Editing Ancel Keys (section)

==Scientific work==

===Early physiology studies===

While doing fish research at Scripps, Keys would use statistical [[regression analysis|regressions]] to estimate the weight of fish from their length, at that time a pioneering use of [[biostatistics]].<ref name='Blackburn1998'>{{cite web |url=http://mbbnet.umn.edu/firsts/blackburn_h.html | title = Ancel Keys | access-date = February 5, 2011 | last = Blackburn, MD| first = Henry | year = 1998 | work = [[University of Minnesota]] | publisher = University of Minnesota}}</ref> 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.<ref name=Zadunaisky1969/><ref name='Keys1932'>{{cite journal | title = 'Chloride secreting cells' in the gills of fishes, with special reference to the common eel | first2 = EN | journal = The Journal of Physiology | last2 = Willmer | year = 1932 | first1 = Ancel | last1 = Keys | volume = 76 | issue = 3 | pages = 368–380| pmid = 16994355 | doi = 10.1113/jphysiol.1932.sp002932 | pmc = 1394694}}</ref><ref name='Keys1931'>{{cite journal | title = The determination of chlorides with the highest accuracy | journal = Z. Vergl. Physiol. | year = 1931 | first = Ancel | last = Keys | volume = 15 | issue = 2 | pages = 352–363| doi = 10.1007/BF00339114 | s2cid = 28971898 }}</ref> He would also use this perfusion method to study the effects of [[adrenaline]] and [[vasopressin]] ("pitressin") on gill fluid flow<ref name='BatemanKeys1932'>{{cite journal | doi = 10.2307/1537248 | title = Branchial Responses to Adrenaline and to Pitressin in the eel | journal = Biological Bulletin | year = 1932 | first = Ancel | last = Keys |author2=J.B. Bateman | volume = 63 | issue = 2 | pages = 327–336|url=http://www.biolbull.org/cgi/reprint/63/2/327.pdf | access-date = February 5, 2011| jstor = 1537248 }}</ref> and osmotic regulation in fishes.<ref name='Keys1933'>{{cite journal | title = The Mechanism of Adaptation to Varying Salinity in the Common Eel and the General Problem of Osmotic Regulation in Fishes | journal = Proceedings of the Royal Society B | year = 1933 | first = Ancel | last = Keys | volume = 112 | issue = 776 | pages = 184–199 | jstor=81638 | doi=10.1098/rspb.1933.0002| bibcode = 1933RSPSB.112..184K | doi-access =  }}</ref> He also designed an improved [[Kjeldahl method|Kjeldahl apparatus]], which improved upon Krogh's earlier design, and allowed for more rapid determination of nitrogen content in biological samples.<ref name='Keys1940'>{{cite journal | title = A Rapid Micro-Kjeldahl Method | journal = The Journal of Biological Chemistry | year = 1939 | first = Ancel | last = Keys | volume = 132 | pages = 181–187|url=http://www.jbc.org/content/132/1/181.short | access-date = February 5, 2011 | quote = A micro-Kjeldahl method is described. The method is more rapid than the ordinary macro-Kjeldahl procedure and is not appreciably less accurate | issue=1| doi = 10.1016/S0021-9258(18)73407-8 | doi-access = free }}</ref> This would prove useful for activities as diverse as determining the protein content in grasshopper eggs<ref>{{cite journal | doi = 10.2307/1537901 | title = Nitrogen content and distribution in eggs of Melanoplus differentialis during embryonic development | journal = Biological Bulletin | year = 1940 | first = Carolyn | last = Trowbridge |author2=Joseph Hall Bodine | volume = 79 | issue = 3 | pages = 452–458|url=http://www.biolbull.org/cgi/reprint/79/3/452.pdf | access-date = February 5, 2011| jstor = 1537901 }}</ref> and anemia in humans.<ref>{{cite journal | doi = 10.1172/JCI103087 | title = The anemia of liver disease: observations on its mechanism. | journal = Journal of Clinical Investigation | year = 1955 | first = James H. | last = Jandi | volume = 34 | issue = 3 | pages = 390–404| pmid = 14354009 | pmc = 438641}}</ref>

While at Harvard's Fatigue Laboratory, he was inspired by his Cambridge mentor [[Joseph Barcroft]]'s ascent to the top of [[Tenerife|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 elevations.<ref name=Hoffman1979/> He was given the go-ahead and, in 1935, assembled a team to study the effects of high altitude on the body,<ref name=Sullivan2004/> such as how it affects blood pressure.<ref name=Brody2004/> He spent a couple of months at 9,500 feet (3,000 m.), and then five weeks at elevations of 15,000  to 20,000 feet (4,500 to 6,000 m.).<ref name=Hoffman1979/>

