis, yet little is known of their epidemiology. The incidence of clinically diagnosed vertebral fractures was therefore directly assessed in the predominantly white (European descent) population of Rochester, Minnesota. Altogether, 341 Rochester residents were radiologically diagnosed for the first time with one or more vertebral fractures in the 5 year study period, 1985-1989. The overall age- and sex-adjusted incidence rate was 117 per 100,000 person-years (95% CI, 105 to 130). The age-adjusted rate in women (145 per 100,000 person-years) was almost twice that in men (73 per 100,000 person-years). Of all fractures, 47 (14%) followed severe trauma, 282 (83%) followed moderate or no trauma, and 12 (3%) were pathologic. Incidence rates for fractures following moderate trauma were higher in women than in men and rose steeply with age in both genders. In contrast, fractures following severe trauma were more frequent in men, and their incidence increased less with age. These Rochester rates are greater than those previously reported from studies in Britain and Sweden but lower than the incidence rates extrapolated from a prevalence study in this population.

In a population-based cross-sectional study, we examined effects of sex and age on bone microstructure at the wrist using high-resolution 3-D pQCT. Compared with women, men had thicker trabeculae in young adulthood and had less microstructural damage with aging. These findings may contribute to the virtual immunity of men to age-related increases in wrist fractures.Introduction: Although changes in bone microstructure contribute to fracture risk independently of BMD, it has not heretofore been possible to assess this noninvasively in population-based studies. Materials and Methods:We used high-resolution 3-D pQCT imaging (voxel size, 89 m) to define, in a random sample of women (n ‫ס‬ 324) and men (n ‫ס‬ 278) 21-97 years of age, sex and age effects on bone microstructure at the wrist. Results: Relative to young women (age, 20-29 years), young men had greater trabecular bone volume/tissue volume (BV/TV; by 26%, p ‫ס‬ 0.001) and trabecular thickness (TbTh; by 28%, p < 0.001) but similar values for trabecular number (TbN) and trabecular separation (TbSp). Between ages 20 and 90 years, cross-sectional decreases in BV/TV were similar in women (−27%) and in men (−26%), but whereas women had significant decreases in TbN (−13%) and increases in TbSp (+24%), these parameters had little net change over life in men (+7% and −2% for TbN and TbSp, respectively; p < 0.001 versus women). However, TbTh decreased to a greater extent in men (−24%) than in women (−18%; p ‫ס‬ 0.010 versus men). Conclusions: Whereas decreases with age in trabecular BV/TV are similar in men and women, the structural basis for the decrease in trabecular volume is quite different between the sexes. Thus, over life, women undergo loss of trabeculae with an increase in TbSp, whereas men begin young adult life with thicker trabeculae and primarily sustain trabecular thinning with no net change in TbN or TbSp. Because decreases in TbN have been shown to have a much greater impact on bone strength compared with decreases in TbTh, these findings may help explain the lower life-long risk of fractures in men, and specifically, their virtual immunity to age-related increases in distal forearm fractures.

BACKGROUND-Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown.

IntroductionWhile the role of estrogen (E) in regulating bone metabolism in women is well established, the relative contributions of E versus testosterone (T) in regulating bone turnover in men remain unclear. Since T is the dominant sex steroid secreted in men, the traditional belief has been that E is the major sex steroid regulating bone metabolism in women and T is the major sex steroid regulating bone metabolism in men. This concept has been challenged, however, by the description of several "experiments of nature." A male carrying homozygous mutations in the E receptor-α (ER-α) gene (who was unable to respond to E) (1) and two males with homozygous mutations in the aromatase gene (who were unable to synthesize E) (2-4) had osteopenia, unfused epiphyses, and elevated indices of bone turnover. Moreover, E therapy in the two aromatasedeficient males corrected these abnormalities (3-5).These reports have led to a reconsideration of the possible role of E in regulating the male skeleton, although several questions remain. The major unresolved issue is whether E acts on the male skeleton mainly to enhance bone mass during growth and maturation, or whether it also acts to retard bone loss in aging individuals. Thus, since the ER-α mutant and aromatase-deficient males had immature skeletons, it is possible that E primarily plays a role in determining skeletal modeling and the acquisition of peak bone mass, but not in regulating bone turnover (and hence, bone loss) in aging men.Several cross-sectional observational studies (6-10) have attempted to address this issue by relating bone mineral density (BMD) to sex steroids in elderly men. In these studies, E (and in particular, the bioavailable or non-sex hormone binding globulin [non-SHBG] bound fraction) did correlate better with BMD than T. However, since both T and E levels are correlated with each other (7), these observational data could not conclusively separate the relative contributions of each to skeletal metabolism in elderly men. In addition, since BMD in elderly men is a function both of peak bone mass and bone loss with aging, they also could not dissociate the effects of E on the acquisition of peak bone mass in early adulthood from its effects on continued bone loss later in life.In addition to its intrinsic importance for our understanding of skeletal physiology, this issue also has significant practical implications. Thus, while men lack the rapid phase of bone loss present at menopause in women, they lose substantial amounts of bone with aging (11)(12)(13)(14). In addition, population-based studies have shown that bone resorption increases with age in Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus...