Biomarkers Of Aging Research Articles

Proteomic aging clock (PAC) predicts age-related outcomes in middle-aged and older adults.

Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all-cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2923 plasma proteins assessed using the Olink Explore 3072 assay®. 10.9% of the participants died during a mean follow-up of 13.3 years, with the mean age at death of 70.1 years. The Spearman correlation between PAC proteomic age and chronological age was 0.77. PAC showed robust age-adjusted associations and predictions for all-cause mortality and the onset of various diseases in general and disease-free participants. The proteins associated with PAC proteomic age deviation were enriched in several processes related to the hallmarks of biological aging. Our results expand previous findings by showing that biological age acceleration, based on PAC, strongly predicts all-cause mortality and several incident disease outcomes. Particularly, it facilitates the evaluation of risk for multiple conditions in a disease-free population, thereby, contributing to the prevention of initial diseases, which vary among individuals and may subsequently lead to additional comorbidities.

Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Childhood obesity accelerates biological ageing: is oxidative stress a link?

Obesity is multifactorial pathophysiological condition with an imbalance in biochemical, immunochemical, redox status and genetic parameters values. We aimed estimate connection between relative leukocyte telomere lengths (rLRL) - biomarker of cellular aging with metabolic and redox status biomarkers values in a group of obese and lean children. The study includes 110 obese and 42 lean children and adolescents, both genders. The results suggested that rLTL are significantly shorter in obese, compared to lean group (p<0,01). Negative correlation of rLTL with total oxidant status, TOS (Spearman's ρ = -0.365, p<0.001) as well as with C reactive protein (Spearman's ρ= -0,363, p<0.001) were observed. Principal component analysis (PCA) extracted three distinct factors (i.e. principal components) entitled as: prooxidant factor with 35% of total variability; antioxidant factor with 30% of total variability and lipid antioxidant - biological ageing factor with 12% of the total variability. The most important predictor of body mass index (BMI) >30kg/m2 according to logistic regression analysis was PCA derived antioxidant factor's score (OR: 1.66, 95th Cl: 1.05-2.6, p=0.029). PCA analysis confirmed oxidative stress importance in biological ageing caused by obesity and its multiple consequences related to prooxidants augmentation and antioxidants exhaustion and gave us clear signs of disturbed cellular homeostasis deepness, even before any overt disease occurrence.

Examining the Effects of Nutrient Supplementation on Metabolic Pathways via Mitochondrial Ferredoxin in Aging Ovaries

As women age, oocytes are susceptible to a myriad of dysfunctions, including mitochondrial dysfunction, impaired DNA repair mechanisms, epigenetic alterations, and metabolic disturbances, culminating in reduced fertility rates among older individuals. Ferredoxin (FDX) represents a highly conserved iron–sulfur (Fe–S) protein essential for electron transport across multiple metabolic pathways. Mammalian mitochondria house two distinct ferredoxins, FDX1 and FDX2, which share structural similarities and yet perform unique functions. In our investigation into the regulatory mechanisms governing ovarian aging, we employed a comprehensive multi-omics analysis approach, integrating spatial transcriptomics, single-cell RNA sequencing, human ovarian pathology, and clinical biopsy data. Previous studies have highlighted intricate interactions involving excessive lipid peroxide accumulation, redox-induced metal ion buildup, and alterations in cellular energy metabolism observed in aging cells. Through a multi-omics analysis, we observed a notable decline in the expression of the critical gene FDX1 as ovarian age progressed. This observation prompted speculation regarding FDX1’s potential as a promising biomarker for ovarian aging. Following this, we initiated a clinical trial involving 70 patients with aging ovaries. These patients were administered oral nutritional supplements consisting of DHEA, ubiquinol CoQ10, and Cleo-20 T3 for a period of two months to evaluate alterations in energy metabolism regulated by FDX1. Our results demonstrated a significant elevation in FDX1 levels among participants receiving nutritional supplementation. We hypothesize that these nutrients potentiate mitochondrial tricarboxylic acid cycle (TCA) activity or electron transport chain (ETC) efficiency, thereby augmenting FDX1 expression, an essential electron carrier in metabolic pathways, while concurrently mitigating lipid peroxide accumulation and cellular apoptosis. In summary, our findings underscore the potential of nutritional intervention to enhance in vitro fertilization outcomes in senescent cells by bolstering electron transport proteins, thus optimizing energy metabolism and improving oocyte quality in aging women.

