Nature aging最新文献

英文中文

Decoding the phenotypic mosaic of aging 解码衰老的表型镶嵌。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-08-09 DOI: 10.1038/s43587-024-00686-0

Liang-Kung Chen

The Integrated Care for Older People program of the World Health Organization is intended as a catalyst to empower communities to cocreate personalized interventions and usher in an era of precision healthy longevity, in which the needs, values and preferences of older people are centered. A study from France now presents early screening data and reveals distinct phenotypic trajectories towards adverse outcomes.

世界卫生组织的 "老年人综合护理计划 "旨在推动社区共同创造个性化干预措施，开创一个以老年人的需求、价值观和偏好为中心的精准健康长寿时代。现在，法国的一项研究提供了早期筛查数据，并揭示了不良后果的独特表型轨迹。

引用次数: 0

Blocking IL-11 improves healthspan and lifespan in mice 阻断 IL-11 可改善小鼠的健康和寿命。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-08-08 DOI: 10.1038/s43587-024-00699-9

Hannah Walters

引用次数: 0

Age-associated clonal B cells drive B cell lymphoma in mice. 与年龄相关的克隆 B 细胞会诱发小鼠 B 细胞淋巴瘤。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-08-08 DOI: 10.1038/s43587-024-00671-7

José P Castro, Anastasia V Shindyapina, Alessandro Barbieri, Kejun Ying, Olga S Strelkova, João A Paulo, Alexander Tyshkovskiy, Rico Meinl, Csaba Kerepesi, Anna P Petrashen, Marco Mariotti, Margarita V Meer, Yan Hu, Alexander Karamyshev, Grigoriy Losyev, Mafalda Galhardo, Elsa Logarinho, Artur A Indzhykulian, Steven P Gygi, John M Sedivy, John P Manis, Vadim N Gladyshev

Although cancer is an age-related disease, how the processes of aging contribute to cancer progression is not well understood. In this study, we uncovered how mouse B cell lymphoma develops as a consequence of a naturally aged system. We show here that this malignancy is associated with an age-associated clonal B cell (ACBC) population that likely originates from age-associated B cells. Driven by c-Myc activation, promoter hypermethylation and somatic mutations, IgM⁺ ACBCs clonally expand independently of germinal centers and show increased biological age. ACBCs become self-sufficient and support malignancy when transferred into young recipients. Inhibition of mTOR or c-Myc in old mice attenuates pre-malignant changes in B cells during aging. Although the etiology of mouse and human B cell lymphomas is considered distinct, epigenetic changes in transformed mouse B cells are enriched for changes observed in human B cell lymphomas. Together, our findings characterize the spontaneous progression of cancer during aging through both cell-intrinsic and microenvironmental changes and suggest interventions for its prevention.

虽然癌症是一种与年龄相关的疾病，但人们对衰老过程如何导致癌症进展还不甚了解。在这项研究中，我们揭示了小鼠 B 细胞淋巴瘤是如何在自然老化的系统中发展起来的。我们在此表明，这种恶性肿瘤与年龄相关克隆 B 细胞（ACBC）群有关，而 ACBC 很可能源自年龄相关 B 细胞。在c-Myc激活、启动子超甲基化和体细胞突变的驱动下，IgM+ ACBC独立于生殖中心进行克隆扩增，并显示出生物年龄的增加。当 ACBC 移植到年轻的受体时，会变得自给自足并支持恶性肿瘤。抑制老龄小鼠的 mTOR 或 c-Myc 可减轻衰老过程中 B 细胞的恶性前变化。虽然小鼠和人类 B 细胞淋巴瘤的病因不同，但转化小鼠 B 细胞的表观遗传学变化与人类 B 细胞淋巴瘤中观察到的变化相似。总之，我们的研究结果描述了衰老过程中癌症通过细胞内在变化和微环境变化自发发展的特点，并提出了预防癌症的干预措施。

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引用次数: 0

Multiorgan biological age shows that no organ system is an island 多器官生物年龄表明，任何器官系统都不是一座孤岛。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-08-02 DOI: 10.1038/s43587-024-00690-4

In our study, we linked machine-learning-derived biological age gaps (BAGs) to common genetic variants in nine human organ systems, which revealed how these BAGs are causally associated with organ health and chronic diseases such as Alzheimer’s disease and diabetes. The findings provide insights into therapeutic and lifestyle interventions that might enhance organ health.

