#61

Maybe I can summarize the amino acid interactions — please correct and edit this so we have the right interactions. From first glance, it would seem that we’d need to “dose” ourselves (with powder mixtures) at least three different points during the day to get glycine, taurine, and carnosine (and/or beta-alanine) to not compete. Plus creatine could be fit in anywhere.

Glycine competes with beta-alanine, and competes with taurine. It does not compete with creatine. I’ve heard glycine helps with sleep but for me it is too much at night so I take it in the morning.

Taurine competes with glycine and beta-alanine (above) and not with creatine. Taurine helps with sleep so better at night?

Beta-alanine doesn’t compete with creatine, but does compete with glycine and taurine.

Carnosine doesn’t appear to compete with anything.

I’m not sure how collagen fits in because (if I understand correctly) it consists of glycine as the largest component.

So, if you are taking glycine and/or collagen, and taurine, glycine and/or collagen should be taken at one end of the day, and taurine at the other. Or perhaps taurine at night and glycine at midday? (Many of us take glycine as a sweetener in coffee so this implies morning)

Creatine can be taken at any time. But if you are looking for exercise performance enhancement, it is best just before or just after exercise.

Beta-alanine can’t be taken with either glycine or taurine. Also if you are looking for exercise performance enhancement, it is best just before or just after exercise. so perhaps taking it in the middle of the day before exercise (with creatine) is best. Or take it first thing in the morning if you exercise then, and then glycine at midday. One caveat: athletic performance enhancement was seen in 3-6g per day of college athletes, but the itching occurs when more than 1.6g were administered at one time, so they appear to be dosing them every few hours of roughly 1g, so this suggests it will be a pain to take this multiple times per day. Or maybe you develop a resistance?

Carnosine can be taken with any of these. But if you are looking for exercise performance enhancement, it is best just before or just after exercise. So taking it with the beta-alanine and creatine just before/after exercise is best.

So if I were “dedicated”, I’d have daily:
o. 6g glycine, 15g collagen and 100mg NACET with my morning coffee (which I’ve done for 8.5 months) — I’m likely to stop the cocoa in the coffee because it seems the polyphenol concentration is too low to bother.
o. 3-5g Creatine (which I have for two weeks), carnosine, and/or 1-3g beta-alanine (not taking yet) just before/after exercise (for me this is midday/afternoon so timing works). I’m unlikely to bother with subsequent daily doses of beta-alanine because at some point this is getting ridiculous.
o. Taurine before bed. (Not taking yet)

Does this sound right? Does this sound overkill?

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#62

AIUI Carsoninase which splits Carnosine into Beta Alanine and Histidine is in serum and cells. Hence if you take Carnosine it will to some extent be the same as taking Beta Alanine (and histidine)

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#63

True (I believe). Which is why I suggested taking it on the same schedule as beta-alanine. Although I didn’t see any literature which specifically suggested an interaction in vivo of carnosine and the others, even with the expectation that it is transformed into beta-alanine/etc.

#64

Thanks. The paper says:

“Carnosine supplementation results in a decrease in HbA1C, but elicits no effect on HOMA-IR, Cholesterol, fasting blood sugar, TG and HDL-C. “

I’m guessing this means Carnosine speeds up postprandial insulin release to lower A1C (estimate of AUC) but it does not improve insulin sensitivity (Homa-ir not changed). So it’s an insulin stage 1 help without helping stage 2 (steady state). Protein in general is reportedly a help in this same way for insulin resistant people.

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#65

The point of contact for the paper;

Author

Peixiang He

View in Scopus

Department of Endocrinology, Yiyang Central Hospital, Yiyang, Hunan, 413000, China

Corresponding author at: Department of Endocrinology, Yiyang central hospital, Yiyang, Hunan, 413000, China.

hpx13607372305@sina.com

#66

I’m very cautious with dosing and try not to overdo it. I also don’t take any supplement for a long time or consistently. Lately I’ve been on a break from almost everything.

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#67

Probably wise, am inching in this direction.

