Pub Date : 2024-11-27DOI: 10.1038/s43587-024-00757-2
Francesco Morandini, Jinlong Y. Lu, Cheyenne Rechsteiner, Aladdin H. Shadyab, Ramon Casanova, Beverly M. Snively, Andrei Seluanov, Vera Gorbunova
Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. DNA 5-methylcytosine (5mC) is one of the main epigenetic modifications by which TEs are silenced and has been used to train highly accurate age predictors. Yet, one common criticism of such predictors is that they lack interpretability. In this study, we investigate the changes in TE 5mC methylation that occur during aging in human blood using published methylation array data. We find that evolutionarily young long interspersed nuclear elements 1 (L1s), the only known TEs capable of autonomous transposition in humans, undergo the fastest loss of 5mC methylation, suggesting an active mechanism of de-repression. The same young L1s also showed preferential gain in chromatin accessibility but not expression. The long terminal repeat retrotransposons THE1A and THE1C also showed very rapid 5mC loss. We then show that accurate age predictors can be trained on both 5mC methylation of individual TE copies and average methylation of TE families genome wide. Lastly, we show that while old L1s gradually lose 5mC during the entire lifespan, demethylation of young L1s only happens late in life and is associated with cancer. Transposable elements activate during aging with negative consequences. Morandini et al. show that transposons show rapid loss of methylation in peripheral blood mononuclear cells during aging and that models trained on transposon methylation accurately predict age.
可转座元件（Transposable elements，TEs）是在基因组中自私扩增的 DNA 序列，可能会对细胞造成严重损伤。可转座元件通常处于沉默状态，但在衰老过程中会被激活。DNA 5-甲基胞嘧啶（5mC）是使TEs沉默的主要表观遗传修饰之一，已被用于训练高度准确的年龄预测器。然而，对这类预测指标的一个常见批评是它们缺乏可解释性。在本研究中，我们利用已发表的甲基化阵列数据研究了人体血液中 TE 5mC 甲基化在衰老过程中发生的变化。我们发现，进化过程中年轻的长穿插核元素 1（L1s）--已知的唯一能在人类中自主转座的 TE--经历了最快的 5mC 甲基化损失，这表明存在一种活跃的去抑制机制。同样年轻的 L1s 也表现出染色质可及性的优先增殖，但没有表达。长末端重复反转座子 THE1A 和 THE1C 也显示出非常快的 5mC 消失。然后我们证明，可以根据单个 TE 拷贝的 5mC 甲基化和全基因组 TE 家族的平均甲基化来训练准确的年龄预测因子。最后，我们还表明，虽然老年 L1 在整个生命周期中会逐渐丢失 5mC，但年轻 L1 的去甲基化只发生在生命晚期，而且与癌症有关。
{"title":"Transposable element 5mC methylation state of blood cells predicts age and disease","authors":"Francesco Morandini, Jinlong Y. Lu, Cheyenne Rechsteiner, Aladdin H. Shadyab, Ramon Casanova, Beverly M. Snively, Andrei Seluanov, Vera Gorbunova","doi":"10.1038/s43587-024-00757-2","DOIUrl":"10.1038/s43587-024-00757-2","url":null,"abstract":"Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. DNA 5-methylcytosine (5mC) is one of the main epigenetic modifications by which TEs are silenced and has been used to train highly accurate age predictors. Yet, one common criticism of such predictors is that they lack interpretability. In this study, we investigate the changes in TE 5mC methylation that occur during aging in human blood using published methylation array data. We find that evolutionarily young long interspersed nuclear elements 1 (L1s), the only known TEs capable of autonomous transposition in humans, undergo the fastest loss of 5mC methylation, suggesting an active mechanism of de-repression. The same young L1s also showed preferential gain in chromatin accessibility but not expression. The long terminal repeat retrotransposons THE1A and THE1C also showed very rapid 5mC loss. We then show that accurate age predictors can be trained on both 5mC methylation of individual TE copies and average methylation of TE families genome wide. Lastly, we show that while old L1s gradually lose 5mC during the entire lifespan, demethylation of young L1s only happens late in life and is associated with cancer. Transposable elements activate during aging with negative consequences. Morandini et al. show that transposons show rapid loss of methylation in peripheral blood mononuclear cells during aging and that models trained on transposon methylation accurately predict age.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 2","pages":"193-204"},"PeriodicalIF":17.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00757-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-27DOI: 10.1038/s43587-024-00744-7
Chung-Yang Yeh, Lucas C. S. Chini, Jessica W. Davidson, Gonzalo G. Garcia, Meredith S. Gallagher, Isaac T. Freichels, Mariah F. Calubag, Allison C. Rodgers, Cara L. Green, Reji Babygirija, Michelle M. Sonsalla, Heidi H. Pak, Michaela E. Trautman, Timothy A. Hacker, Richard A. Miller, Judith A. Simcox, Dudley W. Lamming
Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. Both dietary regimens effectively promote overall metabolic health without reducing calorie intake. Both low AA and low Ile diets improve aspects of frailty and slow multiple molecular indicators of aging rate; however, the low Ile diet reduces grip strength in both sexes and has mixed, sexually dimorphic effects on the heart. These results demonstrate that low AA and low Ile diets can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults. Yeh et al. explore the effects of restricting dietary protein, or isoleucine specifically, in aged mice. They uncover benefits to metabolic health and certain indicators of aging and a sexually dimorphic effect on the heart.
