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1.  Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women 
Objective
Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of the study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women.
Design and methods
A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70–79 years, who participated in the Women’s Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication.
Results
Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/mL. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6%, 24.9%, and 36.7%, respectively (P = 0.002). Serum log FGF23 was associated with cardiovascular disease (Odds Ratio per 1 SD increase = 1.23, 95% Confidence Interval 1.17, 1.30; P <0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, HDL cholesterol, and renal function.
Conclusion
Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.
doi:10.1530/EJE-11-0577
PMCID: PMC3486640  PMID: 21873490
aging; cardiovascular disease; fibroblast growth factor 23; women
2.  Plasma klotho and cardiovascular disease in adults 
OBJECTIVES
To determine whether plasma klotho, a recently discovered hormone that has been implicated in atherosclerosis, is related to prevalent cardiovascular disease in adults.
DESIGN
Cross-sectional.
SETTING
Population-based sample of adults residing in Tuscany, Italy.
PARTICIPANTS
One thousand and twenty-three men and women, aged 24–102, participating in the Invecchiare in Chianti (InCHIANTI) study.
MEASUREMENTS
Anthropometric measures, plasma klotho, fasting plasma total, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose, creatinine, C-reactive protein. Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, peripheral artery disease, cancer, chronic kidney disease. Logistic regression models were used to examine the relationship between plasma klotho and prevalent cardiovascular disease.
RESULTS
Of 1023 participants, 259 (25.3%) had cardiovascular disease. Median (25th, 75th percentile) plasma klotho concentrations were 676 (530, 819) pg/mL. Plasma klotho was correlated with age (r = −0.14, P <0.0001), HDL cholesterol (r = 0.11, P = 0.0004), C-reactive protein (r = −0.10, P = 0.0008), but not systolic blood pressure, fasting plasma glucose, or renal function. Plasma klotho age-adjusted geometric means (95% Confidence Interval [C.I.]) were 626 (601, 658) in participants with cardiovascular disease and 671 (652, 692) pg/mL in those without cardiovascular disease (P = 0.0001). Adjusting for traditional cardiovascular risk factors (age, sex, smoking, total cholesterol, HDL cholesterol, systolic blood pressure, and diabetes), log plasma klotho was associated with prevalent cardiovascular disease (Odds Ratio per 1 standard deviation increase = 0.85, 95% C.I. 0.72, 0.99).
CONCLUSION
In community-dwelling adults, higher plasma klotho concentrations are independently associated with a lower likelihood of having cardiovascular disease.
doi:10.1111/j.1532-5415.2011.03558.x
PMCID: PMC3486641  PMID: 21883107
aging; atherosclerosis; cardiovascular disease; C-reactive protein; klotho
3.  Dietary intake associated with serum versus urinary carboxymethyl-lysine, a major advanced glycation end product, in adults: the Energetics Study 
Background/Objectives
Advanced glycation end products (AGEs) are implicated in the pathogenesis of atherosclerosis, diabetes, and kidney disease. The objective was to describe dietary intake, the dominant source of exposure to AGEs, with carboxymethyl-lysine (CML), a major AGE, in serum and urine, respectively.
Subjects/Methods
Serum and urinary CML were measured in 261 adults, aged 21–69 years, and compared with diet as assessed by six separate 24-hour dietary recalls.
Results
Median (25th, 75th percentile) serum and urinary CML concentrations were 686 (598, 803 μg/L) and 1023 (812, 1238) μg/gm creatinine. There was no correlation between serum and urinary CML (r = −0.02, P = 0.78). Serum CML was positively correlated with intake of soy, fruit juice, cold breakfast cereal, non-fat milk, whole grains, fruit, non-starchy vegetables, and legumes, and negatively correlated with intake of red meat. Intake of fast food was not significantly correlated with serum CML. Urinary CML was positively correlated with intake of starchy vegetables, whole grains, sweets, nuts/seeds, and chicken, and negatively correlated with intake of fast foods. Intake of AGE-rich foods such as fried chicken, French fries, bacon/sausage, and crispy snacks were not significantly correlated with serum or urinary CML, except for a significant negative correlation between fried chicken and serum CML.
