Mechanisms of Ageing and Development最新文献_第3页

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-11-19 DOI: 10.1016/j.mad.2025.112125

Di Hu, Wen Wen, Hui Li, Zuohui Zhang, Hong Lin, Jia Luo

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic protein localized in the endoplasmic reticulum (ER) and pivotally involved in maintaining ER homeostasis. The ER is central to protein synthesis, folding, degradation and secretion (proteostasis), and experiences considerable stress in neurodegenerative diseases (NDDs), which activates the unfolded protein response (UPR). Aging, the primary risk factor for NDDS, is associated with impaired ER function. MANF is shown to be protective in various experimental models of NDDs. We hypothesized that the expression of MANF in the brain declines with age, which may increase the vulnerability to NDDs. We measured MANF levels in the brain and plasma of 1-, 4-, 11-, and 22-month-old male and female mice. A progressive decline of MANF levels was observed, with the lowest levels detected in 22 months. Reduced MANF expression was found in aged mice across several brain areas, including the cerebral cortex, olfactory bulb, thalamus, hypothalamus, hippocampus, and cerebellum. There was a sex difference in MANF levels in aged mice. Aging also altered the expression of UPR and MANF interacting proteins. Using cerebellar Purkinje cell (PC)-specific MANF deficient mice, we showed that MANF deficiency impaired motor coordination in female, but not male mice. MANF deficiency weakened spatial learning and memory in both male and female mice. Male MANF deficient mice displayed increased sociability, whereas female mice exhibit social withdrawal. Taken together, MANF expression in the brain declined with age and MANF deficiency impacted neurobehaviors in a sex-specific manner.

中脑星形胶质细胞衍生神经营养因子（MANF）是一种定位于内质网（ER）的神经营养蛋白，对维持内质网稳态起关键作用。内质网是蛋白质合成、折叠、降解和分泌（蛋白质稳态）的核心，在神经退行性疾病（ndd）中受到相当大的压力，从而激活未折叠蛋白反应（UPR）。衰老是NDDS的主要危险因素，与内质网功能受损有关。在不同的ndd实验模型中，MANF被证明具有保护作用。我们假设大脑中MANF的表达随着年龄的增长而下降，这可能会增加ndd的易感性。我们测量了1个月、4个月、11个月和22个月大的雄性和雌性小鼠大脑和血浆中的MANF水平。观察到MANF水平逐渐下降，达到22个月以来的最低水平。在老年小鼠的几个大脑区域，包括大脑皮层、嗅球、丘脑、下丘脑、海马和小脑，发现MANF表达减少。老年小鼠的MANF水平存在性别差异。衰老也改变了UPR和MANF相互作用蛋白的表达。利用小脑浦肯野细胞（PC）特异性MANF缺陷小鼠，我们发现MANF缺陷损害了雌性小鼠的运动协调能力，而雄性小鼠没有。MANF缺乏削弱了雄性和雌性小鼠的空间学习和记忆能力。雄性MANF缺陷小鼠表现出社交能力增强，而雌性小鼠表现出社交退缩。综上所述，大脑中MANF的表达随着年龄的增长而下降，MANF缺乏以性别特异性的方式影响神经行为。

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引用次数: 0

Circulating mitokines GDF-15 and FGF21 are associated with frailty, sarcopenia, and malnutrition in older adults: Evidence from the FRASNET study 循环分裂因子GDF-15和FGF21与老年人虚弱、肌肉减少症和营养不良有关：来自FRASNET研究的证据

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-11-11 DOI: 10.1016/j.mad.2025.112124

Sarah Damanti , Clara Sciorati , Rebecca De Lorenzo , Amanda Avola , Maria Pia Ruggiero , Simona Santoro , Eleonora Senini , Marco Messina , Francesca Farina , Costanza Festorazzi , Giulia Pata , Martina Laffranchi , Martina Mallus , Elena Brioni , Lorena Citterio , Laura Zagato , Marco Simonini , Chiara Lanzani , Paolo Manunta , Angelo A. Manfredi , Patrizia Rovere-Querini

Background

Mitochondria-derived GDF15 and FGF21, known as mitokines, are emerging biomarkers of metabolic stress and aging-related decline. Their roles in energy balance, inflammation, and muscle metabolism suggest potential for predicting geriatric syndromes, yet prospective evidence is limited.

