Genetically determined blood pressure, antihypertensive drug classes, and frailty: A Mendelian randomization study.

Observational studies have suggested that the use of antihypertensive drugs was associated with the risk of frailty; however, these findings may be biased by confounding and reverse causality. This study aimed to explore the effect of genetically predicted lifelong lowering blood pressure (BP) through different antihypertensive medications on frailty. One-sample Mendelian randomization (MR) and summary data-based MR (SMR) were applied. We utilized two kinds of genetic instruments to proxy the antihypertensive medications, including genetic variants within or nearby drugs target genes associated with systolic/diastolic BP, and expression level of the corresponding gene. Among 298,618 UK Biobank participants, one-sample MR analysis observed that genetically proxied BB use (relative risk ratios, 0.76; 95% CI, 0.65-0.90; p = 0.001) and CCB use (0.83; 0.72-0.95; p = 0.007), equivalent to a 10-mm Hg reduction in systolic BP, was significantly associated with lower risk of pre-frailty. In addition, although not statistically significant, the effect directions of systolic BP through ACEi variants (0.72; 0.39-1.33; p = 0.296) or thiazides variants (0.74; 0.53-1.03; p = 0.072) on pre-frailty were also protective. Similar results were obtained in analyses for diastolic BP. SMR of expression in artery showed that decreased expression level of KCNH2, a target gene of BBs, was associated with lower frailty index (beta -0.02, p = 2.87 × 10-4). This MR analysis found evidence that the use of BBs and CCBs was potentially associated with reduced frailty risk in the general population, and identified KCNH2 as a promising target for further clinical trials to prevent manifestations of frailty.

High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

Dehydroepiandrosterone with a high-fat diet treatment at inducing polycystic ovary syndrome in rat model.

OBJECTIVE: This study aimed to evaluate the effects of dehydroepiandrosterone (DHEA) and DHEA combined with a high-fat diet (HFD) treatment of reproductive and endocrine metabolism in rats and then identify an ideal model of polycystic ovary syndrome (PCOS). METHODS: Three-week-old female Sprague-Dawley rats were injected subcutaneously with DHEA or oil, fed with or without a HFD, for 21 days, during which body weight, feed intake, and estrous cycle monitoring were carried out. Fasting blood glucose was measured, and serum fasting insulin, testosterone, dihydrotestosterone (DHT), estradiol, progesterone, luteinizing hormone (LH), anti-Müllerian hormone (AMH), and follicle-stimulating hormone (FSH) were estimated by ELISA. Serum total cholesterol (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured by colorimetric assay. Whereas, histologic changes in rat ovaries were evaluated by H&E staining. Ovarian steroid hormone synthases and their protein levels (StAR, 3ß-HSD2, 17ß-HSD1, CYP11A1, CYP17A1, and CYP19A1) were examined by Western blotting. RESULTS: Both DHEA and DHEA + HFD-treated rats lost a regular estrous cycle; had polycystic ovarian changes, significantly higher serum fasting insulin and testosterone levels; and increased ovarian StAR, 3ß-HSD2, and CYP11A1 protein levels. Additionally, rats in the DHEA + HFD-treated group were obese; had elevated fasting blood glucose, TG, DHT, AMH levels and LH:FSH ratios; increased ovarian 17ß-HSD1 protein levels. CONCLUSION: DHEA combined with HFD treatment is more effective at inducing PCOS than DHEA alone. The reproductive and endocrine metabolic aspects of this method are more consistent with the clinical characteristics of PCOS patients.

Associations of birth weight, plasma metabolome in adulthood and risk of type 2 diabetes.

AIMS: We aimed to examine the longitudinal associations of birth weight with plasma metabolites in adulthood, and further quantify the proportions of the links between birth weight and incident adult type 2 diabetes (T2D) that were mediated by plasma metabolites. MATERIALS AND METHODS: A total of 62,033 participants with complete nuclear magnetic resonance metabolomics and birth weight data from the UK Biobank were included in this study. Linear regression was used to assess the associations between birth weight and metabolites. Cox regression was used to estimate hazard ratios for T2D associated with metabolites. We further performed mediation analyses to estimate the extent to which metabolites might mediate the association between birth weight and T2D risk. RESULTS: Low birth weight was associated with the adverse metabolic responses across multiple metabolic pathways, including lipoprotein subclasses, amino acids, fatty acids (FA), and inflammation. Metabolites associated with higher birth weight tended to be associated with a lower risk of T2D (Pearson correlation coefficient: -0.85). A total of 62 metabolites showed statistically significant mediation effects in the protective association of higher birth weight and T2D risk, including large-sized very low-density lipoprotein particles and triglyceride concentrations as well as saturated, and monounsaturated FA and glycoprotein acetyls. CONCLUSIONS: We identified a range of metabolites that reflect the adult metabolic response to birth weight, some of which might lie on the pathway between birth weight and adult T2D risk.

