Aging Cell最新文献

Shadfar, S., Farzana, F., Saravanabavan, S., et al. (2025), The Redox Activity of Protein Disulphide Isomerase Functions in Non-Homologous End-Joining Repair to Prevent DNA Damage. Aging Cell, 24: e70079. https://doi.org/10.1111/acel.70079.

In the published version of the above article, we would like to make the following corrections:

1. Comet assay—Figure 3C was labelled incorrectly.

The third column of Figure 3C was incorrectly labelled as ‘PDI + NU7441’; this should be corrected to ‘Etoposide + NU7441’.

2. Comet assay—Figure 3D was labelled incorrectly.

We apologize for these errors.

Stem cell-derived extracellular vesicles (EVs) show promise as a therapeutic approach for neurodegenerative diseases, particularly Alzheimer's Disease (AD), where traditional regenerative interventions have achieved limited success. Our previous research demonstrated the neuroprotective benefits of human neural stem cell (hNSC)-derived EVs in 2- and 6-month-old AD mice (5xFAD) that exibited improved cognitive function and reduced AD-related neuropathology. This study aimed to compare the neuroprotective efficacy of EVs derived from two human cell lines: hNSCs from H9 embryonic stem cells and human iPSC-derived microglia (iMGLs). Additionally, we investigated the efficacy of an expanded EV treatment paradigm at subsequently longer time points. Three-month-old 5xFAD mice received weekly retro-orbital vein injections of either hNSC- or iMGL-derived EVs for 4 weeks. Cognitive function testing revealed comparable cognitive improvements in both EV treatment groups compared to vehicle-injected AD mice. Both iMGL- and hNSC-derived EVs significantly reduced amyloid beta plaques, astrogliosis, and microglial activation, while restoring synaptophysin and postsynaptic density protein PSD-95 to control levels in AD brains. Gene expression analysis revealed significantly reduced neuroinflammation and elevated neuroprotective signatures following both EV treatments. MicroRNA analysis of the EV-derived cargo revealed unique and shared miRNA signatures associated with differentially expressed genes in both cell lines. These findings demonstrate the feasibility and neuroprotective benefits of recurrent systemic injections of EVs derived from human NSCs and differentiated human microglia lines in alleviating cognitive dysfunction and neuropathology in Alzheimer's disease.

Nicotinamide adenine dinucleotide (NAD) has garnered significant attention in recent years due to its central role in cellular metabolism and its potential as a supplement to promote health and longevity. While numerous human studies indicate that NAD supplementation offers benefits with minimal or no side effects, some studies show no observable advantages. This discrepancy highlights the importance of identifying individuals who are most likely to benefit from NAD-based interventions. One critical factor in the efficacy of NAD supplementation relates to its declining levels in certain individuals, driven by various causes of NAD depletion. NAD is a vital substrate for numerous enzymatic processes, notably those involving poly-ADP-ribose polymerase (PARP) enzymes. PARP enzymes, especially PARP1, play a pivotal role in DNA repair by detecting and signaling DNA damage. Excessive activation of PARP, hyperparylation, is frequently observed in DNA repair disorders where DNA damage accumulates due to defective repair mechanisms. This hyperparylation has been implicated in the pathogenesis of several premature aging diseases. Such conditions often involve defective DNA repair pathways, elevated parylation levels, and associated mitochondrial dysfunction, factors that contribute to accelerated cellular aging. In model systems that mimic these disorders, as well as in emerging human studies, NAD supplementation has demonstrated promising benefits, including improved DNA repair capacity and improved mitochondrial function. These findings suggest that NAD supplementation could serve as an effective intervention for rare genetic diseases characterized by premature aging and DNA repair deficiencies. More broadly, these insights open new avenues for general aging research.

