ANNOTATED BIBLIOGRAPHY
Most medical research listed below has to do with the effect of lifestyle on various degenerative diseases, so typically, some experiment will be described where a lifestyle element was varied and its effect on a degenerative disease measured.
On the Internet, you can find research supporting any view you like. This research below obviously supports our own point of view, but we also believe we have chosen research that was well done. Much of the research flew strongly in the face of conventional wisdom at the time of its publication, so the collection represents some studies in courage as well.
One pervasive theme throughout is the glacial pace at which the medical profession revises its thinking. A quicker reaction to the dangers of trans fat could have saved hundreds of thousands. When we look at the possible implications of the high-carb diet, the number affected is considerably greater.
In defense of policy makers, it must be noted that it is not easy to promulgate policy when there may be conflicting interests at stake, and any policy needs to be sufficiently simple to avoid erroneous interpretation.
All these papers were found somewhere on the Internet non-paywalled. If you are interested, the same appendix is repeated at QuantitativeMedicine.net, with live links to the various papers. Search for “bibliography.”
NEJM=New England Journal of Medicine,
JAMA=Journal of the American Medical Association,
BMJ=British Medical Journal.
One or more papers are available on these topics . . .
| CAUSES OF DISEASE – EXCESS GLUCOSE
Glycation, Insulin, and Sugar CAUSES OF DISEASE – CANCER Cancer Screening Prostate Cancer Cancer and Glucose Levels Cancer and High-Protein Diets Cancer Progression Cancer and Sun Exposure Cancer and HDL Cancer and Inflammation CAUSES OF DISEASE – HEART DISEASE Heart Disease and Lifestyle Inflammation The Endothelium Heart Rate Predicting of Heart Attacks Lipoprotein(a) CAUSES OF DISEASE – DEMENTIA Dementia and Lifestyle CAUSES OF DISEASE – OSTEOPOROSIS Osteoporosis CAUSES OF DISEASE – AGING Mitochondria
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CAUSES OF DISEASE – ADULT ONSET DIABETES
Insulin and Glucose Adult Onset Diabetes and Low-Carb Diet Adult Onset Diabetes and Insulin Adult Onset Diabetes and Exercise Adult Onset Diabetes and Glycation EFFECTS OF LIFESTYLE Cancer and Lifestyle EATING Gluttony Low-Carb Diets The Omega-6 – Omega-3 Controversy Nuts Trans Fat Fructose EXERCISE Interval Versus Aerobic Exercise Your Wate and Fate SLEEP AND MEDITATION EVERYTHING ELSE Hunter-Gatherer Health and Lifestyle Pathogens and the Immune System Stem Cells Statins
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CAUSES OF DISEASE – EXCESS GLUCOSE
Glycation, Insulin and Sugar
Glucose, especially in excess, has a tendency to “stick” to other molecules, which are then said to be glycated. This is usually deleterious. The more the glucose, the more the glycation. Glucose that sticks to (glycates) hemoglobin in red blood cells is measured in a standard blood test, as Hemoglobin A1C or simply A1C. This measure is used as a surrogate for average blood glucose level. If this is high, excess glycation is occurring somewhere. Glycation in the brain causes dementia. If in the arteries, atherosclerosis. Adult onset diabetics have elevated blood sugar, and hence are prone to the various problems of excess glycation. These problems include cancer, heart disease, and dementia. Thus glycation would appear to be a major bad actor in most degenerative disease.
The A1C measurement is in percent and indicates the portion of your hemoglobin that is sugar coated. The ideal number for A1C is 5% or less. Listing A1C as a percentage is confusing, and an improvement from say, 7% to 5% would be a huge improvement, but doesn’t sound like much.
This paper rather clearly explains A1C and finds that adult onset diabetics with an A1C greater than 7% have 2½-fold increased all-cause mortality rate and an even higher risk of heart disease.