Reliable detection of stochastic epigenetic mutations and associations with cardiovascular aging.

Stochastic epigenetic mutations (SEMs) have been proposed as novel aging biomarkers to capture heterogeneity in age-related DNA methylation changes. SEMs are defined as outlier methylation patterns at cytosine-guanine dinucleotide sites, categorized as hypermethylated (hyperSEM) or hypomethylated (hypoSEM) relative to a reference. Because SEMs are defined by their outlier status, it is critical to differentiate extreme values due to technical noise or data artifacts from those due to real biology. Using technical replicate data, we found SEM detection is not reliable: across 3 datasets, 24 to 39% of hypoSEM and 46 to 67% of hyperSEM are not shared between replicates. We identified factors influencing SEM reliability-including blood cell type composition, probe beta-value statistics, genomic location, and presence of SNPs. We used these factors in a training dataset to build a machine learning-based filter that removes unreliable SEMs, and found this filter enhances reliability in two independent validation datasets. We assessed associations between SEM loads and aging phenotypes in the Framingham Heart Study and discovered that associations with aging outcomes were in large part driven by hypoSEMs at baseline methylated probes and hyperSEMs at baseline unmethylated probes, which are the same subsets that demonstrate highest technical reliability. These aging associations were preserved after filtering out unreliable SEMs and were enhanced after adjusting for blood cell composition. Finally, we utilized these insights to formulate best practices for SEM detection and introduce a novel R package, SEMdetectR, which uses parallel programming for efficient SEM detection with comprehensive options for detection, filtering, and analysis.

Early life exposure to mercury and relationships with telomere length and mitochondrial DNA content in European children

BackgroundTelomere length (TL) and mitochondrial function expressed as mitochondrial DNA copy number (mtDNAcn) are biomarkers of aging and oxidative stress and inflammation, respectively. Methylmercury (MeHg), a common pollutant in fish, induces oxidative stress. We hypothesized that elevated oxidative stress from exposure to MeHg decreases mtDNAcn and shortens TL. MethodsStudy participants are 6–11-year-old children from the HELIX multi-center birth cohort study, comprising six European countries. Prenatal and postnatal total mercury (THg) concentrations were measured in blood samples, TL and mtDNAcn were determined in child DNA. Covariates and confounders were obtained by questionnaires. Robust regression models were run, considering sociodemographic and lifestyle covariates, as well as fish consumption. Sex, ethnicity, and fish consumption interaction models were also run. ResultsWe found longer TL with higher pre- and postnatal THg blood concentrations, even at low-level THg exposure according to the RfD proposed by the US EPA. The prenatal association showed a significant linear relationship with a 3.46 % increase in TL for each unit increased THg. The postnatal association followed an inverted U-shaped marginal non-linear relationship with 1.38 % an increase in TL for each unit increased THg until reaching a cut-point at 0.96 μg/L blood THg, from which TL attrition was observed. Higher pre- and postnatal blood THg concentrations were consistently related to longer TL among cohorts and no modification effect of fish consumption nor children's sex was observed. No association between THg exposure and mtDNAcn was found. DiscussionWe found evidence that THg is associated with TL but the associations seem to be time- and concentration-dependent. Further studies are needed to clarify the mechanism behind the telomere changes of THg and related health effects.

