Rejuvenation research最新文献

Breast cancer (BC) is a prevalent malignancy among women. Evidence has indicated that F-box/WD repeat-containing protein 5 (FBXW5) is crucial in oncogenesis and progression. However, the function of FBXW5 in BC remains elusive. This work aims to explore the regulatory mechanisms of FBXW5 in the development of BC. The expression of FBXW5 in pan-cancer and breast invasive carcinoma (BRCA) was analyzed using The Cancer Genome Atlas (TCGA) database. FBXW5 level was enhanced in BC tissues. Besides, FBXW5 inhibition significantly decreased cell viability by 49.05% in MDA-MB-231 cells and 62.30% in MCF-7 cells. FBXW5 inhibition significantly inhibited cell proliferation by 66% in MDA-MB-231 cells and 74% in MCF-7 cells. FBXW5 inhibition significantly suppressed cell migration by 77.2% in MDA-MB-231 cells and 82.15% in MCF-7 cells. FBXW5 inhibition significantly inhibited cell invasion by 64.14% in MDA-MB-231 cells and 71.33% in MCF-7 cells. In vivo, FBXW5 depletion reduced tumor weight by 63.39% and tumor volume by 65.17%. Moreover, FBXW5 silencing restrained lung metastases in vivo. Besides, the impact of FBXW5 on the malignant behavior of BC cells was mediated through the regulation of ferroptosis. Mechanically, FBXW5 facilitated Kruppel-like factor 13 (KLF13) degradation by enhancing its ubiquitination. The addition of FBXW5 facilitated cell proliferation, migration, and invasion and inhibited ferroptosis in MDA-MB-231 and MCF-7 cells, which were neutralized by KLF13 overexpression. Besides, the knockdown of KLF13 led to the activation of the PI3K/AKT pathway. KLF13 silencing counteracted the inhibitory effects of FBXW5 depletion on cell proliferation, migration, and invasion, as well as its promotion of ferroptosis, effects that were reversed by LY294002. In conclusion, targeting FBXW5 may serve as a potential therapeutic strategy for BC by modulating the KLF13/PI3K/AKT axis.

The use of external therapies for knee osteoarthritis (KOA) in traditional Chinese medicine (TCM) is supported by several guidelines and systematic reviews. However, the relative advantages and disadvantages of TCM external therapies and their mechanisms of action have not yet been confirmed in evidence-based medicine. We used network meta-analysis to rank the effectiveness and safety of TCM external therapies, screen the optimal TCM external therapies. TCM external therapies for KOA published before October 2024 were comprehensively retrieved from eight electronic databases. Using the Cochrane Reviewers' Handbook, two independent reviewers performed study selection, data extraction, and bias assessment of the included randomized controlled trials (RCTs). Data analysis was conducted using Stata 16.0 and RevMan 5.4 software. A total of 68 RCTs were identified, including 6571 participants, involving 11 interventions, 4.41% of which showed a high risk of bias. The results of the network meta-analysis revealed that in terms of improving Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function scores, each external therapy was better than conventional medicine. Electroacupuncture may be the most effective intervention in improving the VAS score and TNF-α level. Moxibustion resulted in the greatest improvement in WOMAC function and IL-6 levels. The most effective interventions for reducing WOMAC pain scores were the manual needle knife, followed by electroacupuncture and Tuina therapy (SUCRA = 82.9%, 79.0%, and 71.4%, respectively). Warming acupuncture dominantly increased Lysholm scores. The safety results showed that the three safest interventions were the sham intervention, Tuina therapy, and moxibustion (SUCRA = 90.6%, 83.1%, and 68.8%, respectively). Silver needle had the best comprehensive effect. Electroacupuncture has the best effect on improving pain symptoms, and moxibustion can be prioritized when functional limitations are the main symptoms. To some extent, the changes in inflammatory factors correlated with an improvement in KOA symptoms.

