RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman

Mauritio

This is my response to the following video:
Youtube Video

Introduction
Thanks for actually looking into the literature instead of just doing a 10-minute Google search. I appreciate that.

Here are some points I’d like to add, question, or contextualize:

Video:
30:00 – Low Protein Diet and Weight Gain
You make it sound like a low-protein diet only works for 8 weeks, after which weight gain is inevitable. That’s not the case.

In two human studies (lasting 8 and 12 weeks) (1), participants did not gain weight. In fact, in one of the studies, calorie intake had to be increased by 20% to maintain weight.

As you correctly note, the adaptive period might be longer in humans—likely 4–6 months. However, most people won’t follow such a diet without interruption for that long. Whatever consequences emerge afterward may not be relevant for most, and could likely be mitigated with intermittent "refeed" periods.

32:00 – Methionine Restriction and Long-Term Effectiveness
You suggest MR/FGF21 only works for a few months before causing metabolic downregulation and weight gain.
This is inaccurate. In one study, mice fed a lifelong MR diet remained resistant to weight gain:

“MR mice on HFD had lower body weight gain despite increased food intake and absorption efficiency compared to their CF counterparts.” (2)

34:00 – Symptoms of Hypocaloric Diet
The symptoms you mentioned are characteristic of a hypocaloric diet—not specifically of FGF21 elevation or protein restriction.

35:10 – No Human Evidence of Diet “Wearing Off”
As mentioned earlier, I haven’t seen any human studies showing that a low-protein diet eventually leads to weight gain due to "stress catching up." If such a study exists, I’d examine whether the time frame is realistic.

37:30 – FGF21 and Uncoupling
You claim FGF21 increases energy expenditure via uncoupling and browning of adipose tissue.
That’s the same mechanism used by T3 (thyroid hormone) (3), (4). I doubt you would criticize T3 for that.

42:00 – Uncoupling Mischaracterized
You speak of uncoupling as if it's harmful. But this is also a known effect of thyroid hormones.
Uncoupling can increase ATP production over time by stimulating mitochondria and mitophagy (5).

45:00 – Speed of FGF21 Response in Humans
You claim FGF21 takes 7 days to rise, but this is incorrect. In humans, FGF21 increases within 90 minutes post-meal:

“An increase in postprandial plasma FGF21 levels by 63% within 90 min was obtained after the LPHC meal.” (6)

46:00 – AMPK, PPAR-α, and PGC-1α Are Not Bad
Yes, these markers are upregulated by stressors—but they’re also increased by pro-metabolic substances.

AMPK is activated by:
Biotin (7),Aspirin (8) and Methylene Blue (9).

PPAR-α is activated by aspirin (10). Activating PPAR-α increases allopregnanolone (11).

PGC-1α increases mitochondrial biogenesis and is stimulated by T4 (12). Overexpressing PGC-1α in old mice rejuvenates muscle (13).

47:25 – Long-Term FGF21 and Metabolism
You claim FGF21 causes downregulation over time. However, lifelong protein-restricted mice maintain elevated metabolism and FGF21 levels (2).

48:00 – Lipolysis and T3 Comparison
You criticize FGF21 for increasing lipolysis. But T3 does the same (14), (15).

FGF21 also increases carbohydrate oxidation, like thyroid hormones (16), (17).

48:50 – Clarification on FGF21 Timing
Again, FGF21 does not take 7 days to increase. See the 45:00 timestamp.

Also, FGF21 is induced by low protein, not starvation. Starvation may include low protein, but not vice versa.

50:55 – FGF21 and Cortisol
You reference a study on transgenic mice and cortisol. However, in humans with Cushing's syndrome, no correlation was found:

“Neither FGF21 nor FGF19 were significantly related to cortisol concentrations.” (18)

If FGF21 increased cortisol long-term, those mice wouldn’t live 40% longer or age more healthfully (34).

1:00:25 – Reductive Stress Mischaracterization
You claim FGF21 requires reductive stress. But FGF21 is a response to it—it alleviates it:

“FGF21 reduces circulating triglycerides.” (20)

Saying it’s bad because it's triggered by stress is like saying DHEA is bad for the same reason.

