Anti-Fibrotic Drug Rentosertib Reduces Proteomic Clock Age in Humans
Rentosertib is a TNIK inhibitor developed by In Silico Medicine in the course of the company's efforts to find drugs that can affect aging, shown to be anti-fibrotic, and thus recently in a phase 2 trial for the treatment of idiopathic pulmonary fibrosis. Here, the researchers provide evidence from multiple proteomic aging clocks to bolster the claim that this isn't just another anti-fibrotic drug candidate attempting to incrementally improve on what has come before, but does actually affect mechanisms of aging. There are of course already drugs that clearly affect mechanisms of aging to some degree - rapamycin and related rapalog molecules are perhaps the most robust when it comes to available data. But one can't raise the funds needed to run large trials to quantify and prove effects on aging in humans for a low-cost drug with no patent protection, as that drug cannot produce a large enough return on investment to motivate investors to fund the very expensive regulatory process. Thus the first drugs with robust data for modest effects on aging in humans will most likely be expensive, novel therapies. This is unfortunately the way the world works, or at least the way it works given the present approach to regulation of medicine.
Decades of progress in identifying mechanisms of aging and therapeutic targets to modulate them have revealed a tremendous overlap with central regulators of disease. Consequently, recent efforts in developing therapies to treat aging-related diseases often identify regulators of aging as promising disease targets. Drug repurposing efforts have highlighted the potential of treatments developed for one aging-related disease to modulate other aging-related diseases or longevity more generally, due to shared underlying pathway dysregulation coalescing around the hallmarks of aging. The aging field now faces a critical methodological question in translating biological insights into actionable clinical results: how best to measure the effects of an intervention on biological aging from data collected in clinical trials.
Proteomic clocks, by tracking the immediate effectors of biological change, may excel in providing aging biomarkers or mechanistic insight. Here we compare six proteomic clocks (ProtAge, OrganAgemortality, OrganAgechrono, PAC, ipfP3GPT and PAOPAC) on serum proteomes from a published 12-week phase 2a trial of the candidate anti-fibrotic drug rentosertib in idiopathic pulmonary fibrosis. We measure the variance between the clocks and find that all six clocks consistently predicted lower biological age in treated arms. However, proteomic clocks alone cannot deconvolute aging- and disease-specific effects. We addressed this issue indirectly through pathway analyses that identified potential anti-aging shifts in senescence and metabolic processes alongside the anti-fibrotic activity of rentosertib.