Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.

To identify the metabolic underpinnings of retinal aging and examine how it is related to mortality and morbidity of common diseases.

The retinal age gap has been established as essential aging indicator for mortality and systemic health. We applied neural network to train the retinal age gap among the participants in UK Biobank and used nuclear magnetic resonance (NMR) to profile plasma metabolites. The metabolomic signature of retinal ageing (MSRA) was identified using an elastic network model. Multivariable Cox regressions were used to assess associations between the signature with 12 serious health conditions. The participants in Guangzhou Diabetic Eye Study (GDES) cohort were analyzed for validation.

This study included 110 722 participants (mean age 56.5±8.1 years at baseline, 53.8% female), and 28 plasma metabolites associated with retinal ageing were identified. The MSRA revealed significant correlations with each 12 serious health conditions beyond traditional risk factors and genetic predispositions. Each SD increase in MSRA was linked to a 24%-76% higher risk of mortality, cardiovascular diseases, dementia and diabetes mellitus. MSRA showed dose-response relationships with risks of these diseases, with seven showing non-linear and five showing linear increases. Validation in the GDES further established the relation between retinal ageing-related metabolites and increased risks of cardiovascular and chronic kidney diseases (all p<0.05).

The metabolic connections between ocular and systemic health offer a novel tool for identifying individuals at high risk of premature ageing, promoting a more holistic view of human health.

Early clues to tumors and their microenvironments come from embryonic development. Here we review the literature and consider whether the embryonic brain and its pathologies can serve as a better model. Among embryonic organs, the brain is the most heterogenous and complex, with multiple lineages leading to wide spectrum of cell states and types. Its dysregulation promotes neurodevelopmental brain pathologies and pediatric tumors. Embryonic brain pathologies point to the crucial importance of spatial heterogeneity over time, akin to the tumor microenvironment. Tumors dedifferentiate through genetic mutations and epigenetic modulations; embryonic brains differentiate through epigenetic modulations. Our innovative review proposes learning developmental brain pathologies to target tumor evolution-and vice versa. We describe ways through which tumor pharmacology can learn from embryonic brains and their pathologies, and how learning tumor, and its microenvironment, can benefit targeting neurodevelopmental pathologies. Examples include pediatric low-grade versus high-grade brain tumors as in rhabdomyosarcomas and gliomas.

Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine. It is anticipated that, pending results from randomized clinical trials and regulatory approval, gerotherapeutics will be tailored to each person based on their genetic profile, high-dimensional omics-based biomarkers of aging, clinical and digital biomarkers of aging, psychosocial profile, and past or present exposures.

Aging is a complex, universal process characterized by structural and functional decline across multiple organs. Ganoderma lucidum (G. lucidum), a renowned traditional Chinese medicinal fungus, has long been recognized for its anti-aging properties. However, the underlying mechanisms remain incompletely understood.

This study aimed to investigate the anti-aging effects of G. lucidum and its underlying mechanisms.

We investigated the anti-aging effects of G. lucidum sporoderm-broken spore powder (Gl-SBSP) on Caenorhabditis elegans (C. elegans) lifespan and aging across multiple organs using natural aging, D-galactose (D-gal)-induced aging, and radiation-induced premature senescence mouse models. In C. elegans, we assessed lifespan, reproductive capacity, body length, pharyngeal pumping, body bends, fat and lipofuscin levels, as well as reactive oxygen species (ROS) accumulation. In mice, histopathological staining, complete blood counts, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate tissue damage, while quantitative real-time PCR (RT-qPCR) was employed to access small intestine barrier integrity. Western blot (WB) and immunohistochemistry (IHC) were utilized to analyze the distribution of alpha Klotho (α-Klotho) in the kidney, blood, and urine.

Gl-SBSP significantly extended C. elegans lifespan, improved reproductive capacity and mobility, and reduced lipofuscin and ROS levels. In naturally aged mice, Gl-SBSP enhanced physical appearance and performance. Additionally, Gl-SBSP alleviated aging-related structural and functional decline in multiple organs, including the colon, spleen, kidneys, liver, and small intestine, across all aging models. Biochemical analyses revealed that Gl-SBSP increased transmembrane α-Klotho (mα-Klotho) and soluble α-Klotho (sα-Klotho) levels in kidney tissue and elevated sα-Klotho levels in serum and urine.

This study is the first to demonstrate that G. lucidum exerts α-Klotho-associated anti-aging effects in animal models, highlighting its potential as an anti-aging intervention.

Investigating brain-enriched proteins with machine learning methods may enable a brain-specific understanding of brain aging and provide insights into the molecular mechanisms and pathological pathways of dementia. The study aims to analyze associations of brain-specific plasma proteomic aging signature with risks of incident dementia. In 45,429 dementia-free UK Biobank participants at baseline, we generated a brain-specific biological age using 63 brain-enriched plasma proteins with machine learning methods. The brain age gap was estimated, and Cox proportional hazards models were used to study the association with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia. Per-unit increment in the brain age gap z-score was associated with significantly higher risks of all-cause dementia (hazard ratio [95% confidence interval], 1.67 [1.56-1.79], P < 0.001), AD (1.85 [1.66-2.08], P < 0.001), and vascular dementia (1.86 [1.55-2.24], P < 0.001), respectively. Notably, 2.1% of the study population exhibited extreme old brain aging defined as brain age gap z-score > 2, correlating with over threefold increased risks of all-cause dementia and vascular dementia (3.42 [2.25-5.20], P < 0.001, and 3.41 [1.05-11.13], P = 0.042, respectively), and fourfold increased risk of AD (4.45 [2.32-8.54], P < 0.001). The associations were stronger among participants with healthier lifestyle factors (all P-interaction < 0.05). These findings were corroborated by magnetic resonance imaging assessments showing that a higher brain age gap aligns global pathophysiology of dementia, including global and regional atrophy in gray matter, and white matter lesions (P < 0.001). The brain-specific proteomic age gap is a powerful biomarker of brain aging, indicative of dementia risk and neurodegeneration.