Methods

Plasma GDF15 and FGF21 and multidimensional geriatric assessment at baseline and at 6-year follow-up in 52 community-dwelling adults aged ≥ 65 years from the FRASNET cohort.

Results

Over a six-year follow-up, participants exhibited signs of functional decline, including increased waist circumference, greater fatigue severity, and higher medication use. FGF21 levels declined significantly over time (p = 0.03), whereas GDF15 levels remained stable. Higher baseline GDF15 levels identified individuals at higher risk to become frail (AUC= 0.85 with Fried Phenotype and AUC= 0.96 with Clinical Frailty Scale) or malnourished (AUC=0.94) and at risk to fall (AUC=0.98). FGF21 associated to malnutrition (AUC=0.98). GDF15 prospectively associated to high risk of frailty and negatively associated with physical performance and nutritional status after six years.

Conclusions

In this cohort, higher baseline levels of GDF15 and FGF21 were associated with the risk to become frail or malnourished. These findings support the integration of mitokines into early risk stratification tools for older adults. Further validation in larger cohorts is warranted.

背景：线粒体来源的GDF15和FGF21，被称为分裂因子，是代谢应激和衰老相关衰退的新兴生物标志物。它们在能量平衡、炎症和肌肉代谢中的作用提示了预测老年综合征的潜力，但前瞻性证据有限。方法：对来自FRASNET队列的52名年龄≥65岁的社区居民进行基线和6年随访时的血浆GDF15和FGF21和多维老年评估。结果：在六年的随访中，参与者表现出功能衰退的迹象，包括腰围增加，更严重的疲劳和更高的药物使用。随着时间的推移，FGF21水平显著下降（p=0.03），而GDF15水平保持稳定。较高的基线GDF15水平表明个体体弱（Fried表型的AUC= 0.85，临床虚弱量表的AUC= 0.96）或营养不良（AUC=0.94）的风险较高，并且有跌倒的风险（AUC=0.98）。FGF21与营养不良相关（AUC=0.98）。GDF15与6年后身体虚弱的高风险相关，与身体表现和营养状况呈负相关。结论：在该队列中，较高的GDF15和FGF21基线水平与变得虚弱或营养不良的风险相关。这些发现支持将分裂因子整合到老年人早期风险分层工具中。需要在更大的队列中进一步验证。

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引用次数: 0

An atlas of age- and sex-related volumetric alterations of grey matter in subcortical regions: The case of 46,111 UK Biobank participants 皮层下区域灰质年龄和性别相关体积变化图谱：46111名英国生物银行参与者的病例。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-11-08 DOI: 10.1016/j.mad.2025.112123

Fatemeh Tabassi Mofrad, Chris Patrick Pflanz, John Gallacher

Ageing is commonly associated with neuroanatomical changes in brain structure, underscoring the importance of distinguishing normal age-related alterations from those linked to pathological neurodegeneration. Despite this critical need, a standardized benchmark for identifying brain volumetric signatures of ageing remains lacking, and the influence of biological sex on age-related changes in brain volume is not yet fully understood. To address the above-mentioned gaps, we employed T1-weighted MRI images of 46,111 cognitively healthy individuals aged 44–83 from the UK Biobank cohort, and generated comprehensive maps of all the linear and non-linear trajectories of alterations in the grey matter volumes (GMVs) of subcortical regions across males and females. According to our findings, Brainstem, bilateral Amygdala and Hippocampus are the most susceptible subcortical regions to age-related atrophy, with males being generally more prone to such alterations. However, ageing proves to have a dual function as we also observed age-related inflammation in GMVs of Pallidum and Caudate which accelerates during older age and remains consistent across males and females. Our findings guide regenerative strategies and therapeutic interventions by locating subcortical regions most vulnerable to age-related atrophy and inflammation and establish a benchmark for sex-specific typical patterns of subcortical grey matter alterations due to ageing.