Conclusions
These findings suggest that the high consumption of foods considered high in CML is not a major determinant of either serum or urinary CML. Further work is needed to understand the relationship of AGEs in blood and urine with the metabolism of dietary AGEs.
doi:10.1038/ejcn.2011.139
PMCID: PMC3486696  PMID: 21792213
advanced glycation end products; carboxymethyl-lysine; diet; 24-hour dietary recall; food
4.  Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study 
European journal of applied physiology  2011;112(4):1215-1220.
Handgrip strength is a strong indicator of total body muscle strength and is a predictor of poor outcomes in older adults. The aging suppressor gene klotho encodes a single-pass transmembrane protein that is secreted as a circulating hormone. In mice, disruption of klotho expression results in a syndrome that includes sarcopenia, atherosclerosis, osteoporosis, and shortened lifespan, and conversely, overexpression of klotho leads to a greater longevity. The objective was to determine whether plasma klotho levels are related to skeletal muscle strength in humans. We measured plasma klotho in 804 adults, ≥65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. Grip strength was positively correlated with plasma klotho at threshold <681 pg/mL. After adjusting for age, sex, education, smoking, physical activity, cognition, and chronic diseases, plasma klotho (per 1 standard deviation increase) was associated with grip strength (beta = 1.20, standard error = 0.35, P = 0.0009) in adults with plasma klotho <681 pg/mL. These results suggest that older adults with lower plasma klotho have poor skeletal muscle strength.
doi:10.1007/s00421-011-2072-3
PMCID: PMC3435096  PMID: 21769735
aging; klotho; muscle strength; sarcopenia
5.  Plasma Klotho and Mortality Risk in Older Community-Dwelling Adults 
Background.
The aging-suppressor gene klotho encodes a single-pass transmembrane protein that in mice is known to extend life span when overexpressed and resemble accelerated aging when expression is disrupted. It is not known whether there is a relationship between plasma levels of secreted klotho protein and longevity in humans.
Methods.
We measured plasma klotho in 804 adults, greater than or equal to 65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy.
Results.
During 6 years of follow-up, 194 (24.1%) of the participants died. In a multivariate Cox proportional hazards model, adjusting for age, sex, education, body mass index, physical activity, total cholesterol, high-density lipoprotein cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure, and chronic diseases, participants in the lowest tertile of plasma klotho (<575 pg/mL) had an increased risk of death compared with participants in the highest tertile of plasma klotho (>763 pg/mL; hazards ratio 1.78, 95% confidence interval 1.20–2.63).
Conclusions.
In older community-dwelling adults, plasma klotho is an independent predictor of all-cause mortality. Further studies are needed to elucidate the potential biological mechanisms by which circulating klotho could affect longevity in humans.
doi:10.1093/gerona/glr058
PMCID: PMC3143348  PMID: 21474560
Aging; Klotho; Longevity; Mortality
6.  Endogenous Secretory Receptor for Advanced Glycation End Products and Chronic Kidney Disease in the Elderly Population 
American Journal of Nephrology  2011;33(4):313-318.
Background/Aims
The relationship of circulating endogenous secretory receptor for advanced glycation end products (esRAGE) and chronic kidney disease (CKD) has not been well characterized. The aim of the study was to determine whether plasma esRAGE is associated with CKD and is predictive of developing CKD in older adults.
Methods
The relationship between plasma esRAGE and CKD (more than stage 3 of the National Kidney Foundation classification; estimated glomerular filtration rate <60 ml/min/1.73 m2) and CKD over 6 years of follow-up was examined in a cross-sectional and prospective study design in 1,016 men and women, ≥65 years, in the InCHIANTI study, a population-based cohort study of aging in Tuscany, Italy.
