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n-cell structure and snapshots of copia retrotransposons in intact tissue by cryo-ET 2025-06-23 00:00

Sven Klumpe,1,9,* Kirsten A. Senti,2 Florian Beck,1 Jenny Sachweh,3 Bernhard Hampoelz,3 Paolo Ronchi,4 Viola Oorschot,4 Marlene Brandstetter,6 Assa Yeroslaviz,5 John A.G. Briggs,7 Julius Brennecke,2,* Martin Beck,3,8,* and Ju¨ rgen M. Plitzko1,*

1 Research Group CryoEM Technology, Max Planck Institute of Biochemistry, Martinsried, Germany

2 Institute of Molecular Biotechnology Austria (IMBA), Vienna, Austria

3 Department Molecular Sociology, Max Planck Institute of Biophysics, Frankfurt, Germany

4 EMBL EM Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

5 Computational Systems Biochemistry, Bioinformatics Core Facility, Max Planck Institute of Biochemistry, Martinsried, Germany

6 Electron Microscopy Facility, Vienna BioCenter Core Facilities, Vienna, Austria

7 Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany

8 Institute of Biochemistry, Goethe University Frankfurt, Frankfurt, Germany

9 Lead contact

*Correspondence: klumpe@biochem.mpg.de (S.K.), julius.brennecke@imba.oaew.ac.at (J.B.), martin.beck@biophys.mpg.de (M.B.), plitzko@biochem.mpg.de (J.M.P.)

https://doi.org/10.1016/j.cell.2025.02.003

SUMMARY

Long terminal repeat (LTR) retrotransposons belong to the transposable elements (TEs), autonomously replicating genetic elements that integrate into the host,s genome. Among animals, Drosophila melanogaster serves as an important model organism for TE research and contains several LTR retrotransposons, including the Ty1-copia family, which is evolutionarily related to retroviruses and forms viruslike particles (VLPs). In this study, we use cryo-focused ion beam (FIB) milling and lift-out approaches to visualize copia VLPs in ovarian cells and intact egg chambers, resolving the in situ copia capsid structure to 7.7 A˚ resolution by cryoelectron tomography (cryo-ET). Although cytoplasmic copia VLPs vary in size, nuclear VLPs are homogeneous and form densely packed clusters, supporting a model in which nuclear import acts as a size selector. Analyzing flies deficient in the TE-suppressing PIWI-interacting RNA (piRNA) pathway, we observe copia,s translocation into the nucleus during spermatogenesis. Our findings provide insights into the replication cycle and cellular structural biology of an active LTR retrotransposon.
Human trials exploring anti-aging medicines 2025-06-18 00:00

Leonard Guarente,1,2, * David A. Sinclair,2,3 and Guido Kroemer2,4,5,6, *

1 Department of Biology, Massachusetts Institute for Technology, Cambridge, MA 02139

2 Academy for Healthspan and Lifespan Research (AHLR), New York, NY, USA

3 Blavatnik Institute, Genetics Department, Harvard Medical School, Boston, MA 02115, USA

4 Centre de Recherche des Cordeliers, Equipe labellise´ e par la Ligue contre le cancer, Universite´ Paris Cite´ , Sorbonne Universite´ , Inserm U1138, Institut Universitaire de France, Paris, France

5 Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

6 Institut du Cancer Paris CARPEM, Department of Biology, Hoˆ pital Europe´ en Georges Pompidou, AP-HP, Paris, France

*Correspondence: leng@mit.edu (L.G.), kroemer@orange.fr (G.K.)

https://doi.org/10.1016/j.cmet.2023.12.007

SUMMARY

Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD+ precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.
Contrasting somatic mutation patterns in aging human neurons and oligodendrocytes 2025-06-17 00:00

Javier Ganz,1,2,3,8,9 Lovelace J. Luquette,4,8 Sara Bizzotto,1,2,3,5,8 Michael B. Miller,1,3,6 Zinan Zhou,1,2,3 Craig L. Bohrson,4

Hu Jin,4 Antuan V. Tran,4 Vinayak V. Viswanadham,4 Gannon McDonough,6 Katherine Brown,6 Yasmine Chahine,1

Brian Chhouk,1 Alon Galor,4 Peter J. Park,4,7,* and Christopher A. Walsh1,2,3,10,*

1 Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Childrens Hospital, Boston, MA 02115, USA

2 Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA

3 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

4 Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA

5 Sorbonne Universite´ , Institut du Cerveau (Paris Brain Institute) ICM, Inserm, CNRS, Hoˆ pital de la Pitie´ Salpeˆ trie`re, 75013 Paris, France

6 Department of Pathology, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA

7 Division of Genetics, Brigham and Womens Hospital, Boston, MA 02115, USA

8 These authors contributed equally

9 Present address: Merck Research Laboratories, Cambridge, MA 02142, USA

10 Lead contact

*Correspondence: peter_park@hms.harvard.edu (P.J.P.), christopher.walsh@childrens.harvard.edu (C.A.W.)

https://doi.org/10.1016/j.cell.2024.02.025

SUMMARY

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed wholegenome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4–104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.

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主任医师、教授、博导，南方医科大学第三附属医院（广东省骨科医院）院长

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主任医师、教授、博导，南方医科大学第三附属医院（广东省骨科医院）院长

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户外伤口自救：卫生巾好过涂抹各种粉末百倍！

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