Adipose tissue senescence: Biological changes, hallmarks and therapeutic approaches.

Adipose tissue (AT), the largest energy storage reservoir and endocrine organ, plays a crucial role in regulating systemic energy metabolism. As one of the most vulnerable tissues during aging, the plasticity of AT is impaired. With age, AT undergoes redistribution, characterized by expansion of visceral adipose tissue (VAT) and reduction of peripheral subcutaneous adipose tissue (SAT). Additionally, age-related changes in AT include reduced adipogenesis of white adipocytes, decreased proliferation and differentiation capacity of mesenchymal stromal/stem cells (MSCs), diminished thermogenic capacity in brown/beige adipocytes, and dysregulation of immune cells. Specific and sensitive hallmarks enable the monitoring and evaluation of the biological changes associated with aging. In this study, we have innovatively proposed seven characteristic hallmarks of AT senescence, including telomere attrition, epigenetic alterations, genomic instability, mitochondrial dysfunction, disabled macroautophagy, cellular senescence, and chronic inflammation, which are intricately interconnected and mutually regulated. Finally, we discussed anti-aging strategies targeting AT, offering insights into mitigating or delaying metabolic disturbances caused by AT senescence.

Differences in HDL-related coronary heart disease risk between individuals with and without diabetes.

BACKGROUND AND AIMS: High-density lipoprotein (HDL) might lose atheroprotective functions in the presence of diabetes. We sought to examine associations of HDL cholesterol (HDL-C) and HDL particle (HDL-P) subclasses with risk of coronary heart disease (CHD) stratified by diabetes. METHODS: We included 393,516 participants (20,691 diabetics and 372,825 nondiabetics) from the UK Biobank. Restricted cubic splines cooperated with Cox model were used to estimate associations of HDL with CHD. RESULTS: During a median follow-up of 13.0 years, 3398 (16.4 %) and 24,772 (6.6 %) incident CHD events occurred among diabetics and nondiabetics, respectively. HDL-C showed inverse associations with CHD among nondiabetics, whereas U-shaped associations among diabetics. Compared to individuals with normal HDL-C (40th - 60th percentile, 1.32-1.51 mmol/L), those in the top percentile (95th, >2.16 mmol/L) had lower CHD risks among nondiabetics (Hazard Ratio, 0.79; 95 % confidence interval, 0.73-0.86), but higher risks among diabetics (1.38, 1.02-1.88). As for HDL-P, there were inverted U-shaped associations of very large HDL-P and linearly negative associations of large HDL-P with CHD among nondiabetics; however, linearly positive associations of very large HDL-P and null associations of large HDL were observed among diabetics. L-shaped associations of medium and small HDL-P were found both in diabetics and nondiabetics. CONCLUSIONS: Very high HDL-C levels were associated with lower CHD risks in nondiabetics, but higher risks in diabetics. Smaller HDL-P was negatively, whereas very large HDL-P was positively associated with CHD risk in diabetics. These data advance our knowledge about the interactions between HDL and diabetes.

Association of ultraprocessed food consumption with risk of microvascular complications among individuals with type 2 diabetes in the UK Biobank: a prospective cohort study.

