#1

High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants (NCT03946774 and NCT03994367) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.

Paywalled Paper:

Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk

https://www.nature.com/articles/s42255-024-00984-2

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Those who limited their eating to eight hours a day were 91 per cent more likely to die from cardiovascular disease
#2

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The study, which combined small human trials with experiments in mice and cells in a Petri dish, showed that consuming over 22% of dietary calories from protein can lead to increased activation of immune cells that play a role in atherosclerotic plaque formation, driving the disease risk. Furthermore, the scientists showed that one amino acid – leucine – seems to have a disproportionate role in driving the pathological pathways linked to atherosclerosis, or stiff, hardened arteries.

“Our study shows that dialing up your protein intake in pursuit of better metabolic health is not a panacea. You could be doing real damage to your arteries,” said senior and co-corresponding author Babak Razani, M.D., Ph.D., professor of cardiology at Pitt. “Our hope is that this research starts a conversation about ways of modifying diets in a precise manner that can influence body function at a molecular level and dampen disease risks.”

Full writeup:

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#3

From Dudley Lamming:

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#4

I’ve been waiting for this shoe to drop. I’d like to see how Peter Attia and friends handle it. Probably will just dismiss as “a mouse study” unless/until the evidence continues to pile up, followed eventually by lots of somber backpedaling and self-congratulating on doing “what a good scientist does”. :grimacing:. I really admire Attia and listen to all his podcasts, but I’ve always thought he’s gone overboard on the Protein Train.

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#5

Attia probably doesn’t care because his apoB is ultra low and he’s already using rapamycin to inhibit mTOR.

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#6

I’d like to think he cares because he wants to provide accurate health advice to those who aren’t on rapamycin. Also, we don’t know if taking rapamycin once weekly or every other week would be enough to counter the potentially pro-atherogenic mTOR spikes of a high-leucine diet, which are happening 7 days per week.

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#7

Presumably one could eat lower-leucine plant-based sources of protein (except for pea and soy) and get away with more than 25g per serving and 22% of kcals. Still looking for the “sweet spot” of high enough protein to allow lean mass gains from resistance exercise while avoiding pro-aging/pro-atherogenic effects.

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#8

I feel like there’s a lot of things you have to know to determine an answer to this question. I am agnostic about protein, remember, most things said here are wrong. I think about 95% of the scientific content on this site is wrong.

#9

Since what we post here is mostly founded upon scientific papers, claiming that 95% of what is posted here is wrong sounds like a denial of science.

Most of my opinions are based on research. I acknowledge that some of those may be unintentionally false (15%?). But we are all here to help each other interpret the science and make the best decisions.

As @RapAdmin states… Go hard on the science.

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#10

Im going with the idea that we need to have high protein days and low protein days. After I lift / induce autophagy, I want to repair / adapt / build, and after I do cardio / fast / take Rapa, I want to encourage my body to break down proteins that are old. And then repeat.

If successful, I should have and maintain:

  • low body inflammation (CRP) / low body pain
  • high strength and good balance (full body)
  • lowish body fatness
  • have an alertness / tiredness cycle that matches my wake / sleep cycle
  • have good blood markers in general, relative to ACM for my age (or any age if I’m doing very well).
  • a positive mental attitude and a general sense of satisfaction and happiness in life

Is that too much to ask

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#11

Well I also mean my own scientific content but I do think I have a lower percentage but way too high still.

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#12

I admire your “chutzpah” if nothing else. As Woody Allen said “I would never join a club that would accept me as a member”. So I think you’re in the right place.

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#13

That was Groucho Marx but still a good point!

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#14

Correct!
“In Annie Hall, Woody Allen makes reference to the Groucho quote. If I
remember the dialogue correctly, he indicates that his version, “I
wouldn’t want to belong to any club that would have me as member,” is a
paraphrase of the Groucho line.” -from Reddit-

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#15

I think the induce autophagy should be in the fast / take rapa bucket and not in the the lift/build bucket

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#16

My estimate would be that a perfect synthesis/integration of the world’s scientific and medical understanding in itself would have more than 15% things incorrect

And then add that while people are smart here, most are not trained as scientists (in relevant fields) so the understanding we have here often has big gaps to the worlds theoretically obtainable understanding

I personally think there is room within this limited and often gappy/partially incorrect understanding to make expected positive value bets (aggressively go after cardio vascular and metabolic risks and optimization with reasonable doses of reasonable medicines, use rapa - at reasonable doses, (optimize sleep, diet, fast, exercise)

But I also think we have to be incredible humble is how much of our current understanding is limited and often incorrect when it comes to medicine and aging - as a whole species, on the forum collectively and individually in our decision making

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#17

Anyone do any bloodwork testing of this? @AlexKChen ?

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#18

Oh, I agree that there are probably more than 15% of papers that have portions which are wrong. However, I’d say the percentage of blatantly false and untrue studies would be around 15%. This includes cherry picking and making up numbers. However that’s my WAG.

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#19

I can’t eat exclusively protein anyway. Love all my food. :joy:

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#20

Agreed. I was saying AFTER I induce autophagy.

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