在我们的研究中，我们将机器学习得出的生物年龄差距（BAG）与九个人体器官系统中的常见基因变异联系起来，揭示了这些生物年龄差距与器官健康以及阿尔茨海默病和糖尿病等慢性疾病之间的因果关系。这些发现为可能增强器官健康的治疗和生活方式干预提供了启示。

引用次数: 0

Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA 母体年龄增强了对哺乳动物mtDNA I复合基因致病突变的纯化选择。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-07-29 DOI: 10.1038/s43587-024-00672-6

Yanfei Ru, Xiaoling Deng, Jiatong Chen, Leping Zhang, Zhe Xu, Qunyu Lv, Shiyun Long, Zijian Huang, Minghua Kong, Jing Guo, Min Jiang

Mitochondrial diseases, caused mainly by pathogenic mitochondrial DNA (mtDNA) mutations, pose major challenges due to the lack of effective treatments. Investigating the patterns of maternal transmission of mitochondrial diseases could pave the way for preventive approaches. In this study, we used DddA-derived cytosine base editors (DdCBEs) to generate two mouse models, each haboring a single pathogenic mutation in complex I genes (ND1 and ND5), replicating those found in human patients. Our findings revealed that both mutations are under strong purifying selection during maternal transmission and occur predominantly during postnatal oocyte maturation, with increased protein synthesis playing a vital role. Interestingly, we discovered that maternal age intensifies the purifying selection, suggesting that older maternal age may offer a protective effect against the transmission of deleterious mtDNA mutations, contradicting the conventional notion that maternal age correlates with increased transmitted mtDNA mutations. As collecting comprehensive clinical data is needed to understand the relationship between maternal age and transmission patterns in humans, our findings may have profound implications for reproductive counseling of mitochondrial diseases, especially those involving complex I gene mutations. Mitochondrial DNA mutations are subject to purifying selection in the female germline, limiting the transmission of pathogenic variants. In this study, the authors used two mouse models that harbor pathogenic mutations in mitochondrial complex I and observed that maternal age intensifies purifying selection processes.

线粒体疾病主要由致病性线粒体 DNA（mtDNA）突变引起，由于缺乏有效的治疗方法，线粒体疾病构成了重大挑战。研究线粒体疾病的母体传播模式可以为预防方法铺平道路。在这项研究中，我们利用 DddA 衍生的胞嘧啶碱基编辑器（DdCBE）生成了两个小鼠模型，每个模型都有一个复合 I 基因（ND1 和 ND5）的致病突变，与人类患者中发现的突变相同。我们的研究结果表明，这两种突变在母体传播过程中都受到了强烈的净化选择，并且主要发生在出生后卵母细胞成熟过程中，蛋白质合成的增加起到了至关重要的作用。有趣的是，我们发现母体年龄会加强纯化选择，这表明母体年龄越大，对有害 mtDNA 突变的传播越有保护作用，这与母体年龄与传播的 mtDNA 突变增加有关的传统观点相矛盾。由于需要收集全面的临床数据来了解人类母体年龄与传播模式之间的关系，我们的发现可能会对线粒体疾病（尤其是涉及复合 I 基因突变的疾病）的生殖咨询产生深远影响。

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引用次数: 0

mTOR links nutrients, inflammaging and lifespan mTOR 将营养、炎症和寿命联系在一起。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-07-26 DOI: 10.1038/s43587-024-00681-5

Helena M. Cochemé, Jesús Gil

A study from Ortega-Molina and colleagues uses mouse models with mildly elevated mTOR activity to investigate the stepwise process by which increased nutrient signaling affects healthy aging. These findings show how initial parenchymal damage caused by mTOR activity is followed by secondary myeloid inflammation, a multistage process that culminates in organ deterioration and reduced lifespan.

