Altered translation elongation contributes to key hallmarks of aging in the killifish brain

Domenico Di Fraia; Antonio Marino; Jae Ho Lee; Erika Kelmer Sacramento; Mario Baumgart; Sara Bagnoli; Till Balla; Felix Schalk; Stephan Kamrad; Rui Guan; Cinzia Caterino; Chiara Giannuzzi; Pedro Tomaz da Silva; Amit Kumar Sahu; Hanna Gut; Giacomo Siano; Max Tiessen; Eva Terzibasi-Tozzini; Eugenio F. Fornasiero; Julien Gagneur; Christoph Englert; Kiran R. Patil; Clara Correia-Melo; Danny D. Nedialkova; Judith Frydman; Alessandro Cellerino; Alessandro Ori

doi:10.1126/science.adk3079

Altered translation elongation contributes to key hallmarks of aging in the killifish brain

Domenico Di Fraia
, Antonio Marino
, Jae Ho Lee
, Erika Kelmer Sacramento
, Mario Baumgart
, Sara Bagnoli
, Till Balla
, Felix Schalk
, Stephan Kamrad
, Rui Guan
, Cinzia Caterino
, Chiara Giannuzzi
, Pedro Tomaz da Silva
, Amit Kumar Sahu
, Hanna Gut
, Giacomo Siano
, Max Tiessen
, Eva Terzibasi-Tozzini
, Eugenio F. Fornasiero
, Julien Gagneur

Christoph Englert, Kiran R. Patil, Clara Correia-Melo, Danny D. Nedialkova, Judith Frydman, Alessandro Cellerino, Alessandro Ori

Biochemistry and Cell Biology

Leibniz Institute on Aging - Fritz Lipmann Institute
Scuola Normale Superiore di Pisa
Max Planck Institute of Biochemistry
University of Cambridge
Technical University of Munich
Munich Center for Machine Learning
Stazione Zoologica Anton Dohrn Napoli
University of Göttingen
University of Trieste
Helmholtz Zentrum München - German Research Center for Environmental Health
Friedrich Schiller University Jena
Stanford University

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain’s biology—the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.

Original language	English
Article number	eadk3079
Journal	Science
Volume	389
Issue number	6759
DOIs	https://doi.org/10.1126/science.adk3079
State	Published - Jul 31 2025

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Di Fraia, D., Marino, A., Lee, J. H., Sacramento, E. K., Baumgart, M., Bagnoli, S., Balla, T., Schalk, F., Kamrad, S., Guan, R., Caterino, C., Giannuzzi, C., da Silva, P. T., Sahu, A. K., Gut, H., Siano, G., Tiessen, M., Terzibasi-Tozzini, E., Fornasiero, E. F., ... Ori, A. (2025). Altered translation elongation contributes to key hallmarks of aging in the killifish brain. Science, 389(6759), Article eadk3079. https://doi.org/10.1126/science.adk3079

@article{4c95b9b418db4da48c4f30a57b46c576,

title = "Altered translation elongation contributes to key hallmarks of aging in the killifish brain",

abstract = "Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain{\textquoteright}s biology—the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.",

author = "\{Di Fraia\}, Domenico and Antonio Marino and Lee, \{Jae Ho\} and Sacramento, \{Erika Kelmer\} and Mario Baumgart and Sara Bagnoli and Till Balla and Felix Schalk and Stephan Kamrad and Rui Guan and Cinzia Caterino and Chiara Giannuzzi and \{da Silva\}, \{Pedro Tomaz\} and Sahu, \{Amit Kumar\} and Hanna Gut and Giacomo Siano and Max Tiessen and Eva Terzibasi-Tozzini and Fornasiero, \{Eugenio F.\} and Julien Gagneur and Christoph Englert and Patil, \{Kiran R.\} and Clara Correia-Melo and Nedialkova, \{Danny D.\} and Judith Frydman and Alessandro Cellerino and Alessandro Ori",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the authors, some rights reserved.",

year = "2025",

month = jul,

day = "31",

doi = "10.1126/science.adk3079",

language = "English",

volume = "389",

journal = "Science",

issn = "0036-8075",

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Di Fraia, D, Marino, A, Lee, JH, Sacramento, EK, Baumgart, M, Bagnoli, S, Balla, T, Schalk, F, Kamrad, S, Guan, R, Caterino, C, Giannuzzi, C, da Silva, PT, Sahu, AK, Gut, H, Siano, G, Tiessen, M, Terzibasi-Tozzini, E, Fornasiero, EF, Gagneur, J, Englert, C, Patil, KR, Correia-Melo, C, Nedialkova, DD, Frydman, J, Cellerino, A & Ori, A 2025, 'Altered translation elongation contributes to key hallmarks of aging in the killifish brain', Science, vol. 389, no. 6759, eadk3079. https://doi.org/10.1126/science.adk3079

TY - JOUR

T1 - Altered translation elongation contributes to key hallmarks of aging in the killifish brain

AU - Di Fraia, Domenico

AU - Marino, Antonio

AU - Lee, Jae Ho

AU - Sacramento, Erika Kelmer

AU - Baumgart, Mario

AU - Bagnoli, Sara

AU - Balla, Till

AU - Schalk, Felix

AU - Kamrad, Stephan

AU - Guan, Rui

AU - Caterino, Cinzia

AU - Giannuzzi, Chiara

AU - da Silva, Pedro Tomaz

AU - Sahu, Amit Kumar

AU - Gut, Hanna

AU - Siano, Giacomo

AU - Tiessen, Max

AU - Terzibasi-Tozzini, Eva

AU - Fornasiero, Eugenio F.

AU - Gagneur, Julien

AU - Englert, Christoph

AU - Patil, Kiran R.

AU - Correia-Melo, Clara

AU - Nedialkova, Danny D.

AU - Frydman, Judith

AU - Cellerino, Alessandro

AU - Ori, Alessandro

PY - 2025/7/31

Y1 - 2025/7/31

N2 - Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain’s biology—the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.

AB - Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain’s biology—the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.

UR - https://www.scopus.com/pages/publications/105013153058

U2 - 10.1126/science.adk3079

DO - 10.1126/science.adk3079

M3 - Article

AN - SCOPUS:105013153058

SN - 0036-8075

VL - 389

JO - Science

JF - Science

IS - 6759

M1 - eadk3079

ER -

Altered translation elongation contributes to key hallmarks of aging in the killifish brain

Abstract

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