Results
At enrollment, 158 (15.5%) had CKD. Mean (SD) plasma esRAGE was 0.45 (0.24) ng/ml. Plasma esRAGE (ng/ml) was associated with CKD (odds ratio per 1 SD = 1.30; 95% CI 1.1–1.6; p < 0.005) in a multivariable logistic regression model, adjusting for potential confounders. Plasma esRAGE was an independent predictor of incident CKD over 6 years of follow-up (hazard ratio per 1 SD = 1.37; 95% CI 1.1–1.7; p < 0.008) in a multivariable Cox proportional hazards model, adjusting for potential confounders.
Conclusions
Elevated plasma esRAGE is independently associated with CKD and is an independent predictor of incident CKD in older community-dwelling adults.
doi:10.1159/000324846
PMCID: PMC3064940  PMID: 21389696
Advanced glycation end products; Aging; Chronic kidney disease; Endogenous secretory receptor for advanced glycation end products
7.  Endogenous Secretory Receptor for Advanced Glycation End Products Is Associated With Low Serum Interleukin-1 Receptor Antagonist and Elevated IL-6 in Older Community-Dwelling Adults 
Background.
Advanced glycation end products (AGEs) are thought to cause inflammation through interaction with the receptor for AGEs (RAGE), therefore contributing to adverse aging-related processes. The relationship between AGEs, RAGE, and inflammation has not been well characterized.
Methods.
We examined the relationship of plasma endogenous secretory RAGE (esRAGE); carboxymethyl-lysine (CML), a circulating AGE; and inflammatory mediators in 1,298 adults, 20–97 years, who participated in the InCHIANTI study in Tuscany, Italy. Blood levels of esRAGE, CML, interleukin-1 receptor antagonist (IL-1RA), IL-1β, tumor necrosis factor-α (TNF-α), IL-6, IL-6 receptor (IL-6R), IL-18, C-reactive protein (CRP), transforming growth factor-β (TGF-β), and fibrinogen were measured.
Results.
Log plasma esRAGE was associated with log IL-1RA (β = −0.069, SE = 0.036, p = .05) and log IL-6 (β = 0.077, SE = 0.035, p = .03), respectively, in separate multivariable linear regression models, adjusting for potential confounders. Log plasma esRAGE was also negatively associated with log TGF-β but did not reach statistical significance (β = −0.091, SE = 0.053, p = .09). Log plasma esRAGE was not significantly associated with log IL-1β, log TNF-α, IL-6R, log IL-18, or CRP. Log plasma CML was not associated with any of the inflammatory mediators except for IL-6R (β = −14.10, SE = 5.94, p = .02) and fibrinogen (β = 13.95, SE = 7.21, p = .05) in separate multivariable models, adjusting for potential confounders.
Conclusions.
Plasma esRAGE is correlated with higher IL-6 and lower IL-1RA. These findings suggest that plasma esRAGE plays a role in modulating inflammation, although the exact mechanisms remain to be elucidated.
doi:10.1093/gerona/glq225
PMCID: PMC3055279  PMID: 21357189
Advanced glycation end products; C-reactive protein; Endogenous secretory receptor for advanced glycation end products; Interleukin-1 receptor antagonist; Interleukin-6
8.  Reduced Retinal Neovascularization, Vascular Permeability, and Apoptosis in Ischemic Retinopathy in the Absence of Prolyl Hydroxylase-1 Due to the Prevention of Hyperoxia-Induced Vascular Obliteration 
Ischemia-induced retinal NV, vascular leakage, and apoptosis are inhibited in the absence of PHD1 by preventing vessel loss, without which there would be no need to initiate angiogenesis signaling when mice are returned to room air.
Purpose.
Prolyl hydroxylases (PHDs) are oxygen sensors that stabilize hypoxia-inducible factors (HIFs) to induce proinflammatory, vasopermeability, and proapoptotic factors. These may be potential targets to reduce the complications of ischemic retinopathies.
Methods.
Oxygen-induced ischemic retinopathy (OIR) was generated as a model for retinopathy of prematurity (ROP) by placing 7-day-old mice in 75% oxygen for 5 days and returning them to the relative hypoxia of room air for 5 days. Neovascularization (NV) and avascular areas were assessed on retinal flat-mounts by image analysis. Blood-retinal barrier breakdown was assessed using 3H-mannitol as a tracer. Apoptosis was detected with TUNEL staining. HIF-1α and VEGF were quantified using Western blot analysis and ELISA.