He noted there was no good way of predicting how well humans might [[High-altitude adaptation in humans|adapt to high altitude]], even if they adapted well to medium altitudes, a problem for potential pilots in a time before pressure control had become practical.<ref name='Keys1936'>{{cite journal | title = The Physiology of Life at High Altitudes | journal = The Scientific Monthly | year = 1936 | first = Ancel | last = Keys | volume = 43 | issue = 4 | pages = 289–312| jstor = 16163| bibcode = 1936SciMo..43..289K }}</ref> 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.<ref name=Kalm_2005>{{cite journal |vauthors=Kalm L, Semba R |title=They starved so that others be better fed: remembering Ancel Keys and the Minnesota experiment |journal=J Nutr |volume=135 |issue=6 |pages=1347–1352 |year=2005 |pmid=15930436|doi=10.1093/jn/135.6.1347 |doi-access=free }}</ref><ref name='Keys1938'>{{cite journal | doi = 10.1098/rspb.1938.0043 | title = Individual Variations in Ability to Acclimatize to High Altitude | journal = Proceedings of the Royal Society B | year = 1938 | first1 = Ancel | last1 = Keys | first2 = Bryan H. C. |last2=Matthews |first3=W. H. |last3=Forbes |first4=Ross A. |last4=McFarland | volume = 126 | issue = 842 | pages = 1–24| jstor=82153| bibcode = 1938RSPSB.126....1K | s2cid = 128707808 | doi-access =  }}</ref>

===Development of K-rations===
{{Main|K-ration}}
[[File:KRation Dinner.JPG|thumb|left|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, Minnesota|Rochester]], where he continued his studies in physiology.<ref name=Keys1936/> He left after a year, citing an intellectually stifling environment where research was secondary to clinical "doc business" and playing [[Contract bridge|bridge]].<ref name=Hoffman1979/>

In 1937, he left the Mayo Foundation to teach physiology at the University of Minnesota,<ref name='Reed2004'>{{cite news | first = Christopher | last = Reed | title = Ancel Keys The dietician who promoted the virtues of the Mediterranean diet | date = December 8, 2004 |url=https://www.theguardian.com/news/2004/dec/08/guardianobituaries1 | work = [[The Guardian]] | access-date = February 5, 2011}}</ref> where he founded the Laboratory of Physiological Hygiene. His earlier research on human physiology led to an assignment with the [[Quartermaster Corps (United States Army)|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.<ref name='Buskirk1992'>{{cite journal | title = From Harvard to Minnesota: Keys to our History | journal = Exercise and Sport Sciences Reviews | year = 1992 | first = ER | last = Buskirk | volume = 20 | pages = 1–26| pmid = 1623883  | quote = 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&nbsp; ... 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. | doi=10.1249/00003677-199200200-00001| doi-access = free }}</ref>

This development did not begin without some turbulence. His colleague, Elsworth Buskirk, recalled:

{{blockquote|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 [[Wm. Wrigley Jr. Company|William Wrigley's]] office and secured $10,000 for the development of an emergency ration. Then, he went to the [[Cracker Jack|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.<ref name=Buskirk1992/>}}

Once the basic design had been completed, the Navy, through the [[National Research Council (United States)|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.<ref name=Sullivan2004/> The final product was different from Keys' original ingredients, but most of Keys' suggestions made it to the final product.<ref name=Hoffman1979/> The rations weighed only {{convert|28|oz|abbr=on}}, but provided 3200 calories per day.<ref name=Reed2004/> Though several sources claim the name was unrelated to Keys,<ref name=Quartermaster-1>{{cite conference|url=http://qmfound.com/history_of_rations.htm |contribution=Rations: The History of Rations |access-date=February 6, 2011 |archive-url=https://web.archive.org/web/20110208042157/http://www.qmfound.com/history_of_rations.htm |archive-date=February 8, 2011 |publisher=The Quartermaster School |via=U.S. Army Quartermaster Museum |date=January 1949 |title=Conference Notes prepared for the Quartermaster General }}</ref> many historical references support the claim that the K-ration was indeed named after him.<ref name=Hoffman1979/><ref name=Buskirk1992/><ref>{{cite journal | title = Olaf Mickelsen (July 29, 1912 to August 8, 1999)  | journal = Journal of Nutrition | year = 2001 | first = Rachel | last = Schemmel |author2=Simin Vaghefi |author3=Barbara Bowman  | volume = 131 | issue = 2 | pages = 205–210| pmid = 11160534  | quote = 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.| doi = 10.1093/jn/131.2.205 | doi-access = free }}</ref> The K-ration became such a success that it was often used for more than temporary sustenance, becoming a major staple of military nutrition.<ref name=Hoffman1979/><ref name=Buskirk1992/>