Neuroprotection of macamide in a mouse model of Alzheimer’s disease involves Nrf2 signaling pathway and gut microbiota

The underlying mechanisms of macamide’s neuroprotective effects in Alzheimer’s disease (AD) were investigated in the paper. Macamides are considered as unique ingredients in maca. Improvement effects and mechanisms of macamide on cognitive impairment have not been revealed. In this study, Vina 1.1.2 was used for docking to evaluate the binding abilities of 12 main macamides to acetylcholinesterase (AChE). N-benzyl-(9Z,12Z)-octadecadienamide (M 18:2) was selected to study the following experiments because it can stably bind to AChE with a strong binding energy. The animal experiments showed that M 18:2 prevented the scopolamine (SCP)-induced cognitive impairment and neurotransmitter disorders, increased the positive rates of Nrf2 and HO-1 in hippocampal CA1, improved the synaptic plasticity by maintaining synaptic morphology and increasing the synapse density. Moreover, the contents of IL-1β, IL-6, and TNF-α in the hippocampus, serum, and colon were reduced by M 18:2. Furthermore, M 18:2 promoted colonic epithelial integrity and partially restored the composition of the gut microbiota to normal, including decreased genera Clostridiales_unclassified and Lachnospiraceae_unclassified, as well as increased genera Muribaculaceae_unclassified, Muribaculum, Alistipes, and Bacteroides, which may be the possible biomarkers of cognitive aging. In summary, M 18:2 exerted neuroprotective effects on SCP-induced AD mice possibly via activating the Nrf2/HO-1 signaling pathway and modulating the gut microbiota.

Conditional independence as a statistical assessment of evidence integration processes.

Intuitively, combining multiple sources of evidence should lead to more accurate decisions than considering single sources of evidence individually. In practice, however, the proper computation may be difficult, or may require additional data that are inaccessible. Here, based on the concept of conditional independence, we consider expressions that can serve either as recipes for integrating evidence based on limited data, or as statistical benchmarks for characterizing evidence integration processes. Consider three events, A, B, and C. We find that, if A and B are conditionally independent with respect to C, then the probability that C occurs given that both A and B are known, P(C|A, B), can be easily calculated without the need to measure the full three-way dependency between A, B, and C. This simplified approach can be used in two general ways: to generate predictions by combining multiple (conditionally independent) sources of evidence, or to test whether separate sources of evidence are functionally independent of each other. These applications are demonstrated with four computer-simulated examples, which include detecting a disease based on repeated diagnostic testing, inferring biological age based on multiple biomarkers of aging, discriminating two spatial locations based on multiple cue stimuli (multisensory integration), and examining how behavioral performance in a visual search task depends on selection histories. Besides providing a sound prescription for predicting outcomes, this methodology may be useful for analyzing experimental data of many types.

Exploring the Causal Effects of Mineral Metabolism Disorders on Telomere and Mitochondrial DNA: A Bidirectional Two-Sample Mendelian Randomization Analysis

The aim of this study was to assess the causal relationships between mineral metabolism disorders, representative of trace elements, and key aging biomarkers: telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN). Utilizing bidirectional Mendelian randomization (MR) analysis in combination with the two-stage least squares (2SLS) method, we explored the causal relationships between mineral metabolism disorders and these aging indicators. Sensitivity analysis can be used to determine the reliability and robustness of the research results. The results confirmed that a positive causal relationship was observed between mineral metabolism disorders and TL (p &lt; 0.05), while the causal relationship with mtDNA-CN was not significant (p &gt; 0.05). Focusing on subgroup analyses of specific minerals, our findings indicated a distinct positive causal relationship between iron metabolism disorders and both TL and mtDNA-CN (p &lt; 0.05). In contrast, disorders in magnesium and phosphorus metabolism did not exhibit significant causal effects on either aging biomarker (p &gt; 0.05). Moreover, reverse MR analysis did not reveal any significant causal effects of TL and mtDNA-CN on mineral metabolism disorders (p &gt; 0.05). The combination of 2SLS with MR analysis further reinforced the positive causal relationship between iron levels and both TL and mtDNA-CN (p &lt; 0.05). Notably, the sensitivity analysis did not indicate significant pleiotropy or heterogeneity within these causal relationships (p &gt; 0.05). These findings highlight the pivotal role of iron metabolism in cellular aging, particularly in regulating TL and sustaining mtDNA-CN, offering new insights into how mineral metabolism disorders influence aging biomarkers. Our research underscores the importance of trace element balance, especially regarding iron intake, in combating the aging process. This provides a potential strategy for slowing aging through the adjustment of trace element intake, laying the groundwork for future research into the relationship between trace elements and healthy aging.

