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  • Coviello, Andrea D., et al. (författare)
  • A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation
  • 2012
  • Ingår i: PLoS Genetics. - : Public Library of Science. - 1553-7404 .- 1553-7390. ; 8:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5x10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained similar to 15.6% and similar to 8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
  • Bauer, Juergen M., et al. (författare)
  • Effects of a Vitamin D and Leucine-Enriched Whey Protein Nutritional Supplement on Measures of Sarcopenia in Older Adults, the PROVIDE Study : A Randomized, Double-Blind, Placebo-Controlled Trial
  • 2015
  • Ingår i: Journal of the American Medical Directors Association. - 1525-8610 .- 1538-9375. ; 16:9, s. 740-747
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Age-related losses of muscle mass, strength, and function (sarcopenia) pose significant threats to physical performance, independence, and quality of life. Nutritional supplementation could positively influence aspects of sarcopenia and thereby prevent mobility disability. Objective: To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of sarcopenia. Design: A multicenter, randomized, controlled, double-blind, 2 parallel-group trial among 380 sarcopenic primarily independent-living older adults with Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index. The active group (n = 184) received a vitamin D and leucine-enriched whey protein nutritional supplement to consume twice daily for 13 weeks. The control group (n = 196) received an iso-caloric control product to consume twice daily for 13 weeks. Primary outcomes of handgrip strength and SPPB score, and secondary outcomes of chair-stand test, gait speed, balance score, and appendicular muscle mass (by DXA) were measured at baseline, week 7, and week 13 of the intervention. Results: Handgrip strength and SPPB improved in both groups without significant between-group differences. The active group improved more in the chair-stand test compared with the control group, between-group effect (95% confidence interval): -1.01 seconds (-1.77 to -0.19), P = .018. The active group gained more appendicular muscle mass than the control group, between-group effect: 0.17 kg (0.004-0.338), P = .045. Conclusions: This 13-week intervention of a vitamin D and leucine-enriched whey protein oral nutritional supplement resulted in improvements in muscle mass and lower-extremity function among sarcopenic older adults. This study shows proof-of-principle that specific nutritional supplementation alone might benefit geriatric patients, especially relevant for those who are unable to exercise. These results warrant further investigations into the role of a specific nutritional supplement as part of a multimodal approach to prevent adverse outcomes among older adults at risk for disability.
  • Hill, Tom R., et al. (författare)
  • A Vitamin D, Calcium and Leucine-Enriched Whey Protein Nutritional Supplement Improves Measures of Bone Health in Sarcopenic Non-Malnourished Older Adults : The PROVIDE Study
  • 2019
  • Ingår i: Calcified Tissue International. - 0171-967X .- 1432-0827. ; 105:4, s. 383-391
  • Tidskriftsartikel (refereegranskat)abstract
    • Alterations in musculoskeletal health with advanced age contribute to sarcopenia and decline in bone mineral density (BMD) and bone strength. This decline may be modifiable via dietary supplementation. To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of bone health. Participants (n 380) were participants of the PROVIDE study, a 13-week, multicenter, randomized, controlled, double-blind, 2 parallel-group study among non-malnourished older participants (≥ 65 years) with sarcopenia [determined by Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index (SMI; skeletal muscle mass/BW × 100) ≤ 37% in men and ≤ 28% in women using bioelectric impedance analysis] Supplementation of a vitamin D, calcium and leucine-enriched whey protein drink that comprises a full range of micronutrients (active; 2/day) was compared with an iso-caloric control. Serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), biochemical markers of bone formation (osteocalcin; OC, procollagen type 1 amino-terminal propeptide; P1NP) and resorption (carboxy-terminal collagen crosslinks; CTX), insulin like growth factor 1 (IGF-1) and total-body BMD were analysed pre- and post-intervention. Serum 25(OH)D concentrations increased from 51.1 ± 22.9 nmol/L (mean ± SD) to 78.9 ± 21.1 nmol/L in the active group (p < 0.001 vs. control). Serum PTH showed a significant treatment difference (p < 0.001) with a decline in the active group, and increase in the control group. Serum IGF-1 increased in the active group (p < 0.001 vs. control). Serum CTX showed a greater decline in the active group (p = 0.001 vs. control). There were no significant differences in serum OC or P1NP between groups during the intervention. Total body BMD showed a small (0.02 g/cm2; ~ 2%) but significant increase in the active group after supplementation (p = 0.033 vs. control). Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.
