High vs Low Protein

P. D. Mangan Tweeted a quote from a research paper, Reversal of epigenetic aging and immunosenescent trends in humans by Gregory M. Fahy et al. He stated that  the “Most important sentence in aging reversal study” is the following: “Human longevity seems more consistently linked to insulin sensitivity than to IGF‐1 levels, and the effects of IGF‐1 on human longevity are confounded by its inverse proportionality to insulin sensitivity.” Mangan added that “This line agrees with what I wrote a while back” (How Carbohydrates and Not Protein Promote Aging); and in the comments section of that article, someone pointed to a supporting video by Dr. Benjamin Bikman (‘Insulin vs. Glucagon: The relevance of dietary protein’). Here is the context of the entire paragraph from the discussion section of the research paper:

“In this regard, it must be pointed out that GH and IGF‐1 can also have pro‐aging effects and that most gerontologists therefore favor reducing rather than increasing the levels of these factors (Longo et al., 2015). However, most past studies of aging and GH/IGF‐1 are confounded by the use of mutations that affect the developmental programming of aging, which is not necessarily relevant to nonmutant adults. For example, such mutations in mice alter the normal innervation of the hypothalamus during brain development and prevent the hypothalamic inflammation in the adult (Sadagurski et al., 2015). Hypothalamic inflammation may program adult body‐wide aging in nonmutants (Zhang et al., 2017), but it seems unlikely that lowering IGF‐1 in normal non‐mutant adults can provide the same protection. A second problem with past studies is a general failure to uncouple GH/IGF‐1 signaling from lifelong changes in insulin signaling. Human longevity seems more consistently linked to insulin sensitivity than to IGF‐1 levels, and the effects of IGF‐1 on human longevity are confounded by its inverse proportionality to insulin sensitivity (Vitale, Pellegrino, Vollery, & Hofland, 2019). We therefore believe our approach of increasing GH/IGF‐1 for a limited time in the more natural context of elevated DHEA while maximizing insulin sensitivity is justified, particularly in view of the positive role of GH and IGF‐1 in immune maintenance, the role of immune maintenance in the retardation of aging (Fabris et al., 1988), and our present results.”

In the Twitter thread, Командир Гиперкуба said, “So it is insulin [in]sensitivity than drives ageing rather than IGF‐1/GH. Huge if true.” And GuruAnaerobic added that, “I assume this isn’t IR per se, but IR in the presence of carbohydrate/excess food. IOW, the driver is environment.” Mangan then went onto point out that, “It explains the dichotomy of growth vs longevity, and why calorie restriction increases lifespan.” Mick Keith asked, “So drop carbs and sugar?go paleo style?” And Mangan answered, “There are other aspects to insulin sensitivity, but yes.” All of this cuts to the heart of a major issue in the low-carb community, an issue that I only partly and imperfectly understand. What I do get is this has to do with the conclusions various experts come to about protein, whether higher amounts are fine or intake should be very limited. Some see insulin sensitivity as key while others prioritize IGF-1. The confounding requires careful understanding. In the comments section of Mangan’s above linked article, Rob H. summed it up well:

“Great post, very timely too as I believe this is an issue that seems to be polarising the science-based nutrition space at the moment. Personally I fall down on the same side as you Dennis – as per Ben Bikman’s video which has also been posted here, as well as the views of all the main protein researchers including Stuart Philips, Jose Antonio, Donald Layman, Gabrielle Lyon, Ted Naiman, Chris Masterjohn etc who all believe the science clearly supports a high protein intake eg 1.6 -2.2g/kilo of bodyweight – with no upper limit which has yet been observed. At the same time, I have just been reading the new book by Dr Steven Gundry ‘The Longevity Paradox’. Has anyone read this one yet? Whilst about 90% of the content is fairly solid stuff (although nothing that hasn’t already been written about here) he aggressively supports Longo’s view that we should only consume 0.37g protein/ kilo of bodyweight, eg around 25g of protein/ day for most males. Also that animal protein should be avoided wherever possible. Personally I consume double that amount of protein at each meal! It appears that Longo, Gundry, Dr Ron Rosedale and Dr Mercola are all aligned in a very anti-animal protein stance, but also believe their view is backed by science – although the science quoted in Gundry’s book seems to be largely based on epidemiology. Both sides can’t be right here, so I hope more research is done in this field to shut this debate down – personally I feel that advising ageing males to consume only 25g of protein a day is extremely irresponsible.”

