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Background: In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. Methods: A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4–36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. Results: FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. Conclusions: Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. Trial registration: The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic neuropathy (DN) is a generic term for various neuropathies coexisting in a single patient. Clinical diagnosis alone can be misleading, yet routine electrodiagnostic studies in diabetes care are rare. Skin autofluorescence (SAF) is a recognized DN risk factor with potential screening value. This article highlights the diagnostic challenges and raises awareness of the often underdiagnosed neuropathic conditions in diabetes patients. Material and Methods: We present common entrapment neuropathy cases from our diabetes clinic's electrodiagnosis laboratory in Iași, Romania. We selected seven type 2 diabetes patients with sensory or sensory-motor distal polyneuropathy and atypical DN presentations investigated through electroneurography (ENG) and electromyography (EMG) with the Neurosoft® EMG instrument and SAF measured by standard procedures. Subsequently, a narrative literature review was conducted. Results: Entrapment neuropathies were diagnosed in all the patients: three carpal tunnel syndromes, two ulnar neuropathies (one proximal, one distal), one peroneal neuropathy, and one case of meralgia paresthetica. The lower-limb cases showed radiculoplexopathy, and there was one case of superficial radial nerve neuropathy. The SAF values ranged from 2.5 AU to 3.4 AU. Conclusions: Electrodiagnosis is essential for detecting focal neuropathies in patients with sensory-motor distal polyneuropathy. Elevated SAF levels may correlate with symptom severity, although further research, including large cohorts, is needed. [ABSTRACT FROM AUTHOR]

This study explored the link between different types of glaucoma and cognitive function in a cohort of 620 Japanese patients. Participants were categorized into primary open-angle glaucoma (PG), exfoliation glaucoma (EG), and non-glaucomatous control groups. The findings revealed a significant decline in cognitive function as indicated by the Mini-Cog test in the EG group (mean ± SD: 4.0 ± 1, 95% CI: 3.9 to 4.2) compared to the PG group (4.4 ± 0.1, 4.3 to 4.5, p < 0.0001). Levels of fingertip measured advanced glycation end-products (AGEs) were significantly higher in the EG group (mean ± SD: 0.45 ± 0.006, 95% CI: 0.44 to 0.46) compared to the PG group (0.43 ± 0.004, 0.42 to 0.44, p = 0.0014). Although the multivariate analysis initially showed no direct association between glaucoma types and Mini-Cog scores, the EG group exhibited higher age and intraocular pressure (IOP) compared to the PG group. Further analysis revealed that high levels of AGEs were associated with cognitive decline and decreased mean visual fields in the EG group. Age was identified as a cofounding factor in these associations. An inverse correlation was observed between the accumulation of AGEs and skin carotenoid levels. Early detection of cognitive decline in glaucoma patients could enable timely intervention to preserve visual fields. Fingertip measurements of skin carotenoids and AGEs offer promising potential as non-invasive, straightforward diagnostic tools that could be widely adopted for monitoring ophthalmic and cognitive health in glaucoma patients. [ABSTRACT FROM AUTHOR]

Abstract We aimed to assess the association of SAF with cardiovascular mortality in the general population and the possible association between SAF with other disease-specific mortality rates. We evaluated 77,143 participants without known diabetes or cardiovascular disease. The cause of death was ascertained by the municipality database. The associations between SAF and all-cause mortality, cardiovascular mortality and cancer mortality were assessed with Cox proportional hazard analysis.After a median follow-up of 115 months, 1447 participants were deceased (1.9%). SAF and age-adjusted SAF-z score were higher in all mortality groups. Cox regression analysis revealed that the highest quartile of SAF was associated with increased odds of cardiovascular mortality, (HR) 12.6 (7.3–21.7) and after adjusting for age (HR 1.8 (1.0–3.2)). Significance was lost after additional adjustments for sex, smoking status, and BMI (HR 1.4 (0.8–2.5). For cancer-related mortality the highest quartile of SAF was associated with higher probability of mortality in all models (unadjusted HR 8.6 (6.6–11.3), adjusted for age HR 2.1 (1.6–2.8)), adjusted for age, sex, smoking status, and BMI HR 1.7 (1.3–2.4)). SAF is associated with all-cause mortality as well as cardiovascular and cancer-related mortality in the general population.

Skin autofluorescence (sAF) measurement is a non-invasive method used to assess tissue advanced glycation end product (AGE) accumulation. This study aims to characterize sAF's association with (1) glycated hemoglobin (HbA1c) values, (2) cardiovascular risk markers, and (3) common comorbidities (autoimmune thyroiditis, celiac disease) in children with type 1 diabetes (T1D). Materials and methods: A total of 348 children with T1D aged 3–18 years and 85 age- and gender-matched control subjects were enrolled. sAF was quantified using an AGE Reader (Diagnoptics BV, The Netherlands). The analysis covered HbA1c, blood lipid, and C-reactive protein (CRP) levels, ambulatory blood pressure monitoring records, and body composition parameters. The associations between variables and sAF were assessed using the Mann–Whitney U test and Spearman correlation. Results: We observed significantly higher sAF values in the T1D group compared to the control (1.40 [1.27–1.53] vs. 1.20 [1.07–1.30, AU]; p = 0.004), consistent across all tested age groups. In the T1D group, sAF was positively correlated with current HbA1c, mean of historical HbA1c values, and T1D duration (r values, respectively: 0.27, 0.22, 0.14, all p < 0.01). Percentage of body fat was positively correlated with sAF (r = 0.120; p = 0.044). No significant correlations were found between sAF and lipid fractions, Z-score of BMI, parameters from 24 h ambulatory blood pressure monitoring, or the amount of albumin excreted in urine. sAF was positively correlated with CRP (r = 0.17, p < 0.05). sAF was significantly higher in patients with concomitant celiac disease (1.53 [1.43–1.63] vs. 1.40 [1.27–1.53, AU], p = 0.001). Conclusion: Among young T1D patients with relatively brief diabetes duration, sAF effectively mirrors prior glycemic control, as presented by historical average HbA1c. However, associations with conventional CV risk markers are not evident. The higher sAF values in patients with celiac disease warrant further exploration. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) have been reported to be associated with osteoporosis, aging, sarcopenia, and frailty. This study aimed to investigate the association AGEs with locomotive syndrome (LS). Participants were Japanese individuals aged 39 years or older who participated in the Yakumo Study (n=230). AGEs were measured by skin autofluorescence (SAF) using an AGE reader. We investigated SAF values for each locomotive stage. Multivariate logistic regression models were used to calculate the odds ratios of LS-associated factors. The relationships between SAF and physical performance and bone mineral density (BMD) were investigated. A receiver operating characteristic (ROC) curves were generated to determine the optimal cut-off value of SAF for predicting LS. SAF values tended to increase correspondingly with LS severity. SAF was an independently explanatory factor for LS (odds ratio 2.70; 95% confidence interval [CI] 1.040-6.990). SAF was positively correlated with the 10-m walking speed, The Timed Up and Go test results, and was negatively correlated with BMD. ROC curve represented by SAF for the presence or absence of LS risk had an area under the curve of 0.648 (95% CI: 0.571-0.726). High SAF values were identified as an independent risk factor for LS. AGEs could be a potential screening tool for people for LS. [ABSTRACT FROM AUTHOR]

IntroductionThe accumulation of tissue-advanced glycation end products in skin results from complex and consecutive reactions and can be measured by skin autofluorescence (SAF) reader devices. This overview discusses studies evaluating the utilization of SAF in screening renal and cardiac disease.Materials and methodsLiterature search was performed using Google Scholar, PubMed, Springer, Ovid, and ScienceDirect.ResultsSAF was an independent predictor of progression of chronic kidney disease (CKD) and was elevated in subjects on hemodialysis and peritoneal dialysis. Furthermore, SAF was significantly associated with cardiovascular events, cardiovascular mortality, and all-cause mortality in CKD patients. Other studies revealed a correlation between SAF and arterial stiffness, vascular damage, and subclinical atherosclerosis. A vegetarian diet was associated with lower SAF levels, whereas malnutrition was correlated with higher levels and increased mortality.ConclusionsSAF measurement may be useful in managing renal and cardiac disease. Future studies are needed to clarify the specific role of SAF in the management of CKD and its noninvasive office utilization to identify comorbidities in inflammatory diseases, such as psoriasis.

