Jian-Ping Cai

Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)—a major product of NTP oxidation—not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.

Critical illness is characterized by acute, life-threatening organ dysfunction and a highly heterogeneous clinical course [1]. Even after initial stabilization, patients may remain at risk of persi...

Aging induces immunosenescence, a progressive decline in immune function underpinning age‐related pathogen vulnerability, yet T/B cell receptor (TCR/BCR) repertoire remodeling during aging remains incompletely characterized, especially in non‐European populations. Additionally, SARS‐CoV‐2 may perturb immune homeostasis and accelerate aging, but its impact on immune repertoire aging is unclear. Here, we analyzed leukocyte DNA from 195 healthy Chinese individuals (25–93 years) and 94 post‐COVID‐19 cases via CDR3 high‐throughput sequencing. Aging correlated with shorter CDR3 sequences, reduced VDJ gene/V‐J combination diversity, declining TCR/BCR clonotype counts (179.7/507 per 3 years), expanded hyperexpanded TCR/large BCR clones, and reduced diversity (critical turning point ~60 years). These changes were intensified post‐COVID‐19, with altered amino acid usage, diminished diversity, and expanded SARS‐CoV‐2/ Mycobacterium tuberculosis ‐related clones. We developed a LightGBM‐based immune repertoire aging clock, validating accelerated biological aging (increased cAgeDiff) and reduced intrinsic capacity in post‐COVID‐19 individuals. Our findings reveal age‐dependent immune repertoire remodeling exacerbated by COVID‐19, deepening understanding of immunosenescence and post‐viral dysfunction, with potential clinical applications for age‐related immune decline and post‐COVID‐19 syndromes.

Background: Diabetic cardiomyopathy (DCM) is a major complication of diabetes; however, the mechanisms underlying cardiac immune microenvironment dysregulation in early DCM remain to be systematically elucidated. Methods: An early-stage DCM mouse model was induced by a high-fat/high-fructose regimen combined with streptozotocin, characterized by molecular pathology (oxidative stress, apoptosis) without overt cardiac dysfunction. Using an integrated approach including single-cell RNA sequencing, flow cytometry, and immunofluorescence, we systematically analyzed and validated the pathological remodeling of the cardiac immune microenvironment at the transcriptional, protein expression, and tissue-in-situ levels. Results: In early DCM, the cardiac immune microenvironment becomes already dysregulated, with significant increases in monocytes, dendritic cells, basophils, NK cells, and T cells. Macrophages, as the central regulators of cardiac immune homeostasis, undergo profound remodeling during this stage. On the one hand, apoptosis of a subset of resident macrophages leads to a deficiency in endogenous protective mechanisms. On the other hand, macrophage subsets derived from peripheral monocytes expand substantially and differentiate into functionally specialized subpopulations: pro-inflammatory (Ccr2⁺MHCII^hi), pro-fibrotic (Ccr2⁺Spp1⁺), and lipid-reprogrammed (Fabp4⁺) subsets. Further analysis revealed that the Ccr2⁺MHCII^hi macrophage subset may drive a self-amplifying cycle of inflammation by promoting monocyte recruitment. Collectively, these changes establish a self-sustaining pathological immune microenvironment that drives early cardiac injury. Conclusion: Using an early DCM mouse model, this study revealed a profound shift in the cardiac immune microenvironment from homeostasis toward inflammation-fibrosis-lipid reprogramming, with macrophage subset remodeling serving as a central driver of early injury. Targeting the recruitment signals mediated by Ccr2⁺MHCII^hi macrophages or protecting the homeostasis of resident macrophages may offer novel therapeutic strategies for intervening in the progression of diabetic cardiomyopathy. The diagram illustrates two conditions within the heart: homeostasis and early-stage diabetic cardiomyopathy. On the left, under homeostasis, various macrophages are labeled, including TLF plus Cxcl13 minus Mac and Ccr2 minus MHCIIhi Mac. These cells are distributed throughout the heart. On the right, early-stage diabetic cardiomyopathy shows changes in cell types and functions. Monocytes are depicted entering the heart, differentiating into various macrophages such as Ccr2 plus MHCIIhi Mac, which are pro-inflammatory, Ccr2 plus Spp1 plus Mac, which are pro-fibrotic and Fabp4 plus Mac, involved in lipid metabolism. Apoptosis is indicated in some cells. Additional immune cells like dendritic cells, natural killer cells, T cells and basophils are shown outside the heart, suggesting their involvement in the condition. The diagram highlights the shift in cellular composition and function between the two states.Diagram comparing heart cell types in homeostasis and early-stage diabetic cardiomyopathy.

