Aging Cell最新文献

Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD⁺, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-¹³C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD⁺, NADH, and the NAD⁺/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD⁺ from NADH. These data suggest that NAD⁺-generating lipid metabolism reactions may help to maintain the NAD⁺/NADH ratio during healthy aging.

Despite advances in understanding molecular and cellular changes in the aging nervous system, the upstream drivers of these changes remain poorly defined. Here, we investigate the roles of non-neural tissues in neuronal aging, using the cutaneous PVD polymodal sensory neuron in Caenorhabditis elegans as a model. We demonstrate that during normal aging, PVD neurons progressively develop excessive dendritic branching, functionally correlated with age-related proprioceptive deficits. Our study reveals that decreased collagen expression, a common age-related phenomenon across species, triggers this process. Specifically, loss-of-function in dpy-5 or col-120, genes encoding cuticular collagens secreted to the epidermal apical surface, induces early-onset excessive dendritic branching and proprioceptive deficits. Adulthood-specific overexpression of dpy-5 or col-120 mitigates excessive branching in aged animals without extending lifespan, highlighting their specific roles in promoting neuronal health span. Notably, collagen reduction specifically drives excessive branching in select sensory neuron subclasses but does not contribute to PVD dendritic beading, another aging-associated neurodegenerative phenotype associated with distinct mechanosensitive dysfunction. Lastly, we identify that rig-3, an immunoglobulin superfamily member expressed in interneurons, acts upstream of collagen genes to maintain PVD dendritic homeostasis during aging, with collagen's regulatory role requiring daf-16/FOXO. These findings reveal that age-related collagen reduction cues neuronal aging independently of collagen's traditional structural support function, possibly involving bi-directional communication processes between neurons and non-neuronal cells. Our study also offers new insights into understanding selective neuron vulnerability in aging, emphasizing the importance of multi-tissue strategies to address the complexities of neuronal aging.

Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapies due to their self-renewal and differentiation capabilities. Pathological microenvironments expose MSCs to senescence-inducing factors such as reactive oxygen species (ROS), resulting in MSC functional decline and loss of stemness. Oxidative stress leads to mitochondrial dysfunction, a hallmark of senescence, and is prevalent in aging tissues characterized by elevated ROS levels. We hypothesized that overexpression of nuclear respiratory factor-1 (NRF1), a driver of mitochondrial biogenesis, could metabolically potentiate MSCs and prevent MSC senescence. Single-cell RNA sequencing (scRNA-Seq) revealed that MSCs transfected with NRF1 messenger RNA (mRNA) exhibited upregulated expression of genes associated with oxidative phosphorylation (OXPHOS), decreased glycolytic markers, and suppression of senescence-related pathways. To test whether NRF1 induction could mitigate stress-induced premature senescence, we exposed MSCs to hydrogen peroxide (H₂O₂) and validated our findings in a replicative senescence model. NRF1 mRNA transfection significantly increased mitochondrial mass and improved aberrant mitochondrial processes associated with senescence, including reduced mitochondrial and intracellular total ROS production. Mitochondrial health and dynamics were preserved, and respiratory function was restored, as evidenced by enhanced OXPHOS, reduced glycolysis, and increased ATP production. Notably, NRF1 overexpression led to decreased senescence-associated β-galactosidase (SA-β-gal) activity and reduced expression of senescence markers p53, p21, and p16. Our findings demonstrate that NRF1 induction attenuates MSC senescence by enhancing mitochondrial function, suggesting potential translational applications for MSC-based therapies and senescence-targeted interventions.

Perioperative neurocognitive disorder (PND) is a severe postoperative complication in older patients. Epigenetic changes are hallmarks of senescence and are closely associated with cognitive impairment. However, the effects of anesthesia and surgery on the aging brain's epigenetic regulatory mechanisms and its impact on cognitive impairment remain unclear. Using a laparotomy PND model, we report significant reduction in DNA methyltransferase 3a (DNMT3a) in hippocampal neurons of aged mice, which causes global DNA methylation decrease. Knockdown of DNMT3a leads to synaptic disorder and memory impairment in aged mice. Mechanistically, bisulfite sequencing revealed that DNMT3a deficiency reduces methylation in the LRG1 promoter region and promotes its transcription. We also show that activation of TGF-β signaling by the increase in LRG1 level, ultimately impacts the synaptic function. In contrast, both overexpressing DNMT3a or knockdown LRG1 in hippocampus can attenuate the synaptic disorders and rescue postoperative cognitive deficits in aged mice. Our results reveal that DNMT3a is a previously undefined mediator in the pathogenesis of PND, which couples epigenetic regulations with anesthesia/surgery-induced synaptic dysfunction and represents a therapeutic target to tackle PND.

Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased the risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD as they age.

Little evidence exists regarding the associations between clinical parameter-based biological aging and the incidence and outcome of chronic kidney disease (CKD). Thus, we aimed to assess the associations between biological aging, genetic risk, and the risk of CKD, as well as investigate the impact of accelerated biological aging on life expectancy. 281,363 participants free of kidney diseases from the UK Biobank were included in this prospective study. Biological age was measured from clinical traits using the KDM-BA and PhenoAge algorithms, and the discrepancies from chronological age were defined as biological age accelerations. A polygenic score was calculated to indicate the genetic predisposition of the estimated glomerular filtration rate (eGFR). A cause-specific competing risk model was used to estimate hazard ratios (HRs) and the corresponding confidence intervals (CIs) of incident CKD. We found that individuals with more pronounced accelerations in biological age exhibited an elevated risk of developing CKD (HR_{Quartile 4 vs. Quartile 1}, 1.90; 95% CI, 1.77-2.05 for KDM-BA acceleration and HR_{Quartile 4 vs. Quartile 1}, 2.79; 95% CI, 2.58-3.01 for PhenoAge acceleration), with nonlinear relationships. Notably, there were positive additive interactions between biological aging and genetic risk on CKD risk. Among the CKD population, accelerated biological aging was associated with a further decline in life expectancy. Advanced biological aging may potentially increase the vulnerability to developing CKD in individuals aged midlife and beyond, particularly among those with high genetic risk for abnormal kidney function, and could reduce the life expectancy of CKD patients.

Ultraviolet B (UVB) radiation is a major contributor to skin photoaging. Although mainly absorbed by the epidermis, UVB photons managing to penetrate the upper dermis affect human dermal fibroblasts (HDFs), leading, among others, to the accumulation of senescent cells. In vitro studies have shown that repeated exposures to subcytotoxic UVB radiation doses provoke HDFs' premature senescence shortly after the end of the treatment period. Here, we found that repetitive exposures to non-cytotoxic UVB radiation doses after several days lead to mixed cultures, containing both senescent cells and fibroblasts resisting senescence. "Resistant" fibroblasts were more resilient to a novel intense UVB radiation stimulus. RNA-seq analysis revealed that ERCC6, encoding Cockayne syndrome group B (CSB) protein, is up-regulated in resistant HDFs compared to young and senescent cells. CSB was found to be a key molecule conferring protection toward UVB-induced cytotoxicity and senescence, as siRNA-mediated CSB loss-of-expression rendered HDFs significantly more susceptible to a high UVB radiation dose, while cells from a CSB-deficient patient were found to be more sensitive to UVB-mediated toxicity, as well as senescence. UVB-resistant HDFs remained normal (able to undergo replicative senescence) and non-tumorigenic. Even though they formed a distinct population in-between young and senescent cells, resistant HDFs retained numerous tissue-impairing characteristics of the senescence-associated secretory phenotype, including increased matrix metalloprotease activity and promotion of epidermoid tumor xenografts in immunodeficient mice. Collectively, here we describe a novel subpopulation of HDFs showing increased resistance to UVB-mediated premature senescence while retaining undesirable traits that may negatively affect skin homeostasis.