Ortega-Molina 及其同事的一项研究利用 mTOR 活性轻度升高的小鼠模型，研究了营养信号增强对健康衰老的逐步影响过程。这些研究结果表明，mTOR 活性引起的最初实质损伤如何继发骨髓炎症，这一多阶段过程最终导致器官退化和寿命缩短。

引用次数: 0

Separation of reproductive decline from lifespan extension during methionine restriction 蛋氨酸限制过程中生殖能力下降与寿命延长的分离

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-07-26 DOI: 10.1038/s43587-024-00674-4

Fangchao Wei, Shiyu Liu, Juan Liu, Yudong Sun, Annamarie E. Allen, Michael A. Reid, Jason W. Locasale

Lifespan-extending interventions are generally thought to result in reduced fecundity. The generality of this principle and how it may extend to nutrition and metabolism is not understood. We considered dietary methionine restriction (MR), a lifespan-extending intervention linked to Mediterranean and plant-based diets. Using a chemically defined diet that we developed for Drosophila melanogaster, we surveyed the nutritional landscape in the background of MR and found that folic acid, a vitamin linked to one-carbon metabolism, notably was the lone nutrient that restored reproductive capacity while maintaining lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the tricarboxylic cycle and redox coupling as major determinants of the MR-folic acid benefits, in part, as they related to sperm function. Together these findings suggest that dietary interventions optimized for longevity may be separable from adverse effects such as reproductive decline. Methionine restriction decreases fecundity and increases lifespan in flies. Here Wei et al. show that supplementing folic acid, associated with one-carbon metabolism, during methionine restriction in flies, mitigates the decline in fertility while retaining the intervention’s life-extending benefits.

一般认为，延长寿命的干预措施会导致繁殖力下降。这一原理的普遍性以及它如何延伸到营养和新陈代谢方面尚不清楚。我们研究了蛋氨酸饮食限制（MR），这是一种与地中海饮食和植物性饮食相关的延长寿命干预措施。利用我们为黑腹果蝇开发的化学定义饮食，我们调查了MR背景下的营养状况，发现叶酸（一种与一碳代谢有关的维生素）是唯一一种既能恢复生殖能力又能维持寿命延长的营养物质。体内同位素追踪、代谢组学和通量分析发现，三羧酸循环和氧化还原耦合是决定叶酸对MR益处的主要因素，部分原因是它们与精子功能有关。这些发现共同表明，为长寿而优化的膳食干预可能与生殖功能衰退等不利影响相分离。

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引用次数: 0

Gut microbial features and circulating metabolomic signatures of frailty in older adults 老年人肠道微生物特征和循环代谢组特征与虚弱有关。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-07-25 DOI: 10.1038/s43587-024-00678-0

Yanni Pu, Zhonghan Sun, Hui Zhang, Qingxia Huang, Zhengdong Wang, Zhendong Mei, Peilu Wang, Mengmeng Kong, Wenjun Yang, Chenhao Lin, Xiaofeng Zhou, Shuchun Lin, Qiumin Huang, Lili Huang, Liang Sun, Changzheng Yuan, Qian Xu, Huiru Tang, Xiaofeng Wang, Yan Zheng

Frailty, a multidimensional indicator of suboptimal aging, reflects cumulative declines across multiple physiological systems. Although age-related changes have been reported in gut microbiota, their role in healthy aging remains unclear. In this study, we calculated frailty index (FI) from 33 health-related items to reflect the overall health status of 1,821 older adults (62–96 years, 55% female) and conducted multi-omics analysis using gut metagenomic sequencing data and plasma metabolomic data. We identified 18 microbial species and 17 metabolites shifted along with frailty severity, with stronger links observed in females. The associations of nine species, including various Clostridium species and Faecalibacterium prausnitzii, with FI were reproducible in two external populations. Plasma glycerol levels, white blood cell count and kidney function partially mediated these associations. A composite microbial score derived from FI significantly predicted 2-year mortality (adjusted hazard ratio across extreme quartiles, 2.86; 95% confidence interval, 1.38–5.93), highlighting the potential of microbiota-based strategies for risk stratification in older adults. This study reveals gut microbial and metabolomic features associated with the severity of frailty, demonstrating that these microbial features outperform traditional assessment tools in identifying individuals at high risk of frailty and mortality.

