Many including myself had high hopes on Therapeutic Plasma Exchange for longevity effects in healthy elderly. For me, the hopes have faded. Talking to the TPE staff from Kiprov´s clinic at the Berkeley event made me reread the key 2025 paper on TPE in Aging Cell. https://onlinelibrary.wiley.com/doi/10.1111/acel.70103
Buried in the text and severely downplayed is the striking main negative result: “Surprisingly, we observed no significant BA (biological age) differences at time point 3 (the end of the trial) compared to sham in any group, suggesting potential compensatory mechanisms that mitigate the anti-aging effects after multiple sessions”
The only other reference to this surely huge disappointment is “Given the attenuated effect at time point 3, we wondered if it was dependent on the effects observed at the previous session (time point 2), which could indicate a potential compensatory mechanism”. and “Overall, these results indicate that individuals with TPE had most of the rejuvenation effects between the first two collection points”
So the rejuvenation effects were cancelled by time point 3, the end of the trial.
There was no mention of this in the discussion. Those supportive of TPE sail on as if nothing has happened. For mice and people with Alzheimer it may be different, but for healthy elderly TPE is to my understanding very doubtful.
I asked perplexity pro to comment para 2 and 3 above. The answer:
“Your reading of the paper is accurate, and that “hidden” negative result at time point 3 is the most important cautionary signal in the whole trial.
What the paper actually shows
The Aging Cell trial randomized 42 adults over 50 to sham, TPE (Therapeutic Plasma Exchange, various schedules), or TPE+IVIG (intravenous immunoglobulin), and measured biological age with multiple epigenetic and multi‑omic clocks over three time points.
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At time point 2 (roughly mid‑trial, after several sessions), many clocks showed clear “rejuvenation” vs sham, strongest in the biweekly TPE+IVIG arm, with average BA (Biological Age) reductions on the order of 2.6 years vs placebo in that group.
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By time point 3 (end of the intervention protocol), those between‑group differences were no longer statistically significant for any group: the authors explicitly state that there were no significant BA differences vs sham at that final time point.
So the true pattern is: early, fairly robust BA improvements that then fade or are “caught up” by sham by the end of the protocol.
Why this matters scientifically
From a strict trial‑interpretation standpoint, the primary question is usually: “At the predefined primary endpoint, is there a difference vs sham?” Here, the answer is no. That means:
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The paper does not support a claim that “6 months of long‑term TPE±IVIG durably lowers biological age vs sham,” because the primary endpoint shows no lasting between‑group separation.
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The strongest positive statements one can make are time‑limited: “There was a transient mid‑course reduction in several biological age clocks, most pronounced in TPE+IVIG.”
The press releases and many secondary commentaries heavily emphasize the mid‑trial 2.6‑year BA reduction and under‑emphasize the loss of significance at the end. Even the Buck press release notes that the effects were “strongest after the initial three sessions” and that subsequent treatments showed diminishing returns, but does not highlight that the final time point lost significance vs placebo. That framing is understandable from a translational / fundraising viewpoint, but it is not the conservative clinical interpretation.
The “compensatory mechanism” idea
The authors’ phrase about “potential compensatory mechanisms” is basically a hypothesis to explain why:
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Most of the apparent rejuvenation happens between baseline and time point 2.
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Additional TPE sessions do not enlarge the gap and may even pull the clocks back toward baseline relative to sham.
It is also possible that what is being called “compensation” is partly:
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Regression to the mean in clocks with substantial noise.
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Small sample size and multiple comparisons (15+ clocks) inflating early significance.
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Temporal dynamics: clocks may respond strongly to an acute systemic perturbation (change in plasma proteome, immune state, albumin redox, etc.) and then adapt back toward baseline as the organism re‑equilibrates.
The multi‑omics analysis suggests immune and inflammatory pathways shift in a “younger” direction after early TPE, particularly with IVIG, but that these signals are not linearly improved by just continuing the same intervention at the same intensity. That is consistent with many hormetic or homeostatic systems: the first pushes produce marked shifts, then buffers push the system back.
How this should change how we talk about TPE for aging
Putting it all together:
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The trial is a valuable proof‑of‑mechanism that TPE (especially with IVIG) can transiently move certain biological age clocks and molecular networks in a younger direction in older adults.
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It is not evidence that repeated TPE sessions over many months produce a sustained, clinically meaningful reduction in biological age compared with sham, because those differences vanish by the end of the protocol.
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The loss of significance at time point 3 should be front‑and‑center in any responsible discussion and is more important than the mid‑trial peak effect.
For practice and protocol design, the more honest conclusion is something like: “TPE±IVIG produces a short‑term multi‑omic BA shift after the first few sessions, followed by diminishing and possibly vanishing returns; any future longevity protocol needs to rethink dose, spacing, and combination with other interventions rather than simply repeating the same recipe.”
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