Aging Cell最新文献

Successful embryo development, acquisition of uterine receptivity, implantation, and decidualization during the peri-implantation window are essential events that ensure a healthy pregnancy. While ovarian aging has long been considered the primary cause of age-related decline in fertility, emerging evidence demonstrates that uterine aging also compromises the ability to support pregnancy. The chromosomal passenger complex, composed of pIncenp, Aurora B, Survivin, and Borealin, is a critical regulator of cell cycle progression, particularly in chromosome condensation, mitotic spindle organization, and cytokinesis. We investigated age-associated changes in the expression and localization of those members, as well as the proliferation marker Ki-67, at implantation sites in mice during the peri-implantation period. Female mice aged 12, 20, and 26-32 weeks were used, and uterine tissues were collected on Days 5, 6, and 8 of pregnancy. Immunohistochemistry was performed to determine the localization of those proteins and Ki-67, while Western blotting was used to quantify protein expression levels. Our results revealed dynamic and age-dependent alterations in protein expression throughout pregnancy. Ki-67 expression decreased with advancing age in the luminal and glandular epithelium on Day 5, whereas pIncenp and Survivin levels were elevated in the stromal compartment of older mice. On Day 6, pIncenp, Borealin, and Survivin expression increased in the luminal epithelium of aging groups, and Aurora B expression was higher in older mice on Day 8. These findings highlight a potential role for complex dysregulation in impaired implantation/decidualization with maternal aging and may provide insight into mechanisms underlying implantation failure and recurrent pregnancy loss.

Biological aging reflects the progressive decline in cellular and tissue function. Unlike chronological age, biological age is a more accurate indicator of physiological state. Multi-omics organ clocks have been emerging as promising tools to assess biological aging by integrating genomic, epigenomic, transcriptomic, proteomic, and metabolomic data. These conceptual frameworks suggest that individual organs may age at different rates, explaining variability in the onset and progression of age-related diseases. However, separate interpretation may overlook the correlation between different omics analyses. A comprehensive, multidimensional analysis is therefore preferred over individual omics for accurate assessment of biological aging. While a comprehensive, multidimensional analysis may provide more holistic insights than single-omics approaches, the practical implementation of multi-omics clocks remains limited in clinical settings due to technical differences across omics platforms and dataset availability. This review evaluates current biological clock approaches and explores strategies for multi-omics integration. By addressing conceptual and methodological gaps, we propose a framework for the development of robust multi-omics aging clocks.

Biological and synthetic replacement-based ageing interventions hold substantial potential to reverse many forms of age-related damage simultaneously and extend healthy lifespan beyond what can be achieved with conventional therapeutics. In this Perspective, we discuss recent insights, unmet needs, and emerging trajectories that are catalysing research and clinical development of replacement-based treatments and synergistic strategies for multi-targeted damage removal and export at the molecular, organellar, and cellular levels. The first workshop dedicated to replacement as an ageing intervention at the Aging Research & Drug Discovery 2025 conference helped prioritise key challenges, opportunities, and future directions to address the need for preventive replacement and bioengineering technologies capable of inducing systemic and sustained rejuvenation across cells, tissues, and regulatory networks. We propose a roadmap to guide research and innovation integrating replacement and next-generation damage-removal therapeutics to modulate the ageing process in the whole body, restore biological function, and extend healthy lifespan.

Retraction: P. F. Giannopoulos, J. Chiu, and D. Praticò, "Antileukotriene Therapy by Reducing Tau Phosphorylation Improves Synaptic Integrity and Cognition of P301S Transgenic Mice," Aging Cell 17, no. 3 (2018): e12759, https://doi.org/10.1111/acel.12759. The above article, published online on 01 April 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Monty Montano; The Anatomical Society; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by the corresponding author, D. Praticò, and by a third party. This identified image manipulation or duplication within Figures 2C, 3C, 4A, and 4C, as well as with a previously published article by the same author group. As a result, the data and the conclusions are considered unreliable. D. Praticò agreed to the decision to retract. P. F. Giannopoulos and J. Chiu were informed of the decision to retract but remained unresponsive.

