Multi‐Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single‐Blinded Randomized Placebo‐Controlled Therapeutic Plasma Exchange

ABSTRACT We conducted a randomized, placebo‐controlled trial to assess the safety and biological age (BA) effects of various therapeutic plasma exchange (TPE) regimens in healthy adults over 50. Participants received bi‐weekly TPE with or without intravenous immunoglobulin (IVIG), monthly TPE, or placebo. Randomization was based on entry date, and treatments were blinded to maintain objectivity. Primary objectives were to assess long‐term TPE safety and changes in biological clocks. Secondary goals included identifying optimal regimens. Exploratory analyses profiled baseline clinical features and longitudinal changes across the epigenome, proteome, metabolome, glycome, immune cytokines, iAge, and immune cell composition. We demonstrate in 42 individuals randomized to various treatment arms or placebo that long‐term TPE was found to be safe, with only two adverse events requiring discontinuation and one related to IVIG. TPE significantly improved biological age markers, with 15 epigenetic clocks showing rejuvenation compared to placebo (FDR < 0.05). Biweekly TPE combined with intravenous immunoglobulin (TPE‐IVIG) proved most effective, inducing coordinated cellular and molecular responses, reversing age‐related immune decline, and modulating proteins linked to chronic inflammation. Integrative analysis identified baseline biomarkers predictive of positive outcomes, suggesting TPE‐IVIG is particularly beneficial for individuals with poorer initial health status. This is the first multi‐omics study to examine various TPE modalities to slow epigenetic biologic clocks, which demonstrate biological age rejuvenation and the molecular features associated with this rejuvenation. Trial Registration: Registered trial NCT06534450 on clinicaltrials.gov under the purview of the Diagnostic Investigational Review Board.