EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework

Amin Haghani^{1

2}, Ake T Lu^{3

4}, Qi Yan⁴, Juan Carlos Izpisua Belmonte⁴, Pradeep Reddy^{4

5}, Victor Cheng³, X William Yang^{6

7}, Nan Wang^{6

7}, Khyobeni Mozhui^{8

9}, Kevin Murach^{10

11}, Alejandro Ocampo^{12

13}, Robert W Williams¹⁴, Mathias Jucker¹⁵, Carina Bergmann¹⁵, Jesse R Poganik¹⁶, Bohan Zhang¹⁶, Vadim N Gladyshev¹⁶, Steve Horvath^{3

4

17}

Affiliations

¹ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. ahaghani@altoslabs.com.
² Altos Labs, San Diego, CA, USA. ahaghani@altoslabs.com.
³ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Altos Labs, San Diego, CA, USA.
⁵ Salk Institute for Biological Studies, La Jolla, CA, USA.
⁶ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
⁹ Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
¹⁰ Exercise Science Research Center, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, USA.
¹¹ Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, AR, USA.
¹² Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
¹³ EPITERNA SA, Epalinges, Switzerland.
¹⁴ Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
¹⁵ Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁶ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Altos Labs, Cambridge, UK.

PMID: 40768061
DOI: 10.1007/s11357-025-01808-1

EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework

Amin Haghani et al. Geroscience. 2025.

. 2025 Aug 6.

doi: 10.1007/s11357-025-01808-1. Online ahead of print.

Authors

Affiliations

¹ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. ahaghani@altoslabs.com.
² Altos Labs, San Diego, CA, USA. ahaghani@altoslabs.com.
³ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Altos Labs, San Diego, CA, USA.
⁵ Salk Institute for Biological Studies, La Jolla, CA, USA.
⁶ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
⁹ Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
¹⁰ Exercise Science Research Center, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, USA.
¹¹ Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, AR, USA.
¹² Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
¹³ EPITERNA SA, Epalinges, Switzerland.
¹⁴ Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA.
¹⁵ Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁶ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Altos Labs, Cambridge, UK.

PMID: 40768061
DOI: 10.1007/s11357-025-01808-1

Abstract

Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.

Keywords: Aging biomarkers; Biological age; DNA methylation; EnsembleAge; Epigenetic clocks; Healthspan; Lifespan interventions; MethylGauge dataset; Mouse models; Rejuvenation; Stress response.

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Conflict of interest statement

Declarations. Conflict of interest: Steve Horvath is a founder and consultant of the non-profit Epigenetic Clock Development Foundation which licenses several patents (including the mammalian methylation array) from his former employer UC Regents. These patents list SH as inventor. Amin Haghan, Ake T. Lu, Qi Yan, Juan Carlos Izpisua Belmonte, and Pradeep Reddy are working for Altos Labs, Inc. The other authors declare no conflicts of interest.

References

1. Bocklandt S, et al. Epigenetic predictor of age. PLoS One. 2011;6:e14821. https://doi.org/10.1371/journal.pone.0014821 .
1. Hannum G, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49:359–367. https://doi.org/10.1016/j.molcel.2012.10.016 .
1. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115. https://doi.org/10.1186/gb-2013-14-10-r115 .
1. Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018. https://doi.org/10.1038/s41576-018-0004-3 .
1. Wang T, et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 2017;18:57. https://doi.org/10.1186/s13059-017-1186-2 .

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EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework

Affiliations

EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources