A new clinical study involving the artificial intelligence-designed drug Rentosertib has reported significant reductions in predicted biological age among patients receiving the experimental treatment. Researchers analyzing blood proteins from participants in a Phase 2a clinical trial found that six different proteomic aging clocks consistently detected shifts toward younger biological-age profiles following treatment with the drug. The findings were reported in Nature Biotechnology in a study examining whether aging measurements can be incorporated into clinical trials of treatments for age-related diseases.
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Rentosertib, formerly known as INS018_055, is an AI-designed inhibitor of TRAF2- and NCK-interacting kinase, or TNIK. It is being developed for idiopathic pulmonary fibrosis (IPF), an age-associated lung disease characterized by progressive scarring of lung tissue. Researchers are also investigating whether targeting TNIK can affect biological processes associated with aging. In the middle of these developments, this Longevity and Wellness News report highlights findings showing that all six aging clocks used in the analysis detected reductions in predicted biological age following Rentosertib treatment.
AI-Designed Drug Tested in Patients with Pulmonary Fibrosis
The findings came from an analysis of a randomized, double-blind and placebo-controlled Phase 2a clinical trial conducted at 21 locations in China during 2023 and 2024.
The original study enrolled 71 patients with confirmed IPF who were older than 40 years and clinically stable. Participants were assigned to receive Rentosertib at 30 milligrams once daily, 30 milligrams twice daily, 60 milligrams once daily, or placebo.
Blood samples were collected at baseline and again at weeks two, four and 12. Of the participants, 43 consented to serum proteomic analysis, with one subsequently excluded because a final measurement was unavailable. This left 42 participants, with a mean age of 67.1 years, for the biological-aging analysis.
Six Different Aging Clocks Were Used
Rather than relying upon a single measure of biological age, researchers applied six published proteomic aging clocks to participants’ serum samples.
The clocks included ProtAge, OrganAgechrono, OrganAgemortality, PAC, ipfP3GPT and PAOPAC. Four of these models were designed to predict chronological age, while two were trained using mortality-related information.
Proteomic aging clocks estimate aspects of biological aging by analyzing patterns involving proteins circulating in the blood. The study noted that proteins are immediate effectors of biological processes and can therefore potentially provide both aging biomarkers and information about biological pathways affected by treatment.
Despite differences between the six clocks and the methods used to construct them, all detected proteomic changes associated with Rentosertib treatment. Researchers reported consistent reductions in predicted biological age in the treatment groups, while the placebo group showed minimal changes or slight increases during the 12-week period.
Biological Age Measurements Fell by Around Three Years
Some of the largest changes were recorded at week four. Among participants receiving 60 milligrams of Rentosertib once daily, all four chronological aging clocks recorded statistically significant reductions in predicted biological age compared with placebo. The reductions ranged from approximately 2.71 to 3.46 years.
The two mortality-based aging clocks did not record statistically significant changes for this particular dosing regimen.
The 30-milligram twice-daily treatment group produced the broadest agreement across the different aging clocks. Both chronological and mortality-based clocks detected changes in this group.
Across the study, researchers performed comparisons involving six clocks, three timepoints and three Rentosertib dosing regimens. Twenty-one comparisons reached the study’s statistical-significance threshold. Eleven of the 18 comparisons conducted at week four showed significantly lower changes in biological age among treated participants.
Twice-Daily Dose Produced the Most Consistent Signal
The 30-milligram twice-daily regimen generated nine significant comparisons, compared with seven for the 60-milligram once-daily group and five for participants receiving 30 milligrams once daily.
At week four, five of the six aging clocks also showed negative standardized effect sizes for the 30-milligram twice-daily regimen.
Researchers reported that administering 30 milligrams twice daily appeared to produce more consistent aging-related effects than administering the equivalent total daily amount as a single 60-milligram dose.
By week 12, fewer comparisons remained statistically significant. However, direct comparisons between weeks four and 12 did not show significant shifts in predicted biological age, leading researchers to characterize the pattern as a plateau rather than a reversal of the earlier response.
Hundreds of Proteins Changed During Treatment
The investigators also examined individual proteins to determine how Rentosertib affected participants’ serum proteomes.
The analysis identified significant changes in the trajectories of 326 proteins across the Rentosertib treatment groups, compared with only two in the placebo group.
The 30-milligram twice-daily group produced the broadest proteomic response, with 142 uniquely affected proteins. Eighty-nine proteins displayed changes in the same direction in two or more treatment groups.
Among the prominently downregulated proteins were COL1A1, MMP10 and FAP, which are associated with fibrosis and extracellular-matrix remodeling.
Changes were also observed among proteins involved in cellular metabolism and resistance to biological stress, including NAMPT, SOD2 and ALDH1A1. PDGFB, a growth factor involved in proliferative signaling, was among the proteins whose levels decreased.
Aging-Related Protein Changes Continued Through Week 12
Further analysis examined whether the proteomic effects detected earlier in the trial disappeared over time.
Researchers reported that only approximately 5% to 9% of the proteomic changes in the 30-milligram twice-daily and 60-milligram once-daily groups were transient.
The data indicated that proteomic responses at the effective doses continued developing through week 12. Proteins considered particularly relevant to biological aging were also disproportionately represented among the sustained treatment-associated changes.
Important Limitations Remain
The researchers emphasized that proteomic aging clocks alone cannot determine whether reductions in predicted biological age represent direct changes in aging biology or effects associated with Rentosertib’s anti-fibrotic activity.
Because all participants in the analysis had IPF, disease improvement could influence some of the proteins incorporated into biological-aging calculations.
The researchers therefore stated that fully separating aging-related effects from disease-related effects cannot be accomplished within an IPF population alone. Validation of Rentosertib or its underlying mechanism in people without IPF would be required to investigate this question directly.
A New Direction for AI Drug Development and Aging Research
The study demonstrates that proteomic aging clocks can be incorporated into conventional clinical trials to examine whether treatments developed for age-related diseases simultaneously influence biological processes associated with aging.
In this Phase 2a analysis, all six proteomic clocks detected younger predicted biological-age profiles following Rentosertib treatment, with chronological clocks recording reductions of approximately 2.71 to 3.46 years in one dosing group at week four. The study also identified extensive changes across hundreds of circulating proteins and aging-associated biological pathways. Further clinical research will be needed to determine how these biomarker changes relate to aging biology independently of IPF and whether such effects can be reproduced in other populations.
The findings provide new human clinical data on an AI-designed drug while demonstrating how aging measurements can be incorporated into trials targeting age-associated diseases. Researchers have presented the results as evidence supporting further investigation of Rentosertib’s potential geroprotective effects, while acknowledging that biological-age measurements and disease-related effects cannot yet be completely separated in the studied population.
Reference:
https://www.nature.com/articles/s41587-026-03286-y
Medical Disclaimer: All content published by Thailand Wellness News is based on scientific research and is intended for informational and educational purposes only. It is not medical advice, diagnosis, or treatment. Readers must not attempt to use, apply, or experiment with any protocols, compounds, or therapies mentioned without first consulting a qualified and licensed medical doctor. Many findings discussed are experimental or preliminary, and only a licensed healthcare professional can determine what is safe and appropriate for an individual’s specific medical condition.
