Hydroxyprolyl-glycine and prolyl-hydroxyproline from supplements clearly pass through digestion and circulate in the blood. In cell and tissue culture we observe that they seem to have a signaling function. I think we still lack the exact pathway through which this happens, but the story is quite strong that this is how collagen peptides achieve their result to increase collagen production.
I looked into the dipeptide signaling more carefully. Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine activate fibroblasts on collagen gel in vitro, but dietary collagen seems unlikely to be enough to matter systemically. Fibroblast activation in vitro was reported at about 200 nmol/mL for linear Pro-Hyp, and a more potent cyclic form at 7 nmol/mL. After taking collagen orally, human plasma reaches about 6-33 nmol/mL of hydroxyproline peptides, most of which is some form of Pro-Hyp, while cyclic Pro-Hyp alone reaches only about 0.2 nmol/mL.
Gut effects are more mechanistically plausible than systemic fibroblast signaling, since collagen peptides hit the gut first before being diluted into the full blood volume.
One human exercise-GI study was null on permeability and injury markers, though it reported a suggestive attenuation of post-exercise LPS for the collagen-treated group.
Acetic acid-induced colitis in rats: bovine collagen peptides reduced disease activity and histologic damage, restored ZO-1 expression, and improved colon mucosal architecture, consistent with improved barrier integrity
DSS-induced colitis in mice: walleye pollock collagen peptides worsened colitis, kept tight junction proteins low, increased pro-inflammatory M1 macrophage polarization, and shifted gut microbiota toward inflammation-promoting bacteria
The main good argument for collagen over pure glycine is a heuristic argument that favors whole foods over extracts since just because we don’t know about a cofactor doesn’t mean it isn’t helpful.
There seems to be a lot that’s confusing about collagen. I’m thinking about writing a post going deeper into it in the future.
There are five separate things you could eat: Full connective tissue (including collagen and hyaluronic acid) Full collagen as it appear in food, Gelatin (which is shorter collagen that you get by heating collagen), hydrolyzed collagen and straight glycine.
Even when it’s not clear to me how hyaluronic acid is bioavailable, as a supplement it seems to have benefits against wrinkles, so somehow it does something. After pure glycine hydrolyzed collagen seems to be the farthest away from whole foods. Given the report of glycine helping with blood glycose management by spiking insulin, you probably don’t want to ingest 3 gram of glycine before sleeping without anything else. Spiking your insulin levels while consuming no carbohydrates at the same time, seems to be unwise because you don’t want to develop diabetes. I would expect hydrolyzed collagen to have a similar insulin spike given that it also has a lot of free glycine.
Hydrolyzed collagen does contain more hydroxyprolyl-glycine and prolyl-hydroxyproline than you would get by normal digestion of gelatin or full collagen.
When it comes to collagen production it’s also worth thinking about what we actually want. A core problem of normal aging is that you get accumulation of advanced glycation end-products (AGEs) in collagen. This is crosslinks between collagen that make the collagen more brittle. Ideally, you have macrophages eat the collagen that’s contaminated with AGEs and then have the body produce new collagen to replace it. Under normal conditions you this process doesn’t work well and you have more and more AGE accumulation over time in most collective tissue in humans and this drives a lot of effects of skin aging.
The whole business of breaking down collagen and recreating it does look pretty inflammatory but inflammation is complex and has a lot of complex interacting elements.
When it comes to the numbers you cited the tissue study was within an order of magnitude of what’s available in blood. I would expect that in vivo, there are other regulatory factors that can move the point so, that’s enough to have some effect.
The in vitro activation thresholds range from 6-35x the plasma concentrations I cited; ‘within an order of magnitude’ is a stretch. The rest of this feels too handwavy to respond to, but I’ll look at your post going deeper if/when it’s available.
This is the read of the evidence that Gemini has.
Hydroxyprolyl-glycine and prolyl-hydroxyproline from supplements clearly pass through digestion and circulate in the blood. In cell and tissue culture we observe that they seem to have a signaling function. I think we still lack the exact pathway through which this happens, but the story is quite strong that this is how collagen peptides achieve their result to increase collagen production.