Age-related macular degeneration (AMD) and age-related neurological diseases (ANDs), such as Alzheimer's and Parkinson's Diseases, are increasingly prevalent conditions that significantly contribute to global morbidity, disability, and mortality. The retina, as an accessible part of the central nervous system (CNS), provides a unique window to study brain aging and neurodegeneration. By examining the associations between AMD and ANDs, this review aims to highlight novel insights into fundamental mechanisms of aging and their role in neurodegenerative disease progression. This review integrates knowledge from the emerging field of aging research, which identifies common denominators of biological aging, specifically loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, and inflammation. Finally, we emphasize the clinical relevance of these pathways and the potential for cross-disease therapies that target common aging hallmarks. Identifying these shared pathways could open avenues to develop therapeutic strategies targeting mechanisms common to multiple degenerative diseases, potentially attenuating disease progression and promoting the healthspan.

BackgroundAccurate placement of the macaque within the Alzheimer's disease (AD) research framework is essential to discover early-stage predictive biomarkers.ObjectiveTo assess utility of the aging macaque in advancing translational biomarker development for preclinical AD, we evaluated relative signal strength of comparable neuropathologic phenomena in macaques and patients.MethodsWe compared pathology in patient and macaque formalin-fixed paraffin embedded (FFPE) tissues using identical criteria. We quantified expression of amyloid-β (Aβ), pTau, and inflammatory and senescence markers across species. Distribution of AD-relevant markers were compared in FFPE and perfused frozen macaque brain to assess expression of labile proteins that could inform in-life fluid biomarkers.ResultsAβ pathology in macaques closely approximated patient pathology. Complex plaque composition in macaques implied significant disruption of synaptic connectivity. In FFPE tissue, pretangle pTau immunoreactivity placed the macaque in Braak Stage 1b. In perfused frozen tissue, soluble pTau distribution approximated Braak Stage III-IV. In macaque, Aβ, pTau, and acetylcholinesterase labeling co-localized to AD-vulnerable circuits. Significant association of glial fibrillary acidic protein with Aβ occurred in humans only. The senescence marker p16 correlated positively with pTau expression and negatively with Aβ in patients only. Macaques lacked neuropathologic co-morbidities.ConclusionsAD-relevant neuropathologic signals in the macaque support biomarker discovery in the areas of Aβ plaque evolution and associated synaptic disruption as well as early-stage tau phosphorylation. Relative protection from accumulation of senescence markers, fibrillar tau and neuropathologic co-morbidities in macaque implicate species difference in rates of biological brain aging. We provide over 4000 digital slides for further study.

Individual's aging rates vary across organs. However, there are few methods for assessing aging at organ levels and whether they contribute differently to mortalities remains unknown. We analyzed data from 45,821 adults in the UK Biobank, using plasma proteomics and machine learning to estimate biological ages for 12 major organs. The differences between biological age and chronological age, referred to as "age gaps," were calculated for each organ. Partial correlation analyses were used to assess the association between age gaps and modifiable factors. Adjusted multivariable Cox regression models were applied to examine the association of age gaps with all-cause mortality, cause-specific mortalities, and cancer-specific mortalities. We reveal a complex network of varied associations between multi-organ aging and modifiable factors. All age gaps increase the risk of all-cause mortality by 6-60%. The risk of death varied from 5.54 to 29.18 times depending on the number of aging organs. Cause-specific mortalities are associated with certain organs' aging. For mental diseases mortality, and nervous system mortality, only brain aging exhibited a significant increased risk of HR 2.38 (per SD, 95% CI: 2.06-2.74) and 1.99 (per SD, 95% CI: 1.84-2.16), respectively. Age gaps of stomach were also a specific indicator for gastric cancer. Eventually, we find that an organ's biological age selectively influences the aging of other organ systems. Our study demonstrates that accelerated aging in specific organs increases the risk of mortality from various causes. This provides a potential tool for early identification of at-risk populations, offering a relatively objective method for precision medicine.

Recent work leveraging artificial intelligence has offered promise to dissect disease heterogeneity by identifying complex intermediate brain phenotypes, called dimensional neuroimaging endophenotypes (DNEs). We advance the argument that these DNEs capture the degree of expression of respective neuroanatomical patterns measured, offering a dimensional neuroanatomical representation for studying disease heterogeneity and similarities of neurologic and neuropsychiatric diseases. We investigate the presence of nine DNEs derived from independent yet harmonized studies on Alzheimer's disease, autism spectrum disorder, late-life depression, and schizophrenia in the UK Biobank study. Phenome-wide associations align with genome-wide associations, revealing 31 genomic loci (P-value<5×10-8/9) associated with the nine DNEs.The nine DNEs, along with their polygenic risk scores, significantly enhanced the predictive accuracy for 14 systemic disease categories, particularly for conditions related to mental health and the central nervous system, as well as mortality outcomes. These findings underscore the potential of the nine DNEs to capture the expression of disease-related brain phenotypes in individuals of the general population and to relate such measures with genetics, lifestyle factors, and chronic diseases.

