Abstract Maximum lifespan varies more than 100-fold across vertebrates, yet within each species aging emerges as a coordinated syndrome spanning metabolism, immunity, endocrine signaling, cognition, and regeneration. We propose the Metabolic Scope Theory of Aging (MSTA), which treats longevity as the time required to exhaust mitochondrial bioenergetic reserve rather than as a consequence of resting metabolic rate alone. The framework decomposes lifespan into three physical axes: Scope, the reserve capacity that buffers cumulative damage; Stability, the resistance of mtDNA-linked OXPHOS architecture to erosion; and Pace, the temperature-dependent kinetics of lesion accumulation. Using body mass as a Scope proxy, mtDNA GC content as a Stability proxy, and body temperature as Pace, the resulting Scope–Stability–Pace relation, lnMLS = α lnBM + β GC% − γ Tb + c, explains ∼69% of mammalian maximum-lifespan variance across 379 species. Cross-class comparisons reinforce the same constraint structure: birds offset high thermal Pace through elevated mtDNA Stability, and the SSP temperature coefficient derived from mammals matches the temperature dependence of lifespan observed in ectotherms. The framework further connects comparative lifespan scaling to Gompertz-like mortality acceleration through progressive reserve erosion and threshold crossing. Mechanistically, MSTA models cumulative mtDNA-linked damage as rising impedance within OXPHOS. Increasing internal resistance drives mitochondria toward a high-redox-pressure, low-current regime that preserves basal ATP while restricting NAD + regeneration, CoQ acceptor availability, and Δp-dependent work. The earliest failure is therefore not energetic collapse but loss of regenerative scope: NAD + -gated TCA flux, aspartate and nucleotide synthesis, one-carbon metabolism, and redox-buffered repair become progressively harder to sustain, and diverse age- related pathologies emerge as tissue-specific projections of this shared upstream constraint. MSTA separates a reversible, operational impedance (redox poise, membrane potential, endocrine tone) from a fixed, informational one (accumulated mtDNA damage) that sets the hard ceiling on lifespan. Because the informational layer cannot be reversed by regulatory means, the framework predicts that until therapies can directly restore mitochondrial conductance, interventions will be most effective when they relieve redox pressure or bypass constrained biosynthetic gates.

Disclosure: Y. Marcus-Perlman: None. G. Shefer: None. I. Kori: None. M. Ingbir: None. Y. Greenman: None. N. Stern: None. AVS is crucial for diagnosing primary aldosteronism (PA), relying on cortisol-based selectivity and lateralization indices (SI/LI). However, variability in cortisol levels and aldosterone-cortisol co-secretion can hinder diagnostic accuracy. A multicomponent lateralization index incorporating 17-hydroxyprogesterone (17OHP) and the contralateral suppression index (CSI) may improve subtype differentiation between aldosterone-producing adenoma (APA) and bilateral hyperaldosteronism (BHA). In this study, AVS without cosyntropin stimulation was conducted on 27 patients, with 25 successful procedures (14 APA, 11 BHA). Clinical and laboratory data highlighted key differences: APA patients exhibited lower plasma renin activity (0.06 ± 0.04 vs. 0.17 ± 0.13ng/ml/min) and higher aldosterone concentration (38 ± 20 vs. 25 ± 10.3 ng/dL) than BHA patients. APA patients also showed elevated aldosterone-to-cortisol (19.7 ± 14.2 vs. 1.9 ± 0.5), aldosterone-to-17OHP (35.3 ± 44 vs. 4.5 ± 5.2), and aldosterone-to-DHEAS ratios (26.7 ± 33.9 vs. 2.63 ± 1.7). Metabolic abnormalities, including diabetes (3 cases) and impaired fasting glucose (7 cases), and abnormal 1mg dexamethasone suppression test (1 case) were more prevalent in APA than in BHA (1 and 2 cases, respectively). Surgical intervention was performed in 12 APA patients, compared to 1 in the BHA group. We suggest a multicomponent index that improves the interpretation of AVS when LI values are borderline. Index includes cortisol-corrected LI (cutoff>4), 17OHP LI (cutoff>5), and CSI (≤0.5 for cortisol or 17OHP-corrected CSI<3). For example, in a suspected APA case with borderline cortisol LI (2.96), the addition of aldosterone/17OHP LI (>5) and CSI (<0.5) solidified the diagnosis which was then confirmed by surgical cure. Conversely, reliance on marginally positive lateralization such as cortisol LI (4.01) and 17OHP LI (5.14) was offset by high CSI >4 which correctly predicted poor postoperative outcomes. Notably, indices derived from DHEA-S were not helpful in refining diagnoses. These findings highlight the advantage of integrating 17OHP-derived LI and CSI into AVS analyses to enhance diagnostic precision for PA subtyping. Further studies are needed to establish refined cutoff values and to facilitate routine use of 17OHP in clinical practice. Presentation: Monday, July 14, 2025