I looked into the dipeptide signaling more carefully. Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine activate fibroblasts on collagen gel in vitro, but dietary collagen seems unlikely to be enough to matter systemically. Fibroblast activation in vitro was reported at about 200 nmol/mL for linear Pro-Hyp, and a more potent cyclic form at 7 nmol/mL. After taking collagen orally, human plasma reaches about 6-33 nmol/mL of hydroxyproline peptides, most of which is some form of Pro-Hyp, while cyclic Pro-Hyp alone reaches only about 0.2 nmol/mL.
Gut effects are more mechanistically plausible than systemic fibroblast signaling, since collagen peptides hit the gut first before being diluted into the full blood volume.
One human exercise-GI study was null on permeability and injury markers, though it reported a suggestive attenuation of post-exercise LPS for the collagen-treated group.
Animal and cell studies are mixed:
Caco-2 cell monolayers: collagen peptides (especially low molecular weight fraction) attenuated TNF-alpha-induced barrier dysfunction by protecting tight junction proteins ZO-1 and occludin
Acetic acid-induced colitis in rats: bovine collagen peptides reduced disease activity and histologic damage, restored ZO-1 expression, and improved colon mucosal architecture, consistent with improved barrier integrity
DSS-induced colitis in mice: walleye pollock collagen peptides worsened colitis, kept tight junction proteins low, increased pro-inflammatory M1 macrophage polarization, and shifted gut microbiota toward inflammation-promoting bacteria
The main good argument for collagen over pure glycine is a heuristic argument that favors whole foods over extracts since just because we don’t know about a cofactor doesn’t mean it isn’t helpful.
There seems to be a lot that’s confusing about collagen. I’m thinking about writing a post going deeper into it in the future.
There are five separate things you could eat: Full connective tissue (including collagen and hyaluronic acid) Full collagen as it appear in food, Gelatin (which is shorter collagen that you get by heating collagen), hydrolyzed collagen and straight glycine.
Even when it’s not clear to me how hyaluronic acid is bioavailable, as a supplement it seems to have benefits against wrinkles, so somehow it does something.
After pure glycine hydrolyzed collagen seems to be the farthest away from whole foods. Given the report of glycine helping with blood glycose management by spiking insulin, you probably don’t want to ingest 3 gram of glycine before sleeping without anything else. Spiking your insulin levels while consuming no carbohydrates at the same time, seems to be unwise because you don’t want to develop diabetes. I would expect hydrolyzed collagen to have a similar insulin spike given that it also has a lot of free glycine.
Hydrolyzed collagen does contain more hydroxyprolyl-glycine and prolyl-hydroxyproline than you would get by normal digestion of gelatin or full collagen.
When it comes to collagen production it’s also worth thinking about what we actually want. A core problem of normal aging is that you get accumulation of advanced glycation end-products (AGEs) in collagen. This is crosslinks between collagen that make the collagen more brittle. Ideally, you have macrophages eat the collagen that’s contaminated with AGEs and then have the body produce new collagen to replace it. Under normal conditions you this process doesn’t work well and you have more and more AGE accumulation over time in most collective tissue in humans and this drives a lot of effects of skin aging.
The whole business of breaking down collagen and recreating it does look pretty inflammatory but inflammation is complex and has a lot of complex interacting elements.
When it comes to the numbers you cited the tissue study was within an order of magnitude of what’s available in blood. I would expect that in vivo, there are other regulatory factors that can move the point so, that’s enough to have some effect.
The in vitro activation thresholds range from 6-35x the plasma concentrations I cited; ‘within an order of magnitude’ is a stretch. The rest of this feels too handwavy to respond to, but I’ll look at your post going deeper if/when it’s available.
Yes, I think in addition to the post about hyaluronan I will write another 2-3 posts in the space of bone broth and it’s contents.
I’m not able to follow the citation hyperlinks in that summary, can you provide them?