Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging
Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.
Authors
- Steve Horvath (ORCID: https://orcid.org/0000-0002-4110-3589)
- Ioanna Daskalaki (ORCID: https://orcid.org/0000-0002-2423-9660)
- Johan Auwerx (ORCID: https://orcid.org/0000-0002-5065-5393)
- Guillaume Jacot (ORCID: https://orcid.org/0000-0001-5821-2717)
- José Luis Sánchez (ORCID: https://orcid.org/0000-0003-4957-2221)
- Alix Zollinger (ORCID: https://orcid.org/0000-0003-4212-6915)
- Fiorenza Orlando (ORCID: https://orcid.org/0000-0001-7351-4430)
- Lorane Texari
- Myriam Chimen (ORCID: https://orcid.org/0000-0002-3567-1731)
- Marco Malavolta (ORCID: https://orcid.org/0000-0002-8442-1763)
- Amélia Lalou
- Arwen W. Gao (ORCID: https://orcid.org/0000-0001-7687-8926)
- Dhaval S Patel (ORCID: https://orcid.org/0000-0002-1110-0125)
- Federico Sizzano (ORCID: https://orcid.org/0000-0002-2620-0161)
- Bertrand Bétrisey
- Man‐Il Huh
- Kamila Muller
- Jérôme N. Feige (ORCID: https://orcid.org/0000-0002-4751-264X)
- Valeria Tiranti (ORCID: https://orcid.org/0000-0002-3584-7338)
- Aurélie Hermant
- Sylviane Métairon (ORCID: https://orcid.org/0000-0003-2434-8733)
- Ivano Di Meo (ORCID: https://orcid.org/0000-0002-4616-5623)
- Siva A. Vanapalli (ORCID: https://orcid.org/0000-0001-6036-1949)
- Benjamin Brinon
- Robert T. Brooke (ORCID: https://orcid.org/0000-0001-8492-5198)
- Mohammed A. Qureshi (ORCID: https://orcid.org/0000-0003-3091-9555)
- Patrícia Lino
- Gabriele Civiletto (ORCID: https://orcid.org/0000-0002-9818-9942)
- Philipp Gut (ORCID: https://orcid.org/0000-0002-0689-9518)
- Dario Brunetti (ORCID: https://orcid.org/0000-0002-2740-9370)
- Giulia Lizzo
- Mauro Provinciali (ORCID: https://orcid.org/0000-0002-0568-3002)
- J. Wall Richard
- Maria Nicol Colombo (ORCID: https://orcid.org/0000-0001-6735-4119)
- Christopher L. Neal
- Anne-Laure Egesipe
Institutions
- Marche Polytechnic University (IT)
- Texas Tech University (US)
- University of California, Los Angeles (US)
- University of Milan (IT)
- Firmenich (Switzerland) (CH)
- Amsterdam Neuroscience (NL)
- Nestlé (Switzerland) (CH)
- III-N Technology (United States) (US)
- Istituto Nazionale di Riposo e Cura per Anziani (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Altos Labs
- École Polytechnique Fédérale de Lausanne (CH)
- University of Amsterdam (NL)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1038/s43587-025-00957-4
- Citations
- 5
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 6.77