Advanced Glycation End Products (AGEs) contribute to the pathophysiology of type 2 diabetes mellitus (T2DM) and cardiovascular (CV) diseases (CVDs), making their non-invasive assessment through skin autofluorescence (SAF) increasingly important. This study aims to investigate the relationship between SAF levels, cardiovascular risk, and diabetic complications in T2DM patients. We conducted a single-center, cross-sectional study at Consultmed Hospital in Iasi, Romania, including 885 T2DM patients. The assessment of SAF levels was performed with the AGE Reader™, (Diagnoptics, Groningen, The Netherlands). CVD prevalence was 13.9%, and according to CV risk category distribution, 6.1% fell into the moderate-risk, 1.13% into the high-risk, and 92.77% into the very-high-risk category. The duration of DM averaged 9.0 ± 4.4 years and the mean HbA1c was 7.1% ± 1.3. After adjusting for age and eGFR, HbA1c values showed a correlation with SAF levels in the multivariate regression model, where a 1 SD increase in HbA1c was associated with a 0.105 SD increase in SAF levels (Nagelkerke R2 = 0.110; p < 0.001). For predicting very high risk with an SAF cut-off of 2.35, sensitivity was 67.7% and specificity was 56.2%, with an AUC of 0.634 (95% CI 0.560–0.709, p = 0.001). In T2DM, elevated SAF levels were associated with higher CV risk and HbA1c values, with 2.35 identified as the optimal SAF cut-off for very high CV risk. [ABSTRACT FROM AUTHOR]

Abstract Chen et al. recently related the skin autofluorescence (SAF) of Advanced Glycation End-products to subclinical cardiovascular disease in the 3001 participants from the general population (Rotterdam study), with a particularly close relationship for the 413 subjects with diabetes. Because conventional vascular risk factors do not capture the risk in diabetes very well, this relationship may help to select high-risk individuals for the screening of silent myocardial ischemia, which has yet to prove its benefit in randomized controlled trials. Among 477 patients with uncontrolled and/or complicated Type 2 Diabetes, we measured the SAF ten years ago, and we registered new revascularizations during a 54-months follow-up. The patients with SAF > 2.6 Arbitrary units (AUs), the median population value, experienced more revascularizations of the coronary (17/24) and lower-limb arteries (13/17) than patients with a lower SAF, adjusted for age, sex, diabetes duration, vascular complications, and smoking habits: HR 2.17 (95% CI: 1.05–4.48), p = 0.035. The SAF has already been reported to predict cardiovascular events in three cohorts of people with diabetes. We suggest that its measurement may help to improve the performance of the screening before vascular explorations and revascularizations.

This study explored the link between different types of glaucoma and cognitive function in a cohort of 620 Japanese patients. Participants were categorized into primary open-angle glaucoma (PG), exfoliation glaucoma (EG), and non-glaucomatous control groups. The findings revealed a significant decline in cognitive function as indicated by the Mini-Cog test in the EG group (mean ± SD: 4.0 ± 1, 95% CI: 3.9 to 4.2) compared to the PG group (4.4 ± 0.1, 4.3 to 4.5, p < 0.0001). Levels of fingertip measured advanced glycation end-products (AGEs) were significantly higher in the EG group (mean ± SD: 0.45 ± 0.006, 95% CI: 0.44 to 0.46) compared to the PG group (0.43 ± 0.004, 0.42 to 0.44, p = 0.0014). Although the multivariate analysis initially showed no direct association between glaucoma types and Mini-Cog scores, the EG group exhibited higher age and intraocular pressure (IOP) compared to the PG group. Further analysis revealed that high levels of AGEs were associated with cognitive decline and decreased mean visual fields in the EG group. Age was identified as a cofounding factor in these associations. An inverse correlation was observed between the accumulation of AGEs and skin carotenoid levels. Early detection of cognitive decline in glaucoma patients could enable timely intervention to preserve visual fields. Fingertip measurements of skin carotenoids and AGEs offer promising potential as non-invasive, straightforward diagnostic tools that could be widely adopted for monitoring ophthalmic and cognitive health in glaucoma patients.

Chen et al. recently related the skin autofluorescence (SAF) of Advanced Glycation End-products to subclinical cardiovascular disease in the 3001 participants from the general population (Rotterdam study), with a particularly close relationship for the 413 subjects with diabetes. Because conventional vascular risk factors do not capture the risk in diabetes very well, this relationship may help to select high-risk individuals for the screening of silent myocardial ischemia, which has yet to prove its benefit in randomized controlled trials. Among 477 patients with uncontrolled and/or complicated Type 2 Diabetes, we measured the SAF ten years ago, and we registered new revascularizations during a 54-months follow-up. The patients with SAF > 2.6 Arbitrary units (AUs), the median population value, experienced more revascularizations of the coronary (17/24) and lower-limb arteries (13/17) than patients with a lower SAF, adjusted for age, sex, diabetes duration, vascular complications, and smoking habits: HR 2.17 (95% CI: 1.05–4.48), p = 0.035. The SAF has already been reported to predict cardiovascular events in three cohorts of people with diabetes. We suggest that its measurement may help to improve the performance of the screening before vascular explorations and revascularizations. [ABSTRACT FROM AUTHOR]

Background/Aim: Advanced glycation end products (AGEs) accumulate in the body with increasing age. However, their excessive accumulation may lead to various inflammatory and chronic diseases. While it is common for older adults to experience various comorbidities, there is a scarcity of published literature documenting the specific impact of ageing and comorbidities on AGEs in this population. The present study aimed to retrospectively evaluate the correlation among AGEs in the skin, calendar age, and comorbidities in older adults. Patients and Methods: Accumulated AGEs in the skin were assessed by non-invasive measurement of skin autofluorescence (SAF) inside the forearm. This retrospective study included individuals who underwent SAF measurements at Shujitsu University Community Pharmacy with or without a prescription from October 2019 to October 2021. Subsequently, the associations between SAF, calendar age, comorbidities, and blood test parameters were investigated. Results: SAF showed a positive correlation with calendar age for all enrolled participants; the correlation weakened for participants aged ≥50 years and plateaued for those aged ≥60 years. Furthermore, we observed a significant increase in SAF among all participants with comorbidities compared to those without comorbidities. By contrast, among participants aged ≥50 years, SAF did not show a significant association with comorbidities. However, SAF was significantly positively correlated with white blood cell (WBC) counts in these aged populations. Conclusion: The non-invasive assessment of SAF holds promise in evaluating changes in the physical condition associated with WBC counts among older adults. [ABSTRACT FROM AUTHOR]

It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury. [ABSTRACT FROM AUTHOR]

Skin autofluorescence (sAF) measurement is a non-invasive method used to assess tissue advanced glycation end product (AGE) accumulation. This study aims to characterize sAF’s association with (1) glycated hemoglobin (HbA1c) values, (2) cardiovascular risk markers, and (3) common comorbidities (autoimmune thyroiditis, celiac disease) in children with type 1 diabetes (T1D). Materials and methods: A total of 348 children with T1D aged 3–18 years and 85 age- and gender-matched control subjects were enrolled. sAF was quantified using an AGE Reader (Diagnoptics BV, The Netherlands). The analysis covered HbA1c, blood lipid, and C-reactive protein (CRP) levels, ambulatory blood pressure monitoring records, and body composition parameters. The associations between variables and sAF were assessed using the Mann–Whitney U test and Spearman correlation. Results: We observed significantly higher sAF values in the T1D group compared to the control (1.40 [1.27–1.53] vs. 1.20 [1.07–1.30, AU]; p = 0.004), consistent across all tested age groups. In the T1D group, sAF was positively correlated with current HbA1c, mean of historical HbA1c values, and T1D duration (r values, respectively: 0.27, 0.22, 0.14, all p < 0.01). Percentage of body fat was positively correlated with sAF (r = 0.120; p = 0.044). No significant correlations were found between sAF and lipid fractions, Z-score of BMI, parameters from 24 h ambulatory blood pressure monitoring, or the amount of albumin excreted in urine. sAF was positively correlated with CRP (r = 0.17, p < 0.05). sAF was significantly higher in patients with concomitant celiac disease (1.53 [1.43–1.63] vs. 1.40 [1.27–1.53, AU], p = 0.001). Conclusion: Among young T1D patients with relatively brief diabetes duration, sAF effectively mirrors prior glycemic control, as presented by historical average HbA1c. However, associations with conventional CV risk markers are not evident. The higher sAF values in patients with celiac disease warrant further exploration.