SET domain containing 2 promotes megakaryocyte polyploidization and platelet generation through methylation of α-tubulin.

BACKGROUND: Megakaryocytes (MKs) are polyploid cells responsible for producing ∼1011 platelets daily in humans. Unraveling the mechanisms regulating megakaryopoiesis holds the promise for the production of clinical-grade platelets from stem cells, overcoming significant current limitations in platelet transfusion medicine. Previous work identified that loss of the epigenetic regulator SET domain containing 2 (SETD2) was associated with an increased platelet count in mice. However, the role of SETD2 in megakaryopoiesis remains unknown. OBJECTIVES: Here, we examined how SETD2 regulated MK development and platelet production using complementary murine and human systems. METHODS: We manipulated the expression of SETD2 in multiple in vitro and ex vivo models to assess the ploidy of MKs and the function of platelets. RESULTS: The genetic ablation of Setd2 increased the number of high-ploidy bone marrow MKs. Peripheral platelet counts in Setd2 knockout mice were significantly increased ∼2-fold, and platelets exhibited normal size, morphology, and function. By knocking down and overexpressing SETD2 in ex vivo human cell systems, we demonstrated that SETD2 negatively regulated MK polyploidization by controlling methylation of α-tubulin, microtubule polymerization, and MK nuclear division. Small-molecule inactivation of SETD2 significantly increased the production of high-ploidy MKs and platelets from human-induced pluripotent stem cells and cord blood CD34+ cells. CONCLUSION: These findings identify a previously unrecognized role for SETD2 in regulating megakaryopoiesis and highlight the potential of targeting SETD2 to increase platelet production from human cells for transfusion practices.

Differentiation route determines the functional outputs of adult megakaryopoiesis.

Emerging evidence has revealed a direct differentiation route from hematopoietic stem cells to megakaryocytes (direct route), in addition to the classical differentiation route through a series of restricted hematopoietic progenitors (stepwise route). This raises the question of the importance of two alternative routes for megakaryopoiesis. Here, we developed fate-mapping systems to distinguish the two routes, comparing their quantitative and functional outputs. We found that megakaryocytes were produced through the two routes with comparable kinetics and quantity under homeostasis. Single-cell RNA sequencing of the fate-mapped megakaryocytes revealed that the direct and stepwise routes contributed to the niche-supporting and immune megakaryocytes, respectively, but contributed to the platelet-producing megakaryocytes together. Megakaryocytes derived from the two routes displayed different activities and were differentially regulated by chemotherapy and inflammation. Our work links differentiation route to the heterogeneity of megakaryocytes. Alternative differentiation routes result in variable combinations of functionally distinct megakaryocyte subpopulations poised for different physiological demands.

Construction of a glycosylation-mediated fluorescent biosensor for label-free measurement of site-specific 5-hydroxymethylcytosine in cancer cells with zero background signal.