Osteoporosis is characterized by reduced bone mass and structural deterioration, leading to increased fracture risk, particularly in older adults. Parathyroid hormone (PTH) is a widely used anabolic therapy for osteoporosis; however, rapid bone loss after treatment discontinuation presents a significant clinical challenge. Cellular senescence has been implicated in age-related bone fragility. However, its role in PTH-induced bone remodeling and post-treatment bone loss remains unclear. This study aimed to investigate the effects of PTH administration frequency on bone microarchitecture and cellular senescence in young and aged mice. High-frequency PTH administration improved trabecular bone volume in both age groups, but caused cortical bone thinning, increased porosity, and elevated osteoclast activity in aged mice. PTH induces senescent osteoblast-lineage-enriched cell accumulation in aged, but not young mice, accompanied by upregulation of senescence-associated markers and activation of the mechanistic Target of Rapamycin Complex 1 pathway. Co-administration of the senolytic agents dasatinib and quercetin during PTH treatment reduced senescent cell burden, improved cortical porosity, and mitigated rapid bone loss after PTH discontinuation in aged mice. These findings indicate that senescent osteoblast-lineage-enriched cells contribute to bone fragility and post-treatment bone loss in aged individuals, suggesting that targeting senescence may enhance the efficacy and sustainability of PTH therapy for osteoporosis.

DNA methylation variation is associated with chronological ageing. Calorie restriction (CR) prolongs lifespan and healthspan in many species. Our hypothesis is that CR has an impact on DNA methylation patterns with increased CR leading to slower epigenetic ageing. We studied the effects of graded CR in male C57BL/6J mice on liver DNA methylation. Mice were fed ad libitum (AL) in the dark-phase or restricted by 10%, 20%, 30% or 40% from 5-months old for 19-months. Livers were collected in surviving mice at 24-months old and DNA methylation measured. Comparisons were made to 8-month-old AL fed mice. DNA methylation was significantly related to graded CR in a subset of cytosine-guanine dinucleotide (CpG) sites. In a substantially similar subset of CpG sites, DNA methylation in 24-month-old mice fed 40CR moved towards the values in 8-month-old AL fed mice, resulting in an average effective epigenetic age of about 12-months, indicative of slower epigenetic ageing. DNA methylation at several CpG sites was sensitive to glucose intolerance and circulating insulin levels, consistent with the impact of this nutrient sensing pathway on ageing. We focussed on genes where multiple CpG sites were significant for DNA methylation change with CR and found many have been implicated in age-associated liver diseases. In summary, the benefits of CR include modification of epigenetic signatures in the direction of slower ageing, consistent with the life extending effects of CR. Whether this effect is causal for the life extension under CR, and the mechanism by which it occurs remain unanswered questions.

Cellular senescence, defined as the irreversible arrest of cell proliferation in response to stress, contributes to tissue dysfunction and drives the progression of age-related diseases. Accurate detection of senescent states is therefore essential for understanding aging mechanisms and identifying therapeutic targets. However, conventional laboratory assays are time-consuming and difficult to scale. Here, we present SenSeqNet, a deep learning framework that predicts cellular senescence directly from protein sequences. SenSeqNet integrates embeddings from the Evolutionary Scale Modeling (ESM-2) with a hybrid LSTM–CNN architecture to capture both sequential and higher-order structural features. The model achieved 86.43% accuracy in independent testing, outperforming traditional machine learning and deep learning approaches. Importantly, the high-confidence genes predicted by SenSeqNet were significantly enriched in canonical senescence-associated pathways, indicating that the model captures biologically coherent regulatory programs rather than overfitting to sequence labels. These results establish SenSeqNet as a robust and biologically informed tool for senescence detection and provide a foundation for accelerating research into aging and age-related therapeutics.