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#68

Anyone have access or the survival graph from https://www.liebertpub.com/doi/10.1089/rej.1.1999.2.337 ?

Abstract shows +20% longer p50 survival. This is the only lifespan data I found. I assume no p90 increase or it would have been reported.

As an amino acid in common diets safety should be good, if it demonstrates effect I wonder if it warrants placement among the other 4 known effective and safe treatments (rapa, Acarbose, glycine, taurine).

One would also assume the effect more pronounced for vegans who get about zero from diet.

2 Likes
#69

full article:

https://sci-hub.wf/10.1089/rej.1.1999.2.337

#70

Artigo completo: Sci-Hub | Effect of Carnosine on Age-Induced Changes in Senescence-Accelerated Mice. Journal of Anti-Aging Medicine, 2(4), 337–342 | 10.1089/rej.1.1999.2.337
BTW Science Hub: has free access to many pay-walled papers. sci-hub.se

2 Likes
#71

Does anyone know why I can access the Sci-hub links ?
I just get a message saying ‘Safari can’t open the page because it can’t establish a secure connection to the server’

It might have something to do with my country of origin (UK)

‘ In other countries, such as the United Kingdom and Germany, courts have issued injunctions against Sci-Hub and ordered Internet Service Providers (ISPs) to block access to the site.
2 Jun 2023

It’s getting late here, so I’ll have another look at it tomorrow

Also liked to thank @desertshores , @Bicep and @jjrap1 for their help

#72

I don’t really understand sci hub, just keep using it and it works. Maybe people couldn’t see the link I posted? Notice mine is sci hub wf, the other one is sci hub se. Here is a list of different suffix’s and some indication of how fast they are. Just pick one, they usually all work:

I know that occasionally she gets shut down and has to move to another suffix, but don’t think that explains this situation.

2 Likes
#73

Try another browser like Go Go Duck. Sci-hub seems to work fine on Google Chrome Browser.
You can also try the Microsoft Bing search engine.

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#74

@J0hn, make sure you are using https://sci-hub.se/
You can’t get there without https( ssl ).

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#75

This sounds like an internet provider issue blocking certain ip addresses.

2 Likes
#76

I think you might be right. I’m going to try and get the link via a VPN and see if that’s doable.

#77

I get the same response via some ISPs

#78

You shouldn’t probably link to sci-hub directly as you are using their bandwidth and people might be blocked.
Instead press the save button in the left.

image

And drag it to the reply window, so it’s uploaded to the site:

yuneva1999.pdf (6.0 MB)

You can also try anna’s archive:

2 Likes
#79

Yes, we can drag files up to 18 or 20mb in our messages here.

2 Likes
#80

Carnosinase in a nutshell
Humans possess two zinc‑/manganese‑dependent dipeptidases that hydrolyse carnosine (β‑alanyl‑L‑histidine):

Isoform Gene Where it sits Catalyst metal Why we care
CN1 (“serum carnosinase”, CNDP1) CNDP1 Circulates in plasma & CSF; made in liver/kidney Zn²⁺ Dictates the very short plasma half‑life of supplemental carnosine
CN2 (“tissue carnosinase”, CNDP2) CNDP2 Cytosol of many tissues Mn²⁺ (prefers) or Zn²⁺ Intracellular histidine‑dipeptide turnover

Because CN1 clips carnosine almost as soon as it appears in the bloodstream, an inhibitor that slows CN1 (or makes carnosine CN1‑resistant) could prolong carnosine’s antiglycation, anti‑carbonyl and anti‑AGE actions.

How carnosinase inhibitors work

1 Active‑site (competitive) inhibitors – “plug the zinc throat”

Prototype Ki / IC₅₀ vs CN1 Mode Key interaction
Carnostatine (SAN9812) – a boronic‑acid dipeptidomimetic low‑nM Binds in place of carnosine; boronate and carbonyl chelate Zn²⁺; imidazole side chain sits in S1’ pocket High selectivity for CN1 (PMC)
Bestatin (anticancer immunomodulator) 0.5 nM vs CN2; µM–nM vs CN1 (metal‑dependent) Competitive; hydroxyl & α‑amino acid mimic coordinate metal ion Not selective – also blocks aminopeptidases (PubMed )

Mechanistic theme: CN1 is a metalloprotease belonging to the M20 family; the catalytic Zn²⁺ activates a bridging water that attacks the carnosine peptide bond. Molecules that (i) occupy the dipeptide pocket and (ii) tie up the Zn²⁺ deny the water access and halt hydrolysis.