BACKGROUND: 5-hydroxymethylcytosine (5hmC) as an epigenetic modification can regulate gene expression, and its abnormal level is related with various tumor invasiveness and poor prognosis. Nevertheless, the current methods for 5hmC assay usually involve expensive instruments/antibodies, radioactive risk, high background, laborious bisulfite treatment procedures, and non-specific/long amplification time. RESULTS: We develop a glycosylation-mediated fluorescent biosensor based on helicase-dependent amplification (HDA) for label-free detection of site-specific 5hmC in cancer cells with zero background signal. The glycosylated 5hmC-DNA (5ghmC) catalyzed by ß-glucosyltransferase (ß-GT) can be cleaved by AbaSI restriction endonuclease to generate two dsDNA fragments with sticky ends. The resultant dsDNA fragments are complementary to the biotinylated probes and ligated by DNA ligases, followed by being captured by magnetic beads. After magnetic separation, the eluted ligation products act as the templates to initiate HDA reaction, generating abundant double-stranded DNA (dsDNA) products within 20 min. The dsDNA products are measured in a label-free manner with SYBR Green I as an indicator. This biosensor can measure 5hmC with a detection limit of 2.75 fM and a wide linear range from 1 × 10-14 to 1 × 10-8 M, and it can discriminate as low as 0.001% 5hmC level in complex mixture. Moreover, this biosensor can measure site-specific 5hmC in cancer cells, and distinguish tumor cells from normal cells. SIGNIFICANCE: This biosensor can achieve a zero-background signal without the need of either 5hmC specific antibody or bisulfite treatment, and it holds potential applications in biological research and disease diagnosis.

Elevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity.

The connection between triglyceride-rich lipoproteins and cardiometabolic multimorbidity, characterized by the concurrence of at least two of type 2 diabetes, ischemic heart disease, and stroke, has not been definitively established. We aim to examine the prospective associations between serum remnant cholesterol, triglycerides, and the risks of progression from first cardiometabolic disease to multimorbidity via multistate modeling in the UK Biobank. We also evaluate the causality of these associations via Mendelian randomization using 13 biologically relevant SNPs as the genetic instruments. Here we show that elevated remnant cholesterol and triglycerides are significantly associated with gradually higher risks of cardiometabolic multimorbidity, particularly the progression of ischemic heart disease to the multimorbidity of ischemic heart disease and type 2 diabetes. These results advocate for effective management of remnant cholesterol and triglycerides as a potential strategy in mitigating the risks of cardiometabolic multimorbidity.

Prognostic value of coagulation markers in patients with colorectal caner: A prospective study.

Background and Aims: The occurrence, growth, and metastasis of colorectal cancer (CRC) are connected to the hypercoagulable state of blood (CRC). This study aimed to identify significant coagulation factors to predict metastasis and prognosis of CRC. Methods: Thrombomodulin (TM), thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC), and tissue plasminogen activator-inhibitor complex (t-PAIC) were detected by chemiluminescence immunoassay using Sysmex HISCL5000 automated analyzers. The Sysmex CS 5100 automatic blood coagulation analyzer was used to detect d-dimer (DD), fibrin degradation product (FDP), prothrombin time (PT), thrombin time (TT), international normalized ratio (INR), fibrinogen (Fbg), and activated partial thromboplastin time (APTT). Area under the curve (AUC) and the receiver operating characteristic curve (ROC) were used to assess the diagnostic efficacy of markers. Kaplan-Meier analysis was used to calculate survival probabilities. Independent prognostic factors and the nomogram were developed using single-factor and multifactor cox regression analysis model. Results: The following indicators (TM, TAT, PIC, t-PAIC, DD, FDP, PT, INR, APTT, and Fbg) were markedly higher in CRC patients than in healthy controls, and they were higher in the metastasis (M) group than in the nonmetastasis (NM) group. The combination "TAT + PIC + DD + FDP + Fbg" can distinguish M from NM with exceptional sensitivity and specificity. Patients with CRC who had high levels of TAT, PIC, DD, FDP, Fbg, TM, tPAIC, PT, and INR had significantly shorter survival. Conclusion: The prognosis of CRC patients can be predicted by coagulation indicators. The independent predictive variables for overall survival were found to be TM and DD. To forecast CRC patient survival, a nomogram was created.

Examining the relationship between nutritional status and wound healing in head and neck cancer treatment: A focus on malnutrition and nutrient deficiencies.