Context: Some clinical resemblance may exist between obesity, particularly abdominal obesity, and Cushing’s syndrome. This has stimulated ongoing interest in the role of cortisol's secretion pattern, control and metabolism in obesity. Goals: To investigate whether basal and stimulated levels of cortisol differ between healthy people with obesity and individuals with normal weight Design: Total, free, and salivary cortisol were tested at baseline state and after 1 g ACTH stimulation in 60 healthy subjects with obesity and 54 healthy lean controls. Results: Baseline total cortisol was lower in subjects with obesity compared to lean controls 347 (265-452(nmol/L vs. [422 (328-493) nmol/L respectively ; p<0.05]. Similarly, basal salivary cortisol was significantly lower in subjects with obesity [7.5 (5.2-9.7) nmol/L vs 10.7 (7.5-17.6) nmol/L; p<0.05]. Upon challenge with ACTH, total peak serum and salivary peak cortisol responses were significantly lower in people with obesity than in lean subjects [665.16±151.8 vs. 728.64±124.2 nmol/L, p<0.05; and 31.66 (19-38.64) vs. 40.05 (31.46-46.64) nmol/L, p<0.05, respectively]. Additionally, baseline total cortisol and salivary cortisol were inversely related to BMI (r=-0.24, r=-0.27; p<0.05 for both) and waist circumference (r=-0.27, r= -0.34; p<0.05 for both). Conclusion: Baseline as well as peak stimulated total serum and salivary cortisol were significantly lower in subjects with obesity. It thus appears that obesity is not associated with enhanced basal or ACTH-stimulated cortisol.

Abstract Disclosure: E. Osher: None. K.M. Tordjman: None. Y. Sofer: None. N. Stern: None. J. Klausner: None. G. Lahat: None. N. Lubezky: None. Y. Goykhman: None. B. Sagie: None. G. Ravit: None. A. Asaf: None. K. Rivka: None. W. Ido: None. Y. Greenman: None. Background: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Prospective randomized controlled studies to evaluate the optimal treatment modalities are limited. Therefore, retrospective studies are needed. The aim of the study is to describe and summarize additional data and knowledge on treatment modalities in a tertiary medical center treating patients with ACC by a multidisciplinary expert team. Methods: A retrospective study. Results: The study cohort included 42 subjects (57% females), followed for a median of 26 (range 0.3-237) months. The mean age at diagnosis was 54±17 years; 60% of tumors were functioning, 57 % were cortisol-secreting, 41% were androgen-secreting, 12% aldosterone-secreting, and 45% were co-secreting. ENSAT stage at diagnosis was stage 1 in 19%, stage 2 in 26%, stage 3 in 24% and stage 4 in 29%. Eighty-eight % of patients underwent surgery; residual disease was in 21% post surgery. Treatment with mitotane was initiated in 62% of patients, reaching a mean maximal dose of 3.1 ±2 grams/day. Oncologic pharmacological treatment (Chemotherapy, TKI, Immunotherapy) and/or radiation were given in 50 % and 21%, respectively. In 14 /42 patients, genetic evaluation was done, in most cases, no target for treatment was found. 52% of patients died during follow-up; all cohort median time to death was 31(range 0.3-237) months. Time to death longer than 31 months was also seen in advanced disease stage 3- 3/9(33%) and stage 4-4/11(36%). Except association between mitotane and prolonged time to death (p=0.013), no other factors (age, gender, surgery, radiation, residual disease functional status), were associated with prolonged survival. Conclusions: ACC remains a rare disease with a poor prognosis. However, it is a heterogeneous disease, with some patients with advanced disease achieving more prolonged survival. Further characterization of these patients may improve our understanding of the biology and treatment of this rare disease. Presentation: 6/2/2024