Vascular aging, characterized by progressive structural and functional deterioration of the vasculature, serves as a critical pathophysiological nexus between chronological aging and cardiovascular disease (CVD). This study establishes a quantitative vascular age model to decode individualized vascular senescence patterns, thereby enabling early identification of accelerated aging phenotypes for targeted intervention. We collected physical examination records from 2009 to 2019 and a total of 8578 participants aged 20-70 years were enrolled in this study. We constructed sex-specific basic vascular age models based on healthy individuals by Klemera-Doubal method and calculated the normalized cardiovascular age acceleration (NCAA, η) as an estimate of vascular aging status. The association between η and CVD risk were evaluated across subgroups. Furthermore, we developed expanded models by incorporating traditional CVD risk factors that were significantly associated with η index. Male with lower values of η, which meant relatively higher vascular aging velocity, had a higher risk of CVD adjusted by chronological age (HR = 1.21, 95% CI = 1.01-1.45). In subgroup analysis, η index exhibited age- and sex-specific associations with traditional CVD risk factors. After adding body mass index, fasting blood glucose, and triglycerides significantly related to η in male, the CVD prediction by expand η were improved in age-adjusted model (HR = 1.25, 95% CI = 1.04-1.50). The vascular age model emerges as a robust composite biomarker for CVD risk stratification. Our findings establish an evidence-based framework for precision prevention, prioritizing high-risk phenotypes for early intervention to mitigate CVD burden.

While exercise is shown to reduce hippocampal atrophy, the underlying molecular mechanisms remain to be fully elucidated. Animal studies suggest the myokine irisin underlies exercise-related hippocampal benefits, though human evidence is lacking. We cross-sectionally examined 74 healthy older adults (age 65.47 ± 8.56 years). Participants completed Godin Leisure-Time exercise questionnaires, provided fasting blood for irisin measurement and underwent structural MRI with hippocampal subfield segmentation. Hierarchical regression and mediation analyses tested irisin-mediated exercise-hippocampus relationships, controlling for age, sex and education. Exercise positively associated with circulating irisin (β = 0.365, p = 0.003). Irisin positively associated with bilateral hippocampal volumes (right: β = 0.353, p = 0.001; left: β = 0.275, p = 0.012), strongest in right-CA3 (β = 0.530), right-CA4/dentate gyrus (β = 0.471), and bilateral CA1 (β = 0.336-0.373) subfields. Mediation analysis revealed all exercise-hippocampus relationships operated indirectly through irisin. This study provides first human evidence that irisin is a molecular mechanism linking exercise to hippocampal volume, particularly in subfields critical for memory, neurogenesis and Alzheimer's pathology. Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12620000054910.

The Greenland shark (Somniosus microcephalus), with a lifespan estimated around 300 years, represents a unique model for studying vertebrate longevity. Here, we characterize its cardiac aging profile and compare it with two other species: the deep-sea shark Etmopterus spinax and the short-lived teleost Nothobranchius furzeri. Histological analysis revealed extensive interstitial and perivascular fibrosis throughout the ventricular myocardium of S. microcephalus, affecting both compact and spongy layers of both sexes. This fibrotic pattern was absent in E. spinax and N. furzeri, suggesting it is a specific feature of S. microcephalus. We also observed extreme lipofuscin accumulation within cardiomyocytes of S. microcephalus, which correlates at the ultrastructural level with the abundance of damaged mitochondria and the presence of strikingly enlarged lysosomes filled with electrondense material of likely mitochondrial origin. Additionally, in the myocardium of S. microcephalus we found abundant deposition of the oxidative stress marker 3-nitrotyrosine. Remarkably, despite showing multiple canonical markers of aging such as fibrosis, lipofuscin accumulation, and oxidative stress, S. microcephalus individuals appeared healthy and physiologically uncompromised at the time of capture. These findings suggest that S. microcephalus has evolved resilience to molecular and tissue-level aging signs and hallmarks, supporting sustained cardiac function over centuries and offering new insights into the mechanisms of extreme vertebrate longevity.