Elevated tissue status of omega-3 fatty acids protects against age-related telomere attrition in fat-1 transgenic mice

Leukocyte telomere length (LTL) is a biomarker of aging that may be influenced by dietary factors. Omega-3 fatty acids (n-3 FA) have been suggested to affect LTL. However, research on this effect has been inconclusive. The aim of the study was to test the hypothesis about the positive effect of n-3 FA on LTL. Fat-1 transgenic mice, which can convert omega-6 fatty acids (n-6 FA) to n-3 FA and have elevated levels of endogenous n-3 FA in their tissues, were used to study the effects of n-3 FA on LTL at different ages. Blood samples from 10-month-old wild-type (WT) mice (n=10) and fat-1 mice (n=10) and 3-month-old WT mice (n=5) and fat-1 mice (n=5) were used to measure relative and absolute LTL. The levels of proteins critical for telomere maintenance were examined by Western blot analysis. Fat-1 transgenic mice had longer leukocyte telomeres than their WT siblings, suggesting a slower rate of age-related telomere shortening in fat-1 mice. In animals aged 10 months, the LTL was significantly longer in fat-1 than in WT mice (mean±SEM; relative LTL: WT=1.00±0.09 vs. fat-1: 1.25±0.05, P=0.031; absolute LTL: WT=64.41±6.50 vs. fat-1: 78.53±3.86, P=0.048). The difference in LTL observed in three-month-old mice was insignificant, however the mean LTL was still longer in fat-1 mice than in the WT mice. Fat-1 mice also had abundant levels of two shelterin proteins: TRF1 (27%, P=0.028) and TRF2 (47%, P=0.040) (telomeric repeat binding factor 1 and 2) compared to WT animals. This study, for the first time in a unique animal model free of dietary confounders, has demonstrated that increased levels of n-3 FA in tissues can reduce telomere attrition. The data presented indicate the possibility of using omega-3 fatty acids to reduce accelerated telomere attrition and, consequently, counteract premature aging and reduce the risk of age-related diseases.

Clinical validation of C12FDG as a marker associated with senescence and osteoarthritic phenotypes.

Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C12FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C12FDG+ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C12FDG+ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C12FDG+ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C12FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.

Single-sEV profiling identifies the TACSTD2 + sEV subpopulation as a factor of tumor susceptibility in the elderly

BackgroundAging is a very complex physiological phenomenon, and sEVs are involved in the regulation of this mechanism. Serum samples from healthy individuals under 30 and over 60 years of age were collected to analyze differences in sEVs proteomics.ResultsBased on PBA analysis, we found that sEVs from the serum of elderly individuals highly express TACSTD2 and identified a subpopulation marked by TACSTD2. Using ELISA, we verified the upregulation of TACSTD2 in serum from elderly human and aged mouse. In addition, we discovered that TACSTD2 was significantly increased in samples from tumor patients and had better diagnostic value than CEA. Specifically, 9 of the 13 tumor groups exhibited elevated TACSTD2, particularly for cervical cancer, colon cancer, esophageal carcinoma, liver cancer and thyroid carcinoma. Moreover, we found that serum sEVs from the elderly (especially those with high TACSTD2 levels) promoted tumor cell (SW480, HuCCT1 and HeLa) proliferation and migration.ConclusionTACSTD2 was upregulated in the serum of elderly individuals and patients with tumors, and could serve as a dual biomarker for aging and tumors.

Astaxanthin attenuates UV-irradiation aging process via activating JNK-1/DAF-16 in Caenorhabditis elegans.

