BMD levels achieved on osteoporosis treatment are predictive of subsequent fracture risk, and T-score >-2.5 has been proposed as a minimum treatment target for women with osteoporosis. Knowing the likelihood of attaining target T-scores with different medications for different baseline BMD levels can help determine appropriate initial treatment for individual patients. In this post hoc analysis, we estimated the probability of achieving a non-osteoporotic T-score (>-2.5 or >=-2.0) at the TH or LS in postmenopausal women >60 yr old treated with denosumab for either 3 or 10 yr in the FREEDOM trial and its long-term extension. In women with baseline TH T-scores of -2.7, -3.0, and -3.5, the probabilities of achieving target T-scores >-2.5 with 3 yr of denosumab were 71%, 12%, and 0.1%, respectively. At LS, for baseline T-scores of -2.7, -3.0, and -3.5, the probabilities were 86%, 59%, and 11%, respectively. Longer treatment duration of up to 10 yr increased the probability of achieving target T-scores. The baseline T-scores that permitted at least 50% of women to achieve a target T-score >-2.5 were -2.8 at TH and -3.1 at LS after 3 yr and -3.0 at TH and -3.7 at LS after 10 yr of treatment. To achieve higher treatment targets (T-scores >= -2.0), overall probabilities were lower at both skeletal sites, particularly for TH, even with longer treatment duration. Our results demonstrate that the probability of achieving T-score targets with denosumab is dependent on baseline BMD, skeletal site, and treatment duration. Knowing the probability of achieving treatment targets for different baseline TH and LS T-scores can help determine whether denosumab is an appropriate first choice of treatment in individual patients.

Abstract Mitochondrial dysfunction plays an important role in age-related mobility disability. The study of Muscle, Mobility and Aging (SOMMA) is a cohort study designed to identify muscle characteristics associated with worsening mobility. Using vastus lateralis muscle biopsies (n = 724; ages 70+ years; 56% women), we performed bulk RNAseq and used DESeq2 to test whether the expression of preselected muscle RNA transcripts related to mitochondrial energetics were associated with physical traits including cardiorespiratory fitness (VO2peak), leg power, and 400 m walk speed. In our analysis of 288 transcripts from both nuclear and mitochondria-encoded genes, several transcripts were strongly and positively associated with VO2peak. Among the top 20 differentially regulated genes (DEGs, adjusted p < 0.05) were genes involved in oxidative phosphorylation: IDH2, FH, SUCLG1 (Krebs cycle), NDUFA8 and NDUFA9 (complex I), SDHB and SDHC (complex II), CYC1 (complex III), COX5A (complex IV), and ATP5F1B, ATP5F1C, ATP5MC1, ATP5MC3, ATP5PB, and ATP5F1A (complex V). All mitochondrial DNA encoded OXPHOS complex transcripts were significantly associated with VO2peak and mitochondrial energetics. Among the genes we tested, a smaller proportion of the selected transcripts reached statistical significance (adjusted p < 0.05) for leg power and walking speed, with the highest proportion observed for VO2peak: VO2peak (66%), leg power (29%), and walking speed (11%). In summary, transcripts involved in mitochondrial energetics show a strong association with VO2peak, a trait highly dependent on mitochondrial function.

Metabolites associated with longevity in a prospective study could lead to predictive longevity biomarkers. The Longevity Consortium (LC) performed a prospective case-cohort metabolomics study of longevity from four cohort studies of elderly individuals: Study of Osteoporotic Fractures (SOF), Osteoporotic Fractures in Men (MrOS), Health, Aging, and Body Composition (Health ABC) Study, and the Cardiovascular Health Study (CHS). Longevity cases were defined by reaching the age corresponding to the 98th survival percentile from United States Social Security Administration life tables. This longevity definition for the 1910 US birth cohort for males is 95 years and for females is 99 years. There were 827 longevity cases and 2,555 members of the subcohort that did not achieve longevity over follow-up. GC-TOF MS was used to measure 322 serum metabolites. Metabolite associations with age were identified with sex-specific regression models adjusted for race, clinic site, study, body mass index (BMI), and estimated glomerular filtration rate (eGFR). The same covariates were included in sex-specific regression models for longevity associations, but age was additionally adjusted for. In a meta-analysis of age-association results from both sexes, older age was associated with lower levels of tryptophan (P = 4x10-5) and higher levels of cystine (P = 4x10-4) and hypotaurine (P = 9x10-3). In a meta-analysis of prospective longevity results from both sexes, higher levels of tryptophan were associated with higher odds of longevity (OR = 2.7, P = 6x10-5), and higher levels of cystine were associated with lower odds of longevity (OR = 0.81, P = 0.02). These metabolites could serve as biomarkers for human aging and longevity.

