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Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice.

Overview

Authors: Daniela G Costa1,2,3,4,5, Lucy M Gee1,2, Gung Lee1,2, Lilian Sales Gomez1,2, Ana Catarina Franco1,2, Maria Grazia Vizioli1,2, Karla Valdivieso1,2, Lei J Zhang6,7, Nick Pirius1,2, Helene Martini1,2, Rebecca A Porritt8, Dominik Saul9, Claudia Cavadas3,4,5, Scott Ebert10, Nathan K LeBrasseur1,2, Sundeep Khosla1,2,10, João F Passos1,2, Christopher M Adams10, Paul D Robbins7, Diana Jurk1,2,11
ORCID iDs: Lilian Sales Gomez, Ana Catarina Franco, Karla Valdivieso, Lei J Zhang, Helene Martini, Dominik Saul, Claudia Cavadas, Scott Ebert, Nathan K LeBrasseur, Sundeep Khosla, João F Passos, Paul D Robbins, Diana Jurk
  1. Department of Physiology and Biomedical Engineering, Mayo Clinic,Rochester, MN 55905 USA
  2. Robert and Arlene Kogod Center on Aging, Mayo Clinic,200 First Street SW, Rochester, MN 55905 USA
  3. Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra,Coimbra, Portugal
  4. Faculty of Pharmacy, University of Coimbra,Coimbra, Portugal
  5. Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra,Coimbra, Portugal
  6. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia,Athens, GA USA
  7. Masonic Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota,Minneapolis, MN USA
  8. Sanford Burnham Prebys Medical Discovery Institute,La Jolla, CA USA
  9. Robert Bosch Center for Tumor Diseases,Stuttgart, Germany
  10. Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic,Rochester, MN USA
  11. Department of Neurology, Manyo Clinic,Rochester, MN 55905 USA
Institutions: Mayo Clinic (United States); University of Coimbra (Portugal); University of Georgia (United States); University of Minnesota (United States); Sanford Burnham Prebys Medical Discovery Institute (United States); Robert Bosch Center for Tumor Diseases,Stuttgart, Germany
Journal: EMBO molecular medicine, volume 18, issue 5, pages 1530-1550
Dates: received 4 November 2025; accepted 25 February 2026; published online 1 April 2026; in print May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44321-026-00400-0 · PMID 41922652 · PMCID PMC13179369 · OpenAlex W7147008436
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: behavior only (modality), mouse (organism), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Graphs
Keywords: Brain, Aging, Senescence, Senomorphic, Cognition, Autophagy & Cell Death, Neuroscience, Pharmacology & Drug Discovery
MeSH: Aging*, Cellular Senescence*, Cognition*, Senotherapeutics*, Tomatine*, Animals, Biomarkers, Female, Gene Expression Regulation, Male, Maze Learning, Mice, Mice, Inbred C57BL, Tight Junctions (* major topic)
Topic: Telomeres, Telomerase, and Senescence (Physiology, Medicine), according to OpenAlex
Funding: National Institute on Aging (AG068182, AG062413, AG079754, AG076041, AI172501, AG086085, R01AG068048, R01AG82708, U19 AG056278); Hevolution Foundation (HF) (#A22001, P30DK084567)
Citations: cited by 3 papers (Europe PMC); 25 references in the paper
Research resources: C57BL/6 (M.musculus) RRID:IMSR_JAX:000664

Abstract

Cellular senescence drives aging and age-related dysfunction across multiple tissues, including the brain. Through a high-content, senescent cell-based phenotypic screen of a small panel of natural products, we identified tomatidine, an aglycone of tomatine found in tomatoes, as a previously unrecognized senotherapeutic agent. In senescent human brain microvascular endothelial cells and fibroblasts, tomatidine selectively suppressed SASP expression without affecting p16Ink4a or p21Cip1 levels consistent with a senomorphic effect. In aged mice, tomatidine reduced frailty and improved motor coordination and cognitive performance. These functional benefits were accompanied by reduced senescence markers (p16 Ink4a, p21 Cip1, and telomere-associated DNA damage foci) in liver, skin, and hippocampal neurons, along with decreased neuroinflammation and microglial activation. Tomatidine also diminished brain endothelial cell senescence while enhancing tight junction protein expression, suggesting preserved blood–brain barrier integrity. Together, these findings identify tomatidine as a promising senescence-targeting compound with beneficial effects in aged mice and support its further evaluation in mechanistic and translational studies.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

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Data availability

The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE312732 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312732).

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-026-00400-0 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44321-026-00400-0).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 20 authors, 8 keywords, 14 MeSH terms, 2 funders, 25 references, 1 RRID.

Cite

This paper

Costa, D. G., Gee, L. M., Lee, G., Sales Gomez, L., Franco, A. C., Vizioli, M. G., Valdivieso, K., Zhang, L. J., Pirius, N., Martini, H., Porritt, R. A., Saul, D., Cavadas, C., Ebert, S., LeBrasseur, N. K., Khosla, S., Passos, J. F., Adams, C. M., Robbins, P. D., & Jurk, D. (2026). Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice. EMBO molecular medicine, 18(5), 1530-1550. https://doi.org/10.1038/s44321-026-00400-0

BibTeX

@article{costa2026tomatidine,
author = {Costa, Daniela G and Gee, Lucy M and Lee, Gung and Sales Gomez, Lilian and Franco, Ana Catarina and Vizioli, Maria Grazia and Valdivieso, Karla and Zhang, Lei J and Pirius, Nick and Martini, Helene and Porritt, Rebecca A and Saul, Dominik and Cavadas, Claudia and Ebert, Scott and LeBrasseur, Nathan K and Khosla, Sundeep and Passos, João F and Adams, Christopher M and Robbins, Paul D and Jurk, Diana},
title = {{Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice}},
journal = {EMBO molecular medicine},
year = {2026},
month = apr,
volume = {18},
number = {5},
pages = {1530--1550},
publisher = {Nature Publishing Group},
issn = {1757-4676},
doi = {10.1038/s44321-026-00400-0},
url = {https://doi.org/10.1038/s44321-026-00400-0},
pmid = {41922652},
pmcid = {PMC13179369}
}

RIS

TY - JOUR
AU - Costa, Daniela G
AU - Gee, Lucy M
AU - Lee, Gung
AU - Sales Gomez, Lilian
AU - Franco, Ana Catarina
AU - Vizioli, Maria Grazia
AU - Valdivieso, Karla
AU - Zhang, Lei J
AU - Pirius, Nick
AU - Martini, Helene
AU - Porritt, Rebecca A
AU - Saul, Dominik
AU - Cavadas, Claudia
AU - Ebert, Scott
AU - LeBrasseur, Nathan K
AU - Khosla, Sundeep
AU - Passos, João F
AU - Adams, Christopher M
AU - Robbins, Paul D
AU - Jurk, Diana
TI - Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice
T2 - EMBO molecular medicine
J2 - EMBO Mol Med
PY - 2026
DA - 2026/04/01
VL - 18
IS - 5
SP - 1530
EP - 1550
SN - 1757-4676
PB - Nature Publishing Group
DO - 10.1038/s44321-026-00400-0
UR - https://doi.org/10.1038/s44321-026-00400-0
LA - en
ER -

CSL-JSON

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