Advanced glycation end products (AGEs) are represented by heterogeneous molecular structures and their accumulation in organs and tissues reflects the intensity of oxidative stress and glycemia. As a physiological process, aging is associated with AGE accumulation and changing the morphology and functions of the vascular wall. Accelerated AGE accumulation initiates inflammation, contributing to the development of cardiovascular diseases, such as arterial hypertension, coronary heart diseases, and atherosclerosis of peripheral arteries; conditions associated with high cardiovascular risks such as prediabetes, diabetes mellitus type 2, and chronic kidney diseases are also characterized by the accelerated AGEs accumulation. The ability of AGEs to fluorescence underlies noninvasively in blood serum, tissues, and skin using a well-proven technique of autofluorescence, which is little known to domestic specialists. This review presents the possibilities of autofluorescence to reflect arterial wall remodeling, which includes stiffness, vascular endothelial function, atherosclerotic plaque formation, and instability, using modern materials. The review emphasizes the evidence base regarding the ability of this method to predict mortality and cardiovascular events in a large population from low to high risk.

Resistant hypertension is hypertension that cannot be controlled despite the use of three antihypertensive drugs, one of which is a diuretic. Resistant hypertension often coexists with advanced age, obesity, smoking, and diabetes. Advanced glycation end products (AGEs) are substances that are generated as a result of the glycation of proteins, lipids, and nucleic acids due to conditions such as hyperlipidemia, oxidative stress, and hyperglycemia. There are studies showing the relationships between AGE levels and aortic stiffness, hypertension, and microvascular and macrovascular complications in diabetes. In our study, we examined the relationship between resistant hypertension and AGE levels. Our study was planned as a case–control study, and 88 patients with resistant hypertension were included in the focus group, while 88 patients with controlled hypertension were included in the control group. The AGE levels of the patients were measured using the skin autofluorescence method. AGE levels were found to be significantly higher in patients with resistant hypertension than those recorded in the control group. A significant increase in AGE levels was also observed in patients with resistant hypertension and without diabetes compared with the control group. The levels of AGEs, which can be measured cheaply, noninvasively, and quickly with the skin autofluorescence method, may provide benefits in identifying these patients with resistant hypertension. [ABSTRACT FROM AUTHOR]

Despite constant therapeutic achievements as well as technological advances in the treatment and control of diabetes mellitus (DM), the percentage of patients who do not reach their individual glycated hemoglobin (HbA1c) target level is still significant. Large-scale clinical studies prove that effective for prevention of long-term diabetic complications is not only optimal glycemic control itself but its early achievement in the course of the disease. The latter defines the so-called “metabolic memory”, whose pathophysiological mechanisms are not completely known. However, the leading role of advanced glycation end products (AGEs) and associated tissue damage is assumed. AGEs are a heterogeneous group of compounds derived from a nonenzymatic glycation of proteins, lipids and nucleic acids in different tissues and fluids with sufficient glucose concentration. Their formation is increased in a multitude of conditions associated with acute or chronic oxidative stress, including DM. AGEs are believed to play a central role in the pathogenesis of diabetic complications by triggering various signaling pathways related to oxidative stress, chronic inflammation, and apoptosis. It is well known that HbA1c allows for relatively short-term monitoring of glycemic control. On the other hand, the ability of AGEs to irreversibly bind to long-term proteins makes them a potential biomarker for long-term retrospective glycemic control and associated chronic diabetic complications. Skin autofluorescence has been established as a fast, easily applicable, non-invasive technique for the measurement of skin accumulated AGEs. This method relies on the fluorescent properties of several glycated products and has been validated with the “gold standard” for assessment of tissue-bound AGEs – the skin biopsy. [ABSTRACT FROM AUTHOR]

Background: As a clinical and non-invasive tool, the AGE Reader measures skin autofluorescence (SAF) to estimate the accumulation of advanced glycation end products (AGEs) in the skin. Accumulation of AGEs has been implicated in several inflammation-associated diseases, including diabetes and cardio-metabolic diseases. This study aimed to assess SAF in subjects with and without cardiovascular risk (CVR) factors and examine the association between SAF and various bio-clinical parameters. Methods: In a cross-sectional study, we included 250 participants between 19 and 86 years of age divided into two groups: a healthy group (n = 88) and subjects with CVR factors (n = 162 in total, diabetes n = 48, hypertension n = 62, and both n = 52). We assessed skin AGE measures and biological and clinical data. Results: SAF was significantly higher in subjects with CVR factors than in healthy participants (2.42 ± 0.38 vs 1.90 ± 0.29 respectively; p < 0.001). SAF was associated with age, gender, BMI, duration of diabetes, HbA1c, triglyceride, and obesity. Multivariate analysis showed that age and duration of diabetes were the independent determinants of SAF. The ROC analysis indicated that a SAF > 2.25 AU was the optimal cut-off point to predict the presence of diabetes and/or hypertension and dyslipidemia (p < 0.001). Conclusion: This Tunisian population-based study shows an increased SAF level in subjects with diabetes and/or hypertension and dyslipidemia compared to healthy subjects. The AGE Reader device is a rapid and non-invasive tool in clinical practice to evaluate and screen CVR factors in Tunisia with a North African phototype. [ABSTRACT FROM AUTHOR]

Objective: to determine the prognostic value of skin autofluorescence (SAF) as a factor of cardiovascular complications and mortality. Materials and Methods. Our prospective study included 122 patients with peripheral arterial disease (PAD): atherosclerotic stenosis of the brachiocephalic trunk was detected in 95 patient (77.9%), while chronic arterial insufficiency (CAI) of the lower limbs was found in 47 study participants (38.5%). SAF was measured by an original device developed by the authors. Clinical, anthropometric and biochemicalparameters, along with instrumental parameters of the heart and blood vessels, were studied via ultrasound examination. The prospective part of the study (follow-up) was carried out for up to 1,043 (on average, 736) days. Results.The SAF parameter correlated directly and significantly with scores on the scale of clinical prognostic signs, CAIof the lower limbs, and history of surgeries on the leg arteries. In the course of the follow-up period, there were seven deaths and at least one hospitalization for cardiovascular reasons in 42 patients. The most common were hospitalizations due to conservative treatment of CAI, the need for coronary artery bypass grafting, and coronary stenting. Using the logistic regression method, we determined that the incidence of hospitalization or mortality was associated with SAF values, plasma glucosecontent, and the presence of chronic heart failure above functional class 1. The sensitivity and specificity of the model were 71% and 68%, respectively. Conclusion.The SAF parameter can be used as an integral independent predictor in patients with multifocal atherosclerosis.

Advanced Glycation End Products (AGEs) contribute to the pathophysiology of type 2 diabetes mellitus (T2DM) and cardiovascular (CV) diseases (CVDs), making their non-invasive assessment through skin autofluorescence (SAF) increasingly important. This study aims to investigate the relationship between SAF levels, cardiovascular risk, and diabetic complications in T2DM patients. We conducted a single-center, cross-sectional study at Consultmed Hospital in Iasi, Romania, including 885 T2DM patients. The assessment of SAF levels was performed with the AGE Reader™, (Diagnoptics, Groningen, The Netherlands). CVD prevalence was 13.9%, and according to CV risk category distribution, 6.1% fell into the moderate-risk, 1.13% into the high-risk, and 92.77% into the very-high-risk category. The duration of DM averaged 9.0 ± 4.4 years and the mean HbA1c was 7.1% ± 1.3. After adjusting for age and eGFR, HbA1c values showed a correlation with SAF levels in the multivariate regression model, where a 1 SD increase in HbA1c was associated with a 0.105 SD increase in SAF levels (Nagelkerke R2 = 0.110; p < 0.001). For predicting very high risk with an SAF cut-off of 2.35, sensitivity was 67.7% and specificity was 56.2%, with an AUC of 0.634 (95% CI 0.560–0.709, p = 0.001). In T2DM, elevated SAF levels were associated with higher CV risk and HbA1c values, with 2.35 identified as the optimal SAF cut-off for very high CV risk.