限制蛋白质或支链氨基酸异亮氨酸的摄入可促进年轻或成年小鼠的健康并延长其寿命。然而，它们对老年动物的影响尚不清楚。在此，我们研究了雄性和雌性 C57BL/6J.Nia 小鼠从 20 个月大开始摄入所有氨基酸减少 67% 的饮食（低 AA）或仅摄入异亮氨酸饮食（低 Ile）的后果。这两种饮食方案都能在不减少热量摄入的情况下有效促进整体代谢健康。低AA和低Ile饮食都能改善虚弱的各个方面，并减缓衰老速度的多种分子指标；然而，低Ile饮食会降低雌雄小鼠的握力，并对心脏产生不同性别的影响。这些结果表明，低 AA 和低 Ile 饮食可以促进老年小鼠健康老化的各个方面，并表明类似的干预措施可能会促进老年人的健康老化。
{"title":"Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging","authors":"Chung-Yang Yeh, Lucas C. S. Chini, Jessica W. Davidson, Gonzalo G. Garcia, Meredith S. Gallagher, Isaac T. Freichels, Mariah F. Calubag, Allison C. Rodgers, Cara L. Green, Reji Babygirija, Michelle M. Sonsalla, Heidi H. Pak, Michaela E. Trautman, Timothy A. Hacker, Richard A. Miller, Judith A. Simcox, Dudley W. Lamming","doi":"10.1038/s43587-024-00744-7","DOIUrl":"10.1038/s43587-024-00744-7","url":null,"abstract":"Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. Both dietary regimens effectively promote overall metabolic health without reducing calorie intake. Both low AA and low Ile diets improve aspects of frailty and slow multiple molecular indicators of aging rate; however, the low Ile diet reduces grip strength in both sexes and has mixed, sexually dimorphic effects on the heart. These results demonstrate that low AA and low Ile diets can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults. Yeh et al. explore the effects of restricting dietary protein, or isoleucine specifically, in aged mice. They uncover benefits to metabolic health and certain indicators of aging and a sexually dimorphic effect on the heart.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1760-1771"},"PeriodicalIF":17.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8+ tissue resident memory T (TRM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8+ T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8+ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated TRM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8+ T cells by restoring TRM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8+ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced TRM restriction as a key mechanism causing aged CD8+ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy. Exploring how aging compromises antitumor immunity, the authors reveal an age-related impairment of cytotoxic CD8+ TRM cells in mouse tumor models and clinical samples. They implicate BFAR signaling and show that targeting BFAR restores TRM generation and tumor control.
{"title":"Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity","authors":"Siyu Pei, Xiuyu Deng, Ruirui Yang, Hui Wang, Jian-Hong Shi, Xueqing Wang, Jia Huang, Yu Tian, Rongjing Wang, Sulin Zhang, Hui Hou, Jing Xu, Qingcheng Zhu, Huan Huang, Jialing Ye, Cong-Yi Wang, Wei Lu, Qingquan Luo, Zhi-Yu Ni, Mingyue Zheng, Yichuan Xiao","doi":"10.1038/s43587-024-00746-5","DOIUrl":"10.1038/s43587-024-00746-5","url":null,"abstract":"Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8+ tissue resident memory T (TRM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8+ T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8+ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated TRM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8+ T cells by restoring TRM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8+ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced TRM restriction as a key mechanism causing aged CD8+ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy. Exploring how aging compromises antitumor immunity, the authors reveal an age-related impairment of cytotoxic CD8+ TRM cells in mouse tumor models and clinical samples. They implicate BFAR signaling and show that targeting BFAR restores TRM generation and tumor control.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1828-1844"},"PeriodicalIF":17.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-26DOI: 10.1038/s43587-024-00779-w
Nucleolar enlargement during aging alters the biophysical properties of nucleoli, which allows entry of DNA repair machinery that is normally excluded. In budding yeast this event triggers catastrophic global genome instability due to aberrant ribosomal DNA recombination, and imminently ends the yeast’s mitotic lifespan.
