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Saturday, April 17, 2021

Why humans can run marathons and apes cannot

Dr. Gabe Mirkin

Extensive research by Dr. Ajit Varki at UC/San Diego suggest that 2-3 million years ago, our pre-human ancestors had a single genetic mutation that could explain why humans can outrun their primate relatives (J Biol Chem, 1998;273:15 866-871). Most other mammals did not develop this mutation that:
• helped humans to survive an ancient form of malaria, and
• may have given humans more endurance so they could run great distances.

Chimpanzees share more than 99 percent of their genes with modern humans, but the CMAH gene is one of the areas of difference. Two to three million years ago, gorillas, chimpanzees, and other primates were dying from a type of malaria called Plasmodium reichenowi (Science, 2011;331:540-542). At that time, all primates had a surface protein called Neu5Gc on their cells that was made from Neu5Ac. Then along came a primate with a gene that had lost its ability to make Neu5Gc from Neu5Ac, so it had only Neu5Ac (Proc Natl Acad Sci USA, Sept 6, 2005;102(36):12819-12824). That pre-human did not die from malaria like other primates, his and her children lived and proliferated, and today their descendants (all humans) have a gene that makes Neu5Ac instead of Neu5Gc. As often happens in nature, the malaria parasite then modified its genetic makeup into a variant called Plasmodium falciparum which can infect humans, but not chimpanzees, so today humans can be infected only with Plasmodium falciparum and chimpanzees can be infected only with Plasmodium reichenowi. This same genetic mutation gave homo sapiens greater endurance so they were able to run long distances while the apes could not, which gave humans an advantage in hunting for food (J Hum Evol, 2014;66:64-82).

How the Gene for Neu5Gc was Discovered
In 1982, Ajit Varki ground up human muscle and separated around 1450 different sugar-proteins. He did the same thing with cow’s muscle and found close to the same number and types of individual sugar-proteins, but he found one sugar-protein in cow’s muscle that was not in human muscle. He called this sugar-protein Neu5Gc. In humans, but not in most other mammals, he found a different sugar-protein and called it Neu5Ac. Varki postulated that humans are different from apes because of this mutation, and he has spent most of his research career studying the differences. In 1988, scientists located the function of producing Neu5Gc on the CMAH gene in virtually all mammals except humans (Journal of Biological Chemistry, 1988;273(25):15866-71). The only other mammals known not to make Neu5Gc are new world monkeys, European hedgehogs, ferrets, some bats, sperm whales, and the platypus (Genome Biology and Evolution, 2018;10(1):207-219).

Research on Neu5Gc and Endurance
A major breakthrough in Neu5Gc research occurred when researchers developed mice that had human-like Neu5Ac on their cell surfaces in place of their usual Neu5Gc (Mol Cell Biol, Jun 2007;27(12):4340-4346). Varki’s laboratory compared the genetically-modified human-like Neu5Ac mice with normal mice with Neu5Gc (Proc Biol Sci, Sep 12, 2018;285(1886):20181656), and found that the mice with Neu5Ac:
• had muscles that could take in and use oxygen at a much faster and higher rate (the limiting factor to how fast you can run over distance is the time it takes to move oxygen from the bloodstream into muscles)
• had more capillaries in their muscles to supply extra oxygen during running
• were able to run much longer distances
• were able to run significantly faster
• had a markedly delayed muscle fatigue when they ran
• improved even more with training
This research may someday have application to some human muscle diseases, since mice with a type of muscular dystrophy got better when they had their CMAH gene deleted (Sci Transl Med, Jul 28, 2010;2(42):42ra54).

Neu5Gc from Eating Mammal Meat Causes Inflammation
Your immune system recognizes invading germs by the surface proteins on cell membranes. If the surface proteins are different from your own surface proteins, your immune system makes:
• proteins called antibodies that attach to and kill the invading germs, and
• immune cells that eat and destroy germs.
When humans eat the meat of other mammals, the Neu5Gc from the meat enters their cells. Your immune system recognizes the Neu5Gc as foreign and attacks those cells, just as it would attack invading germs. People who eat mammal meat regularly are likely to have an immune system that is overactive all the time, called chronic inflammation (Proc Natl Acad Sci USA, Jan 13, 2015;112(2):542-547). Inflammation can punch holes in the inner linings of your arteries to form plaques, which can break off to cause heart attacks and strokes (Circulation, April 22, 2019). Inflammation can also damage your DNA to cause cancers, and damage various tissues to cause arthritis, fatty liver, diabetes and so forth (Nature, 2002 Dec 19; 420(6917): 860-867).
Neu5Gc: A Genetic Reason Why Humans Have More Heart Attacks Than Other Mammals
Red Meat, Neu5Gc and Risk for Cancer

My Recommendations
Be glad you are part of the human race that has Neu5Ac, which might allow you to run further than an ape can. However, this same genetic change means that when you eat meat from other mammals, you are at increased risk for heart attacks, strokes and some cancers because Neu5Gc turns on your immune system to cause inflammation. I believe that the theory of Neu5Gc causing chronic inflammation is strong enough that you should not eat mammal meat regularly. We do not have enough data to know whether occasionally eating mammal meat is safe.

Dr. Gabe Mirkin is a Villager. Learn more at www.drmirkin.com.

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