Insilico’s rentosertib reduced predicted biological age across six proteomic clocks in a Phase IIa IPF study, supporting further investigation of aging biology.
Written By: Dishali Desai, PharmD
Reviewed By: Pharmacally Editorial Team
Insilico Medicine’s investigational IPF drug rentosertib produced consistent reductions in predicted biological age across six independently developed proteomic aging clocks in a Phase IIa clinical trial, providing early evidence that the TNIK inhibitor may modulate aging-associated biology alongside its antifibrotic activity. The findings, published in Nature Biotechnology, also demonstrate how aging biomarkers can be incorporated into conventional disease-focused clinical trials.
From AI-Discovered Target to Clinical Aging Study
Rentosertib, formerly INS018_055, is an AI-designed small-molecule inhibitor of TNIK, a target linked to both fibrosis and aging biology. Insilico used its PandaOmics target-discovery platform to prioritize TNIK after identifying its association with multiple hallmarks of aging, then used its generative chemistry platform Chemistry42 to design the drug.
The program progressed from target identification to preclinical candidate nomination in about 18 months. Insilico subsequently advanced rentosertib into clinical development for idiopathic pulmonary fibrosis (IPF), a progressive lung disease strongly associated with aging.
42-Patient Proteomic Cohort From a 71-Patient Trial
The randomized, double-blind, placebo-controlled Phase IIa trial enrolled 71 adults with IPF across 22 sites in China and evaluated oral rentosertib at 30 mg once daily, 30 mg twice daily or 60 mg once daily against placebo for 12 weeks.
The proteomic analysis involved a defined subset of the trial. Of the 55 participants who completed the study, 43 consented to the additional proteomic assessment, and one was excluded because of missing Week 12 measurements, leaving 42 participants for the final analysis.
Researchers collected serum at baseline and Weeks 2, 4 and 12 and profiled the samples using the Olink Explore 3072 platform. After quality-control exclusions, the dataset contained 2,841 proteins for longitudinal analysis.
Six Aging Clocks Show Consistent Biological-Age Reduction
The investigators applied six independently developed proteomic clocks: ProtAge, OrganAge chronological and mortality models, PAC, ipfP3GPT and PAOPAC. Despite differences in their training methods, features and objectives, all six showed lower predicted biological age in rentosertib-treated participants compared with placebo.
The strongest and most consistent signal occurred with 30 mg twice daily, particularly at Week 4. Across 54 treatment-versus-placebo comparisons, 21 reached statistical significance at a false-discovery-adjusted Q value below 0.10, with 11 of 18 Week 4 comparisons showing significantly lower changes in predicted biological age.
The study also found evidence that the proteomic changes extended beyond respiratory improvement. The 30 mg twice-daily regimen showed the strongest aging-clock signal, while 60 mg once daily produced the strongest FVC response. That divergence suggests that the biological-age signal cannot be explained entirely by improvement in lung function.
Proteomic Changes Point to Senescence and Aging Pathways
Rentosertib altered the trajectories of 326 proteins across the treatment groups. The 30 mg twice-daily regimen generated the broadest proteomic response, including changes in proteins associated with fibrosis, extracellular-matrix remodeling, metabolism and cellular stress responses.
Comparison with proteomic data from 55,319 UK Biobank participants found that rentosertib-induced changes were enriched among proteins associated with normal aging. The 30 mg twice-daily regimen showed a significant negative correlation with age-related protein trajectories, consistent with a shift opposite to typical aging-associated changes.
Gene-set enrichment analysis also identified reduced signatures of cellular senescence. Proteins including EREG, ESM1, IGFBP4, MMP10, MMP13 and SPP1 showed coordinated changes across treated groups, while several growth-factor signaling pathways linked to aging were downregulated.
Evidence for Geroprotective Activity Remains Preliminary
The findings support the hypothesis that rentosertib may have geroprotective activity, meaning it could influence biological processes associated with aging. However, the study does not establish that the drug slows human aging.
Proteomic clocks cannot fully separate aging-related effects from changes caused by treating IPF. The researchers therefore used pathway analyses, comparisons with normal-aging datasets and senescence signatures to investigate the distinction. Definitive separation will require studies in non-IPF populations, including potentially healthy participants.
A Potential Blueprint for Longevity Drug Development
The study’s broader significance lies in its clinical design. Rather than waiting for a disease drug to reach approval before investigating possible effects on aging, the researchers prospectively incorporated longitudinal proteomic profiling into the Phase IIa trial.
That approach could allow conventional trials in age-related diseases to simultaneously generate evidence about potential aging-modifying activity. The authors propose expanding this framework through validated aging biomarkers and, ultimately, regulatory-qualified endpoints.
Rentosertib has progressed into Phase III development for IPF, making the drug a test case for whether an AI-discovered target selected partly through aging biology can translate into clinically meaningful effects across both disease and aging-related measures.
Reference
Nature Biotechnology | Insilico’s AI-Driven IPF Candidate Rentosertib Shows Potential for Biological Age Reversal, as Assessed by Six Proteomic Aging Clocks, Insilico Medicine, 07 September 2026
Zhavoronkov, A., Galkin, F., Chen, S. et al. Integration of proteomic aging clocks in a phase 2a clinical trial supports simultaneous geroprotective assessment. Nat Biotechnol (2026). https://doi.org/10.1038/s41587-026-03286-y
About the Writer
Dishali Desai (LinkedIn) is a PharmD professional with expertise in clinical pharmacy, evidence-based healthcare writing, and published work on Brugada syndrome and ADR reporting.
Her interests include guideline integration, multimodal therapy, pharmacogenomics, and antibiogram utilization, with a focus on clinical evidence and treatment decisions.
As a healthcare writer, she translates complex clinical information into clear, accurate, and evidence-informed medical content.