AIMS:Circadian syndrome (CircS) is considered a better predictor for cardiovascular disease than the metabolic syndrome (MetS). We aim to examine the associations between CircS and MetS with cognition in Chinese adults. METHOD:We used the data of 8546 Chinese adults aged ≥40 years from the 2011 China Health and Retirement Longitudinal Study. MetS was defined using harmonised criteria. CircS included the components of MetS plus short sleep and depression. The cut-off for CircS was set as ≥4. Global cognitive function was assessed during the face-to-face interview. RESULTS:CircS and MetS had opposite associations with the global cognition score and self-reported poor memory. Compared with individuals without the CircS and MetS, the regression coefficients (95%CI) for global cognition score were -1.02 (-1.71 to -0.34) for CircS alone and 0.52 (0.09 to 0.96) for MetS alone in men; -1.36 (-2.00 to -0.72) for CircS alone and 0.60 (0.15 to 1.06) for MetS alone in women. Having CircS alone was 2.53 times more likely to report poor memory in men (95%CI 1.80-3.55) and 2.08 times more likely in women (95%CI 1.54-2.81). In contrast, having MetS alone was less likely to report poor memory (OR 0.64 (0.49-0.84) in men and 0.65 (0.52-0.81) in women). People with CircS and MetS combined were more likely to have self-reported poor memory. CONCLUSIONS:CircS is a strong and better predictor for cognition impairment than MetS in Chinese middle-aged adults. MetS without short sleep and depression is associated with better cognition.

Tay-Sachs (TS) disease is a neurodegenerative disease resulting from mutations in the gene encoding the α-subunit (HEXA) of lysosomal β-hexosaminidase A (HexA). We report that (1) recombinant HEXA alone increased HexA activity and decreased GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein composed of HEXA linked to two blood-brain barrier (BBB) entry elements, a transferrin receptor binding sequence and granulocyte-colony stimulating factor, associates with HEXB in vitro; reaches human cultured TS cells lysosomes and mouse brain cells, especially neurons, in vivo; lowers GM2 in cultured human TS cells; lowers whole brain GM2 concentration by approximately 40% within 6 weeks, when injected intravenously (IV) to adult TS-mutant mice mimicking the slow course of late-onset TS; and increases forelimbs grip strength. Hence, a chimeric protein equipped with dual BBB entry elements can transport a large protein such as HEXA to the brain, decrease the accumulation of GM2, and improve muscle strength, thereby providing potential treatment for late-onset TS.

Abstract Disclosure: Y. Sofer: None. E. Osher: None. Y. Greenman: None. K.M. Tordjman: None. G. Shenkerman: None. M. Yaron: None. Y. Marcus-Perlman: None. Y. Moshe: None. S. Shaklai: None. R. Limor: None. S. abiri: None. D. Cantrell: None. N. Stern: None. Objective: Some clinical resemblance may exist between obesity, particularly abdominal obesity, and Cushing’s syndrome. This has stimulated ongoing interest in the role of cortisol's secretion pattern, control and metabolism in obesity. Goals: To compare basal and dynamic cortisol response to an intravenous bolus dose of 1 ug ACTH in healthy obese versus lean controlsDesign: Total, free and salivary cortisol were tested at the basal state and after a standard challenge with 1 ug ACTH in 60 healthy obese subjects (mean BMI= 39 kg/m2) and 54 healthy lean controls (mean BMI=23 kg/m2). Results: Basal total cortisol was significantly lower in obese as compared to lean subjects [361.56+/-132 vs 414+/- 121 nmol/L; p=0.019]. Additionally, baseline total cortisol and salivary cortisol were inversely related to BMI (r=-0.24, r=-0.27; p<0.05 for both). Baseline total and salivery cortisol were also negatively correlated with waist circumference (r=-0.27, r= -0.34; p<0.05 for both). Upon challenge with ACTH, total and salivary cortisol response were significantly lower in obese than in lean subjects [665.16+/-151.8 vs. 728.64+/- 124.2 nmol/L, p<0.05; 31.66 (19-38.64) vs. 40.05 (31.46-46.64) nmol/L, p<0.05]. Conclusion: Basal as well as peak stimulated cortisol and integrated post-1ug ACTH-stimulated total serum cortisol levels were significantly lower in obese subjects. Obesity is not associated with enhanced basal cortisol or ACTH-stimulated cortisol reserve. Hence, increased serum or salivary cortisol is atypical for uncomplicated obesity. Presentation: 6/1/2024