Somatic differences in mitochondrial DNA (mtDNA) have been observed with aging and between brain regions for mutations, structural variation, and abundance, which are represented by single nucleotide variants (SNVs), large deletions, and copy number, respectively. We used bioinformatic methods to interrogate mtDNA changes and their relation to cortical and cerebellar aging using whole genome sequencing data from the North American Brain Expression Consortium. This dataset contained 292 unpaired postmortem samples from frontal cortex (n = 143) and cerebellum (n = 149), ranging in age from 0.4 to 100 years and without neurological diagnoses (i.e., controls). Our analyses included (a) evaluation of mtDNA copy number using fastMitoCalc; (b) quantification of large mtDNA deletions using Splice-Break2; (c) analysis of homoplasmic and heteroplasmic SNVs; and (d) mitochondrial genome-wide associations between SNVs and large deletions. For mtDNA deletions specifically, we expanded our previous analyses to include the predicted effects on mitochondrial complexes (I–V), mitochondrial-derived microproteins, and tRNAs. MtDNA copy number significantly decreased in the cortex with age. MtDNA deletions increased in both brain regions with age, with a more dramatic slope in the cortex. These large deletions had significantly more effect on mitochondrial Complex I than other mitochondrial-encoded complexes (III–V); likewise, deletions had significantly more effect on mtALTND4 and SHMOOSE than other annotated microproteins. Heteroplasmic SNVs increased with age in cortex but not cerebellum. Finally, three common SNVs (T14798C, G12372A, and C14766T) significantly associated with large mtDNA deletions (7816–14,807, 12,369–14,004, and 8775–14,771) and altered the length of the repeat sequence associated with the 5′ or 3′ breakpoint.

Targeting senescent pancreatic β-cells represents a promising therapeutic avenue for age-related diabetes; however, current anti-senescence strategies often compromise β-cell mass. In this study, human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve β-cell integrity. We aimed to systemically delineate the molecular mechanisms underlying hAMSC-sEV-mediated reversal of β-cell senescence in age-related diabetes. In oxidative stress-induced and naturally aged β-cell models, hAMSC-sEVs mitigated senescence-associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed β-cell functional decline by reducing senescent β-cell populations, reinstating β-cell identity markers, and suppressing senescence-associated secretory phenotype (SASP) component production. Mechanistic investigations revealed that the miR-21-5p-enriched hAMSC-sEVs directly target the interleukin (IL)-6 receptor α subunit (IL-6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation at tyrosine 705 and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3-mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age-related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR-21-5p/IL-6RA/STAT3/MCU axis in this regulatory cascade. Our findings reveal hAMSC-sEVs as a novel senotherapeutic strategy for age-related diabetes, elucidating the pivotal role of miR-21-5p-driven epigenetic–mitochondrial calcium homeostasis in reversing β-cell dysfunction, establishing a framework for targeting cellular senescence in metabolic disorders.

Cochlear nerve demyelination is a significant pathogenic factor of age-related hearing loss (ARHL), and Schwann cell (SC) migration function plays a key role in the maintenance and regeneration of myelin sheaths. Here, we found that bone marrow stromal antigen 2 (BST2) is significantly upregulated in cochlear SCs during aging following demyelination and hearing loss. However, specific knockdown of BST2 in SCs could obviously improve the SCs migration and the myelin sheath structure manifested in a reduction of E-cadherin expression and increased N-cadherin expression. Further mechanism analysis revealed that POU class 6 homeobox 1 (POU6F1) expression via the NF-κB pathwayleads to enhanced SCs migration ability and increased expression of the myelin protein zero (MPZ), thereby alleviating nerve demyelination and rescuing hearing loss. This study identifies BST2 as a novel therapeutic target for ARHL intervention. In conclusion, the specific downregulation of BST2 in cochlear SCs rescues age-related demyelination and hearing loss by activating the POU6F1/NF-κB pathway, thereby enhancing SC migration capacity and promoting MPZ expression.

Human brain aging involves a variety of cellular and synaptic changes, but how these changes affect brain function and signals remains poorly understood due to experimental limitations in humans, meriting the use of detailed computational models. We identified key human cellular and synaptic changes occurring with age from previous studies, including a loss of inhibitory cells, NMDA receptors, and spines. We integrated these changes into our detailed human cortical microcircuit models and simulated activity in middle age (~50 years) and older (~70 years) microcircuits, and linked the altered mechanisms to reduced spike rates and impaired signal detection. We then simulated EEG potentials arising from the microcircuit activity and found that the emergent power spectral changes due to these aging cellular mechanisms reproduced most of the resting-state EEG biomarkers seen in human aging, including reduced aperiodic offset, exponent, and periodic peak center frequency. Using machine learning, we demonstrated that the changes to the cellular and synaptic aging mechanisms can be estimated accurately from the simulated EEG aging biomarkers. Our results link cellular and synaptic mechanisms of aging with impaired cortical function and physiological biomarkers in clinically relevant brain signals.