Aging is an unavoidable process associated with a progressive decline of muscle mass, strength, and regenerative ability. Satellite cells are a muscle stem cell (MuSC) population that plays a key role in mammalian muscle regeneration, by awakening from quiescence and then migrating to sites of damage, expanding in number to generate progenitor cells, and then either differentiating to rebuild the muscle tissue or self-renewing to repopulate the stem cell pool. Emerging evidence suggests that the aging process impairs the activation potential and the regenerative capacity of MuSCs. This review explores some of the recent discoveries of how mis-regulation of intrinsic and extrinsic mechanisms drive the decline of MuSC function in aging muscles, and we discuss new strategies to rejuvenate aged MuSC function for regenerative medicine. Understanding these processes will speed up the development of novel therapeutics for counteracting muscle loss and improve muscle healing in the elderly.

Age-associated neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are marked by progressive degeneration of the nervous system. Current diagnostic approaches, such as neuroimaging and cerebrospinal fluid biomarkers, are invasive, costly, and lack early diagnostic reliability. Recent studies highlight the potential of extracellular vesicles, particularly exosomes, derived from erythrocytes or red blood cells (RBCs), as emerging indicators of aging and age-associated diseases. Exosomes carry noncoding RNA, lipid, and protein molecules, and modulate cellular pathways at distant sites, providing neuroprotective and anti-inflammatory effects. In this study, we isolated RBC-derived exosomes of young and old mice. MicroRNA sequencing analysis revealed differential expression of several miRNA species between young and old mice. We report an upregulation of miR-125a-5p and a downregulation of miR-302a-5p in old mice that are potentially linked to neurodegenerative pathways. This study underscores the potential of RBC-derived exosomes as noninvasive biomarkers for NDDs.

Aging is associated with a gradual decline in cellular function, largely driven by oxidative stress, which leads to cellular senescence. These processes contribute to tissue degeneration and age-related dysfunction. Human dermal fibroblasts (HDFs), critical for maintaining skin structure, are highly vulnerable to oxidative damage, making them key contributors to skin aging. Umbilical cord blood plasma (UCBP), rich in growth factors and regenerative molecules, has shown potential in preventing cellular senescence and addressing key mechanisms of tissue aging. Based on findings from heterochronic parabiosis experiments that demonstrated the rejuvenating effect of young blood, we investigated the effects of UCBP on hydrogen peroxide (H₂O₂) induced oxidative stress in HDFs and compared its efficacy with adult blood plasma (ABP). Our results indicate that although both UCBP and ABP reduce reactive oxygen species (ROS), UCBP is more effective in suppressing cellular senescence and maintaining fibroblast proliferation. These findings suggest that UCBP's protective effects extend beyond ROS reduction, potentially by modulating the senescence-associated secretory phenotype and the enhancement of tissue repair mechanisms.

Myocardial infarction (MI) remains the leading cause of mortality and morbidity worldwide. It is caused by a thrombotic occlusion of coronary vessel/s that leads to cardiomyocyte death. As a response, inflammatory and fibrotic responses are initiated to replace the necrotic tissue and remodel the heart. However, in most cases, these responses are excessively activated, which accentuates the injury and causes adverse cardiac remodeling, often leading to heart failure. This is highly attributed to the dysregulated repair mechanism brought by reduced regenerative capacity of the adult heart, chronic inflammation, and other patient factors, such as comorbidities, diet, and lifestyle. Because of the negative consequences of excessive inflammation and fibrosis in post-MI responses, inhibiting factors associated with these processes are one of the major approaches in MI management. Several therapies have been developed to broadly and/or selectively inhibit inflammation- and fibrosis-associated proteins over the past decades and have shown promise in addressing post-MI complications. However, challenges (e.g., off-targets, problems with drug delivery, dosage, route, and cost) and efficacy of these interventions in the clinical setting remain. Hence, alternative approaches to optimally alleviate these post-MI processes are still much needed. In this review, we discuss the possible use of plasmapheresis, a technique that involves extracorporeal replacement of blood plasma, as a treatment for MI. We provide an overview of the inflammatory and fibrotic responses after MI and focus on how plasmapheresis can be an approach to target these pathways.