{"title":"Old enlarged nucleoli open the door to the cell’s demise","authors":"","doi":"10.1038/s43587-024-00779-w","DOIUrl":"10.1038/s43587-024-00779-w","url":null,"abstract":"Nucleolar enlargement during aging alters the biophysical properties of nucleoli, which allows entry of DNA repair machinery that is normally excluded. In budding yeast this event triggers catastrophic global genome instability due to aberrant ribosomal DNA recombination, and imminently ends the yeast’s mitotic lifespan.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1678-1679"},"PeriodicalIF":17.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1038/s43587-024-00754-5
J. Ignacio Gutierrez, Jessica K. Tyler
Genome instability is a hallmark of aging, with the highly repetitive ribosomal DNA (rDNA) within the nucleolus being particularly prone to genome instability. Nucleolar enlargement accompanies aging in organisms ranging from yeast to mammals, and treatment with many antiaging interventions results in small nucleoli. Here, we report that an engineered system to reduce nucleolar size robustly extends budding yeast replicative lifespan in a manner independent of protein synthesis rate or rDNA silencing. Instead, when nucleoli expand beyond a size threshold, their biophysical properties change, allowing entry of proteins normally excluded from the nucleolus, including the homologous recombinational repair protein Rad52. This triggers rDNA instability due to aberrant recombination, catastrophic genome instability and imminent death. These results establish that nucleolar expansion is sufficient to drive aging. Moreover, nucleolar expansion beyond a specific size threshold is a mortality timer, as the accompanying disruption of the nucleolar condensate boundary results in catastrophic genome instability that ends replicative lifespan. Gutierrez and Tyler investigate the limits of replicative lifespan in yeast. The authors show that nucleolar expansion during aging is a mortality timer. Enlargement of nucleoli beyond a defined size alters their biophysical properties; normally excluded DNA repair protein enter, causing aberrant rDNA recombination, genome instability and death.
{"title":"A mortality timer based on nucleolar size triggers nucleolar integrity loss and catastrophic genomic instability","authors":"J. Ignacio Gutierrez, Jessica K. Tyler","doi":"10.1038/s43587-024-00754-5","DOIUrl":"10.1038/s43587-024-00754-5","url":null,"abstract":"Genome instability is a hallmark of aging, with the highly repetitive ribosomal DNA (rDNA) within the nucleolus being particularly prone to genome instability. Nucleolar enlargement accompanies aging in organisms ranging from yeast to mammals, and treatment with many antiaging interventions results in small nucleoli. Here, we report that an engineered system to reduce nucleolar size robustly extends budding yeast replicative lifespan in a manner independent of protein synthesis rate or rDNA silencing. Instead, when nucleoli expand beyond a size threshold, their biophysical properties change, allowing entry of proteins normally excluded from the nucleolus, including the homologous recombinational repair protein Rad52. This triggers rDNA instability due to aberrant recombination, catastrophic genome instability and imminent death. These results establish that nucleolar expansion is sufficient to drive aging. Moreover, nucleolar expansion beyond a specific size threshold is a mortality timer, as the accompanying disruption of the nucleolar condensate boundary results in catastrophic genome instability that ends replicative lifespan. Gutierrez and Tyler investigate the limits of replicative lifespan in yeast. The authors show that nucleolar expansion during aging is a mortality timer. Enlargement of nucleoli beyond a defined size alters their biophysical properties; normally excluded DNA repair protein enter, causing aberrant rDNA recombination, genome instability and death.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1782-1793"},"PeriodicalIF":17.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1038/s43587-024-00751-8
Brittany L. Angarola, Siddhartha Sharma, Neerja Katiyar, Hyeon Gu Kang, Djamel Nehar-Belaid, SungHee Park, Rachel Gott, Giray N. Eryilmaz, Mark A. LaBarge, Karolina Palucka, Jeffrey H. Chuang, Ron Korstanje, Duygu Ucar, Olga Anczukόw
Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible links between aging and cancer. Together, these data uncover that epithelial, immune and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment and neoplasia risk. The authors describe how aging rewires the cellular composition of mouse mammary tissues and impacts the transcriptomic and epigenomic programs of mammary epithelial, fibroblast and immune cells, identifying shared signatures of aging and cancer.