This study aimed to evaluate the association between hypertension (HT) onset age and later risks of chronic kidney diseases (CKD) and mortality. Adult patients without CKD from 2008 to 2013 were identified using electronic medical records from United Kingdom (UK) and Hong Kong (HK). Patients newly diagnosed with HT and those without were included in the HT and control groups, respectively. All subjects were stratified into six age groups (18-39, 40-49, 50-59, 60-69, 70-79, ≥80). Multivariable Cox proportional hazard regression, adjusted with baseline characteristics and fine stratification weights, was conducted to investigate the association between HT onset and risks of CKD, renal decline, end-stage renal disease (ESRD), and all-cause mortality. Subjects were followed up from baseline until an outcome event, death, or administrative end of the cohort, whichever occurred first. A total of 4,413,551 and 3,132,951 subjects were included in the UK and HK cohorts, respectively. HT was significantly associated with increased risks of outcome, but the hazard ratios (HRs) decreased with increasing onset age. In the UK cohort, the HRs (95% confidence intervals) for subjects aged 18-39 and ≥80 were 3.69 (3.53, 3.86) and 2.01 (1.96, 2.06) for CKD, 3.83 (3.60, 4.07) and 3.17 (2.97, 3.38) for renal decline, 17.26 (14.34, 20.77) and 2.55 (2.12, 3.07) for ESRD, 2.88 (2.66, 3.11) and 1.09 (1.07, 1.12) for mortality. The HK cohort exhibited a similar pattern. Our study concluded that early onset of HT significantly affects renal health later in life, while the contribution decreases with the onset age of HT.

A strong regularity of human life is Gompertz's law, which predicts a near-perfect exponential increase in mortality with age. In this paper, we take into account that chronological age is not a cause of death and decompose Gompertz's law into two equally strong laws: (i) an exponential increase in health deficits as measured by the frailty index, and (ii) a power law association between the frailty index and the mortality rate. We show how the increase in the frailty index can be derived from the feature of self-productivity of health deficits. We explore the robustness of the Gompertz decomposition across countries, sex, and over time and show how information about mortality rates can be used to infer the state of health of an age-structured population. Finally, we use this method to infer the biological ages of past populations, such as Australians in 1940 and Swedes in 1770.

Approximately 50% of all adults with heart failure (HF) are classified as frail. Frailty is a clinical state of 'accelerated ageing' that complicates management and results in adverse health outcomes. Despite recommendations for frailty assessment in HF guidelines, its implementation into routine clinical practice has been slow. Further, evidence to inform models of care and pharmacological treatment for individuals with HF who are classified as frail is lacking. The complexity of management underscores the importance of tailoring models of care that can improve the focus on frailty through multidisciplinary care teams. Frailty can be reduced in some cases through the comprehensive geriatric assessment model of care, integrating treatment pillars such as exercise, nutrition, social engagement and support networks, and optimised medication use. A national agenda for action on frailty in the context of HF is needed to advance policy, practice, education, and research improve health outcomes for individuals affected. In November 2023 the Australian Cardiovascular Alliance (ACvA) facilitated a national workshop on frailty and HF with key experts. This has led to the development of a frailty and HF national taskforce with the aim to address major priorities and unmet needs. This statement is first step for the taskforce in implementing a national agenda for the management of frailty in HF. Here we outline key considerations for policy, practice, education, and research in Australia.

To observe the role of a public health chronic disease prediction method based on capsule network and information system in clinical treatment and public health management.

Patients with hypertension, diabetes, and asthma admitted from May 2022 to October 2023 were incorporated into the research. They were grouped into hypertension group (n = 341), diabetes group (n = 341), and asthma group (n = 341). The established chronic disease prediction method was used to diagnose these types of public health chronic diseases. The key influencing factors obtained by the prediction method were compared with the regression analysis results. In addition, its diagnostic accuracy and specificity were analyzed, and the clinical diagnostic value of this method was explored. This method was applied to public health management and the management approach was improved based on the distribution and prevalence of chronic diseases. The effectiveness and residents' acceptance of public health management before and after improvement were compared, and the application value of this method in public health management was explored.

The key factors affecting the three diseases obtained by the application of prediction methods were found to be significantly correlated with disease occurrence after regression analysis (p < 0.05). Compared with before application, the diagnostic accuracy, specificity and sensitivity values of the method were 88.6, 89 and 92%, respectively, which were higher than the empirical diagnostic methods of doctors (p < 0.05). Compared with other existing AI-based chronic disease prediction methods, the AUC value of the proposed method was significantly higher than theirs (p < 0.05). This indicates that the diagnostic method proposed in this study has higher accuracy. After applying this method to public health management, the wellbeing of individuals with chronic conditions in the community was notably improved, and the incidence rate was notably reduced (p < 0.05). The acceptance level of residents toward the management work of public health management departments was also notably raised (p < 0.05).

The public health chronic disease prediction method based on information systems and capsule network has high clinical value in diagnosis and can help physicians accurately diagnose patients' conditions. In addition, this method has high application value in public health management. Management departments can adjust management strategies in a timely manner through predictive analysis results and propose targeted management measures based on the characteristics of residents in the management community.

Schizophrenia is conceptualized as a brain connectome disorder that can emerge as early as late childhood and adolescence. However, the underlying neurodevelopmental basis remains unclear. Recent interest has grown in children and adolescent patients who experience symptom onset during critical brain development periods. Inspired by advanced methodological theories and large patient cohorts, Chinese researchers have made significant original contributions to understanding altered brain connectome development in early-onset schizophrenia (EOS).

We conducted a search of PubMed and Web of Science for studies on brain connectomes in schizophrenia and neurodevelopment. In this selective review, we first address the latest theories of brain structural and functional development. Subsequently, we synthesize Chinese findings regarding mechanisms of brain structural and functional abnormalities in EOS. Finally, we highlight several pivotal challenges and issues in this field.