Astaxanthin (AST) is a xanthophyll carotenoid with strong oxidation resistance, which can effectively scavenge various free radicals and protect organisms from oxidative damage. AST is also known to have prominent anti-aging effects, but the underlying mechanism of AST in anti-radiation aging is largely unknown. In this work, we applied ultraviolet (UV) irradiation to accelerate the aging of Caenorhabditis elegans (C. elegans) and treated the nematodes with AST to explore whether and how AST could attenuate the radiation-induced aging effect. Our results showed that AST improved the survival rate of C. elegans, reduced the aging biomarkers, and alleviated the mitochondrial dysfunction caused by the irradiation. Based on the transcriptome sequencing analysis, we identified that the key genes regulated by AST were involved in JNK-MAPK and DAF-16 longevity signaling pathways. Furthermore, we employed jnk-1 and daf-16 mutants and verified the role of the JNK-1/DAF-16 signaling pathway in the anti-aging effect. As such, this study has not only demonstrated that AST can resist the aging process caused by UV-irradiation but also revealed the anti-aging mechanism of AST through JNK-1/DAF-16 activation in C. elegans.

Epigenetic and biological age acceleration in a pediatric cohort of atopic dermatitis

BackgroundAtopic dermatitis is a chronic inflammatory skin disease resulting from the complex interplay of genetic and environmental factors, meriting exploration using temporally-dynamic biomarkers. DNA methylation-based algorithms have been trained to accurately estimate biological age, and deviation of predicted age from true age (epigenetic age acceleration) has been implicated in several inflammatory diseases, including asthma. ObjectiveTo determine the role of epigenetic and biological aging, telomere length, and epigenetically-inferred abundance of seven inflammatory biomarkers in atopic dermatitis. MethodsWe performed DNA methylation-based analyses in a pediatric atopic dermatitis cohort (n=24, mean age 2.56±0.28y) and age-matched healthy subjects (n=24, mean age 2.09±0.15y) derived from blood, using five validated algorithms that assess epigenetic (Horvath, Skin&Blood) and biological age (PhenoAge, GrimAge), telomere length (TelomereLength), and inflammatory biomarker levels. ResultsEpigenetic and biological age, but not telomere length, were accelerated in atopic dermatitis patients for four algorithms: Horvath (+0.88 years; 95%CI 0.33-1.4; p=2.3x10-3), Skin&Blood (+0.95 years; 95%CI 0.67-1.2; p=1.8x10-8), PhenoAge (+8.2 years; 95%CI 3.4-13.0; p=1.3x10-3), and GrimAge (+1.8 years 95%CI 0.22-3.3; p=0.026). Moreover, patients had increased levels of beta-2-microglobulin (+47,584.4 ng/ml; p=0.029), plasminogen activation inhibitor 1 (+3,432.9 ng/ml; p=1.1x10-5) and cystatin C (+31,691 ng/ml; p=4.0x10-5), while levels of tissue inhibitor metalloproteinase 1 (-370.7 ng/ml; p=7.5x10-4) were decreased versus healthy subjects. ConclusionDNA methylation changes associated with epigenetic and biological aging, and inflammatory proteins appear early in life in pediatric atopic dermatitis and may be relevant clinical biomarkers of pathophysiology.

The effects of computerized cognitive training in older adults' cognitive performance and biomarkers of structural brain aging.

Cognitive Training (CT) has been investigated as a means of delaying age-related cognitive decline in older adults. However, its impact on biomarkers of age-related structural brain atrophy has rarely been investigated, leading to a gap in our understanding of the linkage between improvements in cognition and brain plasticity. This study aimed to explore the impact of CT on cognitive performance and brain structure in older adults. 124 cognitively normal older adults recruited from two study sites were randomly assigned to either an adaptive CT (n=60) or a casual game training (Active Control, AC, n= 64). After 10 weeks of training, CT participants showed greater improvements in the overall cognitive composite score (Cohen's d=.66, p<.01) with non-significant benefits after 6 months from the completion of training (Cohen's d=.36, p=.094). The CT group showed significant maintenance of the caudate volume as well as significant maintained fractional anisotropy (FA) in the left Internal Capsule (IC) and in left Superior Longitudinal Fasciculus (SLF) compared to the AC group. The AC group displayed an age-related decrease in these metrics of brain structure. Results from this multi-site clinical trial demonstrate that the CT intervention improves cognitive performance and helps maintain caudate volume and integrity of white matter regions that are associated with cognitive control, adding to our understanding of the changes in brain structure contributing to changes in cognitive performance from adaptive CT.

