#1

Paper:

The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n = 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response.

Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals.

Artigo completo:

https://media.licdn.com/dms/document/media/v2/D561FAQE_P4PzN_rnCA/feedshare-document-pdf-analyzed/B56ZnJSrRXJ8AY-/0/1760018747942?e=1761177600&v=beta&t=o8znFDZ6wpDreJunOAAbeh-D2QEv1aJLS1xB8tFy_6I

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#2

Short answer: dialing down NEU1 can push multiple aging knobs in the right direction. Long answer, since you asked for the nerd candy:

What NEU1 does (and why too much of it ages you gracelessly)

NEU1 is a lysosomal/cell-surface sialidase that clips terminal sialic acids off glycoproteins and glycolipids. Those sugars aren’t décor; they’re control labels. NEU1 activity rewires:

  • Innate immune signaling: Desialylates TLRs and EGFR, usually making them easier to activate. More NEU1 → louder danger sirens → inflammaging. Block some NEU1 and you damp chronic sterile inflammation instead of marinating in it forever.
  • Fibrosis pathways: Desialylation of TGF-β receptors and related co-receptors biases tissues toward myofibroblast activation and scar. NEU1 inhibition tends to blunt pro-fibrotic signaling, the enemy of youthful lungs, liver, heart, and kidneys.
  • Vascular aging via elastin receptor complex (ERC): Elastin fragments (“elastokines”) signal through a complex that includes NEU1. That loop drives vascular stiffness, calcification, and inflammation. Inhibiting NEU1 weakens that maladaptive “broken-elastin feedback,” which is very on-brand for getting old arteries to act less cranky.
  • Metabolic tone: Excess receptor desialylation impairs insulin and leptin receptor dynamics, feeding insulin resistance. Partial NEU1 inhibition helps preserve receptor sialylation and downstream signaling fidelity.
  • Proteostasis & trafficking: NEU1 tunes lysosomal exocytosis and autophagy–lysosome crosstalk. Too much desialylation can jam trafficking and receptor recycling; a modest brake can improve turnover of junk instead of letting aggregates squat rent-free.

Net effect: fewer chronic “danger” pings, less scar, more compliant vessels, better receptor signaling, slightly cleaner cellular housekeeping. All very pro-healthspan, i.e., the part of life where your body still returns your calls.

But don’t get cute: this is a Goldilocks target

  • Total or heavy inhibition is bad. Genetic NEU1 loss causes sialidosis, a nasty lysosomal storage disease. You want selective, partial, context-appropriate inhibition, not “turn it off and vibe.”
  • Immunity trade-offs. Sialylation patterns gate leukocyte adhesion and activation. Over-inhibit NEU1 and you might blunt pathogen responses. Longevity doesn’t help if the flu steamrolls you.
  • Cancer signaling risk goes both ways. Sialylation shields cells; too much can aid immune evasion, too little can fuel hyper-signaling. The sweet spot is real and boringly individualized.
  • Tissue specificity matters. The vascular wall and fibrotic organs look like prime beneficiaries; brain and hematopoietic niches are touchier.

Practical translation

  • The longevity case for selective NEU1 inhibitors is strongest in phenotypes dominated by chronic inflammation, fibrosis, vascular stiffening, and metabolic drift.
  • The win condition is tone-down, not shutdown, ideally targeted to the offending tissue or receptor set.
  • Pairing with exercise, glycemic control, and anti-fibrotic hygiene makes the biology synergize instead of argue with itself.

In short: NEU1 is one of those quiet editors that adds exclamation points to too many cellular sentences after midlife. Trim a few, and the paragraph reads younger. Over-edit, and you lose the plot.

===

Short version: maybe a nudge, not a makeover.