Puffy fingers and Raynaud's phenomenon (RP) are important clinical predictors of the development of systemic sclerosis (SSc). We aim to assess the prevalence of SSc-related symptoms, explore pulmonary symptoms, and test the usefulness of skin autofluorescence (SAF) as a non-invasive marker for Advanced Glycation Endproducts (AGEs). Subjects from the Lifelines Cohort Study with known connective tissue disease (CTD) were excluded. Patient characteristics, SAF, self-reported pulmonary symptoms, and spirometry were obtained. Subjects (n = 73,948) were categorized into definite RP (5.3%) with and without SSc-related symptoms and non-RP. Prevalence of at least one potential SSc-related symptom (other than RP) was 8.7%; 23.5% in subjects with RP and 7.1% without RP (p < 0.001). Subjects with RP and additional SSc-related symptoms more frequently reported dyspnea at rest, dyspnea after exertion, and self-reported pulmonary fibrosis, and had the lowest mean forced vital capacity compared to the other groups (RP without SSc-related symptoms and no RP, both p < 0.001). In multivariate regression, dyspnea at rest/on exertion remained associated with an increased risk of SSc-related symptoms in subjects with RP (both p < 0.001). SAF was higher in subjects with RP and SSc-related symptoms compared to the other groups (p < 0.001), but this difference was not significant after correction for potential confounders. The prevalence of SSc-related symptoms was approximately three-fold higher in subjects with RP. Pulmonary symptoms are more prevalent in subjects with RP who also reported additional potential SSc-related symptoms. This might suggest that (suspected) early SSc develops more insidiously than acknowledged. According to this study, SAF is no marker for early detection of SSc. [ABSTRACT FROM AUTHOR]

Abstract Background Skin autofluorescence (SAF) is a non-invasive measure reflecting accumulation of advanced glycation endproducts (AGEs) in the skin. Higher SAF levels are associated with an increased risk of developing type 2 diabetes and cardiovascular disease. An earlier genome-wide association study (GWAS) revealed a strong association between NAT2 variants and SAF. The aim of this study was to calculate SAF heritability and to identify additional genetic variants associated with SAF through genome-wide association studies (GWAS). Results In 27,534 participants without diabetes the heritability estimate of lnSAF was 33% ± 2.0% (SE) in a model adjusted for covariates. In meta-GWAS for lnSAF five SNPs, on chromosomes 8, 11, 15 and 16 were associated with lnSAF (P T), which results in a Met30Val missense variant in MMP27 exon 1 (NM_022122.3); 2. rs2470893 (Chr15:75,019,449,C > T), in intergenic region between CYP1A1 and CYP1A2; with attenuation of the SNP-effect when coffee consumption was included as a covariate; 3. rs12931267 (Chr16:89,818,732,C > G) in intron 30 of FANCA and near MC1R; and following conditional analysis 4. rs3764257 (Chr16:89,800,887,C > G) an intronic variant in ZNF276, 17.8 kb upstream from rs12931267; finally, 30 kb downstream from NAT2 5. rs576201050 (Chr8:18,288,053,G > A). Conclusions This large meta-GWAS revealed five SNPs at four loci associated with SAF in the non-diabetes population. Further unravelling of the genetic architecture of SAF will help in improving its utility as a tool for screening and early detection of diseases and disease complications.

Objective: The aim of this study was to investigate the role of vitamin D replacement therapy on advanced glycation end-products in prediabetes and type 2 diabetes mellitus patients with vitamin D deficiency. Methods: One hundred twenty subjects with serum 25-hydroxyl vitamin D levels less than 20 ng/mL were included in the study. Forty type 2 diabetes mellitus patients (type 2 diabetes mellitus group), 40 prediabetes patients (prediabetes group), and 40 non-diabetes controls (non-diabetes group) were given oral vitamin D3 50 000 units/week for 8 weeks as loading and followed by 1500 U/day as a maintenance dose. We measured serum 25-hydroxyl vitamin D, glycated hemoglobin, carboxymethyl lysine levels, and skin autofluorescence before and on the fourth month of the therapy. Results: Basal serum carboxymethyl lysine and skin autofluorescence measurement in type 2 diabetes mellitus and prediabetes groups were significantly higher than the non-diabetes group. While no difference was found between glycated hemoglobin and skin autofluorescence, serum carboxymethyl lysine levels were significantly elevated for each group following vitamin D replacement. Conclusions: Vitamin D loading did not affect skin advanced glycation end-product levels and glycated hemoglobin but was associated with increased serum carboxymethyl lysine levels in all groups. [ABSTRACT FROM AUTHOR]

Purpose. The formation and accumulation of advanced glycation end products (AGEs) are enhanced with increased oxidative stress and inflammatory conditions. A hyperthyroid and hypothyroid state is associated with oxidative stress. This study aimed to evaluate skin AGE deposition, serum carboxymethyl-lysine (CML), and serum soluble receptor for AGEs (sRAGE) levels in hypothyroid and hyperthyroid patients. Methods. A total of 203 subjects were included in this cross-sectional study. After excluding diabetes mellitus, 103 newly diagnosed hypothyroid patients, 50 newly diagnosed hyperthyroid patients, and 50 control (euthyroid) subjects were enrolled. All tests were done before beginning the appropriate treatment. Accumulated AGEs in the skin collagen were measured by skin autofluorescence (SAF) using an AGE Reader. Results. SAF measurements were 1.82 ± 0.04, 1.80 ± 0.40, and 1.63 ± 0.30 arbitrary units for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.04). Serum CML levels were 8.2 ± 2.8, 10.2 ± 2.0, and 8.0 ± 3.3 ng/mL for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.01). sRAGE levels were similar between the groups. Serum thyroid-stimulating hormone and SAF measurements were positively correlated (r = 0.25, p = 0.02) in the hypothyroid group and negatively correlated in the hyperthyroid group (r = -0.36, p = 0.04). There was no correlation between CML and sRAGE levels. Conclusion. SAF measurements are increased in both hypo- and hyperthyroid normoglycemic patients. Serum CML levels are increased in hyperthyroid patients. Hypo and hyperthyroid states might be associated with acceleration of AGE accumulation and may have a long term effect on metabolic memory [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) are implicated in vascular aging due to their pro-inflammatory properties. Skin autofluorescence (SAF) is a measure to estimate their deposition. It is an easily quantifiable marker that has been shown to correlate with cardiovascular risk and parameters of metabolic diseases. Herein, we compared skin autofluorescence with other techniques indicating increased cardiovascular diseases, namely, pulse wave velocity (PWVao) and intima–media thickness (IMT). We also studied the impacts of other parameters in deeply phenotyped cohorts of young, middle-aged, and older individuals. SAF, aortic PWVao, and IMT proved to be significantly correlated with each other and with age. However, based on a moderator analysis, we could not show that these associations were affected by age. Some specific parameters such as creatinine and CRP were found to be significantly associated with skin AGE values after adjusting for confounding variables. In conclusion, SAF is a simple screening tool for vascular health with comparable power to more elaborated technical tests. [ABSTRACT FROM AUTHOR]

