Rentosertib shifts multiple proteomic aging clocks toward younger age profiles in IPF trial

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Sep 10 2026

Six different protein-based aging clocks tracked how an experimental IPF drug reshaped biological age signals, revealing a striking disconnect between lung function improvement and broader proteomic responses.

Study: Integration of proteomic aging clocks in a phase 2a clinical trial supports simultaneous geroprotective assessment. Image Credit: Love Employee / Shutterstock

In a recent study published in the journal Nature Biotechnology, a group of researchers determined whether multiple proteomic aging clocks can detect treatment-associated changes in predicted biological age and aging-related proteomic signatures and provided mechanistic insight during a phase 2a trial of rentosertib.

Background

What if a clinical trial could measure not only whether a disease improves, but also whether biological aging changes at the same time? Aging-related diseases share biological pathways, creating opportunities for therapies developed for one condition to influence broader aging processes.

Deoxyribonucleic acid (DNA) methylation-based epigenetic clocks initially enabled biological age measurement, but inconsistent clinical results, limited agreement among models, and indirect mechanistic information have restricted their usefulness. Proteomic clocks offer another approach because proteins are immediate effectors of biological processes and can also support pathway analysis. 

About the study

The investigators analyzed serum proteomic data from a randomized, double-blind, placebo-controlled phase 2a trial of rentosertib in adults with idiopathic pulmonary fibrosis (IPF). The parent trial enrolled patients older than 40 years with confirmed, stable IPF at multiple sites in China.

Participants were randomly assigned to oral rentosertib at 30 mg once daily (QD), 30 mg twice daily (BID), 60 mg QD, or placebo for 12 weeks while continuing standard-of-care medications. Of 55 participants who completed the trial, 43 consented to the proteomic substudy, and 1 was excluded because week-12 proteomic measurements were unavailable, leaving 42 participants for analysis.

Serum samples were collected at baseline and at weeks 2, 4, and 12 and analyzed using the Olink Explore 3072 platform. Raw measurements were converted to normalized protein expression (NPX) values through extension and intensity normalization. After quality-control exclusions, 2,841 proteins remained.

Six proteomic aging clocks: ProtAge, ipfP3GPT, OrganAge chronological, OrganAge mortality, PAOPAC, and PAC were applied using standardized implementations. Linear mixed-effects models (LMEMs) assessed treatment-related protein trajectories while accounting for treatment-group-by-time interactions, age, sex, body mass index (BMI), baseline NPX, and patient-specific differences. Gene set enrichment analysis (GSEA), comparisons with United Kingdom (UK) Biobank aging trajectories, and protein–protein interaction analyses were also performed.

Study results

The analyzed cohort comprised 42 Asian participants with a mean age of 67.1 years. At baseline, the four clocks trained to predict chronological age, OrganAge chronological, ProtAge, ipfP3GPT, and PAOPAC, showed relatively strong agreement with chronological age. In contrast, the mortality-trained PAC and OrganAge mortality clocks were less closely related to chronological age, as expected given their mortality-risk training objective. Agreement was also generally stronger among the chronological-age clocks than between chronological and mortality-based clocks.

Across all six clocks, rentosertib-treated groups generally showed reductions in predicted biological age from baseline, whereas placebo participants showed minimal changes or slight increases. The strongest and most consistent responses were seen at week 4. The 30 mg BID regimen produced the most consistent response across the aging clocks, followed by the 60 mg QD and 30 mg QD regimens.

Removal of six participants with higher-grade adverse events did not materially alter the findings. BMI was not clearly associated with changes in biological age. By week 12, the predicted biological-age signal had largely plateaued.

The 60 mg QD group produced the greatest improvement in forced vital capacity (FVC) in the original trial but showed less consistent aging-clock responses than the 30 mg BID group. At week 4, all four chronological clocks detected biological-age reductions in the 60 mg QD group, ranging from −2.71 to −3.46 years, whereas the mortality-based clocks did not show comparable changes. The 30 mg BID regimen was detected by both clock classes and showed reductions across five of six clocks at week 4. Organ-specific mortality-based clocks also detected reductions in predicted age for the artery, brain, pancreas, stomach, and immune system in selected treatment groups.

Rentosertib significantly altered trajectories of 326 proteins, compared with only two in placebo. The 30 mg BID regimen produced the broadest response, including 142 uniquely affected proteins. Changes included reductions in fibrosis- and extracellular matrix (ECM)-associated proteins and alterations in proteins involved in metabolism and stress resistance. Only 5–9% of proteomic shifts in the 30 mg BID and 60 mg QD groups were transient; most responses were classified as sustained or delayed, indicating that the underlying proteomic effects persisted through week 12 despite the aging-clock plateau.

Comparison with 55,319 older adults in the UK Biobank showed that rentosertib-modulated proteins were enriched 1.74-fold for age-associated proteins. The 30 mg BID regimen showed a pattern opposite to that of normal aging trajectories, whereas the 60 mg QD regimen did not. GSEA also indicated generally opposing senescence-associated patterns between placebo and treated groups. Growth-factor signaling pathways involving receptor tyrosine kinases, mitogen-activated protein kinases, rat sarcoma (RAS), and phosphoinositide 3-kinase–protein kinase B (PI3K–Akt) were downregulated across the treated groups.

Conclusions

The findings indicate that multiple proteomic aging clocks consistently detected reductions in predicted biological age during rentosertib treatment, with the 30 mg BID regimen showing the strongest cross-clock agreement. Proteomic analyses also identified treatment-associated changes in senescence, metabolic, growth-factor, and fibrosis-related pathways.

The results support incorporating aging-related endpoints into disease-focused clinical trials to evaluate potential geroprotective effects alongside conventional therapeutic outcomes. However, the small sample size, short follow-up, the computational nature of much of the analysis, the lack of complementary omics data, and the inability to fully separate anti-fibrotic from anti-aging effects preclude definitive conclusions about geroprotection.  Further research is needed to determine whether proteomic aging signals represent genuine modulation of aging rather than disease-specific treatment effects.

The authors reported no specific funding for this study. However, rentosertib was provided by Insilico Medicine, whose founder and chief executive officer is a study author, while several other authors are company employees; Insilico Medicine developed rentosertib for IPF.