Typical neurodevelopment follows a trajectory characterized by gray matter volume pruning, enhanced structural and functional connectivity, improved structural connectome efficiency, and differentiated modules in the functional connectome during late childhood and adolescence. Conversely, EOS deviates with excessive gray matter volume decline, cortical thinning, reduced information processing efficiency in the structural brain network, and dysregulated maturation of the functional brain network. Additionally, common functional connectome disruptions of default mode regions were found in early- and adult-onset patients.

Chinese research on brain connectomes of EOS provides crucial evidence for understanding pathological mechanisms. Further studies, utilizing standardized analyses based on large-sample multicenter datasets, have the potential to offer objective markers for early intervention and disease treatment.

Brain age gap (BAG), the deviation between estimated brain age and chronological age, is a promising marker of brain health. However, the genetic architecture and reliable targets for brain aging remains poorly understood. In this study, we estimate magnetic resonance imaging (MRI)-based brain age using deep learning models trained on the UK Biobank and validated with three external datasets. A genome-wide association study for BAG identified two unreported loci and seven previously reported loci. By integrating Mendelian Randomization (MR) and colocalization analysis on eQTL and pQTL data, we prioritized seven genetically supported druggable genes, including MAPT, TNFSF12, GZMB, SIRPB1, GNLY, NMB, and C1RL, as promising targets for brain aging. We rediscovered 13 potential drugs with evidence from clinical trials of aging and prioritized several drugs with strong genetic support. Our study provides insights into the genetic basis of brain aging, potentially facilitating drug development for brain aging to extend the health span.

Aging is a complex, progressive, and irreversible biological process that entails numerous structural and functional changes in the organism. These changes affect all bodily systems, reducing their ability to respond and adapt to the environment. Chronic inflammation is one of the key factors driving the development of age-related diseases, ultimately causing a substantial decline in the functional abilities of older individuals. This persistent inflammatory state (commonly known as "inflammaging") is characterized by elevated levels of pro-inflammatory cytokines, an increase in oxidative stress, and a perturbation of immune homeostasis. Several factors, including cellular senescence, contribute to this inflammatory milieu, thereby amplifying conditions such as cardiovascular disease, neurodegeneration, and metabolic disorders. Exploring the mechanisms of chronic inflammation in aging is essential for developing targeted interventions aimed at promoting healthy aging. This review explains the strong connection between aging and chronic inflammation, highlighting potential therapeutic approaches like pharmacological treatments, dietary strategies, and lifestyle changes.

Biological aging exhibits heterogeneity across multi-organ systems. However, it remains unclear how is lifestyle associated with overall and organ-specific aging and which factors contribute most in Southwest China.

This study involved 8396 participants who completed two surveys from the China Multi-Ethnic Cohort (CMEC) study. The healthy lifestyle index (HLI) was developed using five lifestyle factors: smoking, alcohol, diet, exercise, and sleep. The comprehensive and organ-specific biological ages (BAs) were calculated using the Klemera-Doubal method based on longitudinal clinical laboratory measurements, and validation were conducted to select BA reflecting related diseases. Fixed effects model was used to examine the associations between HLI or its components and the acceleration of validated BAs. We further evaluated the relative contribution of lifestyle components to comprehension and organ systems BAs using quantile G-computation.

About two-thirds of participants changed HLI scores between surveys. After validation, three organ-specific BAs (the cardiopulmonary, metabolic, and liver BAs) were identified as reflective of specific diseases and included in further analyses with the comprehensive BA. The health alterations in HLI showed a protective association with the acceleration of all BAs, with a mean shift of -0.19 (95% CI -0.34, -0.03) in the comprehensive BA acceleration. Diet and smoking were the major contributors to overall negative associations of five lifestyle factors, with the comprehensive BA and metabolic BA accounting for 24% and 55% respectively.

Healthy lifestyle changes were inversely related to comprehensive and organ-specific biological aging in Southwest China, with diet and smoking contributing most to comprehensive and metabolic BA separately. Our findings highlight the potential of lifestyle interventions to decelerate aging and identify intervention targets to limit organ-specific aging in less-developed regions.

This work was primarily supported by the National Natural Science Foundation of China (Grant No. 82273740) and Sichuan Science and Technology Program (Natural Science Foundation of Sichuan Province, Grant No. 2024NSFSC0552). The CMEC study was funded by the National Key Research and Development Program of China (Grant No. 2017YFC0907305, 2017YFC0907300). The sponsors had no role in the design, analysis, interpretation, or writing of this article.

B cell-directed CAR T cell therapy has fundamentally changed the treatment of haematological malignancies, and its scope of application is rapidly expanding to include other diseases such as solid tumours or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include the limited access current therapies have to the CNS, as well as enormous inter- and intra-individual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option for overcoming this problem and tackling pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has recently revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further prospect, preclinical data reveal the potential benefits of CAR T cell therapy in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as extension to target different antigens or variation of the modified T cell subtype, new and promising fields of CAR T cell application are rapidly opening up. These innovations offer the potential to address the complex pathophysiological properties of CNS diseases. To use CAR T cell therapy optimally to treat CNS diseases in the future while minimizing therapy risks, further mechanistic research and prospective controlled trials are needed to assess seriously the disease and patient-specific risk-benefit ratio.

Evidence on the association of clinical biomarker-based biological age (BA) with cardiovascular disease (CVD) and mortality remains insufficient, particularly concerning aging trajectories' relationship with these two outcomes.

Seventy-five thousand five hundred thirty-seven Chinese adults from the Kailuan study who participated in the first checkup (2006-2007) were included. BA was predicted by 32 clinical indicators using deep neural networks models. Aging status was divided into decelerated, accelerated, and normal aging based on BA in the first checkup. Six aging trajectories were developed in the initial three checkups. CVD and mortality were followed up till December 31, 2021.