BACKGROUND: The poor nutritional characteristics and potentially harmful molecules in ultraprocessed foods (UPFs) are risk factors for diabetic microvascular complications. However, the evidence regarding UPFs and diabetic microvascular complications remains limited. OBJECTIVES: We aimed to evaluate the associations between UPF consumption and risk of diabetic microvascular complications, to examine the underlying biological pathways (e.g., inflammation and lipid profile), and to identify whether the associations differ by type of UPF dietary patterns. METHODS: We included a prospective cohort of UK Biobank participants with type 2 diabetes (T2D) having at least one 24-h dietary recall (N = 5685). UPFs were defined using the Nova classification. Principal component analysis was used to derive UPF consumption patterns. Associations of UPFs and their consumption patterns with microvascular complications were assessed using Cox proportional hazards regression models. Mediation analyses were used to estimate the mediating effects of 22 biomarkers. RESULTS: During a median of 12.7 y of follow-up, 1243 composite microvascular complications events occurred (599 diabetic retinopathy, 237 diabetic neuropathy, and 662 diabetic kidney disease events). Five consumption patterns were identified (spread and bread, cereal prepared with liquids, dairy-based products, sugary beverage and snack, and mixed beverage and savory snack patterns). A 10% increment in the proportion of UPF was associated with higher hazards of the composite microvascular complications (hazard ratio [HR]: 1.08; 95% confidence interval [CI]: 1.03, 1.13) and diabetic kidney disease (HR: 1.13; 95% CI: 1.06, 1.20). Triglycerides, C-reactive protein, and body mass index collectively explained 22.0% (9.6%-43.0%) of the association between UPF intake and composite microvascular complications. Pattern high in mixed beverage and savory snack was associated with a higher risk of composite microvascular complications. CONCLUSIONS: Higher UPF consumption was associated with higher risks of diabetic microvascular complications, and the association was partly mediated through multiple potential ways.

Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms.

Multiple organs and tissues coordinate to respond to dietary and environmental challenges. It is interorgan crosstalk that contributes to systemic metabolic homeostasis. The liver and brain, as key metabolic organs, have their unique dialogue to transmit metabolic messages. The interconnected pathogenesis of liver and brain is implicated in numerous metabolic and neurodegenerative disorders. Recent insights have positioned the liver not only as a central metabolic hub but also as an endocrine organ, capable of secreting hepatokines that transmit metabolic signals throughout the body via the bloodstream. Metabolites from the liver or gut microbiota also facilitate a complex dialogue between liver and brain. In parallel to humoral factors, the neural pathways, particularly the hypothalamic nuclei and autonomic nervous system, are pivotal in modulating the bilateral metabolic interplay between the cerebral and hepatic compartments. The term "liver-brain axis" vividly portrays this interaction. At the end of this review, we summarize cutting-edge technical advancements that have enabled the observation and manipulation of these signals, including genetic engineering, molecular tracing, and delivery technologies. These innovations are paving the way for a deeper understanding of the liver-brain axis and its role in metabolic homeostasis.

Serum 25-hydroxyvitamin D concentrations, vitamin D receptor polymorphisms, and risk of infections among individuals with type 2 diabetes: a prospective cohort study.

BACKGROUND: Evidence on the association between serum 25-hydroxyvitamin D [25(OH)D] and infections among patients with type 2 diabetes (T2D), a group susceptible to vitamin D deficiency and infections, is limited. OBJECTIVES: We aimed to examine this association in individuals with T2D, and to evaluate whether genetic variants in vitamin D receptor (VDR) would modify this association. METHODS: This study included 19,851 participants with T2D from United Kingdom Biobank. Infections were identified by linkage to hospital inpatient and death registers. Negative binomial regression models were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs), with adjustment of potential confounders. RESULTS: In patients with T2D, the incidence rate of infections was 29.3/1000 person-y. Compared with those with 25(OH)D of 50.0-74.9 nmol/L, the multivariable-adjusted IRRs and 95% CIs of total infections, pneumonia, gastrointestinal infections, and sepsis were 1.44 (1.31, 1.59), 1.49 (1.27, 1.75), 1.47 (1.22, 1.78), and 1.41 (1.14, 1.73), respectively, in patients with 25(OH)D <25.0 nmol/L. Nonlinear inverse associations between 25(OH)D concentrations and the risks of total infections (P-overall < 0.001; P-nonlinear = 0.002) and gastrointestinal infections (P-overall < 0.001; P-nonlinear = 0.040) were observed, with a threshold effect at ∼50.0 nmol/L. The vitamin D-infection association was not modified by genetic variants in VDR (all P-interaction > 0.050). CONCLUSIONS: In patients with T2D, lower serum 25(OH)D concentration (<50 nmol/L) was associated with higher risks of infections, regardless of genetic variants in VDR. Notably, nonlinear inverse associations between 25(OH)D concentrations and the risks of infections were found, with a threshold effect at ∼50.0 nmol/L. These findings highlighted the importance of maintaining adequate vitamin D in reducing the risk of infections in patients with T2D.