Magnetoencephalography-derived oscillatory microstate patterns across lifespan: the Cambridge centre for ageing and neuroscience cohort.

The aging brain represents the primary risk factor for many neurodegenerative disorders. Whole-brain oscillations may contribute novel early biomarkers of aging. Here, we investigated the dynamic oscillatory neural activities across lifespan (from 18 to 88 years) using resting Magnetoencephalography (MEG) in a large cohort of 624 individuals. Our aim was to examine the patterns of oscillation microstates during the aging process. By using a machine-learning algorithm, we identify four typical clusters of microstate patterns across different age groups and different frequency bands: left-to-right topographic MS1, right-to-left topographic MS2, anterior-posterior MS3 and fronto-central MS4. We observed a decreased alpha duration and an increased alpha occurrence for sensory-related microstate patterns (MS1 & MS2). Accordingly, theta and beta changes from MS1 & MS2 may be related to motor decline that increased with age. Furthermore, voluntary 'top-down' saliency/attention networks may be reflected by the increased MS3 & MS4 alpha occurrence and complementary beta activities. The findings of this study advance our knowledge of how the aging brain shows dysfunctions in neural state transitions. By leveraging the identified microstate patterns, this study provides new insights into predicting healthy aging and the potential neuropsychiatric cognitive decline.

Determining the relationship of p16INK4a and additional molecular markers of aging with clinical frailty in hematologic malignancy.

Older adults with hematologic malignancies (HM) have unique challenges due to age and fitness. The primary aim of this pilot study was to benchmark the ability of multiple biomarkers of aging (p16, epigenetic clocks, T cell gene expression profiles, and T cell receptor excision circles (TREC) to identify frailty as measured by a clinical impairment index (I2) in patients with HM. 70 patients newly diagnosed with HM had peripheral blood T lymphocytes (PBTL) analyzed for p16INK4a expression using the OSU_Senescence Nanostring CodeSet. PBTL epigenetic age was measured using 7 epigenetic clocks, and TREC were quantified by qRT-PCR. A composite clinical impairment index (I2) was generated by combining values from 11 geriatric metrics (Independent Activities of Daily Living (iADL), physical health score, Short Physical Performance Battery (SPPB), Body Mass Index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, self-reported KPS, Blessed Orientation Memory Concentration (BOMC), polypharmacy, Mental Health Inventory (MHI)-17, Medical Outcomes Study (MOS) subscales). Clinical frailty was defined as a score of 7 or greater on the I2. Age-adjusted p16INK4a was similar in newly diagnosed patients and healthy controls (p > 0.1). PBTL p16INK4a levels correlated positively with the Hannum [r = 0.35, 95% CI (0.09-0.75); p adj. = 0.04] and PhenoAge [r = 0.37, 95% CI (0.11-0.59); p adj. = 0.04] epigenetic clocks. The discrimination ability of the I2 model was calculated using the area under the receiver operating characteristic curve (AUC). After adjusting for chronologic age and disease group, baseline p16INK4a [AUC = 0.76, 95% CI (0.56-0.98); p = 0.01], Hannum [AUC = 0.70, 95% CI (0.54-0.85); p = 0.01], PhenoAge [AUC = 0.71, 95% CI (0.55-0.86); p = 0.01], and DunedinPACE [AUC = 0.73, 95% CI (0.57-0.88); p =  < 0.01] measures showed the greatest potential to identify clinical frailty using the I2. Our pilot data suggest that multiple blood-based aging biomarkers have potential to identify frailty in older adults with HM. We developed the I2 index to quantify impairments across geriatric domains and discovered that PBTL p16, Hannum, PhenoAge, and DunedinPACE are promising indicators of frailty in HM.