Background: Skin autofluorescence (SAF) is a marker for the accumulation of advanced glycation end products (AGEs), and is associated with diabetic macroangiopathy. However, whether SAF is superior to conventional markers of atherosclerosis such as carotid intima-media thickness (IMT) and pulse wave velocity (PWV) in detecting macroangiopathy remains unclear. Methods: We recruited 845 patients with type 2 diabetes enrolled in a community diabetes cohort (ViNA cohort) who had SAF, IMT, and PWV measured at baseline. The prevalence of macroangiopathy at baseline and new cardiovascular events during the 2-year follow-up period was investigated. SAF was measured using an AGE reader. Coronary artery calcification (CAC) was measured by computed tomography in 485 patients. Peripheral artery disease (PAD) was defined as the ankle-brachial blood pressure ratio of ≤ 0.9. Results: SAF, IMT, and PWV were significantly correlated with each other, and age, diabetes duration, and estimated glomerular filtration rate were their strong confounders. SAF was associated with baseline stroke and new stroke after adjusting for confounders, but not with coronary artery disease (CAD) or PAD. The nonsignificant relationship between SAF and CAD was consistent with the relationship between SAF and CAC. Multivariate analysis showed a significant association of SAF with baseline and new stroke independent of IMT and PWV. Maximum-IMT was significantly associated with baseline CAD, PAD, and stroke, but not with a new stroke, whereas PWV was associated with a new stroke. Conclusion: Among diabetic macroangiopathies, SAF is a good stroke biomarker, but not for CAD and PAD. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this work was to assess the association of advanced glycation end-products (AGEs), measured by skin autofluorescence (SAF), with prevalent heart failure, and with systolic and diastolic cardiac function, in a large population-based cohort study. Methods: We assessed the cross-sectional association between SAF and prevalent heart failure among 2426 participants from the population-based Rotterdam Study, using logistic regression. Next, among individuals free of heart failure (N=2362), we examined the link between SAF (on a continuous scale) and echocardiographic parameters of left ventricular (LV) systolic and diastolic function using linear regressions. Analyses were adjusted for traditional cardiovascular risk factors. Results: Higher levels of SAF were associated with higher odds of prevalent heart failure (multivariable adjusted OR 2.90 [95% CI 1.80, 4.62] for one unit higher SAF value). Among individuals without heart failure, one unit increase in SAF was associated with 0.98% lower LV ejection fraction (mean difference [β] −0.98% [95% CI −1.45%, −0.50%]). The association was stronger among participants with diabetes (β −1.84% [95% CI −3.10%, −0.58%] and β −0.78% [95% CI −1.29%, −0.27%] among participants with and without diabetes, respectively). Associations of SAF with diastolic function parameters were not apparent, except in men with diabetes. Conclusions/interpretation: AGE accumulation was independently associated with prevalent heart failure. Among individuals free of heart failure, AGEs were associated with cardiac function, in particular systolic function. This association was present in participants with and without diabetes and was more prominent in those with diabetes. [ABSTRACT FROM AUTHOR]

Study Design.: A single-center prospective observational study. Objective.: The aim was to clarify the usefulness of assessing advanced glycation end products (AGEs) by noninvasive skin autofluorescence in patients with ossification of the posterior longitudinal ligament (OPLL). Summary of Background Data.: AGE accumulation is associated with various systemic disorders, including aging, diabetes mellitus, and obesity. AGEs have also been associated with OPLL, but their assessment by noninvasive skin autofluorescence has not been yet studied in these patients. Materials and Methods.: We enrolled patients with degenerative spinal spondylosis and divided them into non-OPLL and OPLL groups. The OPLL group was further subdivided into cervical OPLL (C-OPLL) and thoracic OPLL (T-OPLL) groups. We compared patients' characteristics, serum laboratory data (i.e. hemoglobin A1c, total cholesterol, creatinine, and estimated glomerular filtration rate), and the skin autofluorescence intensity of AGEs (the AGE score) between the non-OPLL and OPLL groups and among the non-OPLL, C-OPLL, T-OPLL groups. Finally, the association of the AGE score with the presence of C-OPLL or T-OPLL was assessed by multinomial logistic regression. Results.: Among the 240 eligible patients, 102 were in the non-OPLL group and 138 were in the OPLL group (92 with C-OPLL and 46 with T-OPLL). We observed no significant difference in the AGE score between the non-OPLL and OPLL groups, but when comparing the score among the non-OPLL, C-OPLL, and T-OPLL groups, we found that the T-OPLL group had a significantly higher AGE score. The results of multinomial regression analysis showed that a higher AGE score was significantly associated with T-OPLL (odds ratio: 1.46; 95% CI: 1.01–2.11; P =0.044). Conclusion.: The AGE score determined by noninvasive skin autofluorescence could help to screen for OPLL in the thoracic spine. [ABSTRACT FROM AUTHOR]

It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury.

There is controversial information about the accumulation of advanced glycation end-products (AGEs) in obesity. We assessed the impact of total and abdominal adiposity on AGE levels via a cross-sectional investigation with 4254 middle-aged subjects from the ILERVAS project. Skin autofluorescence (SAF), a non-invasive assessment of subcutaneous AGEs, was measured. Total adiposity indices (BMI and Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE)) and abdominal adiposity (waist circumference and body roundness index (BRI)) were assessed. Lean mass was estimated using the Hume index. The area under the receiver operating characteristic (ROC) curve was evaluated for each index. Different cardiovascular risk factors (smoking, prediabetes, hypertension and dyslipidemia) were evaluated. In the study population, 26.2% showed elevated SAF values. No differences in total body fat, visceral adiposity and lean body mass were detected between patients with normal and high SAF values. SAF levels showed a very slight but positive correlation with total body fat percentage (estimated by the CUN-BAE formula) and abdominal adiposity (estimated by the BRI). However, none of them had sufficient power to identify patients with high SAF levels (area under the ROC curve <0.52 in all cases). Finally, a progressive increase in SAF levels was observed in parallel with cardiovascular risk factors in the entire population and when patients with normal weight, overweight and obesity were evaluated separately. In conclusion, total obesity and visceral adiposity are not associated with a greater deposit of AGE. The elevation of AGE in obesity is related to the presence of cardiometabolic risk. [ABSTRACT FROM AUTHOR]

Background: Skin autofluorescence (SAF) is a non-invasive measure reflecting accumulation of advanced glycation endproducts (AGEs) in the skin. Higher SAF levels are associated with an increased risk of developing type 2 diabetes and cardiovascular disease. An earlier genome-wide association study (GWAS) revealed a strong association between NAT2 variants and SAF. The aim of this study was to calculate SAF heritability and to identify additional genetic variants associated with SAF through genome-wide association studies (GWAS). Results: In 27,534 participants without diabetes the heritability estimate of lnSAF was 33% ± 2.0% (SE) in a model adjusted for covariates. In meta-GWAS for lnSAF five SNPs, on chromosomes 8, 11, 15 and 16 were associated with lnSAF (P < 5 × 10–8): 1. rs2846707 (Chr11:102,576,358,C > T), which results in a Met30Val missense variant in MMP27 exon 1 (NM_022122.3); 2. rs2470893 (Chr15:75,019,449,C > T), in intergenic region between CYP1A1 and CYP1A2; with attenuation of the SNP-effect when coffee consumption was included as a covariate; 3. rs12931267 (Chr16:89,818,732,C > G) in intron 30 of FANCA and near MC1R; and following conditional analysis 4. rs3764257 (Chr16:89,800,887,C > G) an intronic variant in ZNF276, 17.8 kb upstream from rs12931267; finally, 30 kb downstream from NAT2 5. rs576201050 (Chr8:18,288,053,G > A). Conclusions: This large meta-GWAS revealed five SNPs at four loci associated with SAF in the non-diabetes population. Further unravelling of the genetic architecture of SAF will help in improving its utility as a tool for screening and early detection of diseases and disease complications. [ABSTRACT FROM AUTHOR]

Skin autofluorescence is a useful index to estimate the accumulation of advanced glycation end-products in human tissues. Elderly persons with higher skin autofluorescence have lower muscle mass, muscle strength and muscle power, however, little is known about the relationship between the skin autofluorescence level and each muscle activity. We measured the values of skin autofluorescence from five places on a lower limb, and the signals of surface electromyogram during isometric contractions from five muscles on that, simultaneously. The waveforms of surface electromyogram were analyzed by Daubechies-4 wavelet transformation. The value of skin autofluorescence was increased in the proximal part of the lower limb compared with the value of the distal part. The principal component of surface electromyogram activity in a time-frequency domain was lower in the proximal part compared with that of the distal part. There was a weak negative correlation between the value of skin autofluorescence on the gluteal region and the value of the mean wavelet coefficient of the surface electromyogram signals within the gluteus maximus muscle. The higher accumulation of advanced glycation end-products on the gluteal region might suggest the lower muscle activity in aging without disease and disability. [ABSTRACT FROM AUTHOR]

Introduction Advanced glycation end products (AGEs) are frequently increased in the skin of subjects with type 2 diabetes mellitus (T2DM). This study aimed to examine the correlation of AGEs with cardiac autonomic neuropathy (CAN) in T2DM. Methods To this aim, 132 participants (88 men) with a mean age of 64.57 years and a median T2DM duration of 14.5 years were included. Skin AGEs were measured with AGE reader mu connect (Diagnoptics) on the dominant arm (both single and automated triplicate measurements). Diagnosis of CAN, sympathetic and parasympathetic nervous system impairment was based on the four standardised cardiovascular reflex tests (CARTs). Results On a single measurement, AGEs were increased in subjects with vs. those without CAN (3.20±0.74 vs. 2.66±0.66, p<0.001). As compared with normal results, AGEs were increased for each one of the 4 abnormal CARTs: Valsalva Ratio (3.36±0.67 vs. 2.66±0.72, p=0.004), E/I ratio (3.01±0.72 vs. 2.53±0.68, p=0.001), 30:15 ratio (3.08±0.76 vs. 2.75±0.69, p=0.011), postural hypotension (3.30±0.72 vs. 2.75±0.66, p<0.001). Similar results were obtained for triplicate measurements. Discussion Among T2DM subjects, skin AGEs appear to increase in the presence of CAN. This holds true both for sympathetic and parasympathetic nervous system impairment. [ABSTRACT FROM AUTHOR]