  • Kaiser, Matthias J., et al. (författare)
  • Frequency of Malnutrition in Older Adults : A Multinational Perspective Using the Mini Nutritional Assessment
  • 2010
  • Ingår i: Journal of The American Geriatrics Society. - 0002-8614 .- 1532-5415. ; 58:9, s. 1734-1738
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES To provide pooled data on the prevalence of malnutrition in elderly people as evaluated using the Mini Nutritional Assessment (MNA). DESIGN Retrospective pooled analysis of previously published datasets. SETTING Hospital, rehabilitation, nursing home, community. PARTICIPANTS Four thousand five hundred seven people (75.2% female) with a mean age of 82.3. MEASUREMENTS The prevalence of malnutrition in the combined database and in the four settings was examined. RESULTS Twenty-four data sets with information on full MNA classification from researchers from 12 countries were submitted. In the combined database, the prevalence of malnutrition was 22.8%, with considerable differences between the settings (rehabilitation, 50.5%; hospital, 38.7%; nursing home, 13.8%; community, 5.8%). In the combined database, the "at risk" group had a prevalence of 46.2%. Consequently, approximately two-thirds of study participants were at nutritional risk or malnourished. CONCLUSION The MNA has gained worldwide acceptance and shows a high prevalence of malnutrition in different settings, except for the community. Because of its specific geriatric focus, the MNA should be recommended as the basis for nutritional evaluation in older people.
  • Liberman, Keliane, et al. (författare)
  • Thirteen weeks of supplementation of vitamin D and leucine-enriched whey protein nutritional supplement attenuates chronic low-grade inflammation in sarcopenic older adults : the PROVIDE study
  • 2019
  • Ingår i: Aging Clinical and Experimental Research. - : SPRINGER. - 1594-0667 .- 1720-8319. ; 31:6, s. 845-854
  • Tidskriftsartikel (refereegranskat)abstract
    • Background A chronic low-grade infammatory profle (CLIP) is associated with sarcopenia in older adults. Protein and Vitamin (Vit)D have immune-modulatory potential, but evidence for efects of nutritional supplementation on CLIP is limited. Aim To investigate whether 13 weeks of nutritional supplementation of VitD and leucine-enriched whey protein afected CLIP in subjects enrolled in the PROVIDE-study, as a secondary analysis. Methods Sarcopenic adults (low skeletal muscle mass) aged ≥ 65 years with mobility limitations (Short Physical Performance Battery 4–9) and a body mass index of 20–30 kg/m2 were randomly allocated to two daily servings of active (n=137, including 20 g of whey protein, 3 g of leucine and 800 IU VitD) or isocaloric control product (n=151) for a double-blind period of 13 weeks. At baseline and after 13 weeks, circulating interleukin (IL)-8, IL-1 receptor antagonist (RA), soluble tumor-necrosis-factor receptor (sTNFR)1, IL-6, high-sensitivity C-reactive protein, pre-albumin and 25-hydroxyvitamin(OH) D were measured. Data-analysis included repeated measures analysis of covariance (corrected for dietary VitD intake) and linear regression. Results IL-6 and IL-1Ra serum levels showed overall increases after 13 weeks (p=0.006 and p<0.001, respectively). For IL-6 a signifcant time × treatment interaction (p=0.046) was observed, with no signifcant change over time in the active group (p=0.155) compared to control (signifcant increase p=0.012). IL-8 showed an overall signifcant decrease (p=0.03). The change in pre-albumin was a signifcant predictor for changes in IL-6 after 13 weeks. Conclusions We conclude that 13 weeks of nutritional supplementation with VitD and leucine-enriched whey protein may attenuate the progression of CLIP in older sarcopenic persons with mobility limitations.