Khaw et al. “Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk).” BMJ VOLUME 322 6 JANUARY 2001
Glycation causes inflammation. The progression of Advanced Glycation End products (with AGE as its acronym) is discussed in this paper:
Ramasamy et al., “Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation,” Glycobiology vol. 15 no. 7 pp. 16R–28R, 2005
Glycation is further reviewed here:
Singh, A. Barden, T. Mori, L. Beilin., “Advanced glycation end-products: a review,” Diabetologia ?2001) 44: 129±146
Glycation is tied to cancer in this paper:
Louis J Sparvero et al., “RAGE (Receptor for Advanced Glycation Endproducts), RAGE Ligands, and their role in Cancer and Inflammation,” Journal of Translational Medicine 2009, 7:17
Here, glycation’s role in dementia is discussed:
Enzo Emanuele et al., “Circulating Levels of Soluble Receptor for Advanced Glycation End Products in Alzheimer,” Disease and Vascular Dementia.” ARCH NEUROL / VOL 62, NOV 2005
CAUSES OF DISEASE – CANCER
Cancer Screening
Is early screening for colon cancer beneficial? Although something suspicious was found in over 20% of those screened, these doctors conclude that screening for colon cancer for those under 50 is not “cost effective.” They have evidently already decided what we are worth.
Imperiale, D. Wagner, C. Lin, G. Larkin, J. Rogge, and D. Ransohoff, “Results Of Screening Colonoscopy Among Persons 40 To 49 Years Of Age,” N Engl J Med, Vol. 346, No. 23 · June 6, 2002
This prompted a well-deserved scolding in a later issue:
Romagnuolo. “Correspondence: Screening Colonoscopy Among Persons 40 To 49 Years Of Age.” N Engl J Med, Vol. 347, No. 15 · October 10, 2002
Here can be found the survival rate for early versus late detection of colon cancer:
O’Connell, M. Maggard, and C. Ko, “Colon Cancer Survival Rates With the New American Joint Committee on Cancer Sixth Edition Staging,” Journal of the National Cancer Institute, Vol. 96, No. 19, October 6, 2004
Prostate Cancer
The progression of prostate cancer has been dramatically slowed by drinking pomegranate juice and taking other supplements. Here are three papers presenting results:
Allan J. Pantuck et al., “Phase II Study of Pomegranate Juice for Men with Rising Prostate-Specific Antigen following Surgery or Radiation for Prostate Cancer,” Clin Cancer Res 2006;12(13) July 1, 2006
Pantuck et al., “Long Term Follow Up Of Phase 2 Study Of Pomegranate Juice For Men With Prostate Cancer Shows Durable Prolongation Of PSA Doubling Time,” The Journal Of Urology Vol. 181, No. 4, Supplement, Monday, April 27, 2009
R Thomas et al., “A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer—the UK NCRN Pomi-T study,” Prostate Cancer and Prostatic Disease (2014), 1–7
This is an excellent paper comparing the outcomes of a variety of prostate cancer treatments:
Cancer and Glucose Levels
Saydah et al. find that people who fail glucose testing have an 87% higher risk of cancer:
Saydah, C. Loria, M. Eberhardt, and F. Brancati, “Abnormal Glucose Tolerance and the Risk of Cancer Death in the United States,” Am J Epidemiology 2003;157:1092–1100
This study finds a strong relationship between high sugar levels and certain cancers, particularly liver cancer:
K.Rapp et al., “Fasting blood glucose and cancer risk in a cohort of more than 140,000 adults in Austria,” Diabetologia (2006) 49
Here is an article from the New York Times about a doctor who was on the right track in 1887. Look how he was treated:
This group finds a more than doubling of breast cancer risk for women with high blood glucose:
Muti, T. Quattrin, B. Grant, et al. “Fasting Glucose Is a Risk Factor For Breast Cancer: A Prospective Study,” Cancer Epidemiol Biomarkers Prev 2002;11:1361-1368.