In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. PURPOSE:We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. METHODS:The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. RESULTS:As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23-1.52 and 1.19, 1.12-1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. CONCLUSIONS:A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.

Identifying mechanisms that compensate for slow gait speed in older adults is crucial. Dopaminergic neurotransmission curbs deleterious associations of cerebrovascular disease with gait, but whether it compensates for peripheral systemic risk factors (PSRF) for gait slowing has not been studied. In this cross-sectional study of community-dwelling older adults, we examined the relationship between nigrostriatal dopaminergic terminal integrity and gait speed in individuals with and without ≥ 1 PSRF for gait slowing: obesity, joint pain, or reduced muscle strength. The primary outcome was gait speed cost (%GSC) on transition from even to uneven surface. Participants underwent dopaminergic imaging with dihydrotetrabenazine [11C]DTBZ positron emission tomography. Among 197 individuals, (mean (SD) age 74.92 (4.53) years; 61.93 % female; 90.86 % White), 130 (65.99 %) had ≥ 1 PSRF. Relationship between posterior putamen [11C]DTBZ binding and %GSC was modified by PSRF; in those with ≥ 1 PSRF (but not in those with no PSRF), posterior putamen [11C]DTBZ binding was associated with %GSC (β = 0.198, p = 0.03) independent of potential confounders. This cross-sectional study indicates that higher striatal dopaminergic neurotransmission may compensate for the effects of PSRF on gait slowing.

Entropy, characterized by increased disorder throughout biological systems, can be quantified by homeostatic dysregulation (HD). One potential measure of HD is the dispersion of points from a normal value, approximated at the individual level by Mahalanobis distance (DM). We hypothesized that greater HD in electrocardiogram (ECG) would also reflect greater HD in the musculoskeletal system which, in turn, would be associated with age and manifest as an increased risk of fracture independently of age, bone mineral density (BMD), and history of fracture. We further hypothesized that greater ECG-HD would be associated with increased risk of all-cause mortality. A cohort of 7738 individuals aged 40 years or older who underwent a screening 12-lead ECG between 2007 and 2018 was analyzed (mean age 63.5 years; 59.5% women; 5.5 years follow-up). ECG-HD was calculated as the natural log-transformed DM of five ECG measurements (ventricular rate, QRS duration, corrected QT interval, R axis, and T axis) referenced to young individuals (age 19-29). ECG-HD increased with age (r = 0.28). Each standard deviation increment in ECG-HD was associated with a 48% higher unadjusted fracture risk (HR 1.48, 95% CI 1.37-1.58) and remained significant after adjustment for clinical risk factors, ECG diagnoses, and femoral neck BMD (aHR 1.28, 95% CI 1.15-1.42). ECG-HD was also associated with vertebral, nonvertebral, and hip fractures, and with mortality (aHR 1.44, 95% CI 1.18-1.74). ECG-HD, a measurement of entropy in the cardiac system, was associated with fracture risk and mortality in adults, independent of clinical risk factors, BMD, and ECG diagnoses.

