As reported on News-Medical, an experimental treatment for idiopathic pulmonary fibrosis (IPF), rentosertib, was associated with shifts toward younger biological age profiles across multiple protein-based aging measures in a phase 2a clinical trial. The findings suggest that proteomic aging clocks may help researchers evaluate potential anti-aging effects alongside traditional disease outcomes, although larger studies are needed to determine whether these changes reflect true modification of aging biology.
Proteomic Clocks Offer a New Window Into Biological Aging
Researchers investigated whether six distinct proteomic aging clocks could detect biological age changes during treatment with rentosertib, a drug under development for IPF. Unlike DNA methylation clocks, which estimate biological age through epigenetic markers, proteomic clocks assess patterns of circulating proteins that are directly involved in physiological processes.
The analysis was conducted using serum samples collected during a randomized, double-blind, placebo-controlled phase 2a trial involving patients with stable IPF. Participants received one of three rentosertib dosing regimens or placebo over a 12-week period while continuing standard therapies. Proteomic data were available from 42 participants and included measurements of more than 2,800 proteins.
Consistent Declines in Predicted Biological Age
Across all six aging clocks, patients receiving rentosertib generally experienced reductions in predicted biological age, while those in the placebo group showed little change or slight increases. The most pronounced effects emerged by week 4 of treatment.
Among the dosing schedules studied, the 30 mg twice-daily regimen generated the most consistent age-reducing signals across the various clocks. Responses were also observed with 60 mg once daily and 30 mg once daily, although results were less uniform.
Investigators noted that the biological age improvements largely stabilized by week 12, suggesting that the initial response may plateau despite ongoing treatment.
Disconnect Between Lung Function and Aging Measures
One of the study’s notable observations was that the regimen producing the strongest clinical improvement in lung function was not the same regimen generating the most robust aging-clock response.
In the parent trial, the 60 mg once-daily dose delivered the greatest improvement in forced vital capacity (FVC), a key measure of lung function in IPF. However, the 30 mg twice-daily regimen produced broader and more consistent reductions across both chronological-age and mortality-focused proteomic clocks.
This divergence highlights the possibility that disease-specific benefits and broader biological aging effects may not always align, underscoring the value of measuring both outcomes in future clinical studies.
Broad Proteomic Changes Suggest Impact on Aging-Related Pathways
Beyond aging-clock scores, rentosertib altered the expression trajectories of 326 proteins, compared with only two proteins affected in the placebo group. The 30 mg twice-daily regimen produced the most extensive proteomic response, with 142 uniquely affected proteins.
Many of the observed changes involved proteins linked to fibrosis and extracellular matrix remodeling, processes central to IPF progression. Researchers also identified shifts in pathways associated with metabolism, cellular stress responses, and senescence.
Most protein changes persisted through the 12-week study period, indicating sustained biological activity even after aging-clock improvements had plateaued.
Signals Opposed Typical Aging Patterns
To place the findings in context, investigators compared treatment-associated protein changes with age-related protein trajectories observed in more than 55,000 older adults from the UK Biobank.
Proteins influenced by rentosertib were significantly enriched for proteins normally associated with aging. Notably, the 30 mg twice-daily regimen produced a pattern that generally moved in the opposite direction of typical aging-related changes. Gene set enrichment analyses also suggested that treated participants displayed molecular signatures that contrasted with those seen in untreated individuals.
The study further identified downregulation of several growth-factor signaling pathways, including receptor tyrosine kinase, RAS, MAPK, and PI3K-Akt signaling networks, all of which are implicated in aging, cellular growth, and tissue remodeling.
Implications and Limitations
The authors conclude that integrating multiple proteomic aging clocks into clinical trials may provide valuable insights into whether investigational therapies influence aging-related biology in addition to treating disease. In this study, the consistency of findings across several independent aging clocks strengthens the evidence that rentosertib may affect pathways linked to biological aging.
However, the researchers caution that the study was small, involved only 42 participants, and followed patients for just 12 weeks. The analyses were largely computational and did not include complementary omics approaches that could help verify the findings. Additionally, it remains unclear whether the observed changes reflect genuine geroprotective activity or are primarily a consequence of reducing disease-related fibrosis.
Further research will be required to determine whether proteomic aging signatures can serve as reliable indicators of anti-aging effects and whether the benefits observed with rentosertib extend beyond disease-specific treatment responses.