The research was conducted to examine the correlation between nutritional status and wound healing in individuals who were receiving treatment for head and neck cancer. Specifically, this study sought to identify crucial nutritional factors that influenced both the recovery process and efficacy of the treatment. From February 2022 to September 2023, this cross-sectional study was undertaken involving 300 patients diagnosed with head and neck cancer who were treated at Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. In order to evaluate nutritional status, body mass index (BMI), serum protein levels and dietary intake records were utilized. The assessment of wound healing was conducted using established oncological wound healing scales, photographic documentation and clinical examinations. After treatment, we observed a noteworthy reduction in both BMI (p < 0.05) and serum albumin levels (p < 0.05). There was slightly increased prevalence of head and neck cancer among males (61.0%, p < 0.05). Over the course of 6 months, significant enhancement in wound healing scores was noted, exhibiting overall improvement of 86% in the healing process. An inverse correlation was identified between nutritional status and wound healing efficacy through multivariate analysis. A logistic regression analysis revealed a significant positive correlation (p < 0.05) between elevated levels of serum protein and total lymphocytes and enhanced wound healing. Conversely, negative correlation (p < 0.05) was observed between larger wound size at baseline and healing. The research findings indicated noteworthy association between malnutrition and impaired wound repair among individuals diagnosed with head and neck cancer. The results underscored the significance of integrating nutritional interventions into therapeutic protocol in order to enhance clinical results. This research study provided significant contributions to the knowledge of intricate nature of head and neck cancer management by advocating for multidisciplinary approach that incorporates nutrition as the critical element of patient care and highlighted the importance of ongoing surveillance and customized dietary approaches in order to optimize wound healing and treatment efficacy.

Sr4Al2O7: A New Sacrificial Layer with High Water Dissolution Rate for the Synthesis of Freestanding Oxide Membranes.

Freestanding perovskite oxide membranes have drawn great attention recently since they offer exceptional structural tunability and stacking ability, providing new opportunities in fundamental research and potential device applications in silicon-based semiconductor technology. Among different types of sacrificial layers, the (Ca, Sr, Ba)3Al2O6 compounds are most widely used since they can be dissolved in water and prepare high-quality perovskite oxide membranes with clean and sharp surfaces and interfaces; However, the typical transfer process takes a long time (up to hours) in obtaining millimeter-size freestanding membranes, let alone realize wafer-scale samples with high yield. Here, a new member of the SrO-Al2O3 family, Sr4Al2O7 is introduced, and its high dissolution rate, ≈10 times higher than that of Sr3Al2O6 is demonstrated. The high-dissolution-rate of Sr4Al2O7 is most likely related to the more discrete Al-O networks and higher concentration of water-soluble Sr-O species in this compound. This work significantly facilitates the preparation of freestanding membranes and sheds light on the integration of multifunctional perovskite oxides in practical electronic devices.

Hepatoid adenocarcinoma in ureter with next-generation sequencing: A case report and literature review.

BACKGROUND: Hepatoid adenocarcinoma (HAC) is rare in the urinary system, with only 7 reported cases in upper urinary tract. This report aimed to explore the genetic characteristics of ureteral HAC for first time, and to describe the treatment prognosis of ureteral HAC. CASE PRESENTATION: We present a rare case of ureteral HAC in a 53-year-old female, showing elevated serum levels of AFP and CEA, prolonged chronic irritation may be an important cause of her ureteral HAC. Radical nephroureterectomy was performed, the serum levels of AFP and CEA decreased significantly, and metastasis in lymph nodes was found at 9 months after surgery, she had no related symptoms after 18 months postoperatively without adjuvant chemotherapy. Three driver somatic mutations in cancer were identified by NGS testing, including: TP53D281H, KMT2DL1211Ifs*2, KMT2DT1843Nfs*5, demonstrating that ureteral HAC has the similar mutational features to upper tract urothelial carcinoma. Homologous-recombination deficiency (HRD) was positive in this tumor with no mutations in HRD-related genes, which was possibly induced by the copy number deletion of SETD2 gene. CONCLUSIONS: We report a rare case of ureteral HAC with elevated serum levels of AFP and CEA. NGS testing demonstrated that ureteral HAC has the similar mutational features to upper tract urothelial carcinoma, which is an important guide for the diagnosis and treatment of ureteral HAC.

Binder-free barium-implanted MnO2 nanosheets on carbon cloth for flexible zinc-ion batteries.