Results.
PHD1-deficient mice demonstrated reduced hyperoxia-associated vascular obliteration during oxygen-induced ischemic retinopathy. This was associated with subsequent reduced avascularity, vascular leakage, and pathologic NV during the hypoxic phase, which could be accounted for by a reduced expression of HIF-1α and VEGF. Apoptosis in the retina was also reduced in PHD1-depleted mice after 2 days in hyperoxia.
Conclusions.
PHD1 deficiency is associated with a reduction of ischemia-induced retinal NV. The regulatory mechanism in this model appears to be: PHD1 depletion prevents HIF-1α degradation in hyperoxia, which induces VEGF, thus preventing hyperoxia-related vessel loss. Without a vessel deficiency, there would not be relative hypoxia when the mice are returned to room air and there would be no need to initiate angiogenesis signaling. Blocking PHD1 may be beneficial for ischemic retinopathies and inflammatory and neurodegenerative disorders.
doi:10.1167/iovs.11-8002
PMCID: PMC3183980  PMID: 21873682
9.  Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women 
Objective
To characterize the relationship between advanced glycation end products (AGEs) and circulating receptors for AGEs (RAGE) with cardiovascular disease mortality.
Methods
The relationships between serum AGEs, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE), and mortality were characterized in 559 community-dwelling women, ≥65 years, in Baltimore, Maryland.
Results
During 4.5 years of follow-up, 123 (22%) women died, of whom 54 died with cardiovascular disease. The measure of serum AGEs was carboxymethyl-lysine (CML), a dominant AGE. Serum CML predicted cardiovascular disease mortality (Hazards Ratio [H.R.] for highest versus lower three quartiles 1.94, 95% Confidence Interval [C.I.] 1.08-3.48, P = 0.026), after adjusting for age, race, body mass index, and renal insufficiency. Serum sRAGE (ng/mL) and esRAGE (ng/mL) predicted cardiovascular disease mortality (H.R. per 1 Standard Deviation [S.D.] 1.27, 95% C.I. 0.98-1.65, P = 0.07; H.R. 1.28, 95% C.I. 1.02-1.63, P = 0.03), after adjusting for the same covariates. Among non-diabetic women, serum CML, sRAGE, and esRAGE, respectively, predicted cardiovascular disease mortality (H.R. for highest versus lower three quartiles, 2.29, 95% C.I. 1.21-4.34, P = 0.01; H.R. per 1 S.D., 1.24, 95% C.I. 0.92-1.65, P = 0.16; H.R. per 1 S.D. 1.45, 95% C.I. 1.08-1.93, P = 0.01), after adjusting for the same covariates.
Conclusions
High circulating AGEs and RAGE predict cardiovascular disease mortality among older community-dwelling women. AGEs are a potential target for interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.
PMCID: PMC2684987  PMID: 19448391
advanced glycation end products; aging; atherosclerosis; cardiovascular disease; mortality
10.  Advanced Glycation End Products and Their Circulating Receptors and Level of Kidney Function in Older Community-Dwelling Women 
Background
Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) are implicated in the pathogenesis of renal disease but their relation with level of kidney function has not been well characterized.
Study Design
Cross-sectional and prospective.
Setting and Participants
548 moderately to severely disabled community-dwelling women in the Women's Health and Aging Study I in Baltimore, Maryland.
Predictor
Serum L-carboxymethyl-lysine (CML), a dominant AGE, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE).
Outcomes & Measurements
Glomerular filtration rate (GFR), prevalent and incident reduced GFR (GFR <60 mL/min/1.73 m2). Serum CML, sRAGE, and esRAGE.