After adjusting for chronological age, sex, education level, occupation, physical activity, smoking status, alcohol consumption, salt consumption habit, history of hypertension, diabetes, and dyslipidemia, as well as the use of antihypertensive, antidiabetic, and lipid-lowering drugs, Cox proportional hazard models showed that relative to normal aging, accelerated aging was a risk factor for CVD (adjusted hazard ratio [aHR], 1.17 [95% CI 1.11-1.23]) and mortality (aHR, 1.17 [1.12-1.22]), while participants with decelerated aging had a lower risk for CVD (aHR, 0.85 [0.80-0.90]) and mortality (aHR, 0.86 [0.82-0.90]). Relative to low-stable trajectory, other aging trajectories associated with higher risk of CVD and death, and high-stable trajectory associated with the highest risk of CVD (aHR, 1.62 [1.45-1.81]) and mortality (aHR, 1.55 [1.41-1.71]). Relative to high-stable trajectory, high-decreasing trajectory was associated with lower risk of CVD (aHR, 0.76 [0.67-0.86]) and death (aHR, 0.78 [0.70-0.87]), and decreasing-increasing trajectory was associated with lower risk of death (aHR, 0.86 [0.75-0.98]).

Accelerated BA aging is associated with a higher risk of CVD and mortality, whereas decelerated aging is associated with a lower risk compared to normal aging. Those persistently at high aging levels are at the highest risk for both CVD and death; conversely, it is the act of lowering and continually maintaining a reduced aging state that effectively mitigates these risks.

Lung function has been associated with cognitive decline and dementia, but the extent to which lung function impacts brain structural changes remains unclear. We aimed to investigate the association of lung function with structural macro- and micro-brain changes across mid- and late-life.

The study included a total of 37 164 neurologic disorder-free participants aged 40-70 years from the UK Biobank, who underwent brain MRI scans 9 years after baseline. After 2.5 years, a subsample (n = 3895) underwent a second MRI scan. Lung function was assessed using a composite score based on forced expiratory volume in 1 second, forced vital capacity, and peak expiratory flow, and divided into tertiles (i.e., low, moderate, and high). Structural brain volumes (including total brain, gray matter, white matter, hippocampus, and white matter hyperintensities) and diffusion markers (fractional anisotropy [FA] and mean diffusivity [MD]) were assessed. Data were analyzed using linear regression and mixed-effects models.

Compared to high lung function, low lung function was associated with smaller total brain, gray matter, white matter, and hippocampal volume, as well as lower white matter integrity. Over the 2.5-year follow-up, low lung function was associated with reduced white matter and hippocampal volume, reduced FA, and increased white matter hyperintensity volume and MD. After stratification by age, the associations remained significant among adults aged 40-60 years and 60+ years.

Low lung function is associated with macro- and micro-structural brain changes involving both neurodegenerative and vascular pathologies. This association is significant in both mid- and late-life.

Biological ageing is known to vary among different organs within an individual, but the extent to which advanced ageing of specific organs increases the risk of age-related diseases in the same and other organs remains poorly understood.

In this observational cohort study, to assess the biological age of an individual's organs relative to those of same-aged peers, ie, organ age gaps, we collected plasma samples from 6235 middle-aged (age 45-69 years) participants of the Whitehall II prospective cohort study in London, UK, in 1997-99. Age gaps of nine organs were determined from plasma proteins via SomaScan (SomaLogic; Boulder, CO, USA) using the Python package organage. Following this assessment, we tracked participants for 20 years through linkage to national health records. Study outcomes were 45 individual age-related diseases and multimorbidity.

Over 123 712 person-years of observation (mean follow-up 19·8 years [SD 3·6]), after excluding baseline disease cases and adjusting for age, sex, ethnicity, and age gaps in organs other than the one under investigation, individuals with large organ age gaps showed an increased risk of 30 diseases. Six diseases were exclusively associated with accelerated ageing of their respective organ: liver failure (hazard ratio [HR] per SD increment in the organ age gap 2·13 [95% CI 1·41-3·22]), dilated cardiomyopathy (HR 1·65 [1·28-2·12]), chronic heart failure (HR 1·52 [1·40-1·65]), lung cancer (HR 1·29 [1·04-1·59]), agranulocytosis (HR 1·27 [1·07-1·51]), and lymphatic node metastasis (HR 1·23 [1·06-1·43]). 24 diseases were associated with more than one organ age gap or with organ age gaps not directly related to the disease location. Larger age gaps were also associated with elevated HRs of developing two or more diseases affecting different organs within the same individual (ie, multiorgan multimorbidity): 2·03 (1·51-2·74) for the arterial age gap, 1·78 (1·48-2·14) for the kidney age gap, 1·52 (1·38-1·68) for the heart age gap, 1·52 (1·12-2·06) for the brain age gap, 1·43 (1·16-1·78) for the pancreas age gap, 1·37 (1·17-1·61) for the lung age gap, 1·36 (1·26-1·46) for the immune system age gap, and 1·30 (1·18-1·42) for the liver age gap.

Advanced proteomic organ ageing is associated with the long-term risk of age-related diseases. In most cases, faster ageing of a specific organ increases susceptibility to morbidity affecting multiple organs.

Wellcome Trust, UK Medical Research Council, National Institute for Aging, Academy of Finland.

Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.

The structure and function of the brain and cardiovascular system change over the lifespan. In this study, we aim to establish the extent to which age-related changes in these two vital organs are linked. Utilizing normative models and data from the UK Biobank, we estimate biological ages for the brain and heart for 2,904 middle-aged and older healthy adults, including both males and females. Biological ages were based on multiple structural, morphological, and functional features derived from brain and cardiovascular imaging modalities. We find that cardiovascular aging, particularly aging of its functional capacity and physiology, is selectively associated with the aging of specific brain networks, including the salience, default mode, and somatomotor networks as well as the subcortex. Our work provides unique insight into brain-heart relationships and may facilitate an improved understanding of the increased co-occurrence of brain and heart diseases in aging.