Epigenetics, the study of heritable changes in gene expression that do not involve alterations to the deoxyribonucleic acid (DNA) sequence, plays a pivotal role in cellular function, development, and aging. This review explores key epigenetic mechanisms, including DNA methylation (DNAm), histone modifications, chromatin remodeling, RNA-based regulation, and long-distance chromosomal interactions. These modifications contribute to cellular differentiation and function, mediating the dynamic interplay between the genome and environmental factors. Epigenetic clocks, biomarkers based on DNAm patterns, have emerged as powerful tools to measure biological age and predict health span. This article highlights the evolution of epigenetic clocks, from first-generation models such as Horvath's multi-tissue clock to advanced second- and third-generation clocks such as DNAGrimAge and DunedinPACE, which incorporate biological parameters and clinical biomarkers for precise age estimation. Moreover, the role of epigenetics in aging and age-related diseases is discussed, emphasizing its impact on genomic stability, transcriptional regulation, and cellular senescence. Epigenetic dysregulation is implicated in cancer, genetic disorders, and neurodegenerative diseases, making it a promising target for therapeutic interventions. The reversibility of epigenetic modifications offers hope for mitigating age acceleration and enhancing health span through lifestyle changes and pharmacological approaches.

The study aimed to explore the association between different sleep traits and all-cause mortality as well as to validate causality in the association through mendelian randomization (MR). We analyzed 451,420 European ancestry participants from the UK Biobank. Multivariable-adjusted Cox proportional hazards model was conducted to evaluate the association between sleep traits and all-cause mortality. In MR analysis, the inverse variance weighting (IVW) method was applied as the primary analysis to investigate the causal association between sleep traits and mortality. During a median follow-up period of 12.68 years, 34,397 individuals died. Observational analyses showed the multivariate-adjusted hazard ratio (HR) and 95% confidence intervals (CIs) for short sleep, long sleep, early chronotype, daytime sleepiness, daytime napping, and insomnia with mortality, 1.246 (1.195, 1.298), 1.735 (1.643, 1.831), 0.931 (0.909, 0.953), 1.276 (1.212, 1.344), 1.299 (1.254, 1.346), and 1.117 (1.091, 1.142) (All p < 0.0001). Based on UK Biobank, MR analysis indicated the association between daytime napping and an increased risk of all-cause mortality (odd ratio [OR]: 1.219, 95% CI: 1.071-1.387, p = 0.003), which may be largely attributable to cancer disease mortality (OR: 1.188, 95% CI: 1.009-1.399, p = 0.039). We found no causal association between sleep duration, short sleep, long sleep, chronotype, daytime sleepiness, insomnia, and mortality risk. The causal associations between sleep traits and all-cause mortality risk were directionally replicated in FinnGen. Our findings suggest a potential causal association between daytime napping and increased risk of all-cause mortality in middle-aged and older persons. The finding could have important implications for evaluating daytime napping habits to decrease the risk of mortality.

Previous studies have established associations between α-Klotho and frailty or sarcopenia; however, the causal nature of these relationships remains unclear. This study investigates the causal effects of α-Klotho on frailty and sarcopenia-related traits using Mendelian randomization (MR). Genetic instruments for circulating α-Klotho concentrations, frailty index (FI), low grip strength (LGS), appendicular lean mass (ALM), and walking pace were developed based on data from large genome-wide association studies. Two-sample MR analyses were performed, supplemented by sensitivity analyses to ensure the robustness of the findings. Reverse MR analyses were also conducted to explore potential reverse causation. The findings demonstrated an inverse causal relationship of circulating α-Klotho levels with FI (β = -0.020, 95% confidence interval [95% CI] = -0.036 to -0.004; p = 0.017) and LGS (β = -0.033, 95% CI = -0.061 to -0.004; p = 0.023). However, no causal relationship was observed between circulating α-Klotho levels and ALM or walking pace. Additionally, no evidence of reverse causation was identified between FI or sarcopenia-related traits and circulating α-Klotho levels. In conclusion, this MR analysis establishes an inverse causal relationship of circulating α-Klotho levels with both FI and LGS.