1:03:00 – NAD+ and TCA Cycle
You suggest FGF21 reduces NAD+ and TCA activity, but the opposite is true:

“FGF21 treatment increased cellular NAD+ levels…”
“…significantly increased citrate synthase activity, suggesting enhanced TCA cycle activity.” (16), (17)

1:05:00 – Fructose and FGF21
It's interesting that you're pro-fructose, which I agree with. But fructose acutally increases FGF21 the most in humans out of all the common sugars.

“FGF21 levels rose 3.4-fold two hours after fructose ingestion.” (21), (22)

1:07:00 – Lipogenesis Misconceptions
You insinuate that FGF21 increases de novo lipogenesis.

The quotes you cite merely show a correlation. In many diseases FGF21 is high, but similarly to diabetes and insulin,they are resistant to it. So there is such a thing as FGF21 resistance. That does not mean FGF21 is the bad guy here. Thats like saying insulin causes diabetes because it is high in Type 2.

On lipogenesis. FGF21 actually decreases it.
"Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver, which suppresses hepatic de novo lipogenesis." (23)

On top of that, FGF21 activation has been shown to be very pro-liver in various models of liver disease.
Here’s just one example: mice on MR were resistant to weight gain, hepatic steatosis, and insulin resistance on a high-fat diet, despite the mouse strain being especially susceptible to obesity—and despite the fact that the mice were eating more and had better absorption of food.
It also drastically decreased SCD1, which converts saturated into unsaturated fats and is implicated in all types of diseases. So lowering it should very much benefit the liver (24).

1:18:20 – Sugar Diet Not a Panacea
Agreed—the sugar diet is just a tool, not a cure-all. Most advocates acknowledge that context and environment matter.

1:22:30 – Growth, Fertility, and Muscle Loss
Growth stunting only occurs with early-life protein restriction. When started in adulthood, growth and bone loss are minimal (25), (26).

When it comes to bone loss, it is also less pronounced when starting after the major growth phases and could be partly accounted for by a decrease in overall body mass—the bone/body mass ratio is similar to controls.
It seems to me that what is going on is that the mice are in need of collagen and are trying to get it from their bones. So supplementing collagen (which won’t increase FGF21 significantly) might alleviate that.
"...levels of the collagen degradation marker, CTX-1, were significantly higher in the MR animals on HFD by 83%..." (27)
"Plasma biomarkers suggested that the low bone mass in MR mice could be due to increased collagen degradation..." (28)

Infertility: Moderate MR does not affect pregnancy in mice (29). In fact, MR may increase sperm quality in aging males
"Our study suggests that methionine restriction alleviates the decline in sperm quality in aging mice..." (30)

Muscle loss is sex-specific in mice (31). In humans on a 5% protein diet, muscle was largely preserved over 12 weeks (1).

1:28:00 – Glycine ≠ Methionine Restriction
You propose that simply supplementing glycine would give one the same life extension effects as methionine restriction.
That’s not accurate. There is one study showing a small 5% increase in lifespan when 8% of the diet consisted of glycine (32).

There is another study using different amounts of glycine, where 8% glycine led to a 29% increase in lifespan. The problem is that only the 8% group showed that effect—lower amounts weren’t as effective. And 8% translates to about 50g of glycine or 150g of collagen per day. I don’t think anyone can or wants to consume that much for the rest of their life.

Therefore, glycine supplementation is not an adequate replacement for methionine restriction when it comes to longevity—although I do think it can enhance its effectiveness (33).

Conclusion:
The basic argument of this video is that FGF21 works through a stress mechanism, such as an increase in cortisol and adrenaline.
Cortisol has been shown to cause every sign of aging you can think of (19).
So if FGF21 works by increasing cortisol, we should see drastic signs of aging in the long-term studies.

Yet, we see the opposite. In protein restriction studies, we see life extension of up to 44% and an increase in healthspan (34).

So that means either cortisol is somehow healthy—which I don’t believe—or FGF21 simply works through a different mechanism than stress and starvation.
And I think you can make a good case for that. Some of the proposed mechanisms would be: increase in thyroid hormone (35), UCPs (35), klotho (36), and mitochondria (37); a decrease in SCD1 (24), HGH (38), and insulin resistance (2).

