The life-shortening effect of high-protein

Diets come in many forms and some are keen on high protein amounts. While I agree that can be tasty, I’ve come across some material that may put a different light on what that intake means to longevity.

There are many aspects to protein and the different type of sources but I’m more interested in what protein does related to ageing and be conscious about it.

I’m not going to make recommendations on how much protein we should eat. It depends on what you want in life and I don’t know what is ideal for a specific person so this article will not tell you either. This is purely a focus on longevity.

Another aspect is health. Animal sources of protein are complete and are packed with other nutrients. This may be beneficial for health so I’m certainly not saying that protein intake in general is unhealthy. Again, the focus is on longevity.

DNA damage

A recently published article that triggered me to think about it is the following.

“Amino acids regulate energy utilization through mammalian target of rapamycin complex 1 and adenosine monophosphate activated protein kinase pathway in porcine enterocytes.” https://www.ncbi.nlm.nih.gov/pubmed/32211535

In it they checked for a lot of effects and one of the striking things is that the phosphorylated SIRT1 was reduced. What this means is that there was less active SIRT1. SIRT1 is a protein that does DNA repair. If you are not familiar with SIRT1 then I would recommend reading the book “Lifespan: Why We Age―and Why We Don’t Have To” from David Sinclair or check out his publications. You’ll find more information about it on a post I did in December last year.

To explain the concept briefly, cells either grow/proliferate or perform cell maintenance (autophagy, DNA repair). Amino acids (AA) stimulate growth through mTOR and we see that resulting in lowered DNA repair. Energy goes into one or the other, not both.

Ageing sets in due to insufficient DNA repair and reaching the limit of cell proliferation. This creates dedifferentiated cells. They don’t behave properly anymore as a specific liver cell or brain cell but becomes something of a mix, not fully functioning and responsive as it should. A senescent cell. Over time this builds up and leads to diseases of ageing/organ failure.

In this review paper they found the AAs serine, threonine and valine specifically to affect ageing and DNA damage. They also go over the mechanism of why high protein intake leads to a reduction in longevity.

“Protein and Amino Acid Restriction, Aging and Disease: from yeast to humans” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254277/

Growth

Now we can’t live without eating protein, we absolutely require them. There are essential and conditionally essential AA. This means that growth will be stimulated every time we eat. Be it protein or something else like carbohydrates. The carbohydrates stimulate insulin the most and insulin is also an activator of mTOR.

The following publication found the AAs methionine, serine, threonine and phenylalanine specifically to be detrimental to life-span. Out of these, methionine, phenylalanine and threonine are essential. Serine is conditionally essential. This is not really a surprise. Non-essential AAs can be produced endogenously so essential AAs must signal mTOR activation in order to build those other AAs. mTOR is a protein that is made up of serine and threonine which explains their involvement. And I would call phenylalanine very essential, it gets incorporated into many different proteins and is also converted to an other AA called tyrosine.

“Parsing the life-shortening effects of dietary protein: effects of individual amino acids” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247493/

“mTOR signaling at a glance” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758797/

“Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085716/

“Feeding experiments with mixtures of highly purified amino acids. 6. The relation of phenylalanine and tyrosine to growth” https://www.cabdirect.org/cabdirect/abstract/19341405132

Together they are signaling growth and allow growth to take place.

IGF-1

One other promotor of mTOR is insulin-like growth factor 1 (IGF-1). Amino acids trigger the release of IGF-1 in the liver with a seemingly dose-dependent response.

“The Insulin-like Growth Factor-I–mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951771/

“Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation” https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0173174&type=printable

One of the reasons people may survive longer into old age is suspected to be a reduced functioning of IGF-1. Many of the blue zone centenarians are shorter. Even the Okinawans are shorter than mainland Japan.

This raises an interesting question when you look at protein consumption in centenarians. Are they living long because of their protein intake or despite their protein intake? If they have reduced functioning in IGF-1 signaling then it could be despite.

“Height, body size, and longevity: is smaller better for the humanbody?” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071721/

“Extending healthy ageing: nutrient sensitive pathway and centenarian population” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379947/

“Height and Survival at Older Ages among Men Born in an Inland Village in Sardinia (Italy), 1866–2006” https://www.tandfonline.com/doi/abs/10.1080/19485565.2012.666118

“Is height related to longevity?” https://www.sciencedirect.com/science/article/abs/pii/S0024320502025031

If you had your genetics analyzed, you can use the following study to look up your predisposal to longevity.

“Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control.” https://www.ncbi.nlm.nih.gov/pubmed/12843179/

If we know that AAs stimulate growth via IGF-1 then we can also expect growth to be reduced during low protein intake such as the ketogenic diet for treatment of epilepsy in children. In this case they provide protein below 80% of the recommended intake (!!!) and this is naturally affecting their normal growth.

“Linear growth of children on a ketogenic diet: does the protein-to-energy ratio matter?” https://www.ncbi.nlm.nih.gov/pubmed/24309243/

Complexity

A recent report in the Lancet also warns about high protein intake but they, rightfully, also warn about low protein intake. We just saw how that affects children. Both cases are not favorable. The warning goes to longevity but also towards health in both directions.

If you look at the conclusions in humans it is even more important to determine context. Notice how, depending on age, we get a different result with low protein.

The effect of low protein intakeMetabolic benefits of low protein intake
Aged 50 years or older: Diabetes-related mortality↓
Aged 50–65 years: All-cause mortality↓, cancer-related mortality↓, LP intake is more effective than MP or HP intake.Aged 50–65 years: Serum IGF-1↓ in LP intake group compared to IGF-1 in the HP intake group
Aged 66 years or older: All-cause mortality↑, Cancer mortality↓ HP intake is more effective than LP intake.Aged 66 years or older: No change in serum IGF-1 levels between LP and HP intake groups.

“The impact of dietary protein intake on longevity and metabolic health” https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30239-7/fulltext

What it does not tell us is how we arrived in this situation. Disease, ageing builds up over time. How does that affect us at old age to determine what is good for us and what isn’t good for us? If we take a different dietary life path from the start, will we end up differently at old age so that dietary requirements are different? There is plenty of research left to do.

Finally

We all want to live a long and healthy life but I have my doubts if a high protein diet is one of the ways to get you there…

A ketogenic diet may be more favorable. Due to the high fat intake, protein can be spared and can be lowered in the diet, reducing IGF-1 stimulation and giving more time to promote DNA repair.

— THE END —

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