Results
Of 548 women, 283 (51.6%) had reduced GFR at baseline. Serum CML was associated with reduced GFR (Odds Ratios [O.R.; all expressed per 1 Standard Deviation], 1.98, 95% Confidence Interval [C.I.] 1.41-2.76, P <0.001) in a multivariate logistic regression model adjusting for age, race, hemoglobin A1c, and chronic diseases. Serum sRAGE (ng/mL) and esRAGE (ng/mL), respectively, were associated with reduced GFR (O.R. 1.42, 95% C.I. 1.12-1.79, P = 0.003; O.R. 1.42, 95% C.I. 1.14-1.77, P = 0.001) in separate multivariate logistic regression models, adjusting for potential confounders. Of 230 women without reduced GFR at baseline, 32 (13.9%) developed reduced GFR by the follow-up visit 12 months later. Serum CML (μg/mL), sRAGE (ng/mL), and esRAGE (ng/mL), respectively, at baseline was associated with the prevalence of reduced GFR 12 months later (O.R. 1.80, 95% C.I. 1.19-2.71, P = 0.005; O.R. 1.32, 95% C.I. 1.01-1.74, P = 0.05; O.R. 1.33, 95% C.I. 1.01-1.77, P = 0.05) in separate multivariate logistic regression models adjusting for potential confounders.
Limitations
Small number of incident cases, limited follow-up interval, creatinine not standardized.
Conclusions
AGEs and circulating RAGE are independently associated with reduced GFR and seem to predict reduced GFR. AGEs are amenable to interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.
doi:10.1053/j.ajkd.2008.06.018
PMCID: PMC2637807  PMID: 18789567
advanced glycation end products; reduced glomerular filtration rate
11.  Elevated serum advanced glycation end products and poor grip strength in older community-dwelling women 
Background
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetes, heart disease, and kidney failure, and may potential affect skeletal muscle. Whether AGEs are associated with poor muscle strength is unknown.
Methods
Serum carboxymethyl-lysine (CML), a dominant AGE, circulating receptor for AGEs (sRAGE), and endogenous secretory RAGE (esRAGE) and grip strength were measured in 559 moderately to severely disabled women, age ≥65 years, in the Women’s Health and Aging Study I in Baltimore, Maryland.
Results
Mean (SD) grip strength among women in the highest quartile of serum CML compared with women in the lower three quartiles was 18.6 and 20.0 kg, respectively (P = 0.002), adjusting for age, race, body mass index, cognitive dysfunction, depression, and diabetes. Serum sRAGE and esRAGE were not significantly associated with grip strength.
Conclusion
Women with high serum AGEs have greater muscle weakness. Further studies are needed to determine whether AGEs, a potentially modifiable risk factor, are associated with physical performance and disability in older adults.
doi:10.1093/gerona/gln018
PMCID: PMC2645474  PMID: 19182228
advanced glycation end products; aging; inflammation; muscle; sarcopenia
12.  Elevated Serum Advanced Glycation End Products and Poor Grip Strength in Older Community-Dwelling Women 
Background
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetes, heart disease, and kidney failure and may potentially affect skeletal muscle. Whether AGEs are associated with poor muscle strength is unknown.
Methods
Serum carboxymethyl-lysine (CML), a dominant AGE, circulating soluble form of receptor for advanced glycation end products (sRAGE), and endogenous secretory receptor for advanced glycation end product (esRAGE) and grip strength were measured in 559 moderately to severely disabled women, age 65 and older, in the Women's Health and Aging Study I in Baltimore, Md.
Results
Mean (standard deviation) grip strength among women in the highest quartile of serum CML compared with women in the lower three quartiles was 18.6 and 20.0 kg, respectively (p = .002), adjusting for age, race, body mass index, cognitive dysfunction, depression, and diabetes. Serum sRAGE and esRAGE were not significantly associated with grip strength.
Conclusions
Women with high serum AGEs have greater muscle weakness. Further studies are needed to determine whether AGEs, a potentially modifiable risk factor, are associated with physical performance and disability in older adults.
doi:10.1093/gerona/gln018
PMCID: PMC2645474  PMID: 19182228
Advanced glycation end products; Aging; Inflammation; Muscle; Sarcopenia

Results 1-12 (12)