Graphical Abstract

Highlights

● scRNA/CITE-seq and scATAC-seq reveal hallmarks of immune aging in mice and humans

● Clonal exhausted-like GZMK+ CD8+ T cells accumulate in tissues due to old environment

● GZMK secreted by activated GZMK+ CD8+ T cells can promote SASP from senescent cells

● GZMK+ CD8+ Taa rather than GZMB+ CD8+ Tem accumulate in human blood with age

Authors

      Denis A. Mogilenko, Oleg Shpynov, Prabhakar Sairam Andhey, ..., Sheila A. Stewart, Marco Colonna, Maxim N. Artyomov

Correspondence

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In Brief

      Aging affects the immune system and establishes a chronic low-grade inflammation (inflammaging). Mogilenko et al. defined organ-specific and common alterations of immune cell populations in aging and identified a distinct subset of clonal GZMK+ CD8+ T cells as a conserved cellular hallmark of inflammaging in mice and humans.

Denis A. Mogilenko,1 Oleg Shpynov,1,2,6 Prabhakar Sairam Andhey,1,6 Laura Arthur,1 Amanda Swain,1 Ekaterina Esaulova,1 Simone Brioschi,1 Irina Shchukina,1 Martina Kerndl,1,3 Monika Bambouskova,1 Zhangting Yao,4 Anwesha Laha,1 Konstantin Zaitsev,5 Samantha Burdess,1 Susan Gillfilan,1 Sheila A. Stewart,4 Marco Colonna,1 and Maxim N. Artyomov1,7, *

1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA

2 JetBrains Research, Saint Petersburg 197374, Russia

3 Institute for Vascular Biology, Centre for Physiology and Pharmacology & Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna 1090, Austria

4 Department of Cell Biology and Physiology, Department of Medicine and Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA

5 Computer Technologies Department, ITMO University, Saint Petersburg 197101, Russia

6 These authors contributed equally

7 Lead Contact

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https://doi.org/10.1016/j.immuni.2020.11.005

SUMMARY

      Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced in-flammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+ CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.

Graphical abstract

Highlights

● A single-cell transcriptomic atlas across aged tissues and their rejuvenation in HP

● HP systemically rejuvenated senile adult stem cells and their niches across tissues

● Youthful transcriptomes were restored in resident HSPCs upon young blood exposure

● Reintroduction of rejuvenating factors in aged HSCs mitigated lymphopoiesis decline

Authors

Shuai Ma, Si Wang, Yanxia Ye, ..., Jing Qu, Weiqi Zhang, Guang-Hui Liu

Correspondence

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该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (W.Z.),

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In brief

      Ma and colleagues report a multi-tissue single-cell transcriptomic atlas of HP. They reveal that adult stem cells, especially bone marrow HSPCs, are responsive to the changing milieu. Focusing on HSPCs, they uncover HPinduced rejuvenating programs with underlying key mediators, overexpression of which recharges the lymphopoiesis potential of aged HSCs.

Shuai Ma,1,4,7,14,15 Si Wang,3,8,14,15,16 Yanxia Ye,2,4,7,15 Jie Ren,4,5,6,12,15,16 Ruiqing Chen,9,15 Wei Li,3,8,16 Jiaming Li,5,6,12 Liyun Zhao,3,8 Qian Zhao,3,8 Guoqiang Sun,2,6 Ying Jing,2,6 Yuesheng Zuo,5,6 Muzhao Xiong,5,6 Yuanhan Yang,1,6 Qiaoran Wang,5,6 Jinghui Lei,3,8 Shuhui Sun,1,4,7 Xiao Long,11 Moshi Song,1,4,7,16 Shuyang Yu,10,16 Piu Chan,3,16 Jianwei Wang,9,16 Qi Zhou,2,4,6,7,16 Juan Carlos Izpisua Belmonte,13,16 Jing Qu,2,4,6,7, * Weiqi Zhang,4,5,6,7,12,14, * and Guang-Hui Liu1,3,4,6,7,8,17, *

1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

2 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

3 Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China

4 Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China

5 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China

6 University of Chinese Academy of Sciences, Beijing 100049, China

7 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China

8 Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

9 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China

10 State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China

11 Division of Plastic Surgery, Peking Union Medical College Hospital, Beijing 100032, China

12 Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China

13 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA

14 The Fifth People’s Hospital of Chongqing, Chongqing 400062, China

15 These authors contributed equally

16 Senior author

17 Lead contact

*Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (J.Q.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (W.Z.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (G.-H.L.) https://doi.org/10.1016/j.stem.2022.04.017

SUMMARY

      The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. Overall, we provide comprehensive frameworks to explore aging and rejuvenating trajectories at single-cell resolution and revealed cellular and molecular programs that instruct systemic revitalization by blood-borne factors.

