Been going down the Katcher E5 rabbit hole this week after someone in the longevity sub linked the YouTube breakdown. The rat data is interesting but the mechanistic question is what I keep getting stuck on, and I don’t think it gets discussed clearly enough. There are two competing explanations for why young plasma works in parabiosis and heterochronic transfusion experiments: 1. Dilution model (Conboy lab’s position): old blood accumulates pro-aging factors (TGF-beta, CCL11, etc.), and young plasma dilutes them. The “youth signal” is mostly absence of junk. 2. Positive signaling model (closer to Katcher’s framing): young plasma contains actual pro-regenerative proteins that old organisms lack, and adding them back restores function. These aren’t mutually exclusive but they point to completely different intervention strategies. If it’s dilution, plasmapheresis or albumin replacement (the Kiprov/Wyss-Coray approach) gets you most of the benefit without needing donor plasma at all. If it’s positive signaling, you need the actual fraction. Why this matters for people who aren’t waiting on E5 trials: some of what the positive-signaling hypothesis describes looks mechanistically adjacent to what certain peptides are supposedly doing. GDF11 controversy aside, things like MOTS-c and humanin are mitochondrial-derived peptides that decline with age and seem to affect systemic metabolism. Whether they overlap with Katcher’s fraction I genuinely don’t know. The part I can’t resolve: Katcher hasn’t published the full composition of E5 publicly, which makes it hard to evaluate the mechanism claim at all. Has anyone seen a more detailed breakdown of what’s actually in it beyond the basic protein fraction description?