Objectives: Accumulation of advanced glycation end products (AGEs) in articular cartilage during aging has been proposed as a mechanism involved in the development of osteoarthritis (OA). Therefore, we investigated a cross-sectional relationship between skin AGEs, a biomarker for systemic AGEs accumulation, and OA.Methods: Skin AGEs were estimated with the AGE Reader™ as skin autofluorescence (SAF). Knee and hip X-rays were scored according to Kellgren and Lawrence (KL) system. KL-sum score of all four joints was calculated per participant to assess severity of overall radiographic OA (ROA) including or excluding those with prosthesis. Knee MRI of tibiofemoral joint (TFMRI) was assessed for cartilage loss. Sex-stratified regression models were performed after testing interaction with SAF.Results: 2,153 participants were included for this cross-sectional analysis. In women (n = 1,206) for one unit increase in SAF, the KL-sum score increased by 1.15 (95% confidence interval = 1.00-1.33) but excluding women with prosthesis, there was no KL-sum score increase [0.96 (0.83-1.11)]. SAF was associated with higher prevalence of prosthesis [Odds ratio, OR = 1.67 (1.10-2.54)] but not with ROA [OR = 0.83 (0.61-1.14)] when compared to women with no ROA. In men (n = 947), there was inconclusive association between SAF and KL sum score or prosthesis. For TFMRI (n = 103 women), SAF was associated with higher prevalence of cartilage loss, full-thickness [OR = 5.44 (1.27-23.38)] and partial-thickness [OR = 1.45 (0.38-5.54)], when compared to participants with no cartilage loss.Conclusion: Higher SAF in women was associated with higher prosthesis prevalence and a trend towards higher cartilage loss on MRI. Our data presents inconclusive results between SAF and ROA in both sexes. [ABSTRACT FROM AUTHOR]

Background and Aim: Advanced glycation end products are involved in age-related multisystem decline. They accumulate in body tissues with age, diabetes and chronic kidney disease (CKD), and can be measured non-invasively by the skin autofluorescence (SAF). We studied the relation between SAF and later mortality in old adults.Methods and Results: The SAF was measured using an AGE-Reader in 451 individuals from the general population aged over 75 years, and all-cause mortality was assessed during an average follow-up of 6.4 years. The association between SAF and mortality was analyzed using a multivariate Cox survival model, adjusted for age and gender. Analyses were further adjusted for diabetes and stratified on the presence of CKD due to its interaction with SAF for the risk of mortality. Participants were 82 years old on average (SD 4.1). Their mean SAF was 2.8 AU (SD 0.6). One hundred and forty-four individuals (31.9%) died during the follow-up. Adjusted for age and gender, SAF was associated with an increased risk of all-cause mortality (HR 1.44, 95%CI: 1.14-1.82 for a one-AU increase of SAF). The association was no longer significant after adjustment for diabetes. However, after stratification for the presence of CKD, higher SAF was associated with an increased risk of all-cause mortality in the participants with CKD at baseline (HR 1.68, 95%CI: 1.11-2.55), whereas there was no association among participants without CKD (HR 0.95, 95%CI: 0.63-1.44).Conclusion: Skin autofluorescence is associated with increased all-cause mortality in older adults already suffering from CKD. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases. Methods: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status. Results: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 ± 11.77 years, mean ± SD) and had significantly lower SAF (1.90 ± 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 ± 12.07 years; SAF: 2.27 ± 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (β = –0.002, 95% confidence interval (95%CI): –0.002 to –0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (β = 3.2 × 10–5, 95%CI: 0.000–0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (β = 4.2 × 10–4, 95%CI: 0.000–0.001, p < 0.001), but this association was not found in the chronic disease population (β = –3.2 × 10–4, 95%CI: –0.001 to 0.000, p = 0.347). Conclusion: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

Previous studies have shown that skin autofluorescence (SAF), measured with an advanced glycation end product (AGE) reader, estimates the accumulation of AGEs in tissues. SAF is predictive of incident type 2 diabetes, cardiovascular disease (CVD), and CV mortality in the general population. Studies in diabetic mice have shown that activation of the receptor for AGEs in hematopoietic progenitor cells increases blood neutrophils and monocytes, impairing atherosclerosis regression. We asked whether SAF is associated with blood neutrophil and monocyte counts in the general population, and whether this was moderated by prediabetes, diabetes, and sex. We examined the associations between SAF and blood neutrophil/monocyte counts in participants of the Lifelines cohort (n = 58,923: n = 24,382 men, and n = 34,541 women), a prospective population-based cohort from the North of the Netherlands, employing multivariable regression analyses. SAF positively associated with blood neutrophil and monocyte counts in the whole cohort. The positive association between SAF and monocyte, but not neutrophil, counts was moderated by prediabetes and diabetes. Positive associations between SAF and blood neutrophil and monocyte counts were moderated by male sex. Moreover, three-way interaction analyses revealed that the positive associations between SAF and neutrophil and monocyte counts were moderated by prediabetes, but not diabetes, in male sex. SAF is positively associated with blood neutrophil and monocyte counts in the general population, especially in men with prediabetes. This may contribute to the increased CV risk in men with prediabetes. [Display omitted] • Skin autofluorescence (SAF) is positively associated with blood neutrophil and monocyte counts in the Lifelines cohort. • The association between SAF and blood monocyte, but not neutrophil, counts is moderated by prediabetes and diabetes. • The associations between SAF and blood neutrophil and monocyte counts are moderated by male sex. • The associations between SAF and blood neutrophil and monocyte counts are moderated by prediabetes in male sex. [ABSTRACT FROM AUTHOR]

As a person ages, mitral annular calcification develops in the mitral annulus with increasing frequency. Lipid deposition, inflammation, and aging-related degeneration have been cited as potential causes of this pathophysiology, though there is currently no conclusive evidence to support this. AGEs accumulate in tissues due to the glycation of proteins and lipids, increasing the release of proinflammatory cytokines secondary to oxidative stress through the AGE receptor. The AGE levels increase in diabetic microvascular complications and degenerative aortic valve disease. Our study was planned prospectively as a case–control study involving 94 MAC-positive patients and 94 MAC-negative patients. The demographics, echocardiographic data and AGE levels of the patients were measured and recorded using the skin autofluorescence method. AGE levels were significantly higher in the MAC-positive patient group (3.2 vs. 2.7; p < 0.001). The AGE levels were observed as an independent predictor of MAC development in a regression analysis (OR: 8.05, 95% CI: 3.74–17.33, p < 0.001). In a ROC-curve analysis, the AUC was 0.79 (95% CI: 0.72–0.85). At a cut-off value of 2.7, 79.7% sensitivity and 69.1% specificity were observed. AGE levels can be used to cheaply, easily and non-invasively identify patients at risk of developing MAC.