衰老是乳腺癌的最大风险因素；然而，与衰老相关的细胞和分子事件如何影响癌症的发生尚不清楚。在这项研究中，我们以单细胞分辨率研究了衰老如何重写小鼠乳腺的转录组和表观基因组程序，为衰老和癌症生物学提供了全面的资源。衰老的上皮细胞在代谢、促炎症和癌症相关基因方面表现出表观遗传和转录变化。衰老的基质细胞下调成纤维细胞标记基因，上调衰老和癌症相关成纤维细胞标记基因。在免疫细胞中，不同的 T 细胞亚群（Gzmk+、记忆 CD4+、γδ）和 M2 样巨噬细胞随着年龄的增长而扩大。空间转录组学揭示了老化免疫细胞和上皮细胞在原位的共定位。最后，我们在人类乳腺肿瘤中发现了衰老乳腺细胞的转录特征，这表明衰老与癌症之间可能存在联系。这些数据共同揭示了上皮细胞、免疫细胞和基质细胞在比例和细胞特性上的变化，可能会影响细胞的可塑性、衰老的微环境和肿瘤风险。
{"title":"Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer","authors":"Brittany L. Angarola, Siddhartha Sharma, Neerja Katiyar, Hyeon Gu Kang, Djamel Nehar-Belaid, SungHee Park, Rachel Gott, Giray N. Eryilmaz, Mark A. LaBarge, Karolina Palucka, Jeffrey H. Chuang, Ron Korstanje, Duygu Ucar, Olga Anczukόw","doi":"10.1038/s43587-024-00751-8","DOIUrl":"10.1038/s43587-024-00751-8","url":null,"abstract":"Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible links between aging and cancer. Together, these data uncover that epithelial, immune and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment and neoplasia risk. The authors describe how aging rewires the cellular composition of mouse mammary tissues and impacts the transcriptomic and epigenomic programs of mammary epithelial, fibroblast and immune cells, identifying shared signatures of aging and cancer.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 1","pages":"122-143"},"PeriodicalIF":17.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00751-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1038/s43587-024-00762-5
Chen Jin, Xizhe Wang, Jiping Yang, Seungsoo Kim, Adam D. Hudgins, Amir Gamliel, Mingzhuo Pei, Daniela Contreras, Melody Devos, Qinghua Guo, Jan Vijg, Marco Conti, Jan Hoeijmakers, Judith Campisi, Rogerio Lobo, Zev Williams, Michael G. Rosenfeld, Yousin Suh
The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood. Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23–29 years) and four reproductively aged (ages 49–54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary. Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging. The molecular and cellular mechanisms underlying ovarian aging are incompletely understood. Here the authors provide single-nuclei RNA and ATAC-seq of human ovarian tissue from four young and four reproductively aged donors, revealing coordinated transcriptomic and epigenomic changes across cell types and highlighting a role for mTOR signaling in reproductive aging.
{"title":"Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses","authors":"Chen Jin, Xizhe Wang, Jiping Yang, Seungsoo Kim, Adam D. Hudgins, Amir Gamliel, Mingzhuo Pei, Daniela Contreras, Melody Devos, Qinghua Guo, Jan Vijg, Marco Conti, Jan Hoeijmakers, Judith Campisi, Rogerio Lobo, Zev Williams, Michael G. Rosenfeld, Yousin Suh","doi":"10.1038/s43587-024-00762-5","DOIUrl":"10.1038/s43587-024-00762-5","url":null,"abstract":"The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood. Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23–29 years) and four reproductively aged (ages 49–54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary. Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging. The molecular and cellular mechanisms underlying ovarian aging are incompletely understood. Here the authors provide single-nuclei RNA and ATAC-seq of human ovarian tissue from four young and four reproductively aged donors, revealing coordinated transcriptomic and epigenomic changes across cell types and highlighting a role for mTOR signaling in reproductive aging.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 2","pages":"275-290"},"PeriodicalIF":17.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00762-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1038/s43587-024-00777-y
Shirley Genah, Enrico Velardi
Age-related thymic involution compromises immune function, which leaves older adults more vulnerable to infections and to a potentially increased risk of cancer and autoimmune conditions. Jing, Song and colleagues identify the RNA methyltransferase METTL3, whose expression falters with age, as a key player in protecting developing thymocytes from ferroptosis.