Characterization of a human induced pluripotent stem cell line (FDCHi015-A) derived from PBMCs of a patient harbouring ALDOB mutation.

Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease associated with a mutation in the aldolase B gene on chromosome 9q31. In this study, we generated a human-induced pluripotent stem cell (hiPSC) line, FDCHi015-A, from peripheral blood mononuclear cells (PBMCs) of a patient carrying the compound heterozygous mutations c.360_364delCAAA and c.1013C > T in exons 4 and 9 of the ALDOB gene, respectively. The iPSCs with the confirmed patient-specific mutation demonstrate pluripotency markers expression, a normal karyotype, and the ability to differentiate into derivatives of three germ layers.

Association of Ultraprocessed Food Consumption with Risk of Cardiovascular Disease Among Individuals with Type 2 Diabetes: Findings from the UK Biobank.

SCOPE: Among patients with diabetes, who have modified nutritional behavior and a higher risk of cardiovascular disease (CVD), the influence of ultraprocessed foods (UPFs) on CVD remains unknown. The study aims to evaluate the association between UPF intake and the risk of CVD among individuals with type 2 diabetes (T2D) and further examine the potential biological pathways linking the association. METHODS AND RESULTS: This study includes 5405 participants with T2D who provided at least one 24-h dietary recall from the UK Biobank study. In the fully adjusted models, a 10% increase in the proportion of UPFs is associated with higher hazards of overall CVD (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.04, 1.15), coronary heart disease (HR: 1.10; 95% CI: 1.04, 1.16), heart failure (HR: 1.14; 95% CI: 1.05, 1.25), but not stroke (HR: 1.01; 95% CI: 0.90, 1.12). Cystatin C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein A, C-reactive protein, and body mass index collectively explain 26.9% (12.8%, 48.5%) of the association between UPF intake and the risk of overall CVD. CONCLUSION: Higher UPF intakes are associated with increased hazards of CVD among individuals with T2D, and the association is partly mediated through worsening biomarkers of renal function, lipid metabolism, inflammation, and body weight.

Association between sex hormones and gout: An analysis of the UK Biobank cohort.

OBJECTIVES: To investigate the associations between sex hormones and gout. METHODS: A total of 448,836 individuals free of gout at baseline were included from the UK Biobank. Cox regression models were used to estimate hazard ratios (HRs) for gout. Besides, we investigated the causal relationship between bioavailable testosterone (BAT) and gout using mendelian randomization (MR). RESULTS: There were differential effects in different testosterone active states in gout. One-unit higher log-transformed total testosterone (TT) was associated with a 52 % [95 % CI, 0.39-0.58] lower risk of gout in males. In contrast, free testosterone (FT) and BAT were associated with a 74 % [95 % CI, 1.38-2.20] and a 78 % [95 % CI, 1.41-2.25] higher risk of gout in males respectively. For MR, the weighted median [OR, 1.70; 95 % CI, 1.14-2.56;] and inverse variance-weighted [OR, 1.25; 95 % CI, 0.96-1.62; P = 0.09] method revealed significant and approximately significant positive effect of genetic liability to BAT levels on the risk of gout respectively. CONCLUSIONS: Sex hormones were potentially associated with gout. Notably, we were the first to explore different testosterone states on gout and found that FT and BAT may increase the risk of gout in males, which is opposite to TT. And the former are active states of androgens, may be more accurately reflect the association between androgens and gout.

Intermittent hypoxic pretreatment exacerbates house dust mite-induced asthma airway inflammation.

