Evidence Trace, complete trial record
In plain terms
In plain terms: Therapeutic plasma exchange (plasmapheresis for aging) shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
Therapeutic plasma exchange (plasmapheresis for aging)
C
Limited: small, mixed or unreplicated trials
The endpoint this grade is based on: Surrogate biomarker endpoint
The evidence as the record states it
Fuentealba et al. (Aging Cell, 2025; PMID 40424097): single-blinded placebo-controlled trial in 42 healthy adults over 50, comparing bi-weekly plasma exchange with or without intravenous immunoglobulin, monthly exchange, and placebo; allocation was by entry date rather than true random assignment. Primary objectives were long-term safety and change in biological clocks; the procedure was reported safe, with two adverse events requiring discontinuation, one related to the immunoglobulin, and 15 epigenetic clocks moved toward younger values against placebo. The regimen reported as most effective combined bi-weekly exchange with intravenous immunoglobulin. One author is co-founder and chief scientific officer of Circulate Inc., a company offering plasma exchange, and two others are members of it; no specific funding is declared. Borsky et al. (Sci Rep, 2025; PMID 40592961): a different procedure, plasma removal without replacement fluid, in healthy blood donors randomized to 8 or 4 sessions over 18 weeks with no untreated control; no epigenetic rejuvenation, and GrimAge, the Hannum clock and the Dunedin pace of aging increased, with lipids and serum proteins lower. It does not replicate plasma exchange and its direction is unfavorable. Grade C: one small, single-blinded, non-randomly allocated positive trial on surrogate clocks, unreplicated.
PMID 40424097 PMID 40592961
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What this grade covers and what it does not
Grade C. One small trial tested plasma exchange against sham (Fuentealba et al., 2025; PMID 40424097): 42 adults, single-blinded, allocated by entry date rather than random assignment, with epigenetic clocks moving toward younger values, strongest in the arm that also received intravenous immunoglobulin. The only other human trial (Borsky et al., 2025; PMID 40592961) tested a different procedure, plasma removal without replacement, 8 against 4 sessions with no untreated control, and found the clocks moving the wrong way, so it does not replicate plasma exchange. Every endpoint is a surrogate: epigenetic clocks, circulating biomarkers, immune cell composition. Surrogate-only signals cap at B under the EBL rubric, and one unreplicated pilot-scale trial is C. WHAT AN EPIGENETIC CLOCK IS: a model trained to predict chronological age and mortality across populations. Moving one has not been shown to change what happens to a person. Nothing here reports a clinical outcome, and the safety finding, which is the more solid result of the two, is not a benefit finding. WHAT THIS GRADE DOES NOT COVER: the arm the larger trial reports as most effective combined plasma exchange with intravenous immunoglobulin, so the effect cannot be attributed to plasma exchange on its own. That trial was single-blinded and allocated participants by entry date rather than by true random assignment, both of which weaken it further, and one of its authors co-founded a company that sells plasma exchange. The other human trial, of plasma removal without replacement, reported epigenetic age accelerating rather than reversing. Neither trial reports a clinical outcome, so nothing here speaks to survival, disability, frailty, cognition or cardiovascular events. And the letter grades evidence, not procedure risk: this is an invasive extracorporeal procedure carrying the hazards that come with vascular access, citrate anticoagulation and replacement fluids, among them hypotension, hypocalcemia, bleeding, infection, and reactions to the replacement fluid or to immunoglobulin. Two participants among the 42 discontinued for adverse events, one of them related to the immunoglobulin.
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.
How to track whether this is working
Nothing validated. Epigenetic clock scores are the endpoint these trials moved, and they are markers rather than outcomes.