A recent study published in Nature Biotechnology investigated whether multiple proteomic aging clocks could detect changes in biological age and aging-related protein signatures during a phase 2a clinical trial of rentosertib, an experimental treatment for idiopathic pulmonary fibrosis (IPF). The researchers also examined the biological mechanisms associated with these changes.

Researchers analyzed serum samples from a randomized, double-blind, placebo-controlled phase 2a trial involving adults over 40 with confirmed, stable IPF. Participants received rentosertib at 30 mg once daily, 30 mg twice daily, 60 mg once daily, or placebo for 12 weeks. Of the 55 participants who completed the trial, 43 entered the proteomic substudy, with 42 included in the final analysis. Blood samples collected at baseline and weeks 2, 4, and 12 were analyzed using the Olink Explore 3072 platform, with 2,841 proteins assessed using six proteomic aging clocks.

Across the six aging clocks, rentosertib-treated groups generally showed reductions in predicted biological age, while placebo participants showed minimal changes or slight increases. The strongest and most consistent effects occurred at week 4, with the 30 mg twice-daily regimen producing the greatest agreement across the clocks. By week 12, the biological-age signal had largely plateaued.

Interestingly, these aging-related changes did not directly correspond with improvements in lung function. The 60 mg once-daily group achieved the greatest improvement in forced vital capacity (FVC), yet its aging-clock responses were less consistent than those observed with the 30 mg twice-daily dose. At week 4, chronological-age clocks estimated reductions of approximately 2.7 to 3.5 years in the 60 mg once-daily group, while the 30 mg twice-daily group showed reductions across five of the six clocks.

Rentosertib significantly altered the trajectories of 326 proteins, compared with only two in the placebo group. The 30 mg twice-daily regimen generated the broadest response, affecting 142 unique proteins. These changes involved pathways related to fibrosis, extracellular matrix remodeling, metabolism, cellular stress resistance, and growth-factor signaling. Most protein changes were sustained or delayed, persisting through week 12.

Comparison with data from 55,319 older adults in the UK Biobank showed that proteins affected by rentosertib were enriched for proteins associated with aging. The 30 mg twice-daily treatment produced a proteomic pattern that generally moved in the opposite direction of normal aging, while pathway analysis identified changes in senescence-related processes and signaling pathways involving receptor tyrosine kinases, MAPK, RAS, and PI3K-Akt.

Overall, the findings suggest that proteomic aging clocks can detect reductions in predicted biological age during rentosertib treatment. However, the strongest aging-related response did not correspond to the dose that produced the greatest improvement in lung function. The small sample size, short follow-up, and difficulty distinguishing anti-fibrotic effects from genuine anti-aging effects mean that further research is needed to determine whether these changes represent true biological-age modulation.

Source: https://www.news-medical.net/news/20260910/Rentosertib-shifts-multiple-proteomic-aging-clocks-toward-younger-age-profiles-in-IPF-trial.aspx