The Question of Protein

I am everywhere surrounded by friends and family sprinkling creatine onto their protein shakes and shoveling it into their mouths as they compulsively pump iron in an endless attempt to build muscle.  The societal obsession with protein and muscle growth can be directly traced to Peter Attia, who in turn was influenced by a man named Don Layman, a scientist who has financial relationships with the National Cattlemen’s Beef Association and the National Dairy Council (AKA Big Meat) and who touts the more complete amino acid makeup of animal protein.  Even my wife has joined the anabolic stampede, influenced in her case, by the promise of early satiety and weight loss.  Even I, in a prior misguided post, had jumped on the protein band wagon.

And yet there is a dark side to Big Meat (beyond the environmental cost) and to anabolic excess in general.  In the trophic logic of mammalian physiology, growth signaling is unambiguously useful—until it isn’t. The same axis that builds tissue in a child, repairs muscle in an adult athlete, and sustains lean mass against the catabolic erosion of aging is also the axis that, when chronically engaged in midlife, appears to underwrite a measurable fraction of cancer incidence and metabolic disease.  This, based on the work of Valter Longo and Morgan Levine which we will examine below.  Also, I must mention the framework described by Mikhail Blagosklonny who, before he died of brain cancer after taking rapamycin for years, was the first to elaborate hyperfunction theory: that growth programs that build you up during human development do not switch off when you have reached adulthood. They keep running. And the diseases of aging (atherosclerosis, hypertension, hyperinsulinemia, the proliferative cancers) are largely what continued growth looks like in a body that doesn’t need it anymore.  So by this logic, our societal protein feeding frenzy is paradoxically a life-shortening intervention.

In 2014, Morgan Levine and Valter Longo published an analysis using NHANES III mortality data on 6,381 American adults aged 50 and over (1).

• Among 50–65 year olds, high animal protein intake (by self-report) was associated with a 75% increase in all-cause mortality and a 4-fold increase in cancer mortality over 18 years of follow-up.
• Moderate protein intake was associated with roughly a 3-fold increase in cancer mortality.
• The associations were specific to animal protein. Plant protein did not carry the signal.
• Surprisingly, in adults aged 65 and older, high protein intake was associated with a 28% reduction in all-cause mortality and a 60% reduction in cancer mortality.
• The direction of the signal flipped.  Why?

The protein question relates to the primordial levers of growth and proliferation in the body: the GH / IGF-1 / insulin / mTORC1 axis.  Levine and Longo proposed that in midlife, sustained anabolic drive (high IGF-1, tonically activated mTORC1) promotes proliferation in cells that are already accumulating mutations. After age 65, IGF-1 falls due to somatopause (reduced hypothalamic secretion of growth hormone-releasing hormone) and as a result anabolic resistance sets in.  Ultimately sarcopenia and frailty become the life-limiting risks. Once you cross some threshold, adequate protein becomes protective rather than harmful.

Of course, let us remind ourselves that this is the NHANES cohort, the same one that has been used to conclude illogically that people have been eating the same amount of food as society has become progressively more obese.  It is based on 24-hour dietary recall, which is subject to misremembering. While it is the strongest single piece of evidence we have for an age-dependent flip in protein’s effect on human mortality, there should be some reason for skepticism.

And yet, there is more literature that corroborates the midlife signal.  The Harvard Nurses’ Health Study and Health Professionals Follow-up Study pooled 131,342 participants with up to 32 years of follow-up and repeated dietary assessments–about as good as observational nutrition epidemiology gets (2).

• Every 10% increment of calories from animal protein was associated with a 2% higher all-cause mortality and 8% higher cardiovascular mortality.
• Every 3% increment of calories from plant protein was associated with a 10% lower mortality.
• Substitution of plant protein for animal protein (especially processed red meat) was associated with substantially lower mortality.
• The association was concentrated in participants with at least one other risk factor (smoking, heavy drinking, obesity, inactivity). In otherwise healthy people the signal was weaker.

The Harvard cohorts don’t test the age-flip directly because they pool across adult ages. But they confirm the underlying claim that in the middle of life, excess animal protein is a life-shortening strategy.  But why the difference with plant protein?  Keep reading.

Growth Hormone Receptor Knockout Mice

If the mechanism for hyperfunction really is growth signaling, then knocking it out should be protective. We have the answer in long-lived mutant mice.  GHR-knockout mice all share dysfunctional GH / IGF-1 signaling, and all live 30–60% longer than wild-type littermates with corresponding delays in tumor incidence.

The human counterpart is Laron syndrome, or growth hormone receptor deficiency (GHRD), a recessive loss-of-function mutation in GHR that leaves circulating IGF-1 profoundly suppressed. The largest cohort in southern Ecuador and studied by Longo, is a small population descended from Sephardic Jews who fled the Inquisition (3).

• Since 1988, in 99 GHRD subjects followed for over two decades, there has been one non-lethal cancer diagnosis and zero cases of diabetes.
• In the matched unaffected relatives, living in the same villages and eating the same diet, the cancer rate over the same period was 17% and the diabetes rate 5%.
• Laron subjects are often more obese than their relatives by BMI. They are not lean. They are obese and cancer-free and diabetes-free.

Hello? A population that is obese but cancer-proof and diabetes-proof tells you that adiposity, per se, is not what connects metabolic state to cancer risk. The connecting tissue is growth signaling through IGF.