There is substantial interest in using Machine Learning (ML) and Artificial Intelligence (AI) approaches to integrate multi-omics data to identify molecular factors associated with age. Multi-omic AI models can be used to predict “biological age” and to identify age-associated molecular features. To-date, predictions from traditional ML methods like elastic-net have outperformed AI models like deep learning with tabular (spreadsheet-like) data. However, new developments in transformer architectures have led to AI models that can outperform traditional ML methods. In this work, a tabular foundation AI model (TabPFN) built on transformer-based in-context learning (ICL) algorithms is used to integrate proteomics and metabolomics to identify models for age in a cohort study of older men, the Osteoporotic Fractures in Men (MrOS) Study. The serum proteomics assay was the SomaLogic 7K panel, and the serum metabolomics assay was the Metabolon Discovery HD platform. In 493 male participants split into training and test partitions, TabPFN models for age adjusted for body mass index (BMI) and estimated glomerular filtration rate (eGFR) achieved a root mean square error (RMSE) in the test set of 2.75 years, which outperformed an elastic-net model RMSE in the test set of 3.1 years. Proteins and metabolites contributing to the TabPFN model for age identified by Shapley Additive exPlanations (SHAP) included Pleiotrophin, Frizzled-7, secreted frizzled-related protein 1, and N-acetylcarnosine. Multi-omic AI models outperformed traditional ML models for age and identified biologically relevant features. Future directions include replication of findings in other studies and assessment of model performance in females.

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart in silico. Additionally, novel ASAT-secreted proteins such as NID2 and APOA4 were implicated in mediating ASAT crosstalk with skeletal muscle and brain in silico. Our framework provides insights into ASAT-driven tissue crosstalk underlying physical and cognitive performance in older adults and offers a valuable resource for understanding the role of ASAT in human aging.

Osteoporotic vertebral fractures (VFs) are among the most common and clinically significant manifestations of skeletal fragility, contributing substantially to morbidity, disability, and future fracture risk worldwide. Yet, their recognition and management remain inconsistent across regions. To explore differences and similarities in the prevalence, diagnosis, management, and prevention of vertebral fractures, the East Meets West (EmW) Action Group of the European Calcified Tissue Society convened a multi-country exchange among clinical and research experts from Europe, the USA, and East Asia. This report summarizes the discussions and synthesizes current knowledge on the topic. Evidence from China, South Korea, Japan, and Germany shows a wide range in reported VF prevalence and incidence, largely influenced by differences in population aging, imaging access, and diagnostic adjudication methods. While lateral spine radiographs remain the standard for detection in both research and clinical care, variable use of quantitative morphometry (QM), semi-quantitative (SQ), and algorithm-based qualitative (ABQ) methods limits comparability. MRI remains the gold standard for assessing fracture acuity, but is not feasible for widespread screening. VFA via DXA is gaining popularity, although underutilized in several settings. Despite the availability of effective pharmacologic treatments, including bisphosphonates, denosumab, and anabolic agents, treatment rates following VF remain suboptimal across all countries studied. None of the countries currently has a nationwide vertebral fracture screening program, although fracture liaison services (FLS) and AI-assisted imaging offer promising pathways forward. The lack of a universally accepted definition and gold standard for VF adjudication continues to hamper clinical decision-making and data harmonization. This report highlights the need for greater international consensus on diagnostic criteria, improved integration of vertebral fracture screening into clinical workflows, and the development of targeted strategies to close treatment gaps and reduce the global burden of vertebral fractures.

The relationship between rheumatoid arthritis (RA) and fracture risk was estimated in an international meta-analysis of individual-level data from 29 prospective cohorts. RA was associated with an increased fracture risk in men and women, and these data will be used to update FRAX®. RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between rheumatoid arthritis and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD) with a view to updating FRAX. The resource comprised 1,909,896 men and women, aged 20–116 years, from 29 prospective cohorts in which the prevalence of RA was 3