Patients with chronic obstructive pulmonary disease (COPD) frequently experience exacerbations requiring multiple hospitalizations over prolonged disease courses, which predispose them to generalized anxiety disorder (GAD). This comorbidity exacerbates breathing difficulties, activity limitations, and social isolation. While previous studies predominantly employed the GAD 7-item scale for screening, this approach is somewhat subjective. The current literature on predictive models for GAD risk in patients with COPD is limited.

To construct and validate a GAD risk prediction model to aid healthcare professionals in preventing the onset of GAD.

This retrospective analysis encompassed patients with COPD treated at our institution from July 2021 to February 2024. The patients were categorized into a modeling (MO) group and a validation (VA) group in a 7:3 ratio on the basis of the occurrence of GAD. Univariate and multivariate logistic regression analyses were utilized to construct the risk prediction model, which was visualized using forest plots. The model's performance was evaluated using Hosmer-Lemeshow (H-L) goodness-of-fit test and receiver operating characteristic (ROC) curve analysis.

A total of 271 subjects were included, with 190 in the MO group and 81 in the VA group. GAD was identified in 67 patients with COPD, resulting in a prevalence rate of 24.72% (67/271), with 49 cases (18.08%) in the MO group and 18 cases (22.22%) in the VA group. Significant differences were observed between patients with and without GAD in terms of educational level, average household income, smoking history, smoking index, number of exacerbations in the past year, cardiovascular comorbidities, disease knowledge, and personality traits (P < 0.05). Multivariate logistic regression analysis revealed that lower education levels, household income < 3000 China yuan, smoking history, smoking index ≥ 400 cigarettes/year, ≥ two exacerbations in the past year, cardiovascular comorbidities, complete lack of disease information, and introverted personality were significant risk factors for GAD in the MO group (P < 0.05). ROC analysis indicated that the area under the curve for predicting GAD in the MO and VA groups was 0.978 and 0.960. The H-L test yielded χ 2 values of 6.511 and 5.179, with P = 0.275 and 0.274. Calibration curves demonstrated good agreement between predicted and actual GAD occurrence risks.

The developed predictive model includes eight independent risk factors: Educational level, household income, smoking history, smoking index, number of exacerbations in the past year, presence of cardiovascular comorbidities, level of disease knowledge, and personality traits. This model effectively predicts the onset of GAD in patients with COPD, enabling early identification of high-risk individuals and providing a basis for early preventive interventions by nursing staff.

Human social connections are complex ecosystems formed of structural, functional and quality components. Deficits in social connections are associated with adverse age-related health outcomes, but we know little about the ageing-related mechanistic processes underlying this. Using data from 7,047 adults aged 50+ in the English Longitudinal Study of Ageing, we explored associations between diverse aspects of social deficits and both perceived and physiological age acceleration, which provide complementary psycho-behavioural and biological mechanistic explanations. We created and validated a novel physiological ageing index using clinical indicators pertaining to the cardiovascular, respiratory, haematologic, metaboloic and cognitive systems using principal component analysis. Doubly-robust estimations using inverse-probability-weighted regression adjustment estimators showed that living alone, low social integration and high social isolation were risk factors for physiological age acceleration, with those who lived alone on average 1.9 years older than those who lived with others (95% CI 0.9-3.0 years older; 32% greater age acceleration than people who live with others). However, social deficits were not related to accelerations in perceived age. Analyses were robust to multiple sensitivity analyses and maintained four years later. These findings provide important mechanistic insight that helps to explain the relationship between social deficits and age-related morbitidy and mortality outcomes.

Aging is a complex biological process that disrupts tissue structure and impairs physiological function, which contributes to the development of age-related diseases such as cardiovascular disorders. However, effective treatment strategies are lacking.

To investigate the geroprotective effects of Lycium barbarum glycopeptide (LbGp) and its potential mechanisms in a D-galactose-induced accelerated aging mouse model.

Mice were subcutaneously injected with D-galactose (500 mg/kg/day) for 12 weeks to induce aging, while LbGp was orally administered (100 mg/kg/day) throughout the study. The geroprotective effects of LbGp were assessed by behavioral tests, cardiac echocardiography, pathohistological and transcriptomic analyses. Transmission electron microscopy was used to observe the ultrastructure of mitochondria. Mitochondrial stress assays and JC-1 fluorescent probe were conducted to evaluate mitochondrial function. Flow cytometer and western blot were performed to assess mitophagy flux.

LbGp treatment improved the aging phenotypes of D-galactose-induced mice, with a pronounced enhancement in cardiac function compared to neurocognitive and skeletal muscle functions. Transcriptome analysis indicated that LbGp ameliorated energy metabolism in the heart. Mitochondrial assays revealed LbGp improved mitochondrial function and preserved structural integrity of the mitochondrial inner membrane. LbGp attenuated mitochondrial fission and restored impaired PINK1/Parkin-mediated mitophagy pathway caused by D-galactose in cardiomyocytes.

LbGp can ameliorate aging phenotypes and enhance cardiac metabolism by activating the PINK1/Parkin-mediated mitophagy pathway in D-galactose-induced mice. These findings underscore its potential as a therapeutic agent for aging and aging-related cardiovascular diseases.