Design rules: keep the β‑alanine–histidine “skeleton” to fit the pocket, but replace the scissile amide or add a boronate/hydroxamate to grab the metal more tightly than water.

2 Allosteric thiol inhibitors – “cysteinylate the on/off switch”

Human CN1 contains a surface‑exposed Cys‑102. Reduced thiols such as N‑acetyl‑cysteine (NAC), cysteine, or glutathione form a mixed disulfide (or otherwise adduct) at this residue:

  • Cysteinylation triggers a conformational shift near the Zn²⁺ centre, mis‑positioning carnosine and lowering Vmax with little change in Km.
  • 0.2–1 mM NAC or cysteine cut recombinant CN1 activity by 50‑70 % in vitro and normalised the elevated CN1 activity seen in diabetic‑mouse kidneys. (PMC)

Because the modification is redox‑reversible, CN1 activity tracks the plasma redox state; high GSH/thio levels act as natural “brakes”.

3 Brute‑force metal chelators

Broad chelators (e.g., 1,10‑phenanthroline, EDTA) strip the catalytic Zn²⁺ outright, but they are non‑selective and toxic at systemic levels – useful only as mechanistic probes (ScienceDirect).

4 Genetic or biological “inhibitors”

  • (CTG)₅/(CTG)₅ CNDP1 genotype: naturally produces low CN1; carriers show higher carnosine and less diabetic nephropathy .
  • siRNA / CRISPR or monoclonal antibodies against CNDP1 are being explored pre‑clinically (e.g., melanoma brain‑metastasis model) (bioRxiv).

What an inhibitor actually achieves

Endpoint Effect when CN1 is blocked
Plasma half‑life of carnosine ↑ from minutes → hours, allowing μM tissue concentrations
Antiglycation / fructosamine Rodent studies: 30–50 % less fructosamine and AGE adducts when carnosine + inhibitor are co‑given
Renal protection Low CN1 activity (genetic or NAC‑mediated) correlates with slower diabetic‑nephropathy progression
Emerging oncology signal CNDP1 knock‑down reduces melanoma brain colonisation in mice (bioRxiv)

Practical points & current limitations

  • Only two small‑molecule CN1‑specific inhibitors are known – carnostatine (potent, but still pre‑clinical) and bestatin (potent yet off‑target) (ResearchGate, MDPI).
  • Thiol‑based allosteric inhibition (NAC, cysteine): needs mid‑millimolar plasma levels; feasible in pharmacological NAC dosing (e.g., 600 mg TID), but the inhibition is partial and redox‑sensitive.
  • Carnosinase‑resistant analogues (anserine, carcinine, “carnosinol”) can bypass CN1 instead of inhibiting it, offering an alternative development path.
  • Selectivity challenge: CN1 shares the fold with peptide‑processing enzymes; future inhibitors must avoid hitting digestive and renal metallopeptidases.

Take‑home

A “carnosinase inhibitor” works by preventing the Zn‑metallo‑protease CN1 from cleaving carnosine, either competitively (dipeptidomimetic molecules such as carnostatine/bestatin that sit in the catalytic pocket and lock onto the Zn²⁺) or allosterically (thiol compounds like NAC that modify Cys‑102 and distort the active site). The end‑goal is to keep carnosine intact long enough to exert its antiglycation, antioxidant and renoprotective roles—a pharmacokinetic rather than pharmacodynamic trick. Despite promising chemistry, only early‑stage molecules exist today, so extending carnosine’s lifetime currently relies on high‑dose supplementation, thiol boosters, or engineered analogues until a true CN1‑selective drug reaches the clinic.

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