Importance:The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival. Observations:Medical therapies typically alter biologic pathways to treat or prevent specific diseases. For example, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are cholesterol-lowering medications used to prevent development and progression of atherosclerosis. However, disease-focused treatments do not alter aging's effects on disease and declining function (eg, statins do not significantly reduce noncardiovascular mortality or cancer). In animal models, treatments can alter aging's effect on disease. For example, in mice, caloric restriction increases mean lifespan from 10% to 40% compared with mice fed ad libitum and favorably affects multiple cellular pathways implicated in aging including nutrient sensing, protein synthesis, autophagy, and inflammation. In adults with obesity and diabetes, compared with non-caloric restriction intervention groups, randomization to receive caloric restriction was associated with a 15% reduction in all-cause mortality and a lower incidence of weight-related chronic diseases. Rapamycin, a drug approved to suppress posttransplant organ rejection, increased mouse median lifespan by 249 days in females and 154 days in males. A rapamycin analogue, everolimus, improved antibody titers to influenza vaccine in older adults. In humans, senescent cells increase in abundance with age and are characterized by growth arrest, apoptosis resistance, and an altered secretome (the set of proteins secreted by a cell into the extracellular space). A greater abundance of senescent cells is associated with more physical impairments and increased mortality. Reducing the number of these cells in animal models extends lifespan and improves physical function, such as grip strength and mobility, and cardiac ejection fraction. However, potential health benefits of reducing senescent cells in humans remain unclear. Conclusions and Relevance:Therapies that inhibit aging biology, such as caloric restriction, metformin, senolytics, or rapalogs, may slow the development and progression of disease and functional decline in humans.

PURPOSE:It is recognized that disruptions in circadian behavior, such as with shift work or jet lag, are associated with diminished health. This known relationship implies that people with stronger indices of circadian behavior will exhibit improved physiology. To address the association between rhythmic activity behavior and physiology, we proposed that metrics indicative of "more rhythmic" rest-activity patterns would be associated with better cardiorespiratory fitness and walking energetics in a cohort of older adults. METHODS:Using baseline data from the Study of Muscle, Mobility and Aging ( N = 799, age: 76 ± 5 yr, 58% female), we quantified metrics describing rhythmic aspects of rest-activity behavior (amplitude, robustness, time of peak activity, others) from continuous wrist-worn accelerometry. We used linear models to examine cross-sectional associations between rhythmic metrics with V̇O 2peak and walking energetics (cost-capacity ratio at slow and preferred walking speeds) adjusted for age, sex, race, height, health conditions, and other factors. RESULTS:Metrics that reflect more rhythmic behavior were associated with V̇O 2peak (higher amplitude: Q1: 18.4 vs Q4: 22.0 mL·kg -1 ·min -1 ; P -trend < 0.001) higher pseudo- F statistic/robustness (Q1: 19.2 vs Q4: 21.3 mL·kg -1 ·min -1 ; P -trend < 0.001), and earlier time of peak activity (Q1 (earliest): 20.9 vs Q4 (latest): 19.2 mL·kg -1 ·min -1 ; P -trend < 0.001). Similar trends were observed with lower cost-capacity ratio at preferred and slow walking speeds (amplitude, pseudo- F statistic, acrophase: P -trend < 0.001 for all). CONCLUSIONS:More rhythmic activity behavior and earlier time of peak activity were associated with better cardiorespiratory fitness and walking energetics. These findings support the framework that rhythmic activity supports healthy physiology. Further investigations are warranted to determine if declines in rhythmicity of human behavior are predictive of disease.