The intrinsically low electrical conductivity and poor structural fragility of MnO2 have significantly hampered the zinc storage performance. In this work, Ba2+-implanted δ-MnO2 nanosheets have been hydrothermally grown on a carbon cloth (Ba-MnO2@CC) as an extremely stable and efficient cathode material of aqueous zinc-ion batteries. The three-dimensionally porous architecture composed of interwoven thin MnO2 nanosheets effectively shortens the electron/ion transport distances, enlarges the electrode/electrolyte contact area, and increases the active sites for the electrochemical reaction. Meanwhile, Ba2+ could function as an interlayer pillar to stabilize the crystal structure of MnO2. Consequently, the as-optimized Ba-MnO2@CC exhibits remarkable Zn2+ storage capabilities, such as a high capacity (305 mAh g-1 at 0.2 A g-1), prolonged lifespan (95% retention after a 200-cycling test), and superb rate capability. The binder-free cathode is also applicable for flexible energy storage devices with attractive properties. The present investigation provides important insights into designing advanced cathode materials toward wearable electronics.

Application of two-dimensional polymerase chain reaction to detect four types of microorganisms in feces for assisted diagnosis of IBD.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) continues to increase annually, accounting for about 6.8 million cases in 2017 worldwide. However, there is currently no gold standard for the diagnosis of IBD. METHODS: A method for the detection of four microorganisms in feces by two-dimensional polymerase chain reaction (2D-PCR) has been developed. Plasmids were used to validate the sensitivity and specificity of the method. Clinical samples were tested using a 2D-PCR method. Optimal diagnostic thresholds for IBD were determined based on ROC results. RESULTS: Of the 112 samples, 78 were from IBD patients and 34 from patients with other gastrointestinal (GI) diseases. Thomasclavelia ramosum and univ907-1062 positivity are necessary, and two or more positives of the three bacteria (Thomasclavelia spiroforme, Thomasclavelia saccharogumia or Clostridium cluster XVIII) are the optimal diagnostic thresholds for IBD. The area under the curve was 0.826 with a 95% confidence interval of 0.735-0.981 and a p-value of 0.000, corresponding to a sensitivity of 0.769 and a specificity of 0.853. CONCLUSIONS: Based on the detection results of microorganisms, IBD and GI can be effectively distinguished. The detection of four microorganisms in feces can assist clinicians in the differential diagnosis of IBD. Our experiment aims to provide a better program for early clinical diagnosis and regular dynamic monitoring of IBD.

CD44-targeting hyaluronic acid-selenium nanoparticles boost functional recovery following spinal cord injury.

BACKGROUND: Therapeutic strategies based on scavenging reactive oxygen species (ROS) and suppressing inflammatory cascades are effective in improving functional recovery after spinal cord injury (SCI). However, the lack of targeting nanoparticles (NPs) with powerful antioxidant and anti-inflammatory properties hampers the clinical translation of these strategies. Here, CD44-targeting hyaluronic acid-selenium (HA-Se) NPs were designed and prepared for scavenging ROS and suppressing inflammatory responses in the injured spinal cord, enhancing functional recovery. RESULTS: The HA-Se NPs were easily prepared through direct reduction of seleninic acid in the presence of HA. The obtained HA-Se NPs exhibited a remarkable capacity to eliminate free radicals and CD44 receptor-facilitated internalization by astrocytes. Moreover, the HA-Se NPs effectively mitigated the secretion of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) by microglia cells (BV2) upon lipopolysaccharide-induced inflammation. In vivo experiments confirmed that HA-Se NPs could effectively accumulate within the lesion site through CD44 targeting. As a result, HA-Se NPs demonstrated superior protection of axons and neurons within the injury site, leading to enhanced functional recovery in a rat model of SCI. CONCLUSIONS: These results highlight the potential of CD44-targeting HA-Se NPs for SCI treatment.

Frequency of Adding Salt to Foods, Genetic Susceptibility, and Incident Type 2 Diabetes: A Prospective Cohort Study.

