it’s a common issue in ME/CFS
“invasive cardiopulmonary exercise testing”
Great bundle of findings. Here’s a tight, mechanistic way to make them hang together—and also why LPCs keep popping up in aging papers.
Why LPCs show up in aging/“biological age”
Where LPC comes from. In blood, most lysophosphatidylcholines (LPC) are made when:
- LCAT converts HDL-surface PC + free cholesterol → cholesteryl ester + LPC (a core step in reverse cholesterol transport), and
- PLA₂ clips a fatty acid off PC; LPC is then rapidly re-acylated back to PC by LPCATs (the Lands cycle). (PMC, ScienceDirect, E-EnM)
What low circulating LPC often means. Across cohorts, plasma LPC tends to fall with obesity/aging and correlates with lower mitochondrial oxidative capacity—i.e., a sluggish, inflamed metabolic state with weaker HDL remodeling. Mechanistically, that can reflect reduced LCAT activity/HDL function, altered PLA₂/LPCAT balance, and diminished “membrane turnover” capacity. (PMC)
The nuance (why some papers say “LPC bad”). LPC in modified/oxidized LDL or in tissues can be pro-inflammatory and injure mitochondria; but circulating LPC species (especially 18:2/O-16:0) often track better metabolic fitness and sometimes lower T2D risk. Context (carrier, species, and compartment) flips the sign. (PMC, ScienceDirect)
So when a study claims “lower LPC ↔ slower biological aging,” check which species and what model/adjustments they used; large human datasets more commonly report LPC ↓ with aging/IR/frailty, and low LPC 18:2 predicts functional decline. (Oxford Academic, Frontiers)
How the longevity patterns tie together
1) Offspring of nonagenarians: PC/SM ↑; PE(38:6) ↓; long-chain TAG ↓
- Lower long-chain TAGs → less TAG-rich VLDL burden and less spillover of long PUFA into lipoprotein cores—less peroxidation load and TRL stress.
- PC and SM higher (not total TG-driven): those are lipoprotein surface lipids; in these long-lived families they were selectively enriched, independent of total TG. Interpreted with other data in the paper (e.g., lipoprotein size), this points to healthier lipoprotein remodeling/packing rather than overproduction of TAG. (PMC)
- PE(38:6) lower: PE(38:6) is typically DHA-rich and highly peroxidizable. Lower abundance of the most PUFA-rich PE species in plasma membranes can mean less oxidative fragility (PE is the class most prone to peroxidation-mediated curvature defects). Net: more oxidation-resistant surfaces, fewer peroxidation-prone cores. (PMC)
2) Ether lipids: alkyl-PC (O-) ↑ with shorter chains/fewer double bonds; alkenyl-PE (plasmalogens, P-) with long chains/more double bonds ↓
- Ether PCs with shorter, less unsaturated chains are harder to oxidize than long poly-unsaturated plasmalogens; Pradas et al. identified a “longevity ether-lipid signature” precisely along those lines. Mechanistically, ether linkages can buffer oxidative stress, but very long, highly unsaturated plasmalogens become peroxidation liabilities; the long-lived phenotype seems to emphasize oxidation-resistant ether PCs over highly unsaturated PE(P). (PubMed, PMC)
3) Where LPCs fit into that picture
- A lipidome with efficient HDL/LCAT remodeling (and balanced PLA₂↔LPCAT activity) tends to maintain adequate circulating LPC 18:2/18:1, which in turn associates with better mitochondrial oxidative capacity and physical function with age. That coheres with lower TAG burden and more oxidation-resistant surface lipids seen in familial longevity. (PMC, Oxford Academic)
Unifying mechanism (one page)
- Less peroxidation-prone cores: TAG ↓, especially very long, poly-unsaturated TAGs → fewer lipid-peroxide cascades within lipoproteins.
- More resilient surfaces: PC/SM ↑ (and specific ether-PC ↑) → sturdier lipoprotein/membrane monolayers, better receptor handling, less leak of oxidized products.
- Balanced remodeling: Functional LCAT/PLA₂/LPCAT cycles → adequate plasma LPC (marker of active remodeling) and efficient HDL-centric cholesterol handling.
- Membrane class tilt: PE(38:6) ↓ and select ether-PC ↑ reduce curvature/peroxidation stress in membranes that gate signaling (rafts, caveolae).
Together these shifts map to lower oxidative stress, more efficient lipid transport/remodeling, and fewer ceramide/DAG-driven stress signals—all features that show up in familial longevity and, in multi-omic studies, with slower epigenetic/functional aging. (PMC, PubMed)
Quick reality checks you can run (if you have data)
- Look at LPC 18:2 and HDL-centric markers (apoA-I, cholesterol efflux, or at least HDL-C) alongside TG. Expect: LPC 18:2 higher & TG lower in the longevity-leaning profile. (PMC)
- Compute oxidation load proxies: more ether-PC (O-) with fewer double bonds + less PE(38:6) usually tracks lower lipid-peroxidation signatures. (PubMed)
If you share your lipid species (even a handful: LPC 18:2, PC O-36:2, PE P-38:6, total TAG and a few long-chain TAG species), I can tell you how “longevity-like” your profile looks and which levers (diet/training/sleep, or LCAT/LPCAT-targeted angles) would likely move it.