虚弱是衰老的一个多维指标，反映了多个生理系统的累积衰退。虽然有报道称肠道微生物群发生了与年龄相关的变化，但它们在健康老龄化中的作用仍不清楚。在这项研究中，我们从 33 个与健康相关的项目中计算出了虚弱指数（FI），以反映 1821 名老年人（62-96 岁，55% 为女性）的总体健康状况，并利用肠道元基因组测序数据和血浆代谢组数据进行了多组学分析。我们确定了 18 种微生物和 17 种代谢物与虚弱严重程度的关系，其中女性与虚弱严重程度的关系更为密切。包括多种梭状芽孢杆菌（Clostridium）和普氏粪杆菌（Faecalibacterium prausnitzii）在内的九种微生物与虚弱严重程度的关系在两个外部人群中具有可重复性。血浆甘油水平、白细胞计数和肾功能在一定程度上介导了这些关联。从 FI 得出的微生物综合评分可显著预测 2 年死亡率（极端四分位数的调整后危险比为 2.86；95% 置信区间为 1.38-5.93），凸显了基于微生物群的老年人风险分层策略的潜力。

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引用次数: 0

An NAD⁺-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging. 依赖于 NAD+ 的代谢检查点调节造血干细胞的活化和衰老。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-07-23 DOI: 10.1038/s43587-024-00670-8

Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen

How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD⁺-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca²⁺ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD⁺ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca²⁺ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD⁺ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca²⁺ signaling to HSC aging.

造血干细胞（HSCs）如何在整个生命周期内维持代谢平衡以支持组织修复和再生，目前尚无定论。在这里，我们发现，CD38是一种依赖于NAD+的代谢酶，在年轻小鼠体内通过诱导线粒体Ca2+流入和线粒体代谢促进造血干细胞增殖。相反，由于 NAD+ 代谢失调和线粒体应激管理受损，衰老过程中 CD38 的异常上调是老年小鼠造血干细胞退化的驱动因素。线粒体钙离子通道是线粒体 Ca2+ 流入的介质，它也支持年轻小鼠的造血干细胞增殖，但却驱动着老年小鼠造血干细胞的衰退。药物灭活 CD38 可逆转造血干细胞的衰老和衰老小鼠造血系统的病理生理变化。总之，我们的研究强调了一个 NAD+ 代谢检查点，它能平衡线粒体激活以支持造血干细胞增殖和线粒体应激管理以增强造血干细胞在整个生命周期的自我更新，并将异常 Ca2+ 信号传导与造血干细胞衰老联系起来。

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Long-term cognitive change after COVID-19 in older individuals 老年人服用 COVID-19 后的长期认知变化。

IF 17 Q1 CELL BIOLOGY

Nature aging

Pub Date : 2024-07-23 DOI: 10.1038/s43587-024-00687-z

Our study shows that older adults who survive severe COVID-19 suffer accelerated cognitive decline for 1 year after infection, after which the rate of decline decelerates. Long-lasting cognitive impairment occurs mostly in individuals who had severe COVID-19, showed cognitive impairments at 6 months after infection and had coexisting hypertension.

我们的研究表明，感染严重 COVID-19 病毒的老年人在感染后一年内认知能力会加速下降，之后下降速度会减慢。长期认知功能障碍主要发生在那些感染了严重 COVID-19、在感染后 6 个月出现认知功能障碍并同时患有高血压的人身上。

引用次数: 0

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