  • Maggio, Marcello, et al. (författare)
  • SHBG and endothelial function in older subjects
  • 2013
  • Ingår i: International Journal of Cardiology. - 0167-5273 .- 1874-1754. ; 168:3, s. 2825-2830
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Endothelial dysfunction is predictor of cardiovascular diseases that have different prevalence in men and women before menopause. Sex hormones and sex hormone binding globulin (SHBG), novel risk factors for diabetes and cardiovascular diseases even in older individuals, might explain this difference. However, the relationship between these hormones and endothelial function has never been addressed in the elderly. Methods and results: 430 men and, 424 women 70 years older of Prospective Study of the Vasculature in Uppsala Seniors study, with complete data on SHBG, testosterone(T), estradiol(E2), endothelium-independent vasodilation (EIDV), endothelium-dependent vasodilation(EDV), flow-mediated vasodilation (FMD) and the pulse wave analysis (reflection index, RI) were evaluated. Multivariate regression analysis adjusted for confounders was used to assess the relationship between T, E2, SHBG and endothelial function. In men we found a positive relationship between SHBG and EDV (beta +/- SE 3.60 +/- 0.83, p < 0.0001), EIDV (2.42 +/- 0.58, p < 0.0001) but not with FMD. The relationship between SHBG and EDV and EIDV was maintained after adjustment for sex (1.64 +/- 0.47, p < 0.001 and 1.79 +/- 0.35, p < 0.0006, respectively). After adjustment for confounders, the relationship between SHBG and EDV and EIDV was still statistically significant (2.63 +/- 0.90 and 1.86 +/- 0.63, p = 0.004 for both). In women SHBG and EIDV were positively associated (1.58 +/- 0.46; p = 0.0007), and this relationship was independent of sex (1.79 +/- 0.35; p < 0.001). No significant interaction SHBG * SEX was found for EIDV (p = 0.72). In a combined analysis in two sexes, SHBG and EIDV were positively associated (1.13 +/- 0.45; p = 0.01). SHBG was not associated with EDV, FMD and RI. No significant relationship was found between T or E2 and EDV, EIDV, FMD or RI in both sexes. Conclusions: In older men SHBG, but not T and E2, is positively and independently associated with EDV in resistance arteries. In both sexes, SHBG was positively and independently associated with EIDV.
  • Maggio, Marcello, et al. (författare)
  • Vitamin D and Endothelial Vasodilation in Older Individuals : Data From the PIVUS Study
  • 2014
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - 0021-972X .- 1945-7197. ; 99:9, s. 3382-3389
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT:Vitamin D plays a role in a wide range of extraskeletal processes, including vascular function. Endothelial dysfunction is a predictor of cardiovascular disease, especially in older subjects. However, the relationship between vitamin D levels and indexes of endothelial vasodilation has never been fully addressed in older individuals.OBJECTIVE:The objective of this study was to examine the association between vitamin D and endothelial function in a large community-based sample of older subjects.METHODS:This cross-sectional study involved 852 community-dwelling men and women aged 70 years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), with complete data on vascular function and 25-hydroxyvitamin D. We evaluated endothelium-dependent vasodilation by an invasive forearm technique with acetylcholine, endothelium-independent vasodilation by sodium nitroprussiate, flow-mediated vasodilation, and the pulse wave analysis (reflectance index). Vitamin D levels were measured by chemiluminescence. We used multivariate regression models adjusted for body mass index (model 1) and for multiple confounders (high-sensitivity C-reactive protein, insulin, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, smoking, sex hormones, season of blood collection, hypertension, diabetes, cardiovascular medications and diseases, statin usage, plasma calcium and calcium intake, PTH, physical exercise, liver and kidney function tests, albumin; model 2).RESULTS:In women, but not in men, vitamin D levels were positively associated with endothelium-independent vasodilation in both model 1 (β ± SE = 1.41 ± 0.54; P = .001), and model 2 (β ± SE = 2.01 ± 0.68; P = .003).We found no significant relationship between vitamin D levels and endothelium-dependent vasodilation, flow-mediated vasodilation, and reflectance index in both sexes.CONCLUSIONS:In older women, but not in men, vitamin D is positively and independently associated with EIDV.
