#1

https://www.sciencedirect.com/science/article/abs/pii/S0531556517306757

https://journals.sagepub.com/doi/full/10.1177/26330040221150269

Galactose is super-glycating and addition of galactose to IgG seems the main factor in determining Glycanage

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#2

vhttps://genomicpress.kglmeridian.com/view/journals/brainmed/aop/article-10.61373-bm025k.0074/article-10.61373-bm025k.0074.xml?body=FullText

#3

1. Table: IgG vs Ganglioside Sialylation Enzymes

System Main sialyltransferase(s) Linkage added Substrate backbone Where expressed
IgG (Fc N-glycan) ST6GAL1 Adds α2,6 Neu5Ac to terminal galactose on N-glycans N-linked glycan (GlcNAc–Gal) on Fc Asn297 Broadly expressed in B-cells, hepatocytes, Golgi
(minor: ST3GAL4/6) Adds α2,3 Neu5Ac (rare on IgG, more on other glycoproteins) N-linked glycans Hematopoietic & epithelial
Gangliosides ST3GAL5 (GM3 synthase) Adds α2,3 Neu5Ac to galactose in LacCer → GM3 Glycosphingolipid (LacCer) Brain, immune cells
ST8SIA1 Adds second Neu5Ac to GM3 → GD3 (disialylated) Glycosphingolipid Brain, thymus
ST8SIA5 Extends further → GT1b, GQ1b (polysialylated) Glycosphingolipid Brain, especially during development

:point_right: So:

  • IgG = mainly ST6GAL1 (α2,6).
  • Gangliosides = ST3GAL5 / ST8SIA family (α2,3 and polysialylation).
  • Same donor, different enzymes, different linkages.

2. Shared Donor Substrate Pool: CMP-Neu5Ac

All sialyltransferases — whether they act on N-glycans (IgG) or glycolipids (gangliosides) — draw from the same cytosolic pool of activated sialic acid:

Pathway

  1. UDP-GlcNAc → ManNAc-6-P → Neu5Ac (sialic acid)
  • Enzyme: GNE (UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase).
  1. Neu5Ac → CMP-Neu5Ac
  • Enzyme: CMAS (CMP-sialic acid synthetase).
  1. CMP-Neu5Ac transported into the Golgi lumen by SLC35A1 (CMP-sialic acid transporter).
  2. Golgi-resident sialyltransferases (ST6GAL1, ST3GAL5, ST8SIA1/5) all use CMP-Neu5Ac as the activated sugar donor.

Why this matters

  • The cytosolic supply of CMP-Neu5Ac is shared currency.
  • If aging, inflammation, or metabolic shifts reduce Neu5Ac or CMP-Neu5Ac availability, both IgG glycans and gangliosides will show hypo-sialylation, even though they’re modified by different enzymes.
  • Diseases that affect this pathway (e.g., SLC35A1 mutations → congenital disorders of glycosylation) show global hyposialylation across glycoproteins and glycolipids.

3. Aging Context

  • With aging:
    • CMP-Neu5Ac synthesis declines (less GNE activity, lower precursor availability).
    • Golgi trafficking becomes less efficient.
    • Inflammatory cytokines (TNF-α, IL-6) suppress ST6GAL1 and shift toward pro-inflammatory glycoforms.
  • Net result:
    • IgG: less α2,6-sialylation → pro-inflammatory Fc glycoforms (basis of GlycanAge biomarker).
    • Gangliosides: less complex α2,8-polysialylation (loss of GT1b, GQ1b) → reduced synaptic stability, more GM1/GM3 dominance.

:white_check_mark: In short:
IgG glycans and gangliosides don’t share the same enzymes, but they compete for the same activated donor substrate (CMP-Neu5Ac). Aging reduces this pool and alters enzyme regulation, so both systems independently converge on the phenotype of loss of complex sialylation.

  • N-acetylmannosamine (ManNAc)
    • The committed precursor in the GNE step.
    • Supplementing bypasses the rate-limiting GNE epimerase defect.
    • Being clinically trialed for GNE myopathy (a rare disorder of sialic acid deficiency).
    • Much more effective than free Neu5Ac at raising CMP-Neu5Ac pools.
#4

You’re not wrong. GlycanAge is a decent barometer; it’s not the weather station. It mostly reflects how B cells are decorating IgG under the current cytokine/hormone/metabolic mood, not “inflammation in general.”

Here’s the clean split:

What GlycanAge actually tracks

  • Chronic, systemic tone that pushes IgG toward less galactose/sialic acid when IL-6/TNF and metabolic noise are up. Also moves with menopause, adiposity, sleep, exercise, and weight loss.
  • Adaptive humoral bias, not whether you “get sick a lot.” Exposure frequency isn’t the dial; the germinal-center milieu and plasma-cell glycosyltransferases are.

What it doesn’t capture well

  • Tissue-local inflammation (gut, liver, brain microglia) that never bleeds into serum signals.
  • Innate/trained immunity, complement, neutrophil priming, mast cells, NK cytotoxic tone, T-cell exhaustion, mucosal IgA, etc. Whole universes outside IgG.
  • Acute spikes. It’s sluggish compared to hs-CRP or a cytokine panel.

Edge cases you’re hinting at

  • A person with low infections can still have a “pro-inflammatory” IgG glycome if their baseline cytokine/metabolic state is off. Conversely, robust health plus low inflammatory tone can make IgG look “younger” even if they wrestle with germs like a champ. IgG glycan complexity isn’t a needs-based subscription plan.

How to read it like an adult

  • Treat GlycanAge as one dial for chronic inflammatory/metabolic set point.
  • Triangulate with a small, boring bundle: hs-CRP, GlycA (NMR), IL-6 or TNF-α if you must, CBC-diff for NLR, ferritin and fibrinogen, maybe ALT/AST and albumin. If you love data, add resting HRV for autonomic load.
  • Watch directionality over time with stable routines. If the number trends better alongside CRP/GlycA, cool. If it wanders on its own, don’t let one glycan score gaslight you.

Bottom line: GlycanAge is a respectable proxy for the systemic humoral inflammatory set point, not a verdict on your entire immune ecosystem. Use it as a compass, not a courtroom.

also see posts on NEU1