BACKGROUND: Asthma is widely recognized as an inflammatory disorder. In the context of this inflammatory microenvironment, the involvement of hypoxia and its impact on related pathways have drawn considerable attention. However, the exact role of hypoxia, a prevalent environmental factor, in the development and progression of asthma remains poorly understood. METHODS: Mice were treated with house dust mite (HDM) extracts for 23 days to induce asthma. Mice were divided into room air (RA) group and intermittent hypoxic (IH) group by exposing to different conditions and IH preconditioning (IHP) were underwent to the above groups before the hypoxic regimen. Airway inflammation in mice was evaluated by airway hyperresponsiveness, excessive mucus secretion, and recruitment of inflammatory cells. Immunohistochemistry was employed to quantify the expression levels of NF-κB. Subsequently, the dose of allergen was modified to investigate whether the impact of hypoxia on asthma is affected by different doses of allergens. RESULT: Compared to the RA and IH groups, HDM-treated mice in the IHP group exhibited aggravated inflammatory cell infiltration and airway hyperresponsiveness (p＜.05). Moreover, there was an increased release of inflammatory mediators and higher expression levels of NF-κB (p＜.05). Importantly, the impact ia on asthma was found to be influenced by high dose of allergen (p＜.05). CONCLUSION: IHP treatment potentially exacerbates HDM-induced airway inflammation in asthma, with the involvement of NF-κB, particularly under high-dose allergen stimulation.

Associations Between Beverage Consumption and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes.

CONTEXT: The relationship between the consumption of different beverages and the risk of microvascular complications in individuals with type 2 diabetes (T2D) is unclear. OBJECTIVE: To investigate the association of individual beverage consumption, including artificially sweetened beverages (ASBs), sugar-sweetened beverages (SSBs), tea, coffee, natural juice, and yogurt, with the risk of microvascular complications in adults with T2D. METHODS: This cohort study included 6676 participants with T2D who were free of macrovascular and microvascular complications at baseline in the UK Biobank. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 11.7 years, 1116 cases of composite microvascular complications were documented. After multivariable adjustment, a linear dose-response relationship was demonstrated between the consumption of ASBs and SSBs and the risk of microvascular complications. Compared with nonconsumers, those who consumed ≥2.0 units/day of ASBs and SSBs had an HR (95% CI) of 1.44 (1.18-1.75) and 1.32 (1.00-1.76) for composite microvascular complications, respectively. In addition, higher tea consumption was associated with a lower risk of diabetic retinopathy, with an HR (95% CI) of 0.72 (0.57-0.92) for whom consuming ≥4.0 units/day. There was no significant association between individual beverage consumption and the risk of diabetic neuropathy. No significant association was observed between the consumption of coffee, natural juice, or yogurt and the risks of microvascular complications. Moreover, substituting half units/day of ASBs or SSBs with tea or coffee was associated with a 16% to 28% lower risk of microvascular complications. CONCLUSION: Higher consumption of ASBs and SSBs was linearly associated with an increased risk of microvascular complications in adults with T2D.

Circulating concentrations of bile acids and prevalent chronic kidney disease among newly diagnosed type 2 diabetes: a cross-sectional study.

BACKGROUND: The relationship between circulating bile acids (BAs) and kidney function among patients with type 2 diabetes is unclear. We aimed to investigate the associations of circulating concentrations of BAs, particularly individual BA subtypes, with chronic kidney disease (CKD) in patients of newly diagnosed type 2 diabetes. METHODS: In this cross-sectional study, we included 1234 newly diagnosed type 2 diabetes who participated in an ongoing prospective study, the Dongfeng-Tongji cohort. Circulating primary and secondary unconjugated BAs and their taurine- or glycine-conjugates were measured using ultraperformance liquid chromatography-tandem mass spectrometry. CKD was defined as eGFR < 60 ml/min per 1.73 m2. Logistic regression model was used to compute odds ratio (OR) and 95% confidence interval (CI). RESULTS: After adjusting for multiple testing, higher levels of total primary BAs (OR per standard deviation [SD] increment: 0.78; 95% CI: 0.65-0.92), cholate (OR per SD: 0.78; 95% CI: 0.66-0.92), chenodeoxycholate (OR per SD: 0.81; 95% CI: 0.69-0.96), glycocholate (OR per SD: 0.81; 95% CI: 0.68-0.96), and glycochenodeoxycholate (OR per SD: 0.82; 95% CI: 0.69-0.97) were associated with a lower likelihood of having CKD in patients with newly diagnosed type 2 diabetes. No significant relationships between secondary BAs and odds of CKD were observed. CONCLUSIONS: Our findings showed that higher concentrations of circulating unconjugated primary BAs and their glycine-conjugates, but not taurine-conjugates or secondary BAs, were associated with lower odds of having CKD in patients with type 2 diabetes.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Derivation of an induced pluripotent stem cell line (FDCHi014-A) from PBMCs of a seven-year-old patient with a truncating NOVA2 variant (c.625del).

Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is a rare autosomal dominant disorder caused by a heterozygous mutation in the NOVA2 gene on chromosome 19q13. Here, we describe the generation and characterization of an iPSC line derived from the peripheral blood of a 7-year-old patient carrying a novel heterozygous mutation in NOVA2 (c.625 del). The iPSCs with the confirmed patient-specific mutation were demonstrated by pluripotency markers, a normal karyotype, and the ability to differentiate into three germ layers. This NOVA2-mutant iPSC line could facilitate disease modeling and therapy development studies for NEDASB.

Gut microbiota-derived secondary bile acids, bile acids receptor polymorphisms, and risk of cardiovascular disease in individuals with newly diagnosed type 2 diabetes: a cohort study.

BACKGROUND: Secondary bile acids (SBAs), the products of bacterial metabolism, are ligands of the nuclear farnesoid X receptor (FXR) and have been implicated in cardiovascular health. Diet can modulate gut microbiota composition and bile acid metabolism. OBJECTIVES: We aimed to examine the associations of circulating SBAs and their receptor polymorphisms with the risk of incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). METHODS: A total of 1234 participants with newly diagnosed T2D without CVD or cancer were included from the Dongfeng-Tongji Cohort study in China. Circulating SBAs and their conjugated forms were quantified using liquid chromatography-tandem mass spectrometry. Fifteen single-nucleotide polymorphisms in genes encoding bile acid receptors were genotyped. RESULTS: During a median follow-up of 5.7 y, 259 incident CVD cases were documented. After multivariable adjustment, higher levels of unconjugated SBAs [sum of deoxycholic acid (DCA), lithocholic acid, and ursodeoxycholic acid] and DCA were significantly associated with a higher risk of CVD among people with T2D, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.62 (1.12, 2.35) and 1.46 (1.04, 2.06) comparing the extreme quartile of SBAs and DCA, respectively. Restricted cubic spline regression suggested a linear relationship of unconjugated SBAs and DCA with an elevated risk of CVD, and per standard deviation, an increment in natural log-transformed unconjugated SBAs and DCA was associated with an 18% (95% CI: 4%, 34%) and 16% (95% CI: 2%, 33%) higher risk of CVD, respectively. Moreover, genetic variants in FXR (rs56163822 TT compared with GG, and rs17030295 TT compared with CC) were significantly associated with a 121%-129% higher risk of CVD among individuals with T2D. CONCLUSIONS: A higher proportion of unconjugated SBAs, especially DCA, is linearly associated with a higher risk of CVD among people with newly diagnosed T2D. Our findings support the potential role of gut microbiota-derived SBAs in cardiovascular health in individuals with T2D.

Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages.

The mechanisms underlying glucocorticoid (GC)-induced obesity are poorly understood. Macrophages are the primary targets by which GCs exert pharmacological effects and perform critical functions in adipose tissue homeostasis. Here, we show that macrophages are essential for GC-induced obesity. Dexamethasone (Dex) strongly induced Krüppel-like factor 9 (Klf9) expression in macrophages. Similar to Dex, lentivirus-mediated Klf9 overexpression inhibits M1 and M2a markers expression, causing macrophage deactivation. Furthermore, the myeloid-specific Klf9 transgene promotes obesity. Conversely, myeloid-specific Klf9-knockout (mKlf9KO) mice are lean. Moreover, myeloid Klf9 knockout largely blocks obesity induced by chronic GC treatment. Mechanistically, GC-inducible KLF9 recruits the SIN3A/HDAC complex to the promoter regions of Il6, Ptgs2, Il10, Arg1, and Chil3 to inhibit their expression, subsequently reducing thermogenesis and increasing lipid accumulation by inhibiting STAT3 signaling in adipocytes. Thus, KLF9 in macrophages integrates the beneficial anti-inflammatory and adverse metabolic effects of GCs and represents a potential target for therapeutic interventions.