Near doubling of pancreatic risk in the presence of high glucose:
Jee et al, “Fasting Serum Glucose Level and Cancer Risk in Korean Men and Women,” JAMA, January 12, 2005—Vol 293, No. 2
Specific lifestyle changes that affect cancer are broadly examined in this paper:
Anand et al., “Cancer is a Preventable Disease that Requires Major Lifestyle Changes,” Pharmaceutical Research, Vol. 25, No. 9, September 2008 (# 2008) DOI: 10.1007/s11095-008-9661-9
The Warburg effect, which is that cancers need sugar to thrive and have lost much of their mitochondrial function, is discussed here:
Jung-whan Kim1 and Chi V. Dang, “Cancer’s Molecular Sweet Tooth and the Warburg Effect,” Cancer Res 2006; 66: (18). September 15, 2006
Still more on the sugar connection to cancer and the Warburg Effect can be found here:
Patrick Quillin, “Cancer’s Sweet Tooth,” Nutrition Science News, April 2000
More on the Warburg effect and mitochondria:
Boland, A. Chourasia1, and K Macleod, “Mitochondrial Dysfunction in Cancer,” Frontiers in Oncology, 02 December 2013
This paper describes the Warburg effect in breast cancer:
D Ciavardelli, “Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment,” Cell Death and Disease (2014) 5, e1336
Alcohol greatly increases the risk of esophageal cancer; even a single drink a day raises the risk 33%:
Paolo Boffetta, Mia Hashibe, “Alcohol and cancer,” Lancet Oncol 2006; 7: 149–56
Cancer and High-Protein Diets
Despite a steady and shrill stream of warnings from the vegan crowd that high protein kills, we have this:
Victor W. Ho et al., “A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation,” Cancer Res; 71(13) July 1, 2011
Cancer Progression
Michor et al. go through the various steps of cancer progression:
Michor, Y. Iwasa, And M. Nowak, “Dynamics Of Cancer Progression,” Nature Reviews | Cancer, Volume 4, 2004
Cancer and Sun Exposure
It is commonly believed that exposure to the sun is associated with malignant melanoma, but this only appears to be the case if there are repeated instances of sunburn. Magnus examines this and finds more malignant melanoma in parts of the body which have the least exposure toward skin.
Knut Magnus, “Habits of Sun Exposure and Risk of Malignant Melanoma,” Cancer 48:2329-2335, 1981.
Cancer and HDL
This key paper identifies the amazing protective effect of increased HDL. A 10 mg/dl increase in HDL was associated with a 36% reduction in cancer, a very powerful result:
Jafri et al., “Baseline and On-Treatment High-Density Lipoprotein Cholesterol and the Risk of Cancer in Randomized Controlled Trials of Lipid-Altering Therapy,” Journal of the American College of Cardiology, Vol. 55, No. 25, 2010
Another paper on HDL’s tumor-fighting properties:
Feng Su et al., “HDL Mimetics Inhibit Tumor Development in Both Induced and Spontaneous Mouse Models of Colon Cancer,” Mol Cancer Ther; 11(6) June 2012
Cancer and Inflammation
This paper examines the relationship between cancer and inflammation, particularly the specific mechanisms involved:
Seth Rakoff-Nahoum, “Why Cancer and Inflammation?” Yale Journal Of Biology And Medicine 79 (2006), pp.123-130.
CAUSES OF DISEASE – HEART DISEASE
Heart Disease and Lifestyle
Tuzcu et al. examined hearts from relatively young people and found a surprising amount of heart disease. Perhaps atherosclerosis should be considered a childhood disease:
Murat Tuzcu et al, “High Prevalence of Coronary Atherosclerosis in Asymptomatic Teenagers and Young Adults,” Circulation June 5, 2001
A macrophage is a large white cell that “eats” bad stuff. These are handy to have around. How do they know what to eat? They have receptors on their surface that detect various debris. The macrophages described below have receptors that look for damaged LDL (oxidized, glycated, etc.) The paper is a bit technical, but includes a description of the various receptors in the cell’s receptor kit: bad LDL, staph bacteria, hepatitis, pneumonia, and so on. There seems no end to the body’s gadget collection
David R. Greaves1 and Siamon Gordon, “The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges,” Journal of Lipid Research April Supplement, 2009
Inflammation
In 2002, inflammation was beginning to appear on the scene as the new bad guy:
Peter Libby, Paul M. Ridker, Attilio Maseri, “Inflammation and Atherosclerosis,” Circulation. 2002;105:1135-1143.