Often recommended, calcium supplements have been incriminated as increasing the risk of cardiovascular events, whereas dietary calcium has generally been exonerated. As a first step to address the vascular safety of such dietary measures at the clinical nutritionist toolbox, we sought to determine and compare the acute effects of a typical oral calcium load, provided either as a supplement or as food, on vascular parameters assessed noninvasively in healthy subjects.In this acute, cross-over, random-order intervention, 11 young and healthy vitamin D-sufficient volunteers (8 women/3 men, 33±6.1 years, body mass index 22.6±2.3 kg/m(2)), ingested 600 mg of calcium twice, once as calcium citrate and the other time from dairy products. Biochemical, vascular and hemodynamic parameters, before and 2 h after each challenge, were compared. Arterial stiffness was studied by measuring pulse wave velocity, augmentation index and large (C1) and small (C2) arterial compliance. Endothelial function was assessed by flow-mediated dilation (FMD).Despite effective calcium loading accompanied by a significant 60% parathyroid hormone level reduction on both occasions, there were no clinically significant changes in the vascular parameters neither in comparison with baseline, nor between the studies. A decrease in heart rate with no change in cardiac output was noticed after the supplement.An effective calcium load has no clinically significant untoward effect on the vascular properties of young healthy subjects, regardless of its source. Additional studies should determine whether this holds true for chronic calcium supplementation, particularly in subjects with a priori vascular impairment.

PURPOSE:Previous studies have shown differences in baseline and stimulated cortisol levels between men and women. Whether this difference is secondary to sex hormones or to other factors, such as genetic or epigenetic changes, is unknown. We investigated the effect of gender-affirming hormone treatment (GAHT) on the hypothalamo-pituitary-adrenal axis of transgender subjects in an effort to throw light on this question.METHODS:Ten transgender males (TM) and eight transgender females (TF) underwent a low-dose (1 µg) adrenocorticotropic hormone (ACTH) stimulation test before and 6 months after GAHT initiation. Serum total, free and salivary cortisol (SC) levels were measured at baseline and at 20, 30 and 40 min.RESULTS:For the TM, all three levels were significantly lower at several time points after ACTH injection compared to pretreatment levels following 6 months of treatment (p < .05). Likewise, the overall SC response as calculated by the area under the curve was significantly lower (p = .0053). For the TF, the basal total cortisol (TC) level increased after 6 months of treatment (p < .01) while ACTH-stimulated SC levels decreased significantly. The basal ACTH levels were significantly lower following hormonal therapy (p < .001).CONCLUSION:Stimulated salivary cortisol levels decreased significantly after 6 months of GAHT in both male and female transgender subjects, possibly reflecting a decreased state of anxiety associated with treatment initiation. Additionally, basal and stimulated serum TC levels increased after hormonal treatment in the TF, probably secondary to the effect of oestrogen on cortisol-binding globulin.