IGF-1 U Shaped Curve

If the mechanism is real, the dose-response should be visible in people without rare mutations. It is. Two large prospective analyses bracket the finding:

• In the UK Biobank (n = 412,645, median 7.2 years follow-up), each 5-nmol/L increment in circulating IGF-1 was associated with elevated risk of breast (HR 1.10), prostate (1.09), colorectal (1.07), melanoma (1.08), kidney (1.10), and thyroid (1.22) cancers (4). Lung, ovarian, head and neck, and liver cancers ran in the opposite direction — a reminder that IGF-1 is not a uniform poison.
• In EPIC-Heidelberg, higher IGF-1 was directly associated with breast (HR 1.25) and prostate (HR 1.31) cancers. Critically, the relationship between IGF-1 and all-cause mortality was U-shaped: both the lowest and highest quintiles carried higher hazards (5).

Very low IGF-1 in adults appears to carry the costs of frailty and possibly cardiovascular fragility, probably because those people are already sick. Persistently elevated IGF-1 in midlife appears to drive the diseases of adulthood. The optimum is somewhere in the middle, and it most likely drifts upward with age.

Branched Chain Amino Acids (leucine, valine, isoleucine)

Which dietary components raise insulin resistance the most?   In 2009, Christopher Newgard ran targeted mass spectrometry on plasma from obese versus lean subjects, measured more than 100 analytes, and asked which combination most strongly tracked with insulin resistance (6).

• The winning signature was not fats or carbs. It was the branched-chain amino acids (valine, leucine, isoleucine).
• When the same group fed rats a high-fat diet supplemented with BCAAs, the rats developed insulin resistance equivalent to high-fat feeding alone, despite eating less and gaining less weight.

Leucine is the most potent dietary activator of mTORC1 we know of (the enzyme at the center of all metabolism, the cellular switch that says if it’s time to grow or time to freeze). Chronic dietary excess of BCAAs from animal protein, especially in a body that is already insulin-resistant and clearing them poorly, keeps mTORC1 activated. This is Blagosklonny’s hyperfunction. His solution was to take heroic doses of rapamycin and when he developed brain cancer, people said, “well thank goodness he’s on rapamycin.”  Nobody thought to blame the rapamycin, but we digress.

Plant Protein
Plant protein is deficient in BCAA’s.  And while both plant and animal protein raise IGF-1, plant protein does so to a lesser degree.  More interestingly, animal protein is associated with lower IGF binding protein (which increases IGF-1 bioavailability), whereas plant protein was associated with higher IGFBP-1 (which reduces free IGF-1 bioavailability). A cross-sectional study of 292 British women found that vegans had 13% lower serum IGF-1 and 20–40% higher IGFBP compared to meat-eaters and lacto-ovo-vegetarians. (7)

There are four lines of evidence saying the same thing:

• Epidemiology (Levine 2014, NHS/HPFS) says that high animal protein in midlife tracks with cancer and overall mortality, and that the signal weakens or reverses in old age.
• Human genetics (Laron / GHRD) says that knocking out the growth hormone receptor protects against cancer and diabetes with near-perfect penetrance, even in obese subjects.
• Cohort biomarker data (UK Biobank, EPIC-Heidelberg) says that IGF-1 across the normal range tracks with the major epithelial cancers and that mortality versus IGF-1 is U-shaped.
• Metabolomics (Newgard 2009) says that the BCAA-driven anabolic signal is the cause of insulin resistance, which causes many of the diseases of aging.

What this implies in practice

• In midlife, there is a reasonable case for keeping animal protein low, substituting plant protein as much as possible, making sure to maintain lean mass but not so much that you are running IGF-1 on the right side of the U curve.
• Plant protein, on the available data, does not carry the same signal as animal protein because of the IGFBP.  Substituting plant for animal protein is associated with lower mortality in the largest cohorts.
• Resistance training is important because it lets you do more with less protein. Muscle growth justifies anabolic drive.
• After roughly age 65 or 70 (or in anyone showing early sarcopenia) the calculation inverts. Frailty kills, and protein adequacy is protective. This may be the time to start eating steaks.
• Whey protein shakes and BCAA supplements after achievement of the young adult phenotype (and androgenic / anabolic steroids at any point) are life shortening interventions.

References

1. Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 2014 Mar 4;19(3):407-17. doi: 10.1016/j.cmet.2014.02.006.
2. Song M, Fung TT, Hu FB, et al. Association of animal and plant protein intake with all-cause and cause-specific mortality. JAMA Intern Med. 2016;176(10):1453-1463.
3. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13. doi:10.1126/scitranslmed.3001845
4. Knuppel A, Fensom GK, Watts EL, et al. Circulating insulin-like growth factor-I and risk of 19 site-specific cancers: UK Biobank analyses. Cancer Epidemiol Biomarkers Prev. 2020;29(8):1531-1540.
5. Kaaks R, Johnson T, Tikk K, et al. IGF-1 and risk of morbidity and mortality from cancer, cardiovascular diseases, and all causes in EPIC-Heidelberg. J Clin Endocrinol Metab. 2023;108(10):e1092-e1105.
6. Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9(4):311-326.
7. The Associations of Diet With Serum Insulin-Like Growth Factor I and Its Main Binding Proteins in 292 Women Meat-Eaters, Vegetarians, and Vegans.
   Cancer Epidemiology, Biomarkers & Prevention : A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2002. Allen NE, Appleby PN, Davey GK, et al.