High serum levels of CCL11/Eotaxin-1 are associated with diabetic sensorimotor polyneuropathy and peripheral nerve function but not with cardiac autonomic neuropathy in people with type 2 diabetes

ABSTRACT Aims To investigate whether higher serum CCL11/Eotaxin-1, a biomarker for aging and neurodegenerative and neuroinflammatory disorders, is associated with diabetic sensorimotor polyneuropathy (DSPN), peripheral nerve dysfunction, and cardiac autonomic neuropathy in people with type 2 diabetes. Methods This cross-sectional study included 106 patients with type 2 diabetes and 40 healthy controls, matched for the age and sex distribution of the diabetes group as a whole. The CC chemokines CCL11/Eotaxin-1 and CCL22/MDC were measured in fasting serum samples. DSPN and peripheral nerve function were assessed by neurological examination and nerve conduction studies, and cardiac autonomic function, by heart rate variability (HRV) and corrected QT (QTc) time. The cardio-ankle vascular index (CAVI) was measured as a marker for arterial stiffness Results Serum CCL11/Eotaxin-1 levels were significantly higher in diabetic patients than in healthy controls (183 ± 63.5 vs. 113.1 ± 38.5 pg/ml, p < 0.001), but serum CCL22/MDC levels were not significantly different between the two groups. In the diabetes group, the serum CCL11/Eotaxin-1 level was positively correlated with ulnar and sural nerve conduction velocities (p = 0.0009, p = 0.0208, respectively) and sensory nerve action potential (p = 0.0083), and CAVI (p = 0.0005), but not with HRV indices or QTc time, and serum CCL22/MDC was not significantly correlated with any indices of nerve conduction. In a model adjusted for age and duration of diabetes, serum CCL11/Eotaxin-1 was still associated with ulnar nerve conduction velocity (p = 0.02124). Serum CCL11/Eotaxin-1, but not CCL22/MDC, was significantly higher in patients with than in those without DSPN (208.2 ± 71.6 vs. 159.1 ± 45.1 pg/ml, respectively; p < 0.0001). Conclusions Serum CCL11/Eotaxin-1 is elevated in patients with DSPN and is associated with peripheral nerve dysfunction, in particular sensory nerve conduction velocity, suggesting that serum CCL11/Eotaxin 1 May be a potential biomarker for DSPN. Clinical Trial Registration University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000040631).

Multimodal brain age prediction using machine learning: combining structural MRI and 5-HT2AR PET-derived features.

To better assess the pathology of neurodegenerative disorders and the efficacy of neuroprotective interventions, it is necessary to develop biomarkers that can accurately capture age-related biological changes in the human brain. Brain serotonin 2A receptors (5-HT2AR) show a particularly profound age-related decline and are also reduced in neurodegenerative disorders, such as Alzheimer's disease. This study investigates whether the decline in 5-HT2AR binding, measured in vivo using positron emission tomography (PET), can be used as a biomarker for brain aging. Specifically, we aim to (1) predict brain age using 5-HT2AR binding outcomes, (2) compare 5-HT2AR-based predictions of brain age to predictions based on gray matter (GM) volume, as determined with structural magnetic resonance imaging (MRI), and (3) investigate whether combining 5-HT2AR and GM volume data improves prediction. We used PET and MR images from 209 healthy individuals aged between 18 and 85years (mean = 38, std = 18) and estimated 5-HT2AR binding and GM volume for 14 cortical and subcortical regions. Different machine learning algorithms were applied to predict chronological age based on 5-HT2AR binding, GM volume, and the combined measures. The mean absolute error (MAE) and a cross-validation approach were used for evaluation and model comparison. We find that both the cerebral 5-HT2AR binding (mean MAE = 6.63years, std = 0.74years) and GM volume (mean MAE = 6.95years, std = 0.83years) predict chronological age accurately. Combining the two measures improves the prediction further (mean MAE = 5.54years, std = 0.68). In conclusion, 5-HT2AR binding measured using PET might be useful for improving the quantification of a biomarker for brain aging.

Accelerated epigenetic age is associated with whole-brain functional connectivity and impaired cognitive performance in older adults

While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.