===Starvation study===
{{main|Minnesota Starvation Experiment}}

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 [[methyltestosterone|testosterone]] on muscle work<ref name='Samuels1942'>{{cite journal | title = Influence of Methyl Testosterone on Muscular Work and Creatine Metabolism in Normal Young Men | journal = Journal of Clinical Endocrinology and Metabolism | first = Leo | last = Samuels |author2=Austin Henschel |author3=Ancel Keys  | volume = 2 | issue = 11 | pages = 649–654 | year = 1942| doi =  10.1210/jcem-2-11-649 |url=http://jcem.endojournals.org/cgi/content/abstract/2/11/649 | access-date = February 6, 2011}}</ref> and vitamin supplementation as a performance enhancer on adequately fed soldiers,<ref name='Keys1943'>{{cite journal | title = The performance of normal young men on controlled thiamine intakes | journal = Journal of Clinical Nutrition | year = 1943 | first = Ancel | last = Keys |author2=Austin Henschel |author3=Olaf Mickelsen |author4=Josef Brozek  | volume = 26 | issue = 4 | pages = 399–415|url=http://jn.nutrition.org/cgi/reprint/26/4/399.pdf | access-date = February 6, 2011}}</ref><ref name='Keys1942'>{{cite journal | title = Vitamin supplementation of US Army rations in relation to fatigue and the ability to do muscular work | journal = Journal of Clinical Nutrition | year = 1942 | first = Ancel | last = Keys |author2=Austin Henschel | volume = 23 | issue = 3 | pages = 259–269|url=http://jn.nutrition.org/cgi/reprint/23/3/259.pdf | access-date = February 6, 2011}}</ref> 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.<ref name=Buskirk1992/>

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.<ref name=Kalm_2005/><ref name=Buskirk1992/> The original pool of 400 responders was reduced to 36 selectees, of whom 32 would go on to complete the study.<ref name='Keys1950'>{{cite book | last1 = Keys | first1 = Ancel | author-link1 = Ancel Keys | title = The Biology of Human Starvation | publisher = University of Minnesota Press | year = 1950 | location = Minneapolis | pages = 262}}</ref> 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.<ref name=Kalm_2005/> 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.<ref name=Kalm_2005/>

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<ref name=Hoffman1979/> and, by 1950, he completed publication of his two-volume 1385-page ''Biology of Human Starvation''.<ref name=Kalm_2005/><ref name=Buskirk1992/>

===Seven Countries Study===
{{Main|Seven Countries Study}}
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).<ref name=Keys_1963>{{cite journal |vauthors=Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E |title=Coronary heart disease among Minnesota business and professional men followed 15 years |journal=Circulation |volume=28 |issue= 3|pages=381–395 |date=September 1, 1963|pmid=14059458 |doi=10.1161/01.cir.28.3.381|doi-access=free }}</ref> At a 1955 expert meeting at the World Health Organization in Geneva, Keys presented his diet-lipid-heart disease hypothesis.<ref>{{cite web|title=Famous Polemics on Diet-Heart Theory|author=Henry Blackburn|publisher= School of Public Health, University of Minnesota|url=http://www.epi.umn.edu/cvdepi/essay.asp?id=33|archive-url=https://web.archive.org/web/20140327233831/http://www.epi.umn.edu/cvdepi/essay.asp?id=33|archive-date=March 27, 2014}}</ref><ref name=Keys_1980>{{cite book | last = Keys | first = Ancel| title = Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease |url=https://archive.org/details/sevencountriesmu0000keys | url-access = registration | publisher = Harvard University Press | year = 1980 | isbn = 978-0-674-80237-7 }}</ref> As part of his argument, he presented a correlation between deaths from heart disease and percentage of fat in the diet that featured six countries.<ref>{{Cite journal|last=Keys|first=A.|date=July 1953|title=Atherosclerosis: a problem in newer public health|journal=Journal of the Mount Sinai Hospital, New York|volume=20|issue=2|pages=118–139|issn=0099-9695|pmid=13085148}}</ref> His rationale and conclusions were heavily critiqued by two other epidemiologists.<ref>{{Cite journal|last1=Yerushalmy|first1=J.|last2=Hilleboe|first2=H. E.|date=July 15, 1957|title=Fat in the diet and mortality from heart disease; a methodologic note|journal=New York State Journal of Medicine|volume=57|issue=14|pages=2343–2354|issn=0028-7628|pmid=13441073}}</ref>