Aging is a multi-organ disease, yet the traditional approach has been to study each organ in isolation. Such organ-specific studies have provided invaluable information regarding its pathomechanisms. However, an overall picture of the whole-body network (WBN) during aging is still incomplete. In this study, we analyzed the functional magnetic resonance imaging blood-oxygen level-dependent, respiratory rate and heart rate time series of a young and an elderly group during eyes-open resting-state. We constructed WBNs by exploring the time-lagged coupling between the different organs. First, we showed that our analytical pipeline could identify regional differences in the networks of both cohorts, allowing us to proceed with the remaining analyses. The comparison of the WBNs revealed a complex relationship where some connections were stronger and some weaker in the elderly. Finally, the interconnectivity and segregation of the WBNs were negatively correlated with the short-term memory and verbal learning of the young participants. This study: i) validated our methodology, ii) identified differences in the WBNs of the two groups and iii) showed correlations of WBNs with behavioral measures. In conclusion, the concept of WBN shows great potential for the understanding of aging and age-related diseases.

Rapamycin, also known as sirolimus, has demonstrated great potential for application in longevity medicine. However, the dynamics of low-dose rapamycin bioavailability, and any differences in bioavailability for different formulations (e.g., compounded or commercial), remain poorly understood. We thus explored rapamycin bioavailability in two real-world cohorts to begin providing a foundational understanding of differences in effects between formulations over time. The small trial study cohort was utilized to explore the blood rapamycin levels of commercial (n = 44, dosages 2, 3, 6, or 8 mg) or compounded (n = 23, dosages 5, 10, or 15 mg) rapamycin 24 h after dose self-administration. Results suggested dose-to-blood level relationships were linear for both formulations, though compounded had a lower bioavailability per milligram of rapamycin (estimated to be 31.03% of the same dose of commercial). While substantial inter-individual heterogeneity in blood rapamycin levels was observed for both formulations, repeat tests for individuals over time demonstrated relative consistency. Extending exploration to 316 real-world longevity rapamycin users from the AgelessRx Observational Research Database produced similar findings, and additionally suggested that blood rapamycin levels peak after 2 days with gradual decline thereafter. Taken together, our findings suggest that individualized dosing and routine monitoring of blood rapamycin levels should be utilized to ensure optimal dosing and efficacy for healthy longevity.

Objective and subjective aging indicators reflect diverse biological and psychosocial processes, yet their combined association with premature mortality remains underexplored. This study aimed to investigate the association between a multidomain framework of aging indicators and premature mortality, addressing gaps in understanding cumulative effects. We included 369,741 UK Biobank participants initially free of cardiovascular disease (CVD) and cancer, followed until December 31, 2022. Four indicators, hearing loss, tooth loss, falls and subjective aging, were counted, and their joint associations with all-cause and cause-specific premature mortality were analyzed using the Cox proportional hazard models. During a median follow-up of 13.74 years, we documented 22,934 premature mortality. Participants with all indicators had an 81% (95%CI: 59-107%), 96% (47-160%), 55% (26-91%), and 114% (73-165%) higher risk of all-cause, CVD, cancer, and other-cause premature mortality, respectively, compared to those without indicators. The associations were particularly elevated among younger participants, those with unhealthy lifestyles, and those of lower socioeconomic status (P for interactions <0.05). Additive interaction with frailty contributed an additional 16.08% (7.91-24.25%) risk of premature mortality. Findings were replicated in the Health and Retirement Study, supporting the robustness of the multidomain aging framework. This study highlights the potential of integrating objective and subjective aging indicators to refine risk assessments and inform interventions targeting aging-related diseases.

Mechanical information is a medium for perceptual interaction and health monitoring of organisms or intelligent mechanical equipment, including force, vibration, sound, and flow. Researchers are increasingly deploying mechanical information recognition technologies (MIRT) that integrate information acquisition, pre-processing, and processing functions and are expected to enable advanced applications. However, this also poses significant challenges to information acquisition performance and information processing efficiency. The novel and exciting mechanosensory systems of organisms in nature have inspired us to develop superior mechanical information bionic recognition technologies (MIBRT) based on novel bionic materials, structures, and devices to address these challenges. Herein, first bionic strategies for information pre-processing are presented and their importance for high-performance information acquisition is highlighted. Subsequently, design strategies and considerations for high-performance sensors inspired by mechanoreceptors of organisms are described. Then, the design concepts of the neuromorphic devices are summarized in order to replicate the information processing functions of a biological nervous system. Additionally, the ability of MIBRT is investigated to recognize basic mechanical information. Furthermore, further potential applications of MIBRT in intelligent robots, healthcare, and virtual reality are explored with a view to solve a range of complex tasks. Finally, potential future challenges and opportunities for MIBRT are identified from multiple perspectives.

With the global population aging at an unprecedented rate, there is a need to extend healthy productive life span. This review examines how Deep Learning (DL) and Generative Artificial Intelligence (GenAI) are used in biomarker discovery, deep aging clock development, geroprotector identification and generation of dual-purpose therapeutics targeting aging and disease. The paper explores the emergence of multimodal, multitasking research systems highlighting promising future directions for GenAI in human and animal aging research, as well as clinical application in healthy longevity medicine.

Common features of the aging heart are dysregulated metabolism, inflammation, and fibrosis. Elevated oxidative stress is another hallmark of cardiac aging that can exacerbate each of these conditions. We hypothesize that by increasing natural antioxidant levels (glutathione), we will improve cardiac function. Twenty-one-month-old mice were fed glycine and N-acetyl cysteine (GlyNAC; glutathione precursors)-supplemented or control diets for 12 weeks. Heart function was monitored longitudinally, and the exercise performance was determined at the end of the study. We found that the GlyNAC diet was beneficial for old male but not old female mice, leading to an increase of Ndufb8 expression (a subunit of the mitochondrial respiratory chain complex), and higher enzymatic activity for CPT1b and CrAT, 2 carnitine acyltransferases that are critical to cardiomyocyte metabolism. Although no quantifiable change of collagen turnover was detected, hearts from GlyNAC-fed old males exhibited a slight but significant enrichment in Fmod, a protein that can inhibit collagen fibril formation, possibly reducing extracellular matrix stiffness and thus improving diastolic function. Cardiac diastolic function was modestly improved in males but not females, and surprisingly GlyNAC-fed female mice showed a decline in exercise performance. In summary, our work supports the concept that aged male and female hearts are phenotypically different. These basic differences may affect the response to pharmacological and diet interventions, including antioxidants.