As the global population ages, cellular senescence contributes increasingly to the burden of age-related diseases. Hallmarks of this process include telomere shortening and loss of proteostasis, frequently linked to DNA damage-associated transcriptional stress. Although telomere dysfunction-induced foci (TIF) have been well documented in lungs from patients with idiopathic pulmonary fibrosis (IPF), their occurrence and role during physiological lung aging remain unclear. Analysis of senescence markers in lung tissue from organ donors aged 16-88 years showed a linear decline in telomere length with age; however, TIF frequency increased significantly in the airway epithelium only in individuals older than 75 years. Similarly, senescence markers such as p16 tended to rise with age but did not reach the levels observed in IPF lungs. To better delineate the early events driving senescence in the human respiratory epithelium and to expand the cohort size, we collected nasal epithelial cells by brushing from 213 healthy volunteers aged 2-97 years. As in the aging lung, telomere shortening was evident, yet TIF were rare and detected almost exclusively in individuals over 80 years of age. In contrast, indicators of impaired proteostasis, including increased senescence-associated β-galactosidase activity and lysosomal content, were apparent from the age of 40 in nasal epithelial cells and correlated with olfactory decline. Together, these findings suggest that telomere dysfunction is unlikely to be the primary driver of cellular senescence in the human respiratory tract, where proteotoxic stress may instead play a more prominent role.

T cell immunosenescence refers to the progressive functional decline of T lymphocytes with aging, characterized by the phenotypic markers, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP), representing a pivotal aspect of overall immune aging. This review systematically elucidates the critical role of T cell immunosenescence in the pathogenesis of common inflammatory skin diseases, including psoriasis, atopic dermatitis, rosacea, and seborrheic dermatitis. Senescent T cells drive the production of a disease-specific SASP via internally dysregulated signaling networks such as NF-κB, JAK-STAT, p38 MAPK, and PI3K-Akt-mTOR pathways, thereby shaping and sustaining a chronic cutaneous inflammatory microenvironment that promotes disease chronicity and recurrence. Furthermore, this review summarizes current therapeutic strategies targeting these senescence-associated pathways and SASP components, discussing both biological agents and small molecule inhibitors. Finally, we propose future research directions focusing on the direct targeting of senescent T cells or their upstream regulatory hubs to achieve deep disease remission and overcome therapeutic resistance.

Aging is associated with systemic immune remodeling and disease susceptibility, but its impact on intestinal mucosal immunity, particularly changes in M cells, remains largely unknown. This study aimed to investigate how aging alters intestinal mucosal immune phenotypes, specifically follicle-associated epithelial cells (FAE) and the gut microbiota, and to identify interconnected pathways that may be exploited to maintain intestinal immune function in the elderly. Using intestinal tissue from young and aged mice, this study assessed manifestations of intestinal epithelial aging, changes in immune cells in the lamina propria, and microbial composition. Aging was associated with increased expression of senescence-associated secretory phenotype (SASP) markers (IL-1β, TNF-α, p16) and decreased levels of tight junction proteins (Occludin, Tricellulin), suggesting epithelial barrier dysfunction. Aged mice exhibited decreased Naïve Th cells, increased Effector Th and Th17 subsets, and decreased fecal IgA. Microbiome analysis revealed enrichment of inflammatory bacteria, such as Desulfovibrio and Candidatus_Saccharimonas, and elevated dysbiosis indices. RNA sequencing of FAEs revealed 578 differentially expressed genes, including downregulation of Gp2 and Ccl28, indicating impaired M cell function. Association analysis between microbiome changes and mucosal immune aging revealed that enrichment of key inflammatory bacteria may contribute to impaired M cell function and dysregulated intestinal mucosal immunity. These findings reveal a multi-layered disruption of intestinal homeostasis during aging-comprising barrier function, immune imbalance, FAEs dysfunction, and shifts in specific microbial taxa -leading to increased susceptibility to pathogens. Targeting these age-related pathways may provide strategies for maintaining intestinal immunity in the elderly.