Aging Cell最新文献

Aging disrupts systemic metabolism, but the mechanisms by which gut microbial metabolites drive tissue-specific decline remain unclear. We conducted a multi-organ, multi-omics atlas across the gut, serum, liver, lung, and cortex in young and early-aged mice to address this. We identified a conserved aging signature marked by the microbiota-associated depletion of protective circulating metabolites, such as lysophosphatidylcholines (LPCs), concurrently with the systemic accumulation of pro-oxidative microbial catabolites, specifically trimethylamine N-oxide (TMAO) and indole-3-acetic acid (IAA). This microbial-metabolic drift disrupted systemic lipid transport and redox balance, leading to distinct organ-level vulnerabilities: hepatic lipid retention and ferroptosis susceptibility, pulmonary immune-redox activation, and cortical neurochemical dysregulation. To establish functional relevance, we conducted an integrated meta-analysis of 40 independent studies encompassing natural aging models, fecal microbiota transplantation (FMT), and probiotic interventions. This quantitative synthesis provided convergent evidence that microbial remodeling is a functionally relevant correlate associated with systemic aging phenotypes by restoring intestinal barrier integrity (upregulating ZO-1, MUC2), suppressing tissue inflammatory factors (IL-6, IL-1β, TNF-α), and mitigating oxidative stress (reducing MDA and restoring SOD/GSH). Together, our findings highlight gut-derived metabolic reprogramming as a modifiable, upstream driver of systemic aging, offering tractable targets for therapeutic intervention.

Protein phosphatase 2A (PP2A) regulates Tau hyperphosphorylation in Alzheimer's disease (AD). This study hypothesized that exercise increases adiponectin levels, activating PP2A to reduce Tau hyperphosphorylation and enhance hippocampal plasticity. The study utilized adiponectin knockout (Adipo^-/-) and hippocampal-specific PP2A knockdown (PP2A-KD) in mice with 3-week voluntary running and/or chronic stress to assess changes in Tau phosphorylation, adult neurogenesis, and cognitive performance. Running improved cognitive deficits and reduced Tau hyperphosphorylation in association with increased adiponectin levels and enhanced PP2A activity in stressed mice. Adiponectin deficiency impaired cognitive performance, increased Tau phosphorylation, and decreased PP2A activity. Mechanistically, adiponectin is dispensable for running to increase PP2A activity, reduce Tau hyperphosphorylation, and restore hippocampal neurogenesis, leading to cognitive improvement. Hippocampal-specific PP2A knockdown diminished the beneficial effects of running, indicating that PP2A is downstream of adiponectin's action. This study provides mechanistic insights into how exercise reduces AD-like neuropathology, emphasizing the critical role of the adiponectin-PP2A pathway in mitigating Tau hyperphosphorylation and suggesting a potential therapeutic target for AD through modulation of this pathway.

Aging is linked to a higher incidence of gut diseases such as inflammatory bowel disease (IBD), yet the underlying mechanisms remain unclear. We identified an age-related decline in magnesium (Mg) levels specifically in the gut across species, prompting investigation of its role in intestinal health. Functional studies demonstrated that Mg restriction accelerates gut aging in old but not in young mice and aggravates colitis severity. Multi-omics analysis of mouse tissues revealed that dietary Mg deficiency reshapes the phosphoproteome and N-glycoproteome, destabilizing adhesion complexes, a hallmark of intestinal aging and inflammation. In the UK Biobank cohort (n = 182,213), dietary Mg intake was inversely correlated with gut disorder risk, with 334.7-420.0 mg/day conferring significant protection against Crohn's disease, ulcerative colitis, irritable bowel syndrome, and diverticular disease. These findings identify Mg homeostasis as a key regulator of gut health and highlight Mg supplementation as a potential strategy to counteract age-related gut dysfunction.

Interventional therapy and surgery play important roles in the treatment of various diseases, but they cause varying degrees of vascular injury. Currently, the side effects are often overlooked. Here, we observed abnormal nuclear morphology (nuclear dysmorphism) and vascular aging in injured human and rodent arteries. Platelet-derived microvesicles (PMVs) adhere to injured blood vessels, leading to nuclear dysmorphism and cell senescence in vascular smooth muscle cells (VSMCs). This occurs because PMV adherence reduces intracellular Zn²⁺ levels, which impairs Zn²⁺-dependent processing of prelamin A by the enzyme ZMPSTE24. Consequently, prelamin A accumulates in VSMCs, contributing to the observed nuclear dysmorphism and cell senescence. RNA sequencing and loss-of-function assays revealed that Zinc transporter solute carrier family 39 member 4 (SLC39A4, also called ZIP4) deficiency accounts for the decreased Zinc concentration. Consistently, Zmpste24^+/- and Zmpste24^-/- mice displayed significant cumulative prelamin A, deteriorated nuclear dysmorphism and vascular aging. Whole genome bisulfite sequencing (WGBS) and bioinformatic analysis illustrated that demethylation of genes within Lamina-associated domains (LADs) participates in nuclear dysmorphism and cell senescence. Of note, Zinc supplementation, especially using platelet membrane-coated Zn-MOF nanoparticles, robustly alleviated nuclear dysmorphism and vascular aging. Our data established a novel and significant role of pMVs/ZIP4/zinc/prelamin A axis in promoting nuclear dysmorphism and vascular aging after injury.