Purpose. The formation and accumulation of advanced glycation end products (AGEs) are enhanced with increased oxidative stress and inflammatory conditions. A hyperthyroid and hypothyroid state is associated with oxidative stress. This study aimed to evaluate skin AGE deposition, serum carboxymethyl-lysine (CML), and serum soluble receptor for AGEs (sRAGE) levels in hypothyroid and hyperthyroid patients. Methods. A total of 203 subjects were included in this cross-sectional study. After excluding diabetes mellitus, 103 newly diagnosed hypothyroid patients, 50 newly diagnosed hyperthyroid patients, and 50 control (euthyroid) subjects were enrolled. All tests were done before beginning the appropriate treatment. Accumulated AGEs in the skin collagen were measured by skin autofluorescence (SAF) using an AGE Reader. Results. SAF measurements were 1.82 ± 0.04, 1.80 ± 0.40, and 1.63 ± 0.30 arbitrary units for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.04). Serum CML levels were 8.2 ± 2.8, 10.2 ± 2.0, and 8.0 ± 3.3 ng/mL for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.01). sRAGE levels were similar between the groups. Serum thyroid-stimulating hormone and SAF measurements were positively correlated (r = 0.25, p = 0.02) in the hypothyroid group and negatively correlated in the hyperthyroid group (r = -0.36, p = 0.04). There was no correlation between CML and sRAGE levels. Conclusion. SAF measurements are increased in both hypo- and hyperthyroid normoglycemic patients. Serum CML levels are increased in hyperthyroid patients. Hypo and hyperthyroid states might be associated with acceleration of AGE accumulation and may have a long term effect on metabolic memory. [ABSTRACT FROM AUTHOR]

Skin autofluorescence (SAF) can detect advanced glycation end products (AGEs) that accumulate in tissues over time. AGEs reflect patients' general health, and their pathological accumulation has been associated with various diseases. This study aimed to determine whether its measurements can correlate with the liver parenchyma quality. This prospective study included 186 patients who underwent liver resections. Liver fibrosis and/or steatosis > 10% were found in almost 30% of the patients. ROC analysis for SAF revealed the optimal cutoff point of 2.4 AU as an independent predictor for macrovesicular steatosis ≥ 10% with an AUC of 0.629 (95% CI 0.538–0.721, p = 0.006), 59.9% sensitivity, 62.4% specificity, and positive (PPV) and negative (NPV) predictive values of 45.7% and 74.1%, respectively. The optimal cutoff point for liver fibrosis was 2.3 AU with an AUC of 0.613 (95% CI 0.519–0.708, p = 0.018), 67.3% sensitivity, 55.2% specificity, and PPV and NPV of 37.1% and 81.2%, respectively. In the multivariable logistic regression model, SAF ≥ 2.4 AU (OR 2.16; 95% CI 1.05–4.43; p = 0.036) and BMI (OR 1.21; 95% CI 1.10–1.33, p < 0.001) were independent predictors of macrovesicular steatosis ≥ 10%. SAF may enhance the available non-invasive methods of detecting hepatic steatosis and fibrosis in patients prior to liver resection. [ABSTRACT FROM AUTHOR]

Background and Aims: Advanced glycation end-products accumulation in tissue as measured by Skin autofluorescence (SAF) is related to diastolic function in specific patient populations. This analysis aims at investigating this relationship in a general population of older persons.Methods and Results: Based on data from the CARLA cohort at first follow-up, 245 subjects were analyzed and stratified according to cardiovascular risk factors (CVRF). We used linear regression to investigate the association between diastolic function evaluated by echocardiography, HFA-PEFF score, and SAF. Univariable regression analysis showed an association of SAF with septal-E/e' (standardised beta = 1.11, 95% CI = 0.51-1.71) and A (3.42, 95% CI = 0.72-6.12), the former persisting after adjustment for age, sex and CVRF (0.67, 95% CI = 0.05-1.28). Septal-E/e' remained related to SAF only in the high cardiovascular risk stratum (1.16, 95% CI = 0.26-2.06). SAF was related to HFA-PEFF score (0.27, 95% CI = 0.10-0.43) but not after correcting for age and sex (0.16, 95% CI = 0.00-0.32) and CVRF and glomerular filtration rate (0.12, 95% CI = -0.07 - 0.27). SAF was related to the HFA-PEFF score only for participants with high cardiovascular risk (0.23, 95% CI = 0.02-0.45).Conclusion: In a general community-dwelling older population, SAF is related to diastolic function as measured by septal-E/e'. Further research is necessary to assess if SAF is a potential screening tool for diastolic dysfunction in advanced age. [ABSTRACT FROM AUTHOR]

Background: Advanced glycation end products (AGEs) have been shown to accumulate in bone and are gaining interest in connective tissue research. Aims: To investigate the intrarater reliability, two-timepoint agreement and correlations within and between two commercially available skin autofluorescence (SAF) AGE devices. Methods: Healthy volunteers were enrolled in a prospective study at a single academic institution. Each participant underwent SAF analysis by two different, commercially available devices on two occasions, 14 days apart. Upon enrollment, a general survey about the participant's lifestyle and health status was completed and followed up on for any changes at timepoint two. Results: In total, 40 participants (F:M ratio 5:3) with an average age of 39.0 ± 12.5 years were analyzed. For the AGE reader (skin) and AGE sensor (fingertip), both intrarater reliability and two-timepoint agreement were excellent with an interclass correlation coefficient (ICC) > 0.90 and a strong correlation within both machines. However, there was no correlation between both machines for either timepoint. In total, 4 participants were identified as outliers above the +2SD. Additionally, 5 participants with dark-colored skin could not be measured with the AGE reader at timepoint one and 4 at timepoint two. In contrast, all participants were able to undergo SAF analysis with the AGE sensor, irrespective of their skin type. Conclusions: Both machines showed excellent intrarater reliability and two-timepoint agreement, but the skin AGE reader might have limited applicability in individuals with dark-colored skin. Future research on AGEs might take our findings into consideration. [ABSTRACT FROM AUTHOR]

Introduction: Type 1 diabetes is associated with an increased risk of vascular complications. We aimed to investigate the association between serum and tissue advanced glycation end-products (AGEs) and micro- and macrovascular complications in type 1 diabetes (T1D). Methods: We conducted a cross-sectional study on 196 adults with T1D (mean age 44.53 ± 16, mean duration of diabetes 22 ± 12 years, mean HbA1c 8 ± 1.2%). AGEs were measured in blood serum (i.e., carboxymethyllysine (CML), methylglyoxal-hydroimidazolone-1 (MGH1), and pentosidine) and by measurement of skin autofluorescence (SAF). Associations between AGEs levels and vascular complications were analyzed using binary logistic regression. Correlations between AGEs and pulse wave velocity (PWV) were also assessed by linear regressions. Significant differences were set for p values less than 0.05. Results: We found positive associations between different AGEs and vascular complications. SAF was associated with both microangiopathy (retinopathy: OR = 1.92, p = 0.011; neuropathy: OR = 2.02, p = 0.04; any microangiopathy: OR = 2.83, p < 0.0001) and macroangiopathy (coronaropathy: OR = 3.11, p = 0.009; any macroangiopathy: OR = 2.78, p = 0.003). For circulating AGEs, pentosidine was significantly associated with coronaropathy (OR = 1.61, p = 0.01) and any macroangiopathy (OR = 1.52, p = 0.005) while MGH1 was associated with nephropathy (OR 1.72, p = 0.03). Furthermore, a significant linear correlation was found between PWV and SAF (r = 0.43, p < 0.001), pentosidine (r = 0.28, p < 0.001), and MGH1 (r = 0.16, p = 0.031), but not for CML (r = 0.03, p = 0.598). Conclusions: Skin autofluorescence appears to be a useful marker for investigating both micro- and macrovascular complications in T1D. In this study, pentosidine was associated with macroangiopathy and MGH1 with nephropathy among the circulating AGEs. Furthermore, the correlations between PWV and AGEs may suggest their value in early prediction of vascular complications in T1D. [ABSTRACT FROM AUTHOR]

Advanced glycated end products (AGEs) accumulate systemically and cause diabetes complications. However, whether noninvasive measurable AGEs are associated with diabetes status and physical functions remains unclear. One hundred and ten patients with cardiovascular disease (CVD) who underwent outpatient cardiac rehabilitation were included. AGEs scores, using AGEs sensors, were evaluated concomitantly with a physical evaluation, including testing the isometric knee extension strength (IKES) and 6 min walking distance (6MWD). Thirty-three (30%) patients had a history of diabetes mellitus (DM). The AGEs score was not different in the presence of DM history (0.52 ± 0.09 vs. 0.51 ± 0.09, p = 0.768) and was not correlated with blood glucose (r = 0.001, p = 0.995). The AGEs score was positively correlated with hemoglobin A1c (HbA1c, r = 0.288, p = 0.004) and negatively correlated with physical functions (IKES, r = −0.243, p = 0.011; 6MWD, r = −0.298, p = 0.002). The multivariate analysis demonstrated that 6MWD was independently associated with a high AGEs score (>0.52). The AGEs score was associated with HbA1c, IKES, and 6MWD in patients with CVD. The AGEs score might be a useful indicator for evaluating not only glycemic control but also physical functions. [ABSTRACT FROM AUTHOR]