Intrinsic capacity (IC), a composite measure of physical and mental capacities, reflects the functional manifestations of biological aging, yet large-scale population evidence on how IC varies throughout adulthood outside Western settings remains limited. Using data from 17,086 Chinese adults aged 25-89 years in the nationally representative PENG ZU cohort, we characterized age-related variation in IC and its associated factors. IC was assessed across five domains (locomotion, cognition, vitality, psychological, sensory) using self-reported data and physical performance tests. A composite IC score was generated using weighted domain scores and standardized to a 0-100 range. IC levels declined progressively with age, with a sharper decrease and greater variability observed after age 60 in both sexes. The mean IC score was 67.8 (SD = 14) for participants aged < 60 years and 48.6 (SD = 17) for those aged ≥ 60 years. Inflection points were identified at age 60 for men and 62 for women, with significantly faster decline thereafter. The coefficient of variation in IC scores increased with age and differed significantly between adjacent age groups after 60 years. Among those aged ≥ 60, only 6.0% retained high IC, whereas nearly one-third experienced moderate-to-severe loss. Locomotion, cognition, vitality, and sensory domains showed marked age-related decline, with the largest reductions in cognition (60.7%), followed by locomotion (52.9%), vitality (51.0%), and sensory function (39.5%) between ages 50-54 and 85-89, while the psychological domain remained stable. Multivariate ANOVA identified age, education, and health consciousness (assessed via self-reported beliefs about personal responsibility for maintaining health) as the top factors associated with IC. Older age was associated with lower IC, whereas higher education and greater health consciousness were associated with higher IC. Furthermore, health consciousness was inversely associated with ADL/IADL disability across all age groups. These findings identify around 60 years as a critical window for the preservation of intrinsic capacity in Chinese adults and highlight health consciousness as a promising modifiable correlate that merits further investigation in the context of healthy aging.

Background: This study leverages machine learning and cytokine profiles to differentiate liver and renal function abnormalities in the aging population, aiming for advancements in early detection techniques. Methods: The analysis involved data from 760 participants, employing logistic regression, random forest, lasso regression, extreme gradient boosting, and support vector machines to create diagnostic models. Cytokine levels were measured via ELISA, alongside liver and renal clinical function tests. The data were randomly split 3:1 into training and hold-out validation sets; Synthetic Minority Over-sampling Technique (SMOTE) was applied exclusively to the training set to mitigate class imbalance. Models were assessed on precision, recall, F1 score, specificity, and the area under the curve (AUC). Results: Lasso regression was notably effective in identifying renal function abnormalities, delivering AUCs of 0.895 for males and 0.940 for females, pointing to its robustness in feature selection and model accuracy. For liver function, logistic regression was most accurate, with AUCs of 0.918 for males and 0.794 for females, identifying VCAM-1, REG4, Thrombomodulin, Notch-3 for males, and GDF-15, LDL R, CA125, PON1 for females as key discriminative cytokines. These results illustrate the models’ capability in discerning critical biomarkers for early detection, with performance improved by SMOTE through correction of class imbalance in the training data. Conclusion: Integrating machine learning with cytokine profiling emerges as a highly promising method for early detection of liver and renal abnormalities in the aging population, suggesting significant potential for improving preventive healthcare outcomes.