Nonlinear relationship between high-density lipoprotein cholesterol and cardiovascular disease: an observational and Mendelian randomization analysis.

BACKGROUND: Clinical trials and Mendelian randomization (MR) studies reported null effects of high-density lipoprotein cholesterol (HDL-C) on risk of cardiovascular disease (CVD), which might have overlooked a nonlinear causal association. We aimed to investigate the dose-response relationship between circulating HDL-C concentrations and CVD in observational and MR frameworks. METHODS: We included 348,636 participants (52,919 CVD cases and 295,717 non-cases) of European ancestry with genetic data from the UK Biobank (UKB) and acquired genome-wide association summary data for HDL-C of Europeans from the Global Lipids Genetics Consortium (GLGC). Observational analyses were conducted in the UKB. Stratified MR analyses were conducted combing genetic data for CVD from UKB and lipids from GLGC. RESULTS: Observational analyses showed L-shaped associations of HDL-C with CVD, with no further risk reduction when HDL-C levels exceeded 70 mg/dL. Multivariable MR analyses across entire distribution of HDL-C found no association of HDL-C with CVD, after control of the pleiotropic effect on other lipids and unmeasured pleiotropism. However, in stratified MR analyses, significant inverse associations of HDL-C with CVD were observed in the stratum of participants with HDL-C ≤ 50 mg/dL (odds ratio per unit increase, 0.86; 95 % confidence interval, 0.79-0.94), while null associations were observed in any stratum above 50 mg/dL. CONCLUSIONS: Our data suggest a potentially causal inverse association of HDL-C at low levels with CVD risks. These findings advance our knowledge about the role of HDL as a potential target in CVD prevention and therapy.

Associations of Serum Testosterone and Sex Hormone-binding Globulin With Incident Arrhythmias in Men From UK Biobank.

CONTEXT: Sex hormones have been identified as cardiovascular risk factors, whereas the relationship between sex hormones and the risk of arrhythmias in men has not yet been well studied in the prospective cohort study. OBJECTIVE: To analyze associations of serum testosterone and SHBG concentrations and calculate free testosterone (cFT) with arrhythmias in men. METHODS: Sex hormones were measured at baseline from UK Biobank. Main outcomes were incidence of atrial fibrillation/flutter (AF), ventricular arrhythmia (VA), and bradyarrhythmia (BA). RESULTS: Of 173 498 men (aged 37-73 years, followed for 11 years), 11 368 had incident AF, 1646 had incident VA, and 4788 had incident BA. Compared with the third quartiles, the lowest category of serum testosterone was associated with increased risks of AF (hazard ratio [HR], 1.06; 95% CI, 1.00-1.12) and BA (HR, 1.11; 95% CI, 1.02-1.20) after multivariable adjustment, but no VA. Likewise, similar associations were found between cFT values and AF and BA events. Furthermore, higher levels of cFT were associated with increased risks of AF (HR, 1.07; 95% CI, 1.02-1.13) and VA (HR, 1.18; 95% CI, 1.01-1.37). Higher SHBG concentrations were associated with increased risks of AF (HR, 1.44; 95% CI, 1.34-1.54), VA (HR, 1.27; 95% CI, 1.07-1.52), and BA (HR, 1.17; 95% CI ,1.05-1.29). CONCLUSIONS: Lower levels of testosterone and cFT were associated with increased risk of AF and BA. Higher cFT levels were associated with increased risk of AF and VA. Higher SHBG levels were associated with increased risk of AF, VA, and BA.