Researchers have been generating aging clocks for going on twenty years now, and as one might expect there are now lot of these clocks. Even just counting the epigenetic clocks one has a great deal of choice. Most studies that make use of clocks choose to assess only a few of the more prominent options, but as today's report on a clinical trial of therapeutic plasma exchange makes clear, the right way to go about this is to assess every single clock one can obtain access to - more than 30 clocks and clock variants in this case. The primary challenge in the use of aging clocks as a means to assess the quality of a potential rejuvenation therapy is that one has no idea how any given clock will react to a specific class of intervention. Is the clock usefully weighing specific parameters that change in response to the intervention? Or weighing too little? Or weighing too much?
The only way to arrive at a comprehensive answer is to calibrate a clock against a given therapy, a lengthy process of assessing aging the old-fashioned way, by waiting to see what happens. No-one is going to run life span studies of interventions in humans for this purpose any time soon, though we might see results emerge from longitudinal studies of exercise and other lifestyle choices over the next decade or two as the use of aging clocks expands. In the absence of those studies, a next best approach is to assess as many clocks as possible for as many interventions as possible, to get a feel for how the results vary. The data in today's paper shows just how much different clocks can vary for one intervention, therapeutic plasma exchange, where it is reasonable to believe that treatment will to some degree reduce some of the dysfunctions of aging. It would be very interesting to see equivalent data for senolytics, mTOR inhibitors, and so forth.
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. 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.
View the full article at FightAging