Calorie restriction (CR) and physical exercise (EX) are well-established interventions known to extend health span and lifespan in animal models. However, their impact on human biological aging remains unclear. With recent advances in omics technologies and biological age (BioAge) metrics, it is now possible to assess the impact of these lifestyle interventions without the need for long-term follow-up. This study compared BioAge biomarkers in 41 middle-aged and older adult long-term CR practitioners, 41 age- and sex-matched endurance athletes (EX), and 35 sedentary controls consuming Western diets (WD), through PhenoAge: a composite score derived from nine blood-biomarkers. Additionally, a subset of participants (12 CR, 11 EX, and 12 WD) underwent multi-omic profiling, including DNA methylation and RNAseq of colon mucosa, blood metabolomics, and stool metagenomics. A group of six young WD subjects (yWD) served as a reference for BioAge calculation using Mahalanobis distance across six omic layers. The results demonstrated consistently lower BioAge biomarkers in both CR and EX groups compared to WD controls across all layers. CR participants exhibited lower BioAge in gut microbiome and blood-derived omics, while EX participants had lower BioAge in colon mucosa-derived epigenetic and transcriptomic markers, suggesting potential tissue-specific effects. Multi-omic pathway enrichment analyses suggested both shared and intervention-specific mechanisms, including oxidative stress and basal transcription as common pathways, with ether lipid metabolism uniquely enriched in CR. Despite limitations due to sample size, these findings contribute to the broader understanding of the potential anti-aging effects of CR and EX, offering promising directions for further research.

Aging is tightly associated with reduced immune protection but increased risk of autoimmunity and inflammatory conditions. Regulatory T cells are one of the key cells to maintaining immune homeostasis. The age-dependent changes in CD4⁺Foxp3⁺ regulatory T cells (Tregs) have been well documented. However, the nonredundant Foxp3^-CD8⁺ Tregs were never examined in the context of aging. This study first established clear distinctions between phenotypically overlapping CD8⁺ Tregs and virtual memory T cells. Then, we elucidated the dynamics of CD8⁺ Tregs across the lifespan in mice and further extended our investigation to human peripheral blood mononuclear cells (PBMCs). In mice, we discovered a bi-phasic dynamic shift in the frequency of CD8⁺CD44^hiCD122^hiLy49⁺ Tregs, with a steady increase in young adults and a notable peak in middle age followed by a decline in older mice. Transcriptomic analysis revealed that mouse CD8⁺ Tregs upregulated a selected set of natural killer (NK) cell-associated genes, including NKG2D, with age. Importantly, NKG2D might negatively regulate CD8⁺ Tregs. Additionally, by analyzing a scRNA-seq dataset of human PBMC, we found a distinct CD8⁺ Treg-like subset (Cluster 10) with comparable age-dependent frequency changes and gene expression, suggesting a conserved aging pattern in CD8⁺ Treg across mice and humans. In summary, our findings highlight the importance of CD8⁺ Tregs in immune regulation and aging.

The oxidative stress-induced premature senescence of trabecular meshwork (TM) represents a pivotal risk factor for the development of glucocorticoid-induced glaucoma (GIG). This study aimed to elucidate the pathogenesis of TM senescence in GIG. MethodsIntraocular pressure (IOP), transmission electron microscopy and senescence-associated protein expression in TM were evaluated in GIG mice. Protein expression of phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and monoamine oxidase A (MAOA), phosphorylation of AKT were quantified. ROS and mitochondrial superoxide levels were measured to evaluate cellular oxidative stress. Cell cycle analysis, β-galactosidase staining, senescence-associated protein expression were employed to assess the aging status of primary human trabecular meshwork cells (pHTMs). ResultsmRNA-seq and KEGG analysis indicating PI3K/AKT pathway as a key regulator in TM of GIG. PI3K inhibitor significantly prevented IOP elevation and abnormal mitochondrial morphology of TM in the GIG mouse model. PI3K inhibitor or selective silencing of PIK3R1 alleviated dexamethasone (DEX)-induced oxidative stress, also mitochondrial dysfunction, inhibiting MAOA expression in pHTMs. The same phenomenon was observed in the GIG models with inhibition of MAOA. Further KEGG analysis indicates that cellular senescence is the key factor in the pathogenesis of GIG. TM senescence was observed in both GIG mouse and cell models. Inhibition of the PI3K/AKT/MAOA pathway significantly alleviated DEX-induced premature cellular senescence of TM in GIG models. Glucocorticoids activated the PI3K/AKT/MAOA pathway, leading to mitochondrial dysfunction, oxidative stress, and premature aging in TM, elevating IOP. This mechanism could be associated with the onset and progression of GIG, providing a potential approach for its treatment.