  • Teumer, A., et al. (författare)
  • Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits
  • 2016
  • Ingår i: Aging Cell. - : Wiley-Blackwell. - 1474-9718 .- 1474-9726. ; 15:5, s. 811-824
  • Tidskriftsartikel (refereegranskat)abstract
    • The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
  • Ticinesi, Andrea, et al. (författare)
  • Uric acid and endothelial function in elderly community-dwelling subjects
  • 2017
  • Ingår i: ; 89, s. 57-63
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of serum uric acid (SUA), an inflammatory agent and potential mediator of cardiovascular diseases, in endothelial function (EF) has been tested only in middle-aged subjects affected by specific diseases. Our aim was to assess the relationship between SUA and measures of EF in a cohort of elderly community-dwellers. This study involved 424 males and 426 females aged 70years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), having complete data on SUA and EF assessed by flow-mediated vasodilation (FMD) and by intra-arterial infusion of acetylcholine (endothelium-dependent vasodilation, EDV) and sodium nitroprusside (endothelium-independent vasodilation, EIDV). Univariate and multivariate regression models obtained by backward selection from initial fully-adjusted models were built to assess the relationship between SUA and measures of EF in both genders. Cardiovascular risk factors, serum hormonal and metabolic mediators, and body composition were considered as potential confounders. In the univariate model, SUA was inversely associated in both genders with log(EDV) (β±SE males -0.39±0.17, p=0.03; females -0.57±0.19, p=0.003) and log(EIDV) (males -0.23±0.12, p=0.05; females -0.49±0.15, p=0.002), but not with log(FMD). After adjustment for BMI, only the association between SUA and log(EIDV) in females persisted, though attenuated (-0.32±0.16, p=0.049), and was no longer significant in the fully-adjusted multivariate model including waist/hip ratio. In conclusion, in older subjects, especially women, SUA is associated with EF not independently of a list of confounders including BMI and trunk fat mass, suggesting a role as surrogate metabolic marker rather than an active player in EF.
  • Verlaan, Sjors, et al. (författare)
  • Sufficient levels of 25-hydroxyvitamin D and protein intake required to increase muscle mass in sarcopenic older adults - The PROVIDE study
  • 2018
  • Ingår i: Clinical Nutrition. - : Elsevier. - 0261-5614 .- 1532-1983. ; 37:2, s. 551-557
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Inadequate nutritional intake and altered response of aging muscles to anabolic stimuli from nutrients contribute to the development of sarcopenia. Nutritional interventions show inconsistent results in sarcopenic older adults, which might be influenced by their basal nutritional status. Objective: To test if baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations and dietary protein intake influenced changes in muscle mass and function in older adults who received nutritional intervention. Methods and design: Post-hoc analysis was performed in the PROVIDE study that was a randomized controlled, double blind trial among 380 sarcopenic older adults. This study showed that those who received a vitamin D and leucine-enriched whey protein medical nutrition drink for 13 weeks gained more appendicular muscle mass (aMM), and improved lower-extremity function as assessed by the chair stand test compared with controls. To define low and high groups, a baseline serum concentration of 50 nmol/L 25(OH)D and baseline dietary protein intake of 1.0 g/kg/d were used as cut offs. Results: At baseline, participants with lower 25(OH)D concentrations showed lower muscle mass, strength and function compared with participants with a high 25(OH)D, while the group with lower protein intake (g/kg/day) had more muscle mass at baseline compared with the participants with higher protein intake. Participants with higher baseline 25(OH)D concentrations and dietary protein intake had, independent of other determinants, greater gain in appendicular muscle mass, skeletal muscle index (aMM/h(2)), and relative appendicular muscle mass (aMM/body weight x 100%) in response to the nutritional intervention. There was no effect modification of baseline 25(OH)D status or protein intake on change in chair-stand test. Conclusions: Sufficient baseline levels of 25(OH)D and protein intake may be required to increase muscle mass as a result of intervention with a vitamin D and protein supplement in sarcopenic older adults. This suggests that current cut-offs in the recommendations for vitamin D and protein intake could be considered the "minimum" for adults with sarcopenia to respond adequately to nutrition strategies aimed at attenuating muscle loss. (C) 2017 The Author(s). Published by Elsevier Ltd.
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