衰老通常伴随着大脑结构的神经解剖变化，因此区分正常的年龄相关变化与病理性变化至关重要。尽管如此，鉴别大脑结构中异常体积特征的标准基准仍未开发，生物性别在调节这些变化中的作用也未完全了解。为了解决上述空白，我们使用了来自UK Biobank队列的46,111名44-83岁认知健康个体的t1加权MRI图像，并生成了男性和女性皮质下区域灰质体积（gmv）变化的所有线性和非线性轨迹的综合地图。根据我们的研究结果，脑干、双侧杏仁核和海马体是最易受年龄相关萎缩影响的皮层下区域，男性通常更容易发生这种改变。然而，衰老被证明具有双重功能，因为我们还观察到苍白质和尾状核gmv中与年龄相关的炎症，随着年龄的增长，这种炎症会加速，并且在男性和女性中保持一致。我们的研究结果通过定位最容易受到年龄相关萎缩和炎症影响的皮层下区域来指导再生策略和治疗干预，并建立了一个性别特异性的皮层下灰质因衰老而改变的典型模式的基准。

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引用次数: 0

Diminished CEACAM1 level plays a critical role in age-related hepatic fibrosis CEACAM1水平降低在年龄相关性肝纤维化中起关键作用。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-11-04 DOI: 10.1016/j.mad.2025.112122

Sobia Zaidi , Suman Asalla , Raziyeh Abdolahipour , Agnes O. Portuphy , Marziyeh S. Jahromi , Harrison T. Muturi , Getachew D. Belew , Ramiro Malgor , Sivarajan Kumarasamy , Sonia M. Najjar

Background

Hepatic fibrosis increases with aging, but its physiological progression and underlying mechanisms remain poorly defined. Given that CEACAM1 repression causes metabolic dysfunction and liver injury, the current studies investigated whether it mediates age-related hepatic fibrosis.

Materials and methods

The metabolic phenotype, histological, immunochemical and Western blot analyses were performed in male C57BL6/J wild-type and LCC1 mice with liver-specific CEACAM1 overexpression at 2–17 months of age.

Results

Progression of metabolic dysfunction during physiological aging began with increased lipolysis-derived fatty acids, followed by hepatic insulin resistance with compensatory increase in insulin secretion and a decline in hepatic insulin clearance mediated initially by compromised CEACAM1 phosphorylation and then expression. Resultant hyperinsulinemia drove hepatic steatosis, followed by Th1 inflammatory response and subsequently, hepatic fibrosis at 17 months of age. These histological abnormalities regressed in LCC1 mice with protected hepatic CEACAM1 levels. Accordingly, LCC1 mice exhibited survival advantage.

Discussion

This age-related mapping demonstrated that early metabolic alterations impaired insulin clearance with a progressive loss of CEACAM1. Resultant hyperinsulinemia drove hepatic steatosis followed by inflammation and ultimately, hepatic fibrosis in wild-type but not LCC1 mice. Together with survival benefit of LCC1, these observations propose that protecting hepatic CEACAM1 prevents age-related hepatic fibrosis and bestows longevity.

背景：肝纤维化随着年龄的增长而增加，但其生理进程和潜在机制仍不清楚。鉴于CEACAM1抑制导致代谢功能障碍和肝损伤，目前的研究探讨了它是否介导年龄相关性肝纤维化。材料和方法：对2-17月龄C57BL6/J野生型雄性小鼠和肝脏特异性CEACAM1过表达的LCC1小鼠进行代谢表型、组织学、免疫化学和Western blot分析。结果：生理性衰老期间代谢功能障碍的进展始于脂肪酶衍生脂肪酸的增加，随后是肝脏胰岛素抵抗，胰岛素分泌代偿性增加，肝脏胰岛素清除率下降，最初是由CEACAM1磷酸化受损介导的，然后是表达受损。由此产生的高胰岛素血症导致肝脂肪变性，随后是Th1炎症反应，随后在17月龄时发生肝纤维化。这些组织学异常在肝CEACAM1水平受保护的LCC1小鼠中消退。因此，LCC1小鼠表现出生存优势。讨论：这一与年龄相关的图谱表明，早期代谢改变损害了胰岛素清除，并伴有CEACAM1的逐渐丧失。由此产生的高胰岛素血症导致野生型而非LCC1小鼠肝脂肪变性，随后是炎症，然后是肝纤维化。结合LCC1的生存益处，这些观察结果表明，保护肝脏CEACAM1可以预防年龄相关性肝纤维化并延长寿命。

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引用次数: 0

Morin enhances healthspan and neuroprotection in Caenorhabditis elegans via mitochondrial stress adaptation 马桑素通过线粒体应激适应增强秀丽隐杆线虫的健康和神经保护作用。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-10-17 DOI: 10.1016/j.mad.2025.112120

Yong-Ha Jo , Hyun-Ok Song , Dong-Sung Lee , Jeong Hoon Cho

Morin, a dietary flavonoid with antioxidant and metabolic activity, promotes healthy ageing in Caenorhabditis elegans. Morin extended lifespan by ∼18 % and alleviated age-related decline in neuronal integrity, locomotion, learning and memory, and intestinal fat accumulation. Mitochondrial potential was moderately decreased, suggesting mild uncoupler–like activity. Morin downregulated daf-2 and upregulated daf-16, accompanied by enhanced DAF-16::GFP nuclear localization, indicative of IIS/FOXO pathway activation. Gene expression profiling revealed modulation of mitochondrial stress–responsive (atfs-1, fmo-2), antioxidant (gst-4, hsf-1), and lipid metabolism (fat-6, fat-7) genes. Notably, pink-1 and pdr-1 expression increased, whereas morin’s neuroprotective effects were abolished in pink-1; pdr-1 mutants, suggesting that its benefits may involve PINK-1/PDR-1–dependent mitophagy or mitochondrial quality control. Collectively, morin enhances stress resilience and mitochondrial homeostasis through IIS/FOXO-associated regulation, supporting its potential as a natural compound that promotes healthspan.

桑里素是一种具有抗氧化和代谢活性的膳食类黄酮，可促进秀丽隐杆线虫的健康衰老。桑辣素可延长寿命约18%，并可缓解与年龄相关的神经元完整性、运动、学习记忆和肠道脂肪堆积的下降。线粒体电位中度降低，提示轻度解偶联剂样活性。Morin下调daf-2，上调daf-16，同时daf-16::GFP核定位增强，提示IIS/FOXO通路激活。基因表达谱显示线粒体应激反应基因（atfs-1、fmo-2）、抗氧化基因（gst-4、hsf-1）和脂质代谢基因（fat-6、fat-7）受到调节。值得注意的是，pink-1和pdr-1的表达增加，而morin的神经保护作用在pink-1中被消除；提示其益处可能涉及PINK-1/ pdr-1依赖性线粒体自噬或线粒体质量控制。总的来说，桑辣素通过IIS/ foxo相关调节增强应激恢复能力和线粒体稳态，支持其作为促进健康的天然化合物的潜力。

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引用次数: 0

Linking nutrition and aging: A cross-domain analysis of Mediterranean Diet Adhesion Screener components 链接营养和衰老：地中海饮食粘连筛选组件的跨域分析。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-10-15 DOI: 10.1016/j.mad.2025.112119