Objective:Pancreatic neuroendocrine tumors (PNETs) are rare, but their incidence has risen significantly in recent years. Whereas diabetes mellitus (DM) is recognized in association with chronic pancreatitis and pancreatic cancer, it has not been well-characterized concerning non-functioning (NF)-PNETs.Study aim: to determine whether NF-PNETs are associated with DM/ Pre-DM and characterize the features of this putative association. Methods:Retrospective study to evaluate rate of Pre-DM /DM in subjects with NF-PNETs. Results:Study cohort of 129 patients with histologically confirmed NF-PNETs, ∼60% were men (M/F: 77/52). Abnormal glucose metabolism that preceded any treatment was seen in 70% of this cohort: overt DM in 34% and Pre-DM in 36% of the subjects. However, during follow-up, the overall prevalence rose to 80.6%, owing exclusively to newly diagnosed DM in subjects who received treatment.Patients with DM/Pre-DM were older (65 ± 11; 54 ± 14; p < 0.0001), the tumor was more commonly localized in the pancreatic body and tail (76.5% vs. 23.5% p = 0.03), while BMI (27 ± 6 vs. 28 ± 5 kg/m2), and tumor size (2.4 ± 2 vs. 2.9 ± 3.2 cm) were similar. The relative prevalence of DM in our cohort of NF-PNETs was 1.6 higher than that in the age and gender-adjusted general Israeli population (95 %CI: 1.197-2.212p = 0.03). Conclusions:We found a high rate of impaired glucose metabolism, either DM or Pre-DM, in a large cohort of NF-PNETs. The high prevalence of diabetes/pre-diabetes was unrelated to obesity or tumor size. This observation should increase awareness of the presence of DM on presentation or during treatment of "NF"-PNETs.

The objective of this study was to determine the prognostic value of lymph node (LN) involvement and the LN ratio (LNR) and their effect on recurrence rates and survival in patients with pancreatic neuroendocrine tumors (PNETs) undergoing surgery. This single-center retrospective study reviewed the medical records of 95 consecutive patients diagnosed with PNETs who underwent surgery at our medical center between 1997 and 2017. The retrieved information included patient demographics, pathology reports, treatments, and oncological outcomes. Results: 95 consecutive potentially suitable patients were identified. The 78 patients with PNETs who underwent surgery and for whom there was adequate data were included in the analysis. Their mean ± standard deviation age at diagnosis was 57.4 ± 13.4 years (range 20–82), and there were 50 males (64%) and 28 females (36%). 23 patients (30%) had LN metastases (N1). The 2.5- and 5-year disease-free survival (DFS) rates for the entire cohort were 79.5% and 71.8%, respectively, and their 2- and 5-year overall survival (OS) rates were 85.9% and 82.1%, respectively. The optimal value of the LNR was 0.1603, which correlated with the outcome (2-year OS p = 0.002 HR = 13.4 and 5-year DFS p = 0.016 HR = 7.2, respectively, and 5-year OS and 5-year DFS p = 0.004 HR = 9 and p = 0.001 HR = 10.6, respectively). However, the multivariate analysis failed to show that the LNR was an independent prognostic factor in PNETs. Patients with PNETs grade and stage are known key prognostic factors influencing OS and DFS. According to our results, LNR failed to be an independent prognostic factor.

Abstract Background There is recent concern regarding the documented mismatch between demand and supply, vis-à-vis the growing need for trained endocrinologists unmet by parallel rise in the world workforce of endocrinologist. Due to the increasing complexity of disease in inpatients, in recent years we have experienced a growing demand for inpatient endocrine consults. Surprisingly, the need for the endocrinology subspecialty in the overall care of inpatients in the current setting of general hospitals has received little attention. Methods A retrospective analysis of endocrine consult service based on solicited consults carried out during 3 consecutive months. Results During 3 months, there were 767 consults, comprised of 156 diabetes referrals and 611 endocrine/metabolic consult requests. The 611 "non-glucocentric" consult requests were related to 295 inpatients (2.1 ± 2.7 consults/patient). Mean patient age was 58.9 ± .18 years (range 21–92), with some F/M preponderance (58/42%). Requests for endocrine consults were evenly distributed (49.8%, 50.2%) between internal medicine and surgery wards. Case distribution was as follows: thyroid 45.4%, calcium & bone 11.5%, pituitary 12%, adrenal 10% and all others 8.1–0.7%. The mean response time was 4.4 ± 2.7 h. The consults had a discernible effect on the patients' disease management in 60% of the patients. Of these, the consults modified the hospital treatment in 74%, the discharge treatment recommendations in 19% and the diagnosis in 7%. Conclusion At a large medical center, endocrine consults were requested for ~ 3.3% of all admitted inpatients. The endocrine consults modified pre-consult diagnosis or treatment in ~ 60% of the cases. Contrary to its common image as an exclusively outpatient-based subspecialty, endocrinology practiced by specialists and endocrine trainees has a notable role in the daily care of inpatients admitted to a referral general hospital.