Longer, with fewer fairy tales:

  • What GlycanAge is actually measuring. It’s basically reading the “sugar tuning” on your IgG: more agalactosylated, less sialylated IgG trends older and more inflamed; more galactosylated/sialylated looks younger/less inflamed. That’s well-established across cohorts. (PMC)

  • Where that tuning is set. Most of the IgG glycan pattern is set during B-cell/plasma-cell production by enzymes like ST6GAL1 and B4GALT1. There’s also some post-secretion editing from liver-secreted ST6GAL1 that can add sialic acid in circulation. Translation: the “factory” matters more than the street cleaners. (Frontiers)

  • What NEU1 does. NEU1 is a sialidase that removes terminal sialic acids from glycoproteins on cell surfaces and in endolysosomes, tuning immune and receptor signaling. In inflammation, cells can even haul NEU1 to the surface and shed it in vesicles. But whether circulating NEU1 meaningfully desialylates your IgG pool in vivo at scale is… not nailed down. (PMC)

  • So will NEU1 inhibitors drop your GlycanAge?

    • Plausible mechanism: blocking NEU1 could, at least locally, reduce desialylation pressure and slightly shift IgG toward a more sialylated, anti-inflammatory profile. Sialylated IgG is indeed anti-inflammatory in humans and mice. (PubMed )
    • Evidence gap: there are no clinical trials showing that selective NEU1 inhibitors improve GlycanAge in humans. The closest detours are mechanistic/animal studies on NEU1 and inflammation, plus work showing sialylated IgG calms immunity. That’s supportive, not proof. (Nature)
    • Drug reality check: common “neuraminidase inhibitors” like oseltamivir/zanamivir are tuned for viral neuraminidase and show weak or inconsistent inhibition of human NEU1 in vitro. Don’t expect your flu pill to rejuvenate your IgG. (ASM Journals)

  • Bigger levers for GlycanAge than NEU1:

    • Reduce systemic inflammation and metabolic noise; IgG glycan patterns are plastic with lifestyle and disease state. Weight loss, better sleep, exercise, and estrogen status shifts all move galactosylation/sialylation more reliably than speculative NEU1 tinkering. (ScienceDirect)
    • If you’re chasing sialylation specifically, the biology points at upstream synthesis (ST6GAL1 activity, B-cell milieu) more than downstream desialylation. (Frontiers)

Bottom line: selective NEU1 inhibition is a theoretically pro-glycan-youth move, but today it’s a maybe-small effect with no human GlycanAge data. If you want the meter to budge, fix the factory settings (inflammation, metabolism, hormones) before you start arguing with the janitor enzymes.

==

Short answer: no. A high GlycanAge is not a smoking-gun readout of cranked-up NEU1. It mostly reflects how your B cells are decorating IgG at the factory, not what NEU1 might be nibbling off later on the street.

Why:

  • What GlycanAge measures. It tracks the IgG pattern that shifts with age/inflammation: less galactose and sialic acid, more agalactose. That’s a production-line decision inside plasma/B cells. (PubMed )
  • Upstream control beats cleanup crew. IgG sialylation is primarily set by sialyltransferase ST6GAL1 and friends; even post-secretion tweaks still point to synthesis pathways more than to desialylases. (Frontiers)
  • NEU1 is real, just not your gauge. NEU1 is a lysosomal/cell-surface sialidase that modulates receptor signaling and immunity. It can move to the membrane or show up on vesicles during activation, but there’s no clinical evidence that “higher GlycanAge = higher systemic NEU1.” Correlation hasn’t been demonstrated. (PMC)
  • Also, there are other sialidases. Humans have NEU1/2/3/4 in different compartments. If you ever did see extra “sialidase activity” in plasma, NEU3 or NEU4 might be the culprits, or just general inflammation turning over glycans faster. GlycanAge can rise without any measurable NEU1 surge. (MDPI)

Bottom line: high GlycanAge says “your IgG looks pro-inflammatory/older,” not “NEU1 is specifically high.” If you want to nudge that number down, target the upstream biology that sets IgG glycans in the first place; NEU1 is, at best, a supporting character. (PubMed )

What percent of cases with high Glycanage come from basally low D-galactose levels? Are there ppl who do well on ALL other tests and terribly on Glycanage?