Ancel Benjamin Keys (January 26, 1904 – November 20, 2004) was an American physiologist who studied the influence of diet on health. In particular, he hypothesized that dietary saturated fat causes cardiovascular heart disease and should be avoided. Modern dietary recommendations by health organizations, systematic reviews, and national health agencies corroborate this.
Keys studied starvation in men and published The Biology of Human Starvation (1950), which remains the only source of its kind. He examined the epidemiology of cardiovascular disease and was responsible for two famous diets: K-rations, formulated as balanced meals for combat soldiers in World War II, and the Mediterranean diet, which he popularized with his wife Margaret. Science, diet, and health were central themes in his professional and private lives.
Ancel Keys was born in Colorado Springs in 1904 to Benjamin Pious Keys (1883-1961) and Carolyn Emma Chaney (1885-1960), the sister of Lon Chaney. In 1906 they moved to San Francisco before the 1906 San Francisco earthquake struck. Shortly after the disaster, his family relocated to Berkeley where he grew up. Keys was intelligent as a boy; Lewis Terman, a noted psychologist and inventor of the Stanford-Binet IQ Test, described him as intellectually “gifted”. During his youth, he left high school to pursue odd jobs, such as shoveling bat guano in Arizona, a powder monkey in a Colorado mine, and in a lumber camp. He eventually finished his secondary education and was admitted to the University of California at Berkeley in 1922.
While doing fish research at Scripps, Keys would use statistical regressions to estimate the weight of fish from their length, at that time a pioneering use of biostatistics. Once in Copenhagen (1931), he continued to study fish physiology and developed techniques for gill perfusion that provided evidence that fish regulated their sodium by controlling chloride excretion through their gills. He would also use this perfusion method to study the effects of adrenaline and vasopressin (“pitressin”) on gill fluid flow and osmotic regulation in fishes. He also designed an improved Kjeldahl apparatus, which improved upon Krogh’s earlier design, and allowed for more rapid determination of nitrogen content in biological samples. This would prove useful for activities as diverse as determining the protein content in grasshopper eggs and anemia in humans.
While at Harvard’s Fatigue Laboratory, he was inspired by his Cambridge mentor Joseph Barcroft‘s ascent to the top of Tenerife’s highest peak and his subsequent reports. Keys wrote up a proposal for an expedition to the Andes, suggesting the study could have practical value for Chilean miners who worked at high altitudes. He was given the go-ahead and, in 1935, assembled a team to study the effects of high altitude on the body, such as how it affects blood pressure. He spent a couple of months at 9,500 feet (3,000 m.), and then five weeks at altitudes of 15,000 to 20,000 feet (4,500 to 6,000 m.). He noted that there was no good way of predicting how well humans might adapt to high altitude, even if they adapted well to medium altitudes, which would[vague] be a problem for potential pilots in a time before pressure control had become practical. It was from these studies that he outlined the phenomenon of human physiological adaptation to environmental changes as a predictable event, a novel idea in a time when such parameters as blood pressure and resting heart-rate were considered immutable characteristics of individuals.
An example of a K-ration dinner. All the components were intended to fit into a box which would fit into a soldier’s pocket
In 1936, Keys was offered a position at the Mayo Foundation in Rochester, where he continued his studies in physiology. He left after a year, citing an intellectually stifling environment where research was secondary to clinical “doc business” and playing bridge. In 1937 he left the Mayo Foundation to teach physiology at University of Minnesota, where he founded the Laboratory of Physiological Hygiene. His earlier research on human physiology eventually led to an assignment with the Army Quartermaster Corps, where they worked to develop a more portable and nonperishable ration that would provide enough calories to sustain soldiers (such as paratroopers) in the field for up to two weeks. This development did not begin without some turbulence. His colleague, Dr. Elsworth Buskirk, notes:
When it appeared that the U.S. would be in World War II, Keys went to the Quartermaster Food and Container Institute in Chicago to inquire about emergency rations. The story goes that he was told to go home and leave such things to the professionals. Undissuaded, he went to William Wrigley’s office and secured $10,000 for the development of an emergency ration. Then, he went to the Cracker Jack Company. They couldn’t supply money, but did provide the water-tight small box concept. The result was the K-ration in sealed Cracker Jack boxes.