CONTEXT: Excessive salt consumption is known to increase the risk of hypertension and cardiovascular disease, but the association between salt intake and incident type 2 diabetes has not been extensively researched. OBJECTIVE: In this study, we aimed to investigate the relationships between the frequency of adding salt to foods and incident type 2 diabetes, as well as any potential interactions with genetic predisposition. METHODS: We included 368 137 eligible participants, aged 37 to 73 years, from the UK Biobank. The frequency of adding salt to foods was assessed via a food frequency questionnaire. RESULTS: During a median follow-up of 12.6 years, we documented 10 981 incident type 2 diabetes cases. After adjustment for major confounders, participants who sometimes, usually, and always added salt to foods had 7% (hazard ratio [HR]: 1.07; 95% CI, 1.03-1.12), 9% (HR: 1.09; 95% CI, 1.03-1.16), 28% (HR: 1.28; 95% CI, 1.19-1.38) higher risks of developing type 2 diabetes, respectively, than those that never/rarely added salt to foods (P for trend < .001). We found these associations to be consistent across stratified and sensitivity analyses. However, we did not observe any statistically significant multiplicative or additive interactions between the frequency of adding salt to foods and genetic predisposition regarding incident type 2 diabetes. CONCLUSION: Our findings suggest that consuming salt regularly, regardless of genetic susceptibility, may increase the risk of type 2 diabetes. Therefore, public health interventions aimed at reducing excessive salt consumption may help prevent the onset of type 2 diabetes.

Polysocial and Polygenic Risk Scores and All-Cause Dementia, Alzheimer's Disease, and Vascular Dementia.

BACKGROUND: To establish a polysocial risk score (PsRS) incorporating various social factors for capturing the dementia risk and investigate the benefits of favorable social conditions across different genetic backgrounds. METHODS: This prospective cohort study comprised 345 439 participants initially free of dementia from the UK Biobank. A total of 10 social factors were summed to create a PsRS. A polygenic risk score (PRS) was constructed based on genome-wide significant variants. RESULTS: During a median follow-up of 12.5 years, we documented 4 595 incident all-cause dementia events including 2 067 Alzheimer's disease (AD) events and 1 028 vascular dementia (VD) events. Each additional PsRS was associated with a 19% increased risk of all-cause dementia (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.17 to 1.21), a 13% increased risk of AD (1.13; 1.10 to 1.16), and a 24% increased risk of VD (1.24; 1.19 to 1.29). 29% (24% to 33%) of dementia cases, 22% (14% to 29%) of AD cases, and 39% (28% to 48%) of VD cases were associated with a disadvantageous social environment. In addition, among participants at a high genetic risk, the low social risk was linked to a lower incidence rate of all-cause dementia, AD, and VD compared to those who had a high social risk, with reductions of 67.8%, 64.5%, and 84.2%, respectively. CONCLUSIONS: The PsRS could be effectively used in discriminating individuals at high risk of dementia. Around a quarter of dementia events could have a connection with a disadvantageous social environment, especially for those genetically susceptible to dementia.

Associations of healthy aging index and all-cause and cause-specific mortality: a prospective cohort study of UK Biobank participants.

The healthy aging index (HAI) has been recently developed as a surrogate measure of biological age. However, to what extent the HAI is associated with all-cause and cause-specific mortality and whether this association differs in younger and older adults remains unknown. We aimed to quantify the association between the HAI and mortality in a population of UK adults. In the prospective cohort study, data are obtained from the UK Biobank. Five HAI components (systolic blood pressure, reaction time, cystatin C, serum glucose, forced vital capacity) were scored 0 (healthiest), 1, and 2 (unhealthiest) according to sex-specific tertiles or clinically relevant cut-points and summed to construct the HAI (range 0-10). Cox proportional hazard regression models were used to estimate the associations of the HAI with the risk of all-cause and cause-specific mortality. 387,794 middle-aged and older participants were followed up for a median of 8.9 years (IQR 8.3-9.5). A total of 14,112 all-cause deaths were documented. After adjustments, each 1-point increase in the HAI was related to a higher risk of all-cause mortality (hazards ratio [HR], 1.17; 95%CI, 1.15-1.18). Such association was stronger among adults younger than 60 years (1.19, 1.17-1.21) than that among those 60 years and older (1.15, 1.14-1.17) (P interaction < 0.001). For each unit increment of the HAI, the multivariate-adjusted HRs for risk of death were 1.28 (1.25-1.31) for cardiovascular diseases, 1.09 (1.07-1.10) for cancer, 1.36 (1.29-1.44) for digestive disease, 1.42 (1.35-1.48) for respiratory disease, 1.42 (1.33-1.51) for infectious diseases, and 1.15 (1.09-1.21) for neurodegenerative disease, respectively. Our findings indicate that the HAI is positively associated with all-cause and cause-specific mortality independent of chronological age. Our results further underscore the importance of effective early-life interventions to slow aging and prevent premature death.