Fatma Hastaoǧlu , Sonia de Pascual-Teresa

This study explores the scientific landscape linking the Mediterranean Diet Adherence Screener (MEDAS) to aging-related health outcomes through a comprehensive bibliometric and scoping review approach. Given the increasing prevalence of chronic conditions in aging populations, diet has emerged as a modifiable factor with potential to enhance health span. The Mediterranean diet, characterized by high intake of vegetables, fruits, olive oil, and legumes, has shown promise in promoting cardiovascular, neurological, and metabolic health. MEDAS, a validated 14-item questionnaire developed within the PREDIMED study, serves as a practical tool to assess adherence to this dietary pattern. The current analysis spans literature from 2000 to 2025 and includes 203 peer-reviewed publications indexed in Web of Science. Using VOSviewer and CiteSpace software, co-occurrence maps, keyword clusters, and disease associations were visualized. Results indicate that fish, vegetables, nuts, and olive oil are the most frequently studied MEDAS components. Cardiovascular aging emerged as the most researched domain, followed by general aging and neurodegenerative conditions, while dermatological aging remains underexplored. Key themes such as cognitive decline, frailty, inflammaging, and longevity underscore the multidimensional role of MEDAS. Findings suggest that MEDAS is not only a dietary adherence measure but also a valuable instrument in preventive geriatric nutrition. Its global adaptability, simplicity, and strong predictive value make it a suitable tool for clinical and community-based nutritional strategies. This study contributes a consolidated foundation for future interdisciplinary efforts to integrate diet-based approaches into aging research and public health policy.

本研究通过全面的文献计量学和范围审查方法，探讨了地中海饮食依从筛选（MEDAS）与衰老相关健康结果之间的科学联系。鉴于慢性疾病在老年人群中的患病率日益增加，饮食已成为一个可改变的因素，具有提高健康寿命的潜力。地中海饮食的特点是大量摄入蔬菜、水果、橄榄油和豆类，在促进心血管、神经和代谢健康方面表现出了希望。MEDAS是PREDIMED研究中开发的一份经过验证的14项问卷，可作为评估这种饮食模式依从性的实用工具。目前的分析涵盖了2000年至2025年的文献，包括203篇被Web of Science收录的同行评议出版物。使用VOSviewer和CiteSpace软件，对共现图、关键词集群和疾病关联进行可视化。结果表明，鱼类、蔬菜、坚果和橄榄油是最常被研究的MEDAS成分。心血管老化是研究最多的领域，其次是一般老化和神经退行性疾病，而皮肤老化仍未得到充分研究。认知能力下降、虚弱、炎症和长寿等关键主题强调了MEDAS的多维作用。研究结果表明，MEDAS不仅是一种饮食依从性指标，而且是预防老年营养的一种有价值的工具。它的全球适应性、简单性和强大的预测价值使其成为临床和社区营养策略的合适工具。这项研究为未来跨学科的努力奠定了坚实的基础，将基于饮食的方法整合到老龄化研究和公共卫生政策中。

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引用次数: 0

lncRNA EPB41L4A-AS1: A promising therapeutic target for aging and age-related diseases lncRNA EPB41L4A-AS1：一个有希望的治疗衰老和年龄相关疾病的靶点

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-10-09 DOI: 10.1016/j.mad.2025.112118

Minghui Li , Tianzi Li , Xufei Zhang , Kun Li , Ziqiang Wang

Aging is a natural biological process characterized by progressive cellular and functional decline, significantly increasing susceptibility to age-related diseases. Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of cellular processes implicated in aging and age-related diseases. Among these, lncRNA erythrocyte membrane protein band 4.1 like 4 A antisense RNA 1 (EPB41L4A-AS1) has emerged as a key player with significant dysregulation across diverse age-related diseases including cancer, Alzheimer's disease (AD), and type 2 diabetes mellitus (T2DM). This review synthesizes current evidence showing that EPB41L4A-AS1 functions primarily as a tumor suppressor in many cancers, regulates neuronal autophagy and energy metabolism in AD, and modulates inflammatory and metabolic pathways in T2DM. Mechanistically, EPB41L4A-AS1 exerts its effects—via miRNA sponging, regulating key signaling pathways (NF-κB, Rho/ROCK), influencing histone modifications, and modulating cellular metabolism (glycolysis, glutaminolysis, NAD+/ATP synthesis). The compelling evidence positions EPB41L4A-AS1 as a promising, multi-faceted therapeutic target for mitigating the burden of age-related diseases.