Once the basic design had been completed, the Navy, through the National Research Council, funded the testing of the K-rations on its sailors to determine their feasibility as a temporary and mobile food source. The initial ingredients of the K-ration were procured at a local Minneapolis grocery store—hard biscuits, dry sausage, hard candy, and chocolate. The final product was different from Keys’ original ingredients, but most of Keys’ initial suggestions made it to the final product. The rations weighed only 28 oz (790 g), but provided 3200 calories per day. Though a few sources claim the name was unrelated to Keys, many historical references support the claim that the K-ration was indeed named after him. The K-ration became such a success that it was often used for more than temporary sustenance, becoming a major staple of military nutrition.
During World War II, Keys produced various studies related to human physical performance that were of interest to the military, such as studying the effects of testosterone on muscle work and vitamin supplementation as a performance enhancer on adequately fed soldiers, among many other similar studies. It was during the war that Keys and fellow researchers recognized the importance of knowing how to properly treat widespread starvation, since simple overfeeding for so many would be imprecise and there was a potential that the refeeding would fail.
To gain insight into the physiology of starvation, in 1944 Keys carried out a starvation study with 36 conscientious objectors as test subjects in the Minnesota Starvation Experiment. At the time, conscientious objectors were being placed in virtual concentration camps, with a few functioning like the Civilian Public Service, so that recruiting them would prove easier than seeking out volunteers in the general population. The original pool of 400 responders was reduced to 36 selectees, of whom 32 would go on to complete the study. The main focus of the study was threefold: set a metabolic baseline for three months, study the physical and mental effects of starvation on the volunteers for six months, and then study the physical and mental effects of different refeeding protocols on them for three months. The participants would first be placed on the three-month baseline diet of 3200 calories after which their calories were reduced to 1800 calories/day while expending 3000 calories in activities such as walking. The final three months were a refeeding period where the volunteers were divided into four groups, each receiving a different caloric intake.
The war came to an end before the final results of the study could be published, but Keys sent his findings to various international relief agencies throughout Europe and, by 1950, he completed publication of his two-volume 1385-page Biology of Human Starvation.
His interest in diet and cardiovascular disease (CVD) was prompted, in part, by seemingly counter-intuitive data: American business executives, presumably among the best-fed people, had high rates of heart disease, while in post-war Europe CVD rates had decreased sharply in the wake of reduced food supplies. Keys postulated a correlation between cholesterol levels and CVD and initiated a study of Minnesota businessmen (the first prospective study of CVD). At a 1955 expert meeting at the World Health Organization in Geneva, Keys presented his diet-lipid-heart disease hypothesis with “his usual confidence and bluntness”.Naples was the first case study that seemed to support his hypothesis.
Keys had concluded that saturated fats as found in milk and meat have adverse effects, while unsaturated fats found in vegetable oils had beneficial effects. This message was obscured for a 20-year period starting around 1985, when all dietary fats were considered unhealthy. This was driven largely by the hypothesis that all dietary fats cause obesity and cancer. A 2015 systematic review and meta-analysis by the Cochrane Collaboration, an organisation which promotes evidence-based medicine, found that reducing saturated fat intake reduced the risk of cardiovascular disease, concluding: “Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturated fats.” 
After Key’s retirement from the University of Minnesota in 1972, his protege Henry Blackburn, MD became director of the Laboratory of Physiological Hygiene. Blackburn continued research on the role of lifestyle including diet in the cause and prevention of heart disease. The department played an active role in multicenter trials of the 1970s-80s and population strategies of surveillance and preventive interventions in Minnesota.
The Keys equation predicts the effect of saturated and polyunsaturated fatty acids in the diet on serum cholesterol levels. Keys found that saturated fats increase total and LDL cholesterol twice as much as polyunsaturated fats lower them.
Change in serum cholesterol concentration
(mmol/l) = 0.031(2Dsf − Dpuf) + 1.5√Dch
where Dsf is the change in percentage of dietary energy from saturated fats, Dpuf is the change in percentage of dietary energy from polyunsaturated fats, and Dch is the change in intake of dietary cholesterol.
The sugar controversy
In 1972, Pure, White and Deadly was published, written by John Yudkin for a lay readership. Its intention was to summarize the evidence that the over-consumption of sugar was leading to a greatly increased incidence of coronary thrombosis, and that in addition it was certainly involved in dental caries, probably involved in obesity, diabetes and liver disease, and possibly involved in gout, dyspepsia and some cancers.