OBJECTIVES:Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN:The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a "successful aging" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING:Recruitment occurred at eight centers in the United States. PARTICIPANTS:We included 1,373 participants enrolled in the study with baseline measures of 27 biomarkers of cellular senescence and adjudication of mild cognitive impairment (MCI) and dementia at baseline and 24-month follow-up. At baseline, participants were aged 70-80, sedentary, and at high risk of mobility disability. MEASUREMENTS:A neuropsychological assessment was administered at baseline and 24 months post-randomization. At both timepoints, a clinical adjudication committee determined whether individuals had a diagnosis of cognitively normal, MCI, or dementia; individuals with dementia at baseline were excluded. The concentrations of 26 of the 27 plasma proteins identified as components of the SASP were measured with commercially available Luminex xMAP multiplex magnetic bead-based immunoassays analyzed on the MAGPIX System while 1 protein (Activin A) was measured using an enzyme-linked immunosorbent assay. RESULTS:Logistic regression models were used to examine the associations of each senescence biomarker, in quartiles, with baseline or incident MCI. Models stratified by clinical site and adjusted for intervention assignment, age, gender, race, and education. Among 1,373 participants, 117 (8.5%) were diagnosed with MCI at baseline. Increasing quartiles of myeloperoxidase (MPO) was associated with higher odds of MCI compared to quartile 1 (Q2: OR = 1.34, 95% CI: 0.74-2.45; Q3: OR = 1.43, 95% CI: 0.80-2.59; Q4: OR = 1.79, 95% CI: 1.02-3.22). Additionally, matrix metalloproteinase 1 (MMP1) quartiles 2-4 had lower odds of MCI compared to quartile 1 (Q2: OR = 0.61, 95% CI: 0.35-1.02; Q3: OR = 0.58, 95% CI: 0.33-0.98; Q4: OR = 0.64, 95% CI: 0.37-1.08). Of the 1,256 cognitively unimpaired participants at baseline, 141 (11.2%) were diagnosed with incident MCI or dementia at the 24-month follow-up. Compared to quartile 1, increasing baseline quartiles of MPO (Q2: OR = 1.10, 95% CI: 0.63-1.92; Q3: OR = 1.36, 95% CI: 0.80-2.33; Q4: OR = 1.92, 95% CI: 1.16-3.25) and matrix metalloproteinase 7 (MMP7, Q2: OR = 0.88, 95% CI: 0.47-1.62; Q3: OR = 1.46, 95% CI: 0.85-2.55; Q4: OR = 2.14, 95% CI: 1.28-3.65) were associated with increased odds of MCI or dementia at 24 months. CONCLUSIONS:Among older adults at high risk of mobility disability, high plasma MPO was cross-sectionally and, along with MMP7, longitudinally associated with increased odds of MCI and dementia. In contrast, high MMP1 was cross-sectionally associated with reduced odds of MCI.

BACKGROUND:Peak oxygen consumption during exercise (VO2peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO2peak variation are not clear. Our objective is to understand the microRNA (miRNA) signatures that relate to VO2peak variation, which could provide insights to novel mechanisms that contribute to low VO2peak. METHODS:We used small RNA sequencing to analyze baseline, cross-sectional serum samples from 72 participants (70- to 91-year old). We analyzed samples from individuals with low or high VO2peak (N = 18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO2peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. RESULTS:We identified 1055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO2peak (P < .05). After P-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The Area Under the Curve for the five miRNAs ranged from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70% to 80% and 80% to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO2peak (P < .05) and miR-519a-3p remained significant based on adjusted P-values. CONCLUSIONS:We identified a miRNA signature of VO2peak in older individuals that might provide insights to novel mechanisms that drive low VO2peak. Future studies will validate the findings in a larger, longitudinal study cohort.

Spine age estimated from lateral spine radiographs and DXA VFAs could be associated with fracture and mortality risk. In the VERTE-X cohort (n = 10,341, derivation set) and KURE cohort (n = 3517; external test set), spine age discriminated prevalent vertebral fractures and osteoporosis better than chronological age. Predicted age difference was associated with overall (adjusted HR [aHR] 1.22 per 1 SD increment, p < 0.001), vertebral, non-vertebral incident fractures, and mortality (aHR 1.31, p = 0.001) during a median 6.6 years follow-up in KURE, independent of chronological age and covariates. Spine age to estimate FRAX hip fracture probabilities, instead of chronological age, improved the discriminatory performance for incident hip fracture (AUROC 0.83 vs. 0.78, p = 0.027). Shorter height, lower femoral neck BMD, diabetes, vertebral fractures, and surgical prosthesis were associated with higher predicted age difference, explaining 40% of variance. Spine age estimated from lateral spine radiographs and DXA VFA enhanced fracture risk assessment and mortality prediction over chronological age.