Vascular cognitive impairment (VCI) stresses the vascular contributions to cognitive decline, ranging from mild to major forms. Except for symptomatic treatment for relevant vascular diseases, the other recommended strategy is to intervene in key vascular risk factors (VRFs) as early as possible. A considerable amount of previous research delineated the association of a specific factor with dementia, involving each risk factor discussed in the present review. However, due to the heterogeneity and complexity of VCI, managing a single factor is insufficient to reduce its incidence and prevalence. Ongoing studies suggest differences in the impact of various combinations of risk factors on dementia. Here in this review, we aimed to provide an updated overview of clinical evidence and implications of complex interactions among various risk factors of VCI, including common VRFs and modifiable dementia-related risk factors. Understating the effect of comorbid risk factors on VCI and underlying mechanisms of them during VCI progression is essential for identifying high-risk population and developing preventive strategies. Furthermore, we summarized common composite risk scores and models used for risk evaluation and prediction of VCI, involving conventional risk scores, subclinical vascular composites, and novel risk models driven by intelligent algorithms. Lastly, we discussed potential gaps and research directions on searching specific clinical risk profiles, constructing effective risk scores, and implementing targeted risk interventions.

Cognition and behavior are emergent properties of brain systems that seek to maximize complex and adaptive behaviors while minimizing energy utilization. Different species reconcile this trade-off in different ways, but in humans the outcome is biased towards complex behaviors and hence relatively high energy use. However, even in energy-intensive brains, numerous parsimonious processes operate to optimize energy use. We review how this balance manifests in both homeostatic processes and task-associated cognition. We also consider the perturbations and disruptions of metabolism in neurocognitive diseases.

As global life expectancy increases, age-related brain diseases such as stroke and dementia have become leading causes of death and disability. The aging of the neurovasculature is a critical determinant of brain aging and disease risk. Neurovascular cells are particularly vulnerable to aging, which induces significant structural and functional changes in arterial, venous, and lymphatic vessels. Consequently, neurovascular aging impairs oxygen and glucose delivery to active brain regions, disrupts endothelial transport mechanisms essential for blood-brain exchange, compromises proteostasis by reducing the clearance of potentially toxic proteins, weakens immune surveillance and privilege, and deprives the brain of key growth factors required for repair and renewal. In this review, we examine the effects of neurovascular aging on brain function and its role in stroke, vascular cognitive impairment, and Alzheimer's disease. Finally, we discuss key unanswered questions that must be addressed to develop neurovascular strategies aimed at promoting healthy brain aging.

Circadian rhythm is the internal homeostatic physiological clock that regulates the 24-hour sleep/wake cycle. This biological clock helps to adapt to environmental changes such as light, dark, temperature, and behaviors. Aging, on the other hand, is a process of physiological changes that results in a progressive decline in cells, tissues, and other vital systems of the body. Both aging and the circadian clock are highly interlinked phenomena with a bidirectional relationship. The process of aging leads to circadian disruptions while dysfunctional circadian rhythms promote age-related complications. Both processes involve diverse physiological, molecular, and cellular changes such as modifications in the DNA repair mechanisms, mechanisms, ROS generation, apoptosis, and cell proliferation. This review aims to examine the role of aging and circadian rhythms in the context of lung cancer. This will also review the existing literature on the role of circadian disruptions in the process of aging and vice versa. Various molecular pathways and genes such as BMAL1, SIRT1, HLF, and PER1 and their implications in aging, circadian rhythms, and lung cancer will also be discussed.

Posttraumatic stress disorder (PTSD) is associated with mortality and increased risk of diseases of aging, but underlying mechanisms remain unclear. We examine associations of PTSD with one potential pathway, accelerated epigenetic aging. In a longitudinal cohort of trauma-exposed middle-aged women (n = 831, n observations = 1,516), we examined cross-sectional and longitudinal associations between PTSD, with and without comorbid depression, and epigenetic aging measured by six clocks at two time points approximately 13.5 years apart: Hannum, Horvath, PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE. We further examined associations of 3 well-established predictors of aging and mortality also linked with PTSD, namely, body mass index (BMI), diet quality, and physical activity, with epigenetic aging. Cross-sectionally, across all six clocks, epigenetic aging in women with PTSD alone, depression alone, and co-occurring depression and PTSD did not differ from the reference group of women without PTSD or depression in analyses adjusted for age, self-reported race, cell proportions, and ancestry principal components. In longitudinal analyses, we similarly did not find any difference in change in epigenetic age over time by PTSD and depression status at baseline. Among the health factors, in cross-sectional analyses, higher BMI was significantly and consistently associated with greater epigenetic aging measured by the PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE clocks, but not measured by the Hannum or Horvath clocks. Physical activity was not consistently associated with epigenetic aging measured by Hannum, Horvath, PhenoAge, or GrimAge. In analyses with the DunedinPoAm and DunedinPACE clocks, women who reported exercise equivalent to 1 or more hours/week walking had slower epigenetic aging than women with less exercise. Diet quality was not consistently associated with epigenetic aging measured by any of the clocks. Our data do not provide evidence that biological aging, as measured by any of the six epigenetic clocks, is a pathway linking PTSD with mortality and diseases of aging.