Yudkin ended the first Chapter: “I hope that when you have read this book I shall have convinced you that sugar is really dangerous.” This message was extremely unwelcome to the sugar industry and manufacturers of processed foods. The final Chapter of Pure, White and Deadly lists several examples of attempts to interfere with the funding of his research and to prevent its publication. It also refers to the rancorous language and personal smears used by Ancel Keys to dismiss the evidence that sugar was the true culprit.
Keys wrote, for example:
It is clear that Yudkin has no theoretical basis or experimental evidence to support his claim for a major influence of dietary sucrose in the etiology of CHD; his claim that men who have CHD are excessive sugar eaters is nowhere confirmed but is disproved by many studies superior in methodology and/or magnitude to his own; and his “evidence” from population statistics and time trends will not bear up under the most elementary critical examination. But the propaganda keeps on reverberating … Unfortunately, Yudkin’s views appeal to some commercial interests with the result that this discredited propaganda is periodically rebroadcast to the general public of many countries.
The efforts to discredit the case against sugar were largely successful, and by the time of Yudkin’s death in 1995 his warnings were, for the most part, no longer being taken seriously.
Yudkin’s arguments and evidence for the dangers of sugar were the focus of several articles in the British Medical Journal of 19 January 2013.
In 2009, Robert Lustig, a pediatric endocrinologist of the University of California, San Francisco, Medical School who has a special interest in childhood obesity, made a video called Sugar: The Bitter Truth. Lustig had independently re-discovered and confirmed Yudkin’s findings and, pointing to “a hole as big as the one in the USS Cole” in Keys’ regression analysis of CHD versus fat and sugar, asked his audience, “Am I debunking?”
Keys was always considered an interventionist. He generally shunned food fads and vigorously promoted the putative benefits of the “reasonably low-fat diets” which he contrasted with “the North American habit for making the stomach the garbage disposal unit for a long list of harmful foods.” Because of his influence in dietary science, Keys was featured on the cover of the January 13, 1961, issue of Time magazine.
Later years and death
When Keys was hired at the Mayo Foundation in 1936, he hired Margaret Haney (1909–2006) as a medical technologist. In 1939 they married and had three children: Carrie D’Andrea, Henry Keys, and Martha McLain. Carrie became a clinical psychologist and Henry became a physician and cancer researcher. Both are well respected contributors to their fields. Martha was shot dead by a thief in 1991 when she was 42.
Together, Margaret and Keys co-authored three books, two of them bestsellers. They earned enough royalties to build Minnelea, their villa one hundred miles south of Naples. They also traveled the world, going to places like Japan and South Africa to record data for Ancel’s published works such as the Seven Countries Study.
Keys appeared on the To Tell The Truth game show as the inventor of K-Rations, fooling two of the four panelists.
Keys died on November 20, 2004, two months before his 101st birthday. A year earlier, he had left Pioppi, his beloved village in the Cilento region located on the southwest coast of Italy, where he had spent 28 years of his life.
Criticism Some doctors and nutritionists have been critical of Keys’ implications. His famous seven countries study, which led to the medical opinion regarding the dangers of cholesterol, fat and substances containing the same, has been criticized as ignoring the cases of Denmark, France and Norway (countries where the diet is rich in fat, but occurrence of heart disease is low) and Chile (where diet is low in fat, yet occurrence of heart disease is high). Yet based on the total body of scientific literature, American College of Cardiology/American Heart Association Guidelines of 2019 recommend that dietary saturated fat intake be replaced by monounsaturated and polyunsatured fat for prevention of heart disease.
Keys, A.; Brozek, J.; Henschel, A.; Mickelsen, O.; Taylor, H. L. (1950). The Biology of Human Starvation (2 volumes). University of Minnesota Press. ISBN978-0816672349.
—; Keys, Margaret (1959). Eat Well and Stay Well. Doubleday. LCCN59-6361.