During aging, decreased intestinal barrier function and its ability to synthesize metabolites are closely associated with various age-related diseases. However, the mechanism by which impaired intestinal synthesis contributes to gut-liver axis aging remains unclear. This study reveals that aging induces a mitochondrial energy crisis and defective membrane localization of ABCA1, significantly inhibiting the biosynthesis of high-density lipoprotein 3 (HDL3) in the intestine. Exogenous supplementation with β-nicotinamide mononucleotide (NMN) restores intestinal NAD⁺ homeostasis, enhances oxidative phosphorylation efficiency, and promotes ATP-dependent lipid transport, thereby rejuvenating the production of gut-derived HDL3. Further investigations demonstrate that gut-originated HDL3 neutralizes lipopolysaccharide (LPS) in the liver and attenuates TLR4-mediated inflammatory cascades, ultimately ameliorating age-related liver injury. These findings elucidate a novel mechanism whereby NMN modulates the NAD⁺-mitochondria-ABCA1-HDL3 axis to preserve gut-liver axis function, offering a promising therapeutic strategy for mitigating aging-related pathologies in this metabolic cross-talk.

Cover legend: The cover image is based on the Research Article Oculopharyngeal muscular dystrophy mutations link the RNA-binding protein HNRNPQ to autophagosome biogenesis by Hasan Ishtayeh et al., https://doi.org/10.1111/acel.13949

Recent research revealed a rejuvenation event during early development of mice. Here, by examining epigenetic age dynamics of human embryogenesis, we tested whether a similar event exists in humans. For this purpose, we developed an epigenetic clock method, the intersection clock, that utilizes bisulfite sequencing in a way that maximizes the use of informative CpG sites with no missing clock CpG sites in test samples and applied it to human embryo development data. We observed no changes in the predicted epigenetic age between cleavage stage and blastocyst stage embryos; however, a significant decrease was observed between blastocysts and cells representing the epiblast. Additionally, by applying the intersection clock to datasets spanning pre and postimplantation, we found no significant change in the epigenetic age during preimplantation stages; however, the epigenetic age of postimplantation samples was lower compared to the preimplantation stages. We further investigated the epigenetic age of primed (representing early postimplantation) and naïve (representing preimplantation) pluripotent stem cells and observed that in all cases the epigenetic age of primed cells was significantly lower than that of naïve cells. Together, our data suggest that human embryos are rejuvenated during early embryogenesis. Hence, the rejuvenation event is conserved between the mouse and human, and it occurs around the gastrulation stage in both species. Beyond this advance, the intersection clock opens the way for other epigenetic age studies based on human bisulfite sequencing datasets as opposed to methylation arrays.

Aging is a natural process associated with declined organ function and higher susceptibility to developing chronic diseases. A systemic single-cell type-based study provides a unique opportunity to understand the mechanisms behind age-related pathologies. Here, we use single-cell gene expression analysis comparing healthy young and aged human lungs from nonsmoker donors to investigate age-related transcriptional changes. Our data suggest that aging has a heterogenous effect on lung cells, as some populations are more transcriptionally dynamic while others remain stable in aged individuals. We found that monocytes and alveolar macrophages were the most transcriptionally affected populations. These changes were related to inflammation and regulation of the immune response. Additionally, we calculated the LungAge score, which reveals the diversity of lung cell types during aging. Changes in DNA damage repair, fatty acid metabolism, and inflammation are essential for age prediction. Finally, we quantified the senescence score in aged lungs and found that the more biased cells toward senescence are immune and progenitor cells. Our study provides a comprehensive and systemic analysis of the molecular signatures of lung aging. Our LungAge signature can be used to predict molecular signatures of physiological aging and to detect common signatures of age-related lung diseases.

Wu, S. K., Ariffin, J., Chian, T. S., & Picone, R. (2023). The variant senescence-associated secretory phenotype induced by centrosome amplification constitutes a pathway that activates hypoxia-inducible factor-1α. Aging Cell, 22, e13766. https://doi.org/10.1111/acel.13766.

In the published version of Wu et al (2023), the current affiliation, Mechanobiology Institute & Department of Biological Sciences, National University of Singapore, Singapore is incorrectly linked to the authors' Juliana Arrifin and Remigio Picone instead of Selwin K. Wu.

The present address should be displayed as follows:

Present address.

Selwin K. Wu, Mechanobiology Institute & Department of Biological Sciences, National University of Singapore, Singapore.

Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only CS patients display a progeroid and neurodegenerative phenotype, providing a unique conceptual and experimental paradigm. As DNA methylation (DNAm) remodelling is a major ageing marker, we performed genome-wide analysis of DNAm of fibroblasts from healthy, UVSS and CS individuals. Differential analysis highlighted a CS-specific epigenomic signature (progeroid-related; not present in UVSS) enriched in three categories: developmental transcription factors, ion/neurotransmitter membrane transporters and synaptic neuro-developmental genes. A large fraction of CS-specific DNAm changes were associated with expression changes in CS samples, including in previously reported post-mortem cerebella. The progeroid phenotype of CS was further supported by epigenomic hallmarks of ageing: the prediction of DNAm of repetitive elements suggested an hypomethylation of Alu sequences in CS, and the epigenetic clock returned a marked increase in CS biological age respect to healthy and UVSS cells. The epigenomic remodelling of accelerated ageing in CS displayed both commonalities and differences with other progeroid diseases and regular ageing. CS shared DNAm changes with normal ageing more than other progeroid diseases do, and included genes functionally validated for regular ageing. Collectively, our results support the existence of an epigenomic basis of accelerated ageing in CS and unveil new genes and pathways that are potentially associated with the progeroid/degenerative phenotype.