衰老是一个自然的生物学过程，其特征是细胞和功能的进行性衰退，显著增加对年龄相关疾病的易感性。长链非编码rna （lncRNAs）越来越被认为是涉及衰老和年龄相关疾病的细胞过程的关键调节因子。其中，lncRNA红细胞膜蛋白带4.1如4A反义RNA 1 （EPB41L4A-AS1）已成为多种年龄相关疾病（包括癌症、阿尔茨海默病（AD）和2型糖尿病（T2DM））中显著失调的关键参与者。本综述综合了目前的证据，表明EPB41L4A-AS1在许多癌症中主要作为肿瘤抑制因子，调节AD中的神经元自噬和能量代谢，并调节T2DM中的炎症和代谢途径。在机制上，EPB41L4A-AS1通过miRNA海绵作用发挥作用，调节关键信号通路（NF-κB, Rho/ROCK），影响组蛋白修饰，调节细胞代谢（糖酵解，谷氨酰胺解，NAD+/ATP合成）。令人信服的证据表明，EPB41L4A-AS1是一个有希望的、多方面的治疗靶点，可以减轻年龄相关疾病的负担。

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引用次数: 0

The stress-responsive cytokine GDF-15 and sarcopenia: A systematic review and meta-analysis on aging muscle decline 应激反应细胞因子GDF-15和肌肉减少症：衰老肌肉衰退的系统回顾和荟萃分析。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-09-26 DOI: 10.1016/j.mad.2025.112117

Mario Virgilio Papa , Chiara Ceolin , Francesco Boschele , Raffaele Pagliuca , Giuseppe Sergi , Marina De Rui

Background

Given the increasing interest for Growth Differentiation Factor-15 (GDF-15) in muscle decline, this study aims to evaluate the association between circulating levels of GDF-15 and muscle mass and sarcopenia through a systematic review and meta-analysis.

Methods

The research, in accordance with PRISMA and MOOSE guidelines, involved PubMed, Embase, and Cochrane Libraries. Two meta-analyses were performed: (1) comparison of GDF-15 levels in sarcopenic vs non-sarcopenic individuals; (2) correlation between GDF-15 and muscle mass.

Results

A total of 7 studies met the inclusion criteria (total n = 2344) enrolling both adults aged ≥ 60 years (6/7 studies) and a younger cohort (42 years [IQR 31.8–51]). The first meta-analysis, based on 4 studies (n = 1393), showed significantly higher levels of GDF-15 in sarcopenic individuals (r = 0.482). The second meta-analysis, involving 4 studies (n = 1400), found a significant inverse correlation between GDF-15 and muscle mass (r = -0.221).

Conclusions

Sarcopenic individuals had higher circulating GDF-15. Together with the inverse correlation between GDF-15 and muscle mass observed, these findings show a small-to-moderate association between elevated GDF-15 and sarcopenic phenotypes in older adults. However, the limited number of studies and high heterogeneity for the sarcopenia comparison warrant cautious interpretation and underscore the need for larger, longitudinal investigations.