Authors

Victoria Eugenia Martinez-Miguel, Celia Lujan, Tristan Espie–Caullet, ..., Tobias von der Haar, Filipe Cabreiro, Ivana Bjedov

Correspondence

该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (F.C.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (I.B.)

In brief

Martinez-Miguel et al. demonstrate that improving translation fidelity by mutating a single amino acid in the decoding center of the ribosome suffices to improve health and longevity in yeast, worms, and flies. This work provides a direct link between fewer errors in translation and longevity.

Highlights

● Evolutionarily selected arginine in RPS23 is present only in hyperthermophilic archaea

● RPS23 K60R mutation in flies leads to improved accuracy of protein synthesis with age

● Yeast, worm, and fly RPS23 K60R mutants are longer-lived, healthier, and heat resistant

● Anti-aging drugs, rapamycin, torin1, and trametinib, increase translation accuracy

Martinez-Miguel et al., 2021, Cell Metabolism 33, 2288–2300 November 2, 2021 ª 2021 The Author(s). Published by Elsevier Inc. https://doi.org/10.1016/j.cmet.2021.08.017

Victoria Eugenia Martinez-Miguel,1 Celia Lujan,1 Tristan Espie–Caullet,1 Daniel Martinez-Martinez,2,3 Saul Moore,2,3 Cassandra Backes,2,3 Suam Gonzalez,4 Evgeniy R. Galimov,2,3 Andre´ E.X. Brown,2,3 Mario Halic,5 Kazunori Tomita,6 Charalampos Rallis,4,11 Tobias von der Haar,7 Filipe Cabreiro,2,3,8, * and Ivana Bjedov1,9,10, *

1 UCL Cancer Institute, Paul O’Gorman Building, University College London, 72 Huntley Street, London WC1E 6DD, UK

2 MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK

3 Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK

4 School of Health, Sport and Bioscience, University of East London, Water Lane, London E15 4LZ, UK

5 Department of Structural Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA

6 Centre for Genome Engineering and Maintenance, College of Health, Medicine and Life Sciences, Brunel University London, London UB8 3PH, UK

7 Kent Fungal Group, School of Biosciences, Division of Natural Sciences, University of Kent, Canterbury CT2 7NJ, UK

8 Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany

9 Department of Medical Physics and Biomedical Engineering, University College London, Malet Place Engineering Building, Gower Street, London WC1E 6BT, UK

10 Lead contact

11 Present address: School of Life Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK

*Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (F.C.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (I.B.) https://doi.org/10.1016/j.cmet.2021.08.017

SUMMARY

      Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.

Antoine E. Roux,1 Chunlian Zhang,1 Jonathan Paw,1 Jose´ Zavala-Solorio,1 Evangelia Malahias,1 Twaritha Vijay,1 Ganesh Kolumam,1 Cynthia Kenyon,1 and Jacob C. Kimmel1,2,3, * 1Calico Life Sciences, LLC, 1170 Veterans Blvd, South San Francisco, CA 94080, USA

2Present Address: NewLimit, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA

3Lead contact

*Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 https://doi.org/10.1016/j.cels.2022.05.002

SUMMARY

Partial pluripotent reprogramming can reverse features of aging in mammalian cells, but the impact on somatic identity and the necessity of individual reprogramming factors remain unknown. Here, we used single-cell genomics to map the identity trajectory induced by partial reprogramming in multiple murine cell types and dissected the influence of each factor by screening all Yamanaka Factor subsets with pooled single-cell screens. We found that partial reprogramming restored youthful expression in adipogenic and mesenchymal stem cells but also temporarily suppressed somatic identity programs. Our pooled screens revealed that many subsets of the Yamanaka Factors both restore youthful expression and suppress somatic identity, but these effects were not tightly entangled. We also found that a multipotent reprogramming strategy inspired by amphibian regeneration restored youthful expression in myogenic cells. Our results suggest that various sets of reprogramming factors can restore youthful expression with varying degrees of somatic identity suppression. A record of this paper’s Transparent Peer Review process is included in the supplemental information.