Sources:

Mulloch94

Nice, yeah the FGF21 thing has been pretty confusing. I like the cautionary inputs by some of these people like Jay and Mike. But I also can't deny I feel really good eating a pretty damn low amount of protein. Especially for me. Like I'm 6'3-6'4ish, and consuming only 60-70 grams a day is insane for someone of my stature, but I still feel pretty damn good. Way better than doing the low-fat, moderate protein, high carb thing I was doing beforehand.

I think the one trap people may get themselves caught up in is assuming their benefits are from FGF21 when they could be from various different things associated with lower protein diets. Lower protein diets also reduce mTOR, ACTH, cortisol, gluconeogenesis, prolactin, serotonin, etc. So I think if the pro-FGF21 side should caution themselves on anything it's assuming they know what mechanism from a low-protein diet is actually making them feel better.

Mauritio

@Mulloch94 said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

I think the one trap people may get themselves caught up in is assuming their benefits are from FGF21 when they could be from various different things associated with lower protein diets. Lower protein diets also reduce mTOR, ACTH, cortisol, gluconeogenesis, prolactin, serotonin, etc. So I think if the pro-FGF21 side should caution themselves on anything it's assuming they know what mechanism from a low-protein diet is actually making them feel better.

True, but I'd argue the reduction in those things is downstream from FGF21 as well.

The benefits of MR are almost exclusviely downstream from FGF21. ("...mice lacking FGF21 fail to exhibit metabolic responses to protein restriction...")
https://pubmed.ncbi.nlm.nih.gov/35393401/

Mulloch94

@Mauritio said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

@Mulloch94 said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

I think the one trap people may get themselves caught up in is assuming their benefits are from FGF21 when they could be from various different things associated with lower protein diets. Lower protein diets also reduce mTOR, ACTH, cortisol, gluconeogenesis, prolactin, serotonin, etc. So I think if the pro-FGF21 side should caution themselves on anything it's assuming they know what mechanism from a low-protein diet is actually making them feel better.

True, but I'd argue the reduction in those things is downstream from FGF21 as well.

The benefits of MR are almost exclusviely downstream from FGF21. ("...mice lacking FGF21 fail to exhibit metabolic responses to protein restriction...")
https://pubmed.ncbi.nlm.nih.gov/35393401/

I think it's possible some of the benefits are due to maximizing muscle-protein synthesis. This pathway typically gets overloaded on normal protein diets. It's never really a good idea of have more than 20-30 grams in one sitting, because the rest of it is just going to get converted to glucose via gluconeogenesis and this will raise cortisol.

Naturally a restricted protein intake will maximize this pathway because you're really never taking in more protein than you can send down this pathway. And the only thing that can really raise this threshold is to get bigger (more muscle) and/or do steroids. So for most average sized people that aren't juicing, this would be perfect.

I do think some of that stuff about "FGF21 resistance" needs better research. People shouldn't just be passing this off as a thing when there's not a lot of evidence that supports it. Especially when you got guys like Durianrider who've been eating high-sugar for like 30+ fucking years without getting "resistant" to it. So I'm inclined to think that's bullshit.

Mauritio

@Mulloch94 said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

I do think some of that stuff about "FGF21 resistance" needs better research. People shouldn't just be passing this off as a thing when there's not a lot of evidence that supports it. Especially when you got guys like Durianrider who've been eating high-sugar for like 30+ fucking years without getting "resistant" to it. So I'm inclined to think that's bullshit.

You seem to think that FGF21 resistance is caused by staying on a low protein diet. Yet there's many people that are FGF21 resistant that haven't even tried it. It also has to do with your general health, especially liver health. So if you're unhealthy to begin with you might be FGF21 resistant that probably goes hand in hand with leptin and insulin resistance.

ThinPicking

https://pubmed.ncbi.nlm.nih.gov/30106981/

https://pmc.ncbi.nlm.nih.gov/articles/PMC6311457/

https://pmc.ncbi.nlm.nih.gov/articles/PMC7406048/

https://pmc.ncbi.nlm.nih.gov/articles/PMC10058321/

Mulloch94

@ThinPicking Thanks for more papers. I take it you're a FGF21 skeptic?

ThinPicking

It's just another abstraction to me. Why someone like Anabology would take an interest in it and seem to do well with protein restriction is going to have something to do with his recent behaviour and long standing context. Mauritio's right, it's another tool.