In response, Mangan wrote, “I agree that is irresponsible. Recently Jason Fung and James DiNicolantonio jumped on the anti animal protein bandwagon. My article above is my attempt (successful, I hope) to show why that’s wrong.” Following that, Rob added, “Humans have been consuming animal proteins for most or all of our evolutionary history. And certainly, large quantities of animal protein were consumed at times (as when a kill of a large animal was made). So, I cannot imagine that the “evidence” supporting an anti-animal protein stance can be solid or even science-based. This sounds like a case of certain researchers trying their best to find support for their pre-determined dietary beliefs (vegan proponents do this all the time). I’m not buying it.” It’s very much an ongoing debate.

I have suspicions about the point of confusion that originated this disagreement. Fear of promoting too much growth through protein is basically the old Galenic argument based on humoral physiology. The belief is that too much meat as a stimulating/nurturing substance built up the ‘blood’ with too much heat and dryness which would burn up the body and cause a shortened lifespan. This culturally inherited bias about meat has since been fancied up with scientific language. But ancient philosophy is not the best source for formulating modern scientific theory. Let me bring this back to insulin sensitivity and insulin resistance that appears to play the determining role. Insulin is a hormone and so we must understand this from an endicrinological approach, quite different than Galenic-style fears about meat that was filtered through the Christian theology of the Middle Ages.

Hormones are part of a complex hormonal system going far beyond macronutrients in the diet, although it does appear that the macronutrient profile is a major factor. Harry Serpano, in a discussion with Bart Kay, said that: “In a low insulin state, when you’re heavy meat and fat and your insulin is at 1.3, as Dr. Paul Mangan has actually shown in one of his videos, it’s quite clear; and in what I’m showing in one of the studies, it’s quite clear. It’s so close to basically fasting which is 0.8 — it’s very low. You’re not going to be pushing up these growth pathways like mTOR or IGF-1 in any significant way.” Like with so much else, there is strong evidence that what we need to be worrying about is insulin, specifically on a high-carb diet that causes insulin resistance and metabolic syndrome. That is what is guaranteed to severely decrease longevity.

This question about too much protein recently came up in my own thoughts while reading Dr. Stephen Gundry’s new book, The Longevity Paradox. As mentioned above, he makes a case against too much animal protein. But it sounds like there is more information to be considered in the affect on health, growth, and longevity. In a dialogue with Gundry, Dr. Paul Saladino defended meat consumption (Gundry’s Plant Paradox and Saladino’s Carnivory). What Mangan has added to this debate strengthens this position.

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In one of the above quoted comments, Robert H. mentions that Dr. Joseph Mercola is one of those “aligned in a very anti-animal protein stance, but also believe their view is backed by science.” It’s interesting that I’m just now listening to a discussion between Mercola and Siim Land. They met at a conference and got to talking. Mercola then read Land’s book, Metabolic Autophagy. Land is more in the camp supporting the value of protein. His view is nuanced and the debate isn’t entirely polarized. The role protein plays in health depends on the health outcomes being sought and the health conditions under which protein is being eaten: amounts, regularity of meals, assimilation, etc. It’s about how one’s body is able to use protein and to what end.

Right at the beginning of their talk, Mercola states that he is impressed by Land’s knowledge and persuaded by his view on protein. Land makes the simple point that one doesn’t want to be in autophagy all the time but to cycle between periods of growth and not. Too much protein restriction, especially all the time, is not a good thing. Mercola seems to have come around to this view. So, it’s a shifting debate. There is a lot of research and new studies are coming out all the time. But obviously, context is important in making any statement about protein in the diet. Maybe Saladino will similarly bring Gundry on board with greater protein being a good thing for certain purposes or maybe come to a middle ground. These dialogues are helpful, in particular for an outsider like me who is listening in.

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On a personal note, I’m not sure I take a strong position either way. But I’ve long been persuaded by Siim Land’s view. It feels more moderate and balanced. The opposite side can sound too fear-mongering about protein, not seeming to allow as much differences in contexts and conditions. From a low-carb perspective, one has to replace carbs with something and that means either protein or fat, and one can only consume so much fat. Besides, proteins really are important for anabolism and activating mTOR, for building of the body. Maybe if you’re trying to lose weight or simply maintaining where you’re at with no concern for healing or developing muscle then protein would play less of a role. I don’t know.