After observing in southern Italy the highest concentration of centenarians in the world, Keys hypothesized that a Mediterranean-style diet low in animal fat protected against heart disease and that a diet high in animal fats led to heart disease. This finding helped Keys initiate a long-term observational study, known as the [[Seven Countries Study]], which appeared to show that serum cholesterol was strongly related to [[coronary artery disease|coronary heart disease]] mortality both at the population and individual levels.<ref>Kromhout D: "Serum cholesterol in cross-cultural perspective. The Seven-Countries Study". ''Acta Cardiol'' 1999;54:155–158</ref><ref name=Katan>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</ref>

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. Keys stated that of the 12,000 men in seven countries studied in 1960, those least likely to develop cardiovascular disease lived in [[Crete]].<ref>[http://www.nytimes.com/1998/02/10/science/personal-health-pass-the-wine-and-olive-oil-and-other-lessons-from-crete.html "Personal Health; Pass the Wine and Olive Oil, and Other Lessons From Crete"]. nytimes.com. Retrieved May 4, 2024.</ref>

After Keys' retirement from the [[University of Minnesota]] in 1972, his protege Henry Blackburn, MD became director of the Laboratory of Physiological Hygiene.<ref>{{cite web |title=Blackburn, Henry « Heart Attack Prevention |url=http://www.epi.umn.edu/cvdepi/bio-sketch/blackburn-henry/ |website=University of Minnesota |access-date=March 28, 2020}}</ref>  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.

===Keys equation===
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.<ref>{{cite web|url=https://www.lipid.org/sites/default/files/images/mwall/Ancel_Keys.pdf|title=Ancel Keys, PhD (1904–2004)|publisher=National Lipid Association|access-date=August 15, 2016}}</ref><div style="margin:1em;>
:Change in serum cholesterol concentration

:{{math|1=(mmol/L) {{=}} 0.031(2D<sub>sf</sub> − D<sub>puf</sub>) + 1.5{{sqrt|D<sub>ch</sub>}}}}

:where D<sub>sf</sub> is the change in percentage of dietary energy from saturated fats, D<sub>puf</sub> is the change in percentage of dietary energy from polyunsaturated fats, and D<sub>ch</sub> is the change in intake of dietary cholesterol.<ref>{{cite journal|volume=320|issue=7230|pages=301–5|date=January 29, 2000|journal=BMJ|title=Exploring a fiscal food policy: the case of diet and ischaemic heart disease|author=Marshall, Tom|pmc=1117490|pmid=10650031|doi=10.1136/bmj.320.7230.301}}</ref></div>

===BMI and other contributions===
In a 1972 article, Keys and his coauthors promoted{{citation needed|date=June 2022}} [[Adolphe Quetelet]]'s [[body mass index]] (BMI) as "preferable over other indices of relative weight on [correlation with height and measures of body fatness] as well as on the simplicity of the calculation and, in contrast to percentage of average weight, the applicability to all populations at all times",<ref>{{cite journal|title=Reprints and Reflections: Indices of relative weight and obesity|author1=Ancel Keys |author2=Flaminio Fidanza |author3=Martti J Karvonen |author4=Noburu Kimura |author5=Henry L Taylor |journal=Int. J. Epidemiol.|year=2014|volume=43|issue=3|pages=655–665 first published online April 1, 2014|doi=10.1093/ije/dyu058|pmid=24691951 |doi-access=free |quote=Reprint of Keys A, Fidanza F, Karvonen MJ, Kimuru N, Taylor HL. "Indices of relative weight and obesity". ''J Chron Dis'' 1972. Vol. 25. pp. 329–343. }}</ref> which the U.S. [[National Institutes of Health]] then popularized in 1985.<ref>{{cite news|title=Beyond BMI|author=Singer-Vine, Jeremy|date=July 20, 2009|url=http://primary.slate.com/articles/health_and_science/science/2009/07/beyond_bmi.html|publisher=The Slate Group|newspaper=Slate|access-date=February 10, 2016|archive-url=https://web.archive.org/web/20160216130711/http://primary.slate.com/articles/health_and_science/science/2009/07/beyond_bmi.html|archive-date=February 16, 2016}}</ref><ref>{{cite web|url=https://consensus.nih.gov/1985/1985Obesity049html.htm|title=Health Implications of Obesity|date=February 11, 1985|access-date=February 10, 2016|publisher=National Institutes of Health, U.S. Department of Health and Human Services}}</ref>

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."<ref>[https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4830a1box.htm Ancel Keys, Ph.D.], Morbidity and Mortality Weekly Report, [[Centers for Disease Control and Prevention]]</ref> Because of his influence in dietary science, Keys was featured on the cover of the January 13, 1961, issue of [[Time magazine|''Time'' magazine]].