Likewise for someone like me who prefers a lot of everything (spiritually fat or something). I only found protein restriction helpful when I was more in to taking isolated amino's and trying to understand what they were doing to me.

Mulloch94

@ThinPicking said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

Likewise for someone like me who prefers a lot of everything (spiritually fat or something). I only found protein restriction helpful when I was more in to taking isolated amino's and trying to understand what they were doing to me.

Reply

I found protein restriction to be helpful before I was taking thyroid. I think from just my anecdotal experience it has a glycogen sparing effect for me. Essentially filling in the role thyroid hormone should be doing. However I still notice benefits from even today. I stay satiated much longer....which may be a sign I haven't actually dialed in the perfect thyroid dose for me yet idk.

As a disclaimer I don't do the so called "honey diet." I think a lot of people can mess up by backloading there calories to their final meal of the day. Excellent way to overeat without thinking about it.

dapose

Great breakdown of the fgf21 literature. A nice contrast to Jays fear mongering “ahhh sugars gonna kill you ahhhh!” Ha! That’s a joke, and a Cole Robinson quote.
My question is, anabologies honey diet formulation was eating one pound of ground beef a night… every night. Are you guys @ThinPicking @Mauritio calling this MR or protein restriction? That seems wrong if you are. Or am I wrong? I know Jay is saying this throughout his worst YouTube video but I think he was just ripping on guys like Cole Durianrider etc that tell people to just eat sugar for days on end. In my estimation the Honey Diet is the only “sugar diet” I’ve heard of that is based in pro metabolic ideas and should be the one scrutinized. And if that’s the case I like to add to Maurito’s thinking, on fructose… I heard Ray in an old generative energy ep talk about fructose specifically lowers reductive stress.
Jay was slamming on fgf21 increasing reductive stress.
Well maybe it balances out?
Then Georgi chimes in later on fructose lowers phosphorus to calcium ratio, by conversion of fructose into glucose consumes phosphorus Georgi adds.
GE#36 @52:30.
I am grateful to anabolgy for the honey diet even though I very loosely fallow it. It has inspired my eating way, and I’ve gained energy, brain function and lost some fat. And I think it was unproductive of Jay to engage in the debate on too broad of a generalization whilst just picking about the fgf21 component.
Protein restriction for most of the day is not the same as living a protein restricted life.
Id be interested in hearing actual criticism of the honey diet rather than Jays knee jerk reaction.

Mauritio

@dapose said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

My question is, anabologies honey diet formulation was eating one pound of ground beef a night… every night. Are you guys @ThinPicking @Mauritio calling this MR or protein restriction? That seems wrong if you are

No you're right that's not protein restriction. The honey diet would fall under the category of "intermittent protein restriction".
The sugar diet/ sugar fast would be real protein restriction.
They're all grouped together in this video and in my response as well, because they all increase FGF21. And contrary to Jay's statement it does not take 7 days to increase FGF21 significantly, but less than 2 h. See the OP.
So, the honey diet qualifies for " things that increase FGF21" since for a significant part of the day you do get the FGF21 increase.

@dapose said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

Jay was slamming on fgf21 increasing reductive stress.
Well maybe it balances out?

I have a part on that in the OP. Look for "Reductive stress" and the following part on the ETC. If you read those quotes and studies it seems clear to me that FGF21 isn't a cause of reductive stress but a reaction to it.

@dapose said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

Then Georgi chimes in later on fructose lowers phosphorus to calcium ratio, by conversion of fructose into glucose consumes phosphorus

Klotho lowers phosphate. And FGF21 increases Klotho. So FGF21 lowers phosphate, thereby increasing the calcium/phosphorus ratio. Making it possible to have a decent ratio while mostly consuming fruit and sugar and little dairy.
I have a post about Klotho and FGF21 on X.

@dapose said in RE: The Sugar Diet/Honey Diet and FGF21: The Research (EB #133) My Response to Jay Feldman:

Id be interested in hearing actual criticism of the honey diet rather than Jays knee jerk reaction.

Same! I'm not saying the honey diet is the end all be all. Or that it is the perfect diet.

I think it's a good diet, for some people, for a limited amount of time.
It's a good tool.

I'd love to hear a more nuanced criticism, because what Jay put out was quite twisted and one sided. It's like he had his conclusion first and then looked at the studies.