{"title":"Linking ferroptosis to thymic involution","authors":"Shirley Genah, Enrico Velardi","doi":"10.1038/s43587-024-00777-y","DOIUrl":"10.1038/s43587-024-00777-y","url":null,"abstract":"Age-related thymic involution compromises immune function, which leaves older adults more vulnerable to infections and to a potentially increased risk of cancer and autoimmune conditions. Jing, Song and colleagues identify the RNA methyltransferase METTL3, whose expression falters with age, as a key player in protecting developing thymocytes from ferroptosis.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1673-1675"},"PeriodicalIF":17.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1038/s43587-024-00756-3
Lauren D. Walter, Jessica L. Orton, Ioannis Ntekas, Ern Hwei Hannah Fong, Viviana I. Maymi, Brian D. Rudd, Iwijn De Vlaminck, Jennifer H. Elisseeff, Benjamin D. Cosgrove
In aging, skeletal muscle regeneration declines due to alterations in both myogenic and non-myogenic cells and their interactions. This regenerative dysfunction is not understood comprehensively or with high spatiotemporal resolution. We collected an integrated atlas of 273,923 single-cell transcriptomes and high-resolution spatial transcriptomic maps from muscles of young, old and geriatric mice (~5, 20 and 26 months old) at multiple time points following myotoxin injury. We identified eight immune cell types that displayed accelerated or delayed dynamics by age. We observed muscle stem cell states and trajectories specific to old and geriatric muscles and evaluated their association with senescence by scoring experimentally derived and curated gene signatures in both single-cell and spatial transcriptomic data. This revealed an elevation of senescent-like muscle stem cell subsets within injury zones uniquely in aged muscles. This Resource provides a holistic portrait of the altered cellular states underlying muscle regenerative decline across mouse lifespan. Skeletal muscle regeneration declines during aging but the underlying processes are incompletely understood. Here the authors generated single-cell and spatial transcriptomics data from uninjured and injured muscles across mouse lifespan and observed age-specific immune cell dynamics and an elevation of senescent-like muscle stem cells in aged muscles.
{"title":"Transcriptomic analysis of skeletal muscle regeneration across mouse lifespan identifies altered stem cell states","authors":"Lauren D. Walter, Jessica L. Orton, Ioannis Ntekas, Ern Hwei Hannah Fong, Viviana I. Maymi, Brian D. Rudd, Iwijn De Vlaminck, Jennifer H. Elisseeff, Benjamin D. Cosgrove","doi":"10.1038/s43587-024-00756-3","DOIUrl":"10.1038/s43587-024-00756-3","url":null,"abstract":"In aging, skeletal muscle regeneration declines due to alterations in both myogenic and non-myogenic cells and their interactions. This regenerative dysfunction is not understood comprehensively or with high spatiotemporal resolution. We collected an integrated atlas of 273,923 single-cell transcriptomes and high-resolution spatial transcriptomic maps from muscles of young, old and geriatric mice (~5, 20 and 26 months old) at multiple time points following myotoxin injury. We identified eight immune cell types that displayed accelerated or delayed dynamics by age. We observed muscle stem cell states and trajectories specific to old and geriatric muscles and evaluated their association with senescence by scoring experimentally derived and curated gene signatures in both single-cell and spatial transcriptomic data. This revealed an elevation of senescent-like muscle stem cell subsets within injury zones uniquely in aged muscles. This Resource provides a holistic portrait of the altered cellular states underlying muscle regenerative decline across mouse lifespan. Skeletal muscle regeneration declines during aging but the underlying processes are incompletely understood. Here the authors generated single-cell and spatial transcriptomics data from uninjured and injured muscles across mouse lifespan and observed age-specific immune cell dynamics and an elevation of senescent-like muscle stem cells in aged muscles.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1862-1881"},"PeriodicalIF":17.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00756-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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