Abstract Background Skin autofluorescence (SAF) reflects accumulation of advanced glycation end-products (AGEs). The aim of this study was to evaluate predictive usefulness of SAF measurement in prediction of acute kidney injury (AKI) after liver resection. Methods This prospective observational study included 130 patients undergoing liver resection. The primary outcome measure was AKI. SAF was measured preoperatively and expressed in arbitrary units (AU). Results AKI was observed in 32 of 130 patients (24.6%). SAF independently predicted AKI (p = 0.047), along with extent of resection (p = 0.019) and operative time (p = 0.046). Optimal cut-off for SAF in prediction of AKI was 2.7 AU (area under the curve [AUC] 0.611), with AKI rates of 38.7% and 20.2% in patients with high and low SAF, respectively (p = 0.037). Score based on 3 independent predictors (SAF, extent of resection, and operative time) well stratified the risk of AKI (AUC 0.756), with positive and negative predictive values of 59.3% and 84.0%, respectively. In particular, SAF predicted AKI in patients undergoing major and prolonged resections (p = 0.010, AUC 0.733) with positive and negative predictive values of 81.8%, and 62.5%, respectively. Conclusions AGEs accumulation negatively affects renal function in patients undergoing liver resection. SAF measurement may be used to predict AKI after liver resection, particularly in high-risk patients.

Puffy fingers and Raynaud’s phenomenon (RP) are important clinical predictors of the development of systemic sclerosis (SSc). We aim to assess the prevalence of SSc-related symptoms, explore pulmonary symptoms, and test the usefulness of skin autofluorescence (SAF) as a non-invasive marker for Advanced Glycation Endproducts (AGEs). Subjects from the Lifelines Cohort Study with known connective tissue disease (CTD) were excluded. Patient characteristics, SAF, self-reported pulmonary symptoms, and spirometry were obtained. Subjects (n = 73,948) were categorized into definite RP (5.3%) with and without SSc-related symptoms and non-RP. Prevalence of at least one potential SSc-related symptom (other than RP) was 8.7%; 23.5% in subjects with RP and 7.1% without RP (p < 0.001). Subjects with RP and additional SSc-related symptoms more frequently reported dyspnea at rest, dyspnea after exertion, and self-reported pulmonary fibrosis, and had the lowest mean forced vital capacity compared to the other groups (RP without SSc-related symptoms and no RP, both p < 0.001). In multivariate regression, dyspnea at rest/on exertion remained associated with an increased risk of SSc-related symptoms in subjects with RP (both p < 0.001). SAF was higher in subjects with RP and SSc-related symptoms compared to the other groups (p < 0.001), but this difference was not significant after correction for potential confounders. The prevalence of SSc-related symptoms was approximately three-fold higher in subjects with RP. Pulmonary symptoms are more prevalent in subjects with RP who also reported additional potential SSc-related symptoms. This might suggest that (suspected) early SSc develops more insidiously than acknowledged. According to this study, SAF is no marker for early detection of SSc.

Tissue concentrations of advanced glycation end product (AGE) and peripheral soluble receptor of AGE (sRAGE) levels may be associated with periodontitis severity. Both parameters and periodontitis might serve as outcome predictors for patients undergoing coronary artery bypass grafting (CABG). This study aimed to investigate possible associations between periodontitis and AGE/sRAGE. Ultimately, we wanted to examine whether AGE, sRAGE, and severe periodontitis are associated with the incidence of new cardiovascular events within 3 years of follow-up after CABG. Ninety-five patients with coronary vascular disease (CVD) (age 69 years, 88.3% males) needing CABG surgery were included. Periodontal diagnosis was made according to the guidelines of the "Centers for Disease Control and Prevention (CDC)" (2007) and staged according to the new classification of periodontal diseases (2018). AGE tissue concentrations were assessed as skin autofluorescence (sAF). sRAGE levels were determined by using a commercially available enzyme-linked immunoabsorbance assay (ELISA) kit. Univariate and multivariate baseline and survival analyses were carried out with Mann–Whitney U test, Chi² test, Kaplan–Meier curves with Log-Rank test, and logistic and Cox regression. sAF was identified as an independent risk indicator for severe periodontitis with respect to the cofactors age, gender, plaque index, and diabetes (adjusted odds ratio [OR] = 2.9, p = 0.028). The degree of subgingival inflammation assessed as a percentage of sites with bleeding on probing (BOP) was inversely correlated with sRAGE concentration (r = −0.189, p = 0.034). Both sAF (Hazard Ratio [HR] = 2.4, p = 0.004) and sRAGE (HR = 1.9, p = 0.031) increased the crude risk for new adverse events after CABG. The occurrence of severe periodontitis trends towards a higher risk for new cardiovascular events (HR = 1.8, p = 0.115). Applying multivariate Cox regression, only peripheral arterial disease (adjusted HR = 2.7, p = 0.006) and history of myocardial infarction (adjusted HR = 2.8, p = 0.010) proved to be independent risk factors for cardiovascular outcome. We conclude that sAF may represent a new, independent risk indicator for severe periodontitis. In contrast, sAF, sRAGE, and severe periodontitis were not independent prognostic factors for postoperative outcome in patients undergoing CABG. [ABSTRACT FROM AUTHOR]

Background/aim: Obesity, diabetes mellitus, and metabolic syndrome (MetS) are associated with increased accumulated skin advanced glycation end products. We aimed to evaluate the association of MetS components with skin autofluorescence (SAF) in patients with morbid obesity. Material and methods: Eight hundred and one patients with morbid obesity and 94 age-matched controls with normal body mass index (BMI) and normal glucose metabolism were included. Advanced glycation end products (AGEs) were measured using SAF in the forearm, with an AGE reader. Results: The prevalence of MetS in patients with morbid obesity was 65.5% (n = 525). Type 2 diabetes mellitus (type 2 DM) and hypertension were present in 40.9% (n = 328) and 43.7% (n = 357). Patients with morbid obesity and those with MetS had higher SAF measurements compared with the control group, 1.85 ± 0.44 arbitrary unit (AU) and 1.86 ± 0.43 AU vs. 1.72 ± 0.30 AU, respectively (p = 0.016). There was no difference in SAF levels between patients with and without MetS. SAF measurements of patients without MetS were not statistically different from the control group (p = 0.076). Patients with five MetS criteria had higher SAF measurements compared with patients with fewer MetS components (p = 0.019). There was no difference in SAF levels between patients with type 2 DM, impaired glucose metabolism, and patients with normal glucose metabolism (p = 0.513). Conclusion: Although MetS and type 2 DM are known as factors related to increased SAF levels, obesity can cause elevated SAF measurements in different ways independent of concomitant comorbid diseases. Larger studies with longer follow-ups are needed to enlighten the underlying mechanism. [ABSTRACT FROM AUTHOR]

• SAF is a validated marker of AGE accumulation in the skin. • SAF may be influenced by several factors which should be addressed when used as a systemic biomarker of AGEs. • Studies focusing on eliminating confounding factors of the AGE Reader measurement should be encouraged. Advanced glycation endproducts (AGEs) are sugar-modified adducts which arise during non-enzymatic glycoxidative stress. These compounds may become systemically elevated in disease states, and accumulate in tissue, especially on long-lived proteins. AGEs have been implicated in various acute, and chronic diseases, stressing the need for reliable and comprehensive measuring techniques. Measurement of AGEs in tissue such as skin requires invasive skin biopsies. The AGE Reader has been developed to assess skin autofluorescence (SAF) non-invasively using the fluorescent properties of several AGEs. Various studies have shown that SAF is a useful marker of disease processes associated with oxidative stress. It is prospectively associated with the development of cardiovascular events in patients with diabetes, renal or cardiovascular disease, and it predicts diabetes, cardiovascular disease, and mortality in the general population. However, when measuring SAF in individual subjects, several factors may limit the reliability of the measurement. These include endogenous factors present in the skin that absorb emission light such as melanin in dark-skinned subjects, but also factors that lead to temporal changes in SAF such as acute diseases and strenuous physical exercise associated with glycoxidative stress. Also, exogenous factors could potentially influence SAF levels inadvertently such as nutrition, and for example the application of skin care products. This review will address the AGE Reader functionality and the endogenous, and exogenous factors which potentially influence the SAF assessment in individual subjects. [ABSTRACT FROM AUTHOR]