背景：鉴于人们对生长分化因子-15 （GDF-15）在肌肉衰退中的作用越来越感兴趣，本研究旨在通过系统回顾和荟萃分析来评估循环中GDF-15水平与肌肉质量和肌肉减少症之间的关系。方法：根据PRISMA和MOOSE指南，研究涉及PubMed、Embase和Cochrane图书馆。进行了两项荟萃分析：(1)比较肌肉减少症患者与非肌肉减少症患者的GDF-15水平；(2) GDF-15与肌肉质量的相关性。结果：共有7项研究符合纳入标准（总n=2,344），纳入年龄≥60岁的成人（6/7项研究）和年龄较小的队列（42岁[IQR 31.8-51]）。基于4项研究（n=1393）的第一项荟萃分析显示，肌肉减少症患者的GDF-15水平显著较高（r=0.482）。第二项荟萃分析涉及4项研究（n= 1400），发现GDF-15与肌肉质量之间存在显著的负相关（r= -0.221）。结论：肌少症患者有较高的循环GDF-15。再加上观察到的GDF-15与肌肉质量之间的负相关，这些发现表明，老年人GDF-15升高与肌肉减少表型之间存在小到中度的关联。然而，有限的研究数量和肌肉减少症比较的高度异质性需要谨慎的解释，并强调需要更大规模的纵向研究。

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引用次数: 0

Clinical data-driven classification of pre-frailty reveals sex-specific patterns – Data from the Berlin Aging Study II (BASE-II) 临床数据驱动的虚弱前分类揭示了性别特异性模式——来自柏林老龄化研究II （BASE-II）的数据

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-09-24 DOI: 10.1016/j.mad.2025.112114

Jeff Didier , Sébastien De Landtsheer , Maria Pires Pacheco , Ali Kishk , Jochen G. Schneider , David Goldeck , Graham Pawelec , Dominik Spira , Ilja Demuth , Thomas Sauter

Frailty is a geriatric condition with multidimensional consequences that strongly affect older adults’ quality of life. The lack of a universal standard to describe, diagnose, and treat frailty further complicates this situation. Nowadays, multitudinous frailty assessment tools are applied depending on the regional and clinical context, adding complexity by increasing heterogeneity in the definition and characterization of frailty. Better insights into the causes and pathophysiology of frailty and its early stages are required to establish strong and accurately tailored treatment rationales for frail patients. We analysed participants aged 60 and above using cross-sectional biochemical and survey data from the Berlin Aging Study II (BASE-II, N = 1512, pre-frail=470, frail=14), applying machine-learning techniques to investigate determinants of physical frailty measured by Fried et al.’s 5-item frailty phenotype. Our findings highlight new prognostic sex-specific biomarkers of pre-frailty (the early stage of frailty) with possible clinical applications, enriching the current sex-agnostic diagnostic scores with easy monitorable physical and physiological characteristics. Low appendicular lean mass and high fat composition in men, or vitamin D deficiency and high white blood cell counts in women, emerged as strong indicators of the respective pre-frailty profiles. Because the number of fully frail individuals was extremely small (n = 14, <1 %), our findings should be interpreted as reflecting predictors of pre-frailty, not of frailty itself. We conclude that understanding the development of frailty remains a complex challenge, and that sex-specific differences must be considered by clinical geriatricians and researchers.

虚弱是一种老年疾病，具有多方面的后果，严重影响老年人的生活质量。缺乏描述、诊断和治疗虚弱的通用标准使这种情况进一步复杂化。如今，根据地区和临床情况，应用了多种虚弱评估工具，这增加了虚弱定义和特征的异质性，从而增加了复杂性。需要更好地了解虚弱的原因和病理生理学及其早期阶段，以便为虚弱患者建立强有力和准确定制的治疗依据。我们使用来自柏林老龄化研究II （BASE-II, N = 1512，pre-虚弱=470，虚弱=14）的横断面生化和调查数据分析了60岁及以上的参与者，并应用机器学习技术来研究Fried等人的5项虚弱表型测量的身体虚弱的决定因素。我们的研究结果强调了具有潜在临床应用价值的新的预脆弱（脆弱的早期阶段）预后性别特异性生物标志物，丰富了目前的性别不可知的诊断评分，具有易于监测的生理和生理特征。男性阑尾瘦质量低、脂肪含量高，女性缺乏维生素D、白细胞数量高，这些都是各自脆弱前特征的有力指标。由于完全虚弱个体的数量非常少（n = 14,<1 %），我们的发现应该被解释为反映了虚弱前期的预测因子，而不是虚弱本身。我们的结论是，了解衰弱的发展仍然是一个复杂的挑战，临床老年病学家和研究人员必须考虑到性别特异性差异。

