Aging Cell最新文献

Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer's disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a doxycycline-inducible system to trigger p16 up-regulation in human-induced pluripotent stem cells (iPSCs) and neurons differentiated from iPSCs. We demonstrated that up-regulated p16 expression in iPSCs reduces cell proliferation, down-regulates cell cycle genes, and up-regulates genes involved in focal adhesion, interferon α response and PI3K-Akt signaling. Our approach enables temporal control of p16 induction upon differentiation from iPSCs to neurons. In differentiated cortical neurons, we found that up-regulation of p16 increases tau phosphorylation at Ser202/Thr205 and Thr231 in a cell-autonomous manner, while amyloid beta secretion is not affected. These data suggest a critical role of p16 in regulating tau phosphorylation in neurons, and thereby contributing to pathological progression of AD. As pathological tau tangles have been shown to induce p16 expression, our studies suggest a positive feedback loop between p16 and tau to exacerbate tau pathologies.

Microglia, as resident immune cells in the central nervous system (CNS), play a crucial role in maintaining homeostasis and phagocytosing metabolic waste in the brain. Senescent microglia exhibit decreased phagocytic capacity and increased neuroinflammation through senescence-associated secretory phenotype (SASP). This process contributes to the development of various neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we found that SASP was elevated in senescent microglia, and proteomics showed that Tgm2 was upregulated. Mechanistically, we revealed that Tgm2-catalyzed covalent cross-linking of IκBα at K22 and Q248 residues in the cytoplasm of microglia, resulting in the reduction of IκBα and nuclear translocation of NF-κB to promote SASP production. Treatment of senescent microglia with Tgm2 inhibitors (Tg2-IN1 and Cys-D) resulted in reduced NF-κB nuclear translocation and decreased SASP. Additionally, oral administration of Cys-D significantly improved the aging phenotype in aged mice. To summarize, Tgm2 is a potential target for antiaging, and inhibitors of Tgm2 can serve as novel prophylactics or senomorphics.

Endothelial dysfunction, characterized by a decline in endothelial physiological functions, is a significant aspect of cardiovascular aging, contributing notably to arterial stiffness, atherosclerosis, and hypertension. Transient receptor potential channel V4 (TRPV4), a key member of Ca²⁺-permeable channels, plays a crucial role in maintaining vascular functions. However, the role and mechanisms of TRPV4 in aging-related endothelial dysfunction remain incompletely understood. Here, we demonstrated a marked reduction in endothelial TRPV4 function without alterations in its expression, leading to abnormal endothelial Ca²⁺ signaling and impaired vasodilation in aging mesenteric arteries. Employing transcriptome sequencing, co-IP, and PLA assays, we characterized G protein-coupled receptor 35 (GPR35) interacting with TRPV4, and abnormally enhanced interactions were found in aging endothelial cells. Subsequently, we revealed that intensive GPR35-TRPV4 interaction significantly contributes to endothelial dysfunction during aging, utilizing TRPV4 endothelial-specific knockout (TRPV4_EC ^-/-), AAV-FLT1-shRNA (GPR35) mice, and GPR35 overexpressed/knocked-down HUVECs. Furthermore, molecular docking analysis and subsequent co-IP and pressure myograph experiments indicated that both Thonningianin A and Carfilzomib efficiently restored the GPR35-TRPV4 interaction, preventing endothelial dysfunction and vasodilation impairment. Our study identifies the crucial role of GPR35-TRPV4 interaction in aging-associated abnormal endothelial function and vascular tone modulation. Restoring GPR35-TRPV4 interaction via Thonningianin A or Carfilzomib represents a promising precision approach for aging-related endothelial dysfunction.

With advancing age, significant changes occur in the female reproductive system, the most notable of which is the decline in oocyte quality, a key factor affecting female fertility. However, the mechanisms underlying oocyte aging remain poorly understood. In this study, we obtained oocytes from aged and young female mice and performed single-cell transcriptome sequencing, comparing our findings with existing proteomic analyses. Our analysis revealed that one of the primary characteristics of aging oocytes is the disruption of calcium ion homeostasis. Specifically, we identified two key genes involved in the oocyte aging process, Calb1 and Rpl23. Experimental validation demonstrated that knockdown of CALB1 in oocytes led to reduced calcium ion levels in the endoplasmic reticulum and mitochondria, resulting in mitochondrial dysfunction and meiotic defects. Further experiments suggested that RPL23 may function as a downstream gene of CALB1, and its knockdown caused mitochondrial dysfunction, excessive accumulation of reactive oxygen species (ROS), and spindle assembly defects. Notably, overexpression of these two genes in aging oocytes partially rescued the maternal age-related defective phenotypes, underscoring their crucial roles in oocyte aging. This study provides a comprehensive understanding of the specific mechanisms underlying mouse oocyte aging at single-cell resolution, supported by experimental validation, and offers new directions and potential targets for future research into age-related reproductive health issues.

As the aging population continues to grow, the incidence of osteoporotic fractures increases and is compounded by our lack of therapeutic strategies that increase bone formation. Although exercise and physical activity play a key role in maintaining bone mass throughout our lives, the loads and exertion required to elicit an anabolic response becomes exceedingly difficult to achieve with age. Based on previous work, the P2Y₂ receptor offers a unique therapeutic target to increasing bone mass by modifying the mechanotransduction. Others have also shown P2Y₂ to have a negative effect on osteoblast function. However, the extent to which inhibiting P2Y₂ pharmaceutically improves bone mass or the mechanotransduction of bone remains unknown. Our central hypothesis for this study states that inhibiting P2Y₂ activity can enhance the anabolic response to loading in an aging population. To test this hypothesis, the anabolic response to exercise was examined by treating adult mice, which typically display a minimal response, with the P2Y₂ inhibitor AR-C118925XX (ARC). Our findings from this study demonstrate that ARC treatment of adult mice increases periosteal bone formation in response to exercise. The enhanced response to exercise was characterized by a reduction in osteocytes' induction of osteoclast activity. Endocortical bone formation also increased with treatment independently of exercise, providing gains in mechanical strength and tissue level properties. Overall, inhibiting P2Y₂ activation has a beneficial effect on bone formation and the anabolic response to loading, namely by limiting osteoclast activation.

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.