Traditional societies don’t seem to worry about protein amounts. When they have access to it, they eat it, at times even to the point of their bellies distending. And when not, they don’t. Those populations with greater access don’t appear to suffer any harm from greater protein intake. Then again, these traditional societies tend to do a lot of strenuous physical activity. They also usually mix it up with regular fasting, intermittent and extended. I’m not sure how optimal protein levels may differ depending on lifestyle. Still, I’d think that the same basic biological truths would apply to all populations. For most people in most situations, increased protein will be helpful at least some of the time and maybe most of the time. Other than fasting, I’m not sure why one needs to worry about it. And with fasting, protein restriction happens naturally.

So, maybe eat protein to satiation. Then throw in some fasting. You’ll probably be fine. There doesn’t seem to be anything to be overly concerned about, based on what evidence I’ve seen so far.

Too Much Protein?

A ketogenic diet is any diet that puts you into ketosis. The issue isn’t only what raises your ketone levels but also what lowers them. It is glucose that keeps you out of ketosis and that generally means restricting carbohydrates. But glucose can come from other sources. This is where protein come in. It has been a common view that too much protein would keep you out of ketosis. The theory was that gluconeogenesis, the process that turns proteins into glucose, could interfere with ketosis. So, some have worried that too much protein was basically no different than too many starches and sugar.

That view has been challenged by more recent research. The newer understanding is that gluconeogenesis is mostly demand-driven, not supply driven. That said, it’s more complicated than that. There are conditions that can alter demand or else signaling. Benjamin Bikman, an insulin researcher, advocates a higher protein ketogenic diet. He says that initially it might matter when someone first goes onto a ketogenic diet, if they have hyperglycemia and hyperinsulinemia, a problem for far too many Americans. But as insulin levels are normalized, which can happen quickly, gluconeogenesis is not a problem.

So, it depends on how healthy you are. With insulin resistance, high protein intake might spike insulin and cause the insulin glucagon/ratio to become imbalanced. Yet for a person with a healthy metabolism, the glucose/insulin ratio might not change at all. As Ben Wagenmaker explains it, “Studies do show that GNG affects obese people and diabetics, in that excess protein produces measurable spikes in blood glucose levels, although this same effect has not been observed and quantified in non-diabetics that are not obese” (Gluconeogenesis, Chocolate Cake, and the Straw Man Fallacy).

Considering that most Americans are obese, diabetic, pre-diabetic or insulin resistant, it might be advisable to limit protein until one has become fat-adapted and metabolically flexible. It’s easy to figure out for yourself, though. You can simply measure such things and see how it is affecting you. Or you can go by an even simpler method. Once your body is regularly in ketosis, fasting should become easy. If you can skip meals or go a day without eating at all and not be particularly bothered by it, then you know you’re body has fully adjusted to ketosis. At that point, protein should no longer be a concern.

This is good to keep in mind, considering most people turn to specific diets later in life. Bikman points out that, as people age, the body requires more protein for health. That is because the body becomes less effective at using protein. And if you don’t get enough protein on a keto diet, the body will cannibalize muscle.  A lack of protein, in general, can be problematic — look at how lacking in musculature are many vegans with limited protein and lower quality protein. Muscle loss is a major health hazard for senior citizens, but muscle loss can begin much earlier in life.

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Dietary Proteins Contribute Little to Glucose Production, Even Under Optimal Gluconeogenic Conditions in Healthy Humans
by Claire Fromentin et al

Dietary Protein and the Blood Glucose Concentration
by Frank Q. Nuttall & Mary C. Gannon

The relationship between gluconeogenic substrate supply and glucose production in humans
by F. Jahoor, E. J. Peters & R. R. Wolfe

More Than You Ever Wanted to Know About Protein & Gluconeogenesis
by Amy Berger

If You Eat Excess Protein, Does It Turn Into Excess Glucose?
by L. Amber O’Hearn

Protein, Gluconeogenesis, and Blood Sugar
by L. Amber O’Hearn

Ketosis Without Starvation: the human advantage
by L. Amber and Zooko Wilcox-O’Hearn

The Ultimate Guide to the Carnivore Diet:
How can carnivore diets be ketogenic when they have so much protein?
by L. Amber O’Hearn and Raphael Sirtoli

What is gluconeogenesis? How does does it control blood sugars?
by Raphael Sirtoli

the blood glucose, glucagon and insulin response to protein
by Marty Kendall

why do my blood sugars rise after a high protein meal?
by Marty Kendall

Gluconeogenesis – The worst name for a rock band ever
by Tyler Cartwright

Protein Over-consumption in Ketogenic Diets Explained
by Ken Adkins

Will This Kick Me Out Of Ketosis?
by Dustin Sikstrom

Keto Problems: Too Much Protein?
by Keto Sister

Dietary protein does not negatively impact blood glucose control.
by Bill Lagakos