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引用次数: 0

Human astrocytes from healthy individuals and Alzheimer’s patients respond differently to Aβ1–42 oligomers, triggering distinct paths of reactivity and senescence 健康个体和阿尔茨海默病患者的人类星形胶质细胞对Aβ1-42寡聚物的反应不同，引发不同的反应性和衰老途径。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-09-24 DOI: 10.1016/j.mad.2025.112116

Sara Ristori , Gianmarco Bertoni , Alessandra Bigi , Cristina Cecchi , Manuela Sollazzo , Luisa Iommarini , Daniela Monti , Elisa Bientinesi

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by cognitive decline, amyloid-β (Aβ) plaques, and neurofibrillary tangles. Aβ_1–42 oligomers exert neurotoxic and pro-inflammatory effects. Astrocytes maintain brain homeostasis, and their dysfunction contributes to AD progression. This study investigates the impact of Aβ_1–42 oligomers on primary human astrocytes from healthy individuals and AD patients. Our findings show that astrocytes from both groups internalise Aβ_1–42 oligomers. In healthy astrocytes, internalisation enhances proteasome activity, whereas in AD astrocytes, it reduces it. Aβ_1–42 oligomers induce calcium dyshomeostasis and mitochondrial membrane potential alterations in both groups. Interestingly, oligomers induce apoptosis in a subset of healthy astrocytes, while surviving ones become reactive and hyperproliferative, releasing neuroinflammatory and neurotrophic molecules. Conversely, Aβ_1–42 drives AD astrocytes into senescence, characterised by increased β-galactosidase activity, p14^ARF expression, senescence-associated secretory phenotype (SASP), and heterochromatin foci. Importantly, conditioned media from Aβ_1–42-treated AD astrocytes, but not from healthy ones, cause death of differentiated SH-SY5Y neuron-like cells, suggesting that senescent astrocytes contribute to neurotoxicity. These findings reveal differential astrocytic responses to Aβ_1–42 oligomers, emphasising the importance of astrocyte senescence in AD pathogenesis. This research offers insight into cellular mechanisms underlying AD and may support the development of innovative therapeutic strategies for neurodegenerative diseases.

阿尔茨海默病（AD）是一种神经退行性疾病，其特征是认知能力下降、淀粉样蛋白-β (a β)斑块和神经原纤维缠结。a - β1-42低聚物具有神经毒性和促炎作用。星形胶质细胞维持大脑内稳态，其功能障碍有助于AD的进展。本研究探讨了Aβ1-42寡聚物对健康人及阿尔茨海默病患者原代人星形胶质细胞的影响。我们的研究结果表明，两组的星形胶质细胞都内化了Aβ1-42低聚物。在健康的星形胶质细胞中，内化增强蛋白酶体活性，而在AD星形胶质细胞中，内化则降低蛋白酶体活性。a - β1-42低聚物诱导两组钙平衡失调和线粒体膜电位改变。有趣的是，低聚物在一部分健康星形胶质细胞中诱导凋亡，而存活的星形胶质细胞变得反应性和超增殖，释放神经炎症和神经营养分子。相反，a - β1-42驱动AD星形胶质细胞衰老，其特征是β-半乳糖苷酶活性、p14ARF表达、衰老相关分泌表型（SASP）和异染色质灶增加。重要的是，来自a β1-42处理的AD星形胶质细胞的条件培养基，而不是来自健康的星形胶质细胞的条件培养基，导致分化的SH-SY5Y神经元样细胞死亡，这表明衰老的星形胶质细胞有助于神经毒性。这些发现揭示了星形细胞对a - β1-42寡聚物的不同反应，强调了星形细胞衰老在阿尔茨海默病发病中的重要性。这项研究为阿尔茨海默病的细胞机制提供了见解，并可能支持神经退行性疾病的创新治疗策略的发展。

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引用次数: 0