Integration of proteomic aging clocks in a phase 2a clinical trial supports simultaneous geroprotective assessment
Abstract Drugs for aging-related diseases may modulate aging itself, but standard clinical trial designs cannot detect such effects. Aging clocks could close this gap, but epigenetic models often yield inconsistent, hard-to-interpret results. In contrast, proteomic clocks, by tracking the immediate effectors of biological change, may excel in providing aging biomarkers or mechanistic insight. Here we compare six proteomic clocks (ProtAge, OrganAge mortality , OrganAge chrono , PAC, ipfP3GPT and PAOPAC) on serum proteomes from a published 12-week phase 2a trial of the candidate anti-fibrotic drug rentosertib in idiopathic pulmonary fibrosis. We measure the variance between the clocks and find that all six clocks consistently predicted lower biological age in treated arms. However, proteomic clocks alone cannot deconvolute aging- and disease-specific effects. We addressed this issue indirectly through pathway analyses that identified potential anti-aging shifts in senescence and metabolic processes alongside the anti-fibrotic activity of rentosertib. This work supports the goal of dual-purpose clinical trial designs that integrate aging endpoints into studies for specific disease indications.
Authors
- Fedor Galkin (ORCID: https://orcid.org/0000-0002-5709-9529)
- Alexander Tyshkovskiy (ORCID: https://orcid.org/0000-0002-6215-190X)
- Vadim N. Gladyshev (ORCID: https://orcid.org/0000-0002-0372-7016)
- Mahdi Moqri (ORCID: https://orcid.org/0000-0001-6675-0566)
- Alex Zhavoronkov (ORCID: https://orcid.org/0000-0001-7067-8966)
- Denis Sidorenko (ORCID: https://orcid.org/0009-0004-0571-5192)
- Ludger J.E. Goeminne (ORCID: https://orcid.org/0000-0002-8285-7766)
- M. Austin Argentieri (ORCID: https://orcid.org/0000-0003-0242-853X)
- Christoph Kuppe (ORCID: https://orcid.org/0000-0003-4597-9833)
- Shan Chen (ORCID: https://orcid.org/0000-0002-6177-5980)
- Xiaodong Liu (ORCID: https://orcid.org/0000-0002-9315-3406)
- Feng Ren (ORCID: https://orcid.org/0000-0001-9157-9182)
- Jing‐Dong J. Han (ORCID: https://orcid.org/0000-0002-9270-7139)
- Alex Aliper
- Hui Cui
- Hao Xu
- Mikhail Durymanov
- Kejun Ying
- Zuojun Xu
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Neurosciences Institute (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University of Washington (US)
- Peking University (CN)
- Peking Union Medical College Hospital (CN)
- Westlake University (CN)
- Massachusetts General Hospital (US)
- Insilicos (United States) (US)
- INSEAD (AE)
- Insilicogen (South Korea) (KR)
- Center for Life Sciences (CN)
- RWTH Aachen University (DE)
- Stanford University (US)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2026-09-07
- DOI
- https://doi.org/10.1038/s41587-026-03286-y
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00