Purpose. This pilot study aimed to explore the feasibility of scanning the human distal radius bone marrow in vivo to detect osteoporosis-related changes using magnetic resonance and evaluate whether the radius may serve as an accessible probing site for osteoporosis. This may lead in the future to the use of affordable means such as low-field MRI scanners for the monitoring of disease progression. Methods. A clinical trial was performed using a 3T MR scanner, including 26 women assigned into three study groups: healthy-premenopausal (n = 7; mean age 48.6 ± 3.5 years), healthy-postmenopausal (n = 10; mean age 54.5 ± 5.6 years), and osteoporotic-postmenopausal (n = 9; mean age 61.3 ± 5.6 years). Marrow fat composition was evaluated using T2 maps, a two-compartment model of T1, and a Dixon pulse sequence. Results. The osteoporotic group exhibited higher fat content than the other two groups and lower T2 values than the healthy-premenopausal group. Conclusions. Osteoporosis-related changes in the composition of the distal radius bone marrow may be detected in vivo using MRI protocols. The scanning protocols chosen here can later be repeated using low-field MRI scanners, thus offering the potential for early detection and treatment monitoring, using an accessible, affordable means that may be applied in small clinics. This trial is registered with MOH_2018-05-23_002247, NCT03742362.

The study aimed to compare the predictive value of the Circadian Syndrome (CircS) and Metabolic Syndrome (MetS) for cardiovascular disease (CVD). We used data of 12,156 adults aged ≥20 years who attended National Health and Nutrition Examination Survey (NHANES) 2005–2016. Mortality was obtained from the registry updated to 2019. The CircS was defined based on components of the MetS, in addition to short sleep and depression. Both the MetS and CircS were directly associated with self-reported history of CVD. The odds ratios for prevalent CVD associated with the CircS and MetS, respectively, were 2.92 (95% confidence interval (CI) 2.21–3.86) and 3.20 (2.38–4.30) in men, and 3.27 (2.34–4.59) and 3.04 (2.15–4.30) in women. The CircS had a better predictive power for prevalent CVD than that of MetS, as indicated by the higher positive predictive value (PPV); in men, the PPV for prevalent CVD with CircS was 23.1% and with MetS 20.9%, and in women these were 17.9% vs. 16.4%, respectively. However, the PPV of the CircS and MetS did not differ for the CVD mortality prediction. Women with CircS alone had a higher risk for both prevalent CVD and CVD mortality than those with MetS alone. In conclusion, the CircS is a significant and stronger predictor for CVD than the MetS in US adults.

This study covers a new method and related instrumentation for whole blood analysis for medical diagnostics. Two-μL whole blood samples were collected using "minimal invasive" diabetes lancet and placed on a thin glass rod mounted on a newly designed BloodProbe. The BloodProbe with the whole blood sample was inserted directly into a ChromatoProbe mounted on the GC inlet, and thus, no sample preparation was involved. The analysis was performed within 10 min using a GC-MS with Cold EI that is based on interfacing GC and MS with supersonic molecular beams (SMB) along with electron ionization of vibrationally cold sample compounds in the SMB (hence the name Cold EI). Our blood analysis revealed several observations: (1) Detailed mass chromatograms were generated with full range of all the nonpolar lipids in blood including fatty acids, cholesterol, cholesteryl esters, vitamin E, monoglycerides, diglycerides, and triglycerides. (2) The analysis of whole blood was found to be as informative as the conventional clinical analysis of blood serum. (3) Cholesteryl esters were more sensitive than free cholesterol alone to the effect of diet of obese people. (4) Major enhancement of several fatty acid methyl esters was found in the blood of a cancer patient with liver dysfunction. (5) Vitamin E as both α- and β-tocopherol was found with person-dependent ratio of these two compounds. (6) Elemental sulfur S8 was identified in blood. (7) Several drugs and other compounds were found and need further study of their correlation to medical issues.

Abstract Background Aging and type 2 diabetes (T2DM) are associated with an increased risk of sarcopenia. Diagnosis of sarcopenia is commonly done using dual-energy X-ray absorptiometry (DXA) in specialized settings. Another available method for assessing body composition is direct segmental multi-frequency bioelectrical impedance analysis (DSMF-BIA). Here, we examine the accuracy of a DSMF-BIA (InBody-770) for assessing body composition in older adults with T2DM when compared to DXA. Methods Eighty-four obese/overweight older adults (49 women, 71 ± 5 years) with T2DM who were recruited for the CEV-65 study and had both DSMF-BIA and DXA assessments at baseline were included. The analysis included Bland–Altman plots and intra class correlation coefficients. Sub-analyses were performed according to gender and following 10 weeks of interventions (diet, circuit training, and Empagliflozin). Results The leg lean mass results according to DSMF-BIA and DXA were 14.76 ± 3.62 kg and 15.19 ± 3.52 kg, respectively, with no difference between devices according to Bland–Altman analyses (p = 0.353). Assessment of appendicular skeletal mass index did not differ between DSMF-BIA and DXA (7.43 vs. 7.47 kg/m2; p = 0.84; ICC = 0.965, p < 0.0001; mean difference −0.068, p = 0.595). Gender and treatment interventions did not modify the accuracy of the DSMF-BIA when compared to DXA. Conclusions In older adults with T2DM the degree of agreement between DSMF-BIA and DXA, was high, supporting the use of DSMF-BIA to measure muscle mass.

Background Aging is linked to hypermethylation of CpG sites on promoters and enhancers, along with loss of methylation in intergenic zones. That such changes are not necessarily a continuous process is exemplified by the extensive changes in DNA methylation during development with another significant time of change during adolescence. However, the relation between age and DNA methylation during adult life has not been systematically evaluated. In particular, potential changes in methylation trends in the same CpGs over the years that may occur with aging remain largely unexplored. Methods Here we set out to determine the average trends by age of the CpG sites represented in the Illumina 450 platform, based on data from 2143 subjects of the age range of 20 to 80 years, compiled from 24 different cohorts. Using several mathematical procedures, we initially separated stationary probes from probes whose methylation changes with age. Among the latter, representing ∼20% of the probes, we then focused on the identification of CpG sites with switch points, i.e., a point where a stable trend of change in the age-averaged methylation is replaced by another linear trend. Results Using several mathematical modeling steps, we generated a machine learning model that identified 5175 CpG sites with switch points in age-related changes in the trend of methylation over the years. Switch points reflect acceleration, deceleration or change of direction of the alteration of methylation with age. The 5175 switch points were limited to 2813 genes in three waves, 80% of which were identical in men and women. A medium-size wave was seen in the early forties, succeeded by a dominant wave as of the late fifties, lasting up to 8 years each. Waves appeared∼4-5 years earlier in men. No switch points were detected on CpGs mapped to the X chromosome. Conclusion In non-stationary CpG sites, concomitant switch points in age related changes in methylations can be seen in a defined group of sites and genes, which cluster in 3 age- and sex-specific waves.

Since low serum l-arginine (Arg) and high asymmetric dimethylarginine (ADMA) can predict microvascular complications in type 2 diabetes mellitus (T2DM), we tested whether Arg and ADMA are affected by diet and physical activity in overweight/obese and T2DM subjects. We tested the effects on serum Arg and ADMA of single loads of dextrose, protein, fat, or alcohol (∼300 calories each); one episode of physical exercise; and 12 weeks of standard lifestyle modification (dietary and physical activity counseling). Alcohol drink was followed by ∼30% lowering in Arg. Arg and ADMA increased after a protein load but remained stable after glucose or fat load or 30 min of treadmill walk. Following 12 weeks of lifestyle modification, ADMA declined only in subjects achieving weight loss >5%. In conclusion, alcohol is a previously unrecognized acute suppressor of serum Arg. Lifestyle modification lowers ADMA in subjects who achieve weight loss >5%. Clinical Trial Registration Number: NCT04406402.