One of HDL’s tricks in inflammation reduction:
Marcus D. Saemann et al., “The versatility of HDL: a crucial anti-inflammatory Regulator,” European Journal of Clinical Investigation Vol 40.
The Endothelium
For decades, the endothelium was thought to be merely a blood vessel lining and of little importance. It is now viewed as essential to arterial health. Here is a good survey paper from 2005:
Lerman and Zeiher, “Endothelial Function Cardiac Events,” Circulation. 2005;111;363-368.
One important endothelial function is nitric oxide synthesis. Low nitric oxide is a cause of high blood pressure.
Forstermann and Sessa, “Nitric oxide synthases: regulation and function,” European Heart Journal (2012) 33, 829–837
“You are only as old as your arteries” is respun here in medicalese:
Zoltan Ungvari et al., “Mechanisms of Vascular Aging: New Perspectives,” J Gerontol A Biol Sci Med Sci. 2010 October;65A(10):1028–1041
Most atherosclerosis forms in places where the endothelium is frequently replaced. Here, a researcher determines that LDL (and everything else) leaks through during replacement, and replacement happens frequently in areas of low or no blood flow.,
HDL, on the other hand, is welcome behind the artery wall, and the endothelial cells will escort it right through. This paper reviews this amazing process:
Heart Rate
Resting heart rate, maximum heart rate during exercise, and heart rate recovery after peak exercise all provide substantial information about heart attack risk. (Again, don’t attempt extreme exercise without your doctor’s blessing.) Resting heart rate should be taken before you get out of bed in the morning. There is considerably more detail in the paper, but here is a quick summary. Those with a resting heart rate over 75 bpm (beats per minute) had a fourfold higher risk than those 60 or less. For peak heart rate, those whose peak was less than 90 bpm higher than their resting heart rate also had a four-fold higher risk than those whose peak rate exceeded their resting rate by more than 113. Finally, for recovery after peak exercise, those whose heart rate dropped more than 25 bpm one minute after peak exercise had more then a twofold risk increase over those whose rate declined by more than 40. If you have a watch that will monitor heart rate, you can track your progress.
Jouven et al., “Heart-Rate Profile during Exercise as a Predictor of Sudden Death,” NEJM 352;19 May 12, 2005
Predicting Heart Attacks
Coronary calcium directly measures plaque load. One would think a “direct view” of the problem would be a no-brainer, yet this test remains an outlier. Insurance won’t pay for it and so on. This paper is a bit obfuscated by statistical analysis, but, in fact, the rate of heart attacks between the highest to lowest heart calcium groups was a whopping 20:1. Are you at risk? Forget cholesterol—get a heart scan. This paper is 10 years old, yet a heart scan is still not a standard procedure for determining cardiac risk. (An interesting aside: statins have no effect on heart calcium.)
Michael J. LaMonte et al., “Coronary Artery Calcium Score and Coronary Heart Disease Events in a Large Cohort of Asymptomatic Men and Women,” Am J Epidemiol 2005;162:421–429
On the other hand, here we have a paper trying to predict heart attacks from cholesterol, triglycerides, and the other typical measurements. Instead of getting results like 20 times more likely, we get results for high LDL or high triglycerides of 0.3 times more likely. This is a weak predictor at best. Yet this is the standard procedure for determining heart risk. Go figure.
A.R. Sharrett et al., “Coronary Heart Disease Prediction From Lipoprotein Cholesterol Levels, Triglycerides, Lipoprotein(a), Apolipoproteins A-I and B, and HDL Density Subfractions: The Atherosclerosis Risk in Communities (ARIC) Study,” Circulation. 2001;104:1108-1113
CAUSES OF DISEASE – DEMENTIA
Dementia and Lifestyle
Here cortisol level is shown to have an adverse effect on the hippocampus.
Lupien et al., “Cortisol levels during human aging predict hippocampal atrophy and memory deficits,” Nature Neuroscience