In the United States, older adults who self-identify as Black have a disproportionately higher incidence of mobility disability compared to those who are White. Whether older adults who are Black also have lower fitness and mitochondrial energetics has not been adequately investigated. The study of muscle, mobility and aging (SOMMA) examined 879 participants aged ≥ 70 years old, including 116 who self-identified as Black. Mitochondrial respiration (Max OXPHOS) was measured in permeabilized fibers from muscle biopsies. Cardiorespiratory fitness (VO2 peak) was determined by a cardiopulmonary exercise test. Education, income, financial resources, race, sex, and age were determined by self-report. We used propensity score matching to match Blacks with Whites with a 1:1 ratio. Black (n = 90) and White (n = 90) groups were matched for age, sex, SOMMA multimorbidity index, BMI, muscle mass, physical activity, marital status, educational achievement, and whether financial needs were met (all p > 0.05). Despite being well matched for these variables, those who identified as Black had a slower 400-m walking speed (0.97 vs. 1.03 m/s, p = 0.014), lower Max OXPHOS (50.8 vs. 60.9 (pmol/(s*mg)), p = 0.0002), and lower cardiorespiratory fitness (1391 vs. 1566 mL/min, p = 0.007) when compared to those who identified as White. Multivariate regression showed that VO2 peak and Max OXPHOS, but not socioeconomic factors, attenuated the race difference in 400-m walking speed. In conclusion, while the etiology of race differences in mobility is multifactorial, our data indicate that muscle mitochondrial respiration and cardiorespiratory fitness may contribute to the slower walking speed of individuals who identify as Black compared to White.

The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival. Medical therapies typically alter biologic pathways to treat or prevent specific diseases. For example, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are cholesterol-lowering medications used to prevent development and progression of atherosclerosis. However, disease-focused treatments do not alter aging’s effects on disease and declining function (eg, statins do not significantly reduce noncardiovascular mortality or cancer). In animal models, treatments can alter aging’s effect on disease. For example, in mice, caloric restriction increases mean lifespan from 10% to 40% compared with mice fed ad libitum and favorably affects multiple cellular pathways implicated in aging including nutrient sensing, protein synthesis, autophagy, and inflammation. In adults with obesity and diabetes, compared with non–caloric restriction intervention groups, randomization to receive caloric restriction was associated with a 15% reduction in all-cause mortality and a lower incidence of weight-related chronic diseases. Rapamycin, a drug approved to suppress posttransplant organ rejection, increased mouse median lifespan by 249 days in females and 154 days in males. A rapamycin analogue, everolimus, improved antibody titers to influenza vaccine in older adults. In humans, senescent cells increase in abundance with age and are characterized by growth arrest, apoptosis resistance, and an altered secretome (the set of proteins secreted by a cell into the extracellular space). A greater abundance of senescent cells is associated with more physical impairments and increased mortality. Reducing the number of these cells in animal models extends lifespan and improves physical function, such as grip strength and mobility, and cardiac ejection fraction. However, potential health benefits of reducing senescent cells in humans remain unclear. Therapies that inhibit aging biology, such as caloric restriction, metformin, senolytics, or rapalogs, may slow the development and progression of disease and functional decline in humans.

BACKGROUND AND AIMS:Vitamin D deficiency is a global public health concern, yet data on its prevalence across China's diverse demographics remain limited. This study aimed to evaluate vitamin D status and deficiency prevalence across various demographic and geographic groups in China. METHODS AND RESULTS:This cross-sectional analysis included 19,845 participants from the China Osteoporosis Prevalence Study, conducted between December 2017 and August 2018. Serum 25-hydroxyvitamin D (25OHD) was measured by electrochemiluminescence. Vitamin D levels and deficiency prevalence were assessed across demographic groups and provinces using weighted analysis. The mean 25OHD level in the general population was 26.00 ng/mL, with an average of 29.1 ng/mL in males and 22.84 ng/mL in females. Vitamin D deficiency (defined as 25OHD <20 ng/mL) was notably prevalent in China, affecting 29.89 % of the population. Deficiency rates were particularly high in northern China (44.02 %), females (39.95 %), individuals under 40 years old (33.46 %), individuals with obesity (32.54 %), and urban residents (39.44 %). Geographic disparities were also apparent at the provincial level, with southern provinces generally exhibiting lower prevalence and northwestern regions the highest. CONCLUSIONS:This study provides important evidence for public health policies to prevent and manage vitamin D deficiency, highlighting the need for targeted interventions among high-risk populations such as women, urban residents, individuals with high BMI, and those with conditions like diabetes.

DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life. Koch and colleagues report that epigenetic clocks mirror age predictions based on the accumulation of somatic mutations and show that somatic mutations at CpG sites coincide with extensive remodeling of the surrounding methylome.