^ Jump up to:abcZadunaisky, JA (1969). “The Chloride Cell: The Active Transport of Chloride and the Paracellular Pathways”. In William Stewart Hoar; David J. Randall (eds.). Fish Physiology. Part 1 of Fish Physiology: Anatomy, Gas Transfer, and Acid-base Regulation. 10. Academic Press. pp. 130–136. ISBN978-0-12-350430-2. Retrieved 2011-02-05. Ancel Keys was a fellow of the National Research Council of America, who did the perfusion experiment leading to the observation of chloride secretion in the Zoophysiological Laboratory in Copenhagen, Denmark, under the direction of August Krogh.
^Keys, Ancel (1939). “A Rapid Micro-Kjeldahl Method”. The Journal of Biological Chemistry. 132 (1): 181–187. Retrieved 2011-02-05. A micro-Kjeldahl method is described. The method is more rapid than the ordinary macro-Kjeldahl procedure and is not appreciably less accurate
^ Jump up to:abcdefghBuskirk, ER (1992). “From Harvard to Minnesota: Keys to our History”. Exercise and Sport Sciences Reviews. 20: 1–26. doi:10.1249/00003677-199200200-00001. PMID1623883. “Based on an appeal from the Army Quartermaster Corps, experiments to design and test rations for the promotion and maintenance of combat effectiveness for paratroopers were undertaken. Neither Keys nor the military was particularly interested in vitamins, but rather they wanted to put calories into a small packet of nonperishable food … the Keys or K-ration was designed in the Laboratory and at field test sites in both hot and cold areas on the North American continent.
^Schemmel, Rachel; Simin Vaghefi; Barbara Bowman (2001). “Olaf Mickelsen (July 29, 1912 to August 8, 1999)”. Journal of Nutrition. 131 (2): 205–210. doi:10.1093/jn/131.2.205. PMID11160534. During World War II, I worked with Dr. Ancel Keys on the K ration. This emergency ration was named after Dr. Keys because of the pioneering work he did in getting our country conscious of the fact that a ration of this type would be surely needed if we became embroiled in war.
^Keys, Ancel (1950). The Biology of Human Starvation. Minneapolis, MN: University of Minnesota Press. p. 262.
^Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E (1 September 1963). “Coronary heart disease among Minnesota business and professional men followed 15 years”. Circulation. 28 (3): 381–95. doi:10.1161/01.cir.28.3.381. PMID14059458.
^Kromhout D: Serum cholesterol in cross-cultural perspective. The Seven-Countries Study. Acta Cardiol 1999;54:155–158
^Katan MB, Beynen AC. Linoleic acid consumption and coronary heart disease in U.S.A. and U.K. Lancet. 1981 Aug 15;2(8242):371
^Prentice RL, Sheppard L. Dietary fat and cancer: consistency of the epidemiologic data, and disease prevention that may follow from a practical reduction in fat consumption. Cancer Causes Control. 1990 Jul;1(1):81-97
^Lustig, Robert H., MD (26 May 2009). Sugar: the Bitter Truth. Osher Center for Integrative Medicine, San Francisco: UCTV. Event occurs at 36:30. Lustig09. Archived from the original(Flash video) on 28 February 2020. Retrieved 28 February 2020. Am I debunking?
^“Ancel Keys” (Press release). The American Physiological Society. 2004. Archived from the original on 2007-09-27. Retrieved 2007-11-13.
^Todd Tucker (2008). The Great Starvation Experiment: Ancel Keys and the Men Who Starved for Science. U of Minnesota Press. p. 146. ISBN978-0-8166-5161-0. Max’s advocates made up a diverse cast of characters, from the Jewish Peace Fellowship leader Rabbi Isador Hoffman to the atheist Ancel Keys, who wrote the committee that Max “proved to be a highly reliable and conscientious man who comported himself well under the most rigorous and demanding circumstances.”
^Arnett, Donna K.; Blumenthal, Roger S.; Albert, Michelle A.; Buroker, Andrew B.; Goldberger, Zachary D.; Hahn, Ellen J.; Himmelfarb, Cheryl Dennison; Khera, Amit; Lloyd-Jones, Donald; McEvoy, J. William; Michos, Erin D.; Miedema, Michael D.; Muñoz, Daniel; Smith, Sidney C.; Virani, Salim S.; Williams, Kim A.; Yeboah, Joseph; Ziaeian, Boback (10 September 2019). “2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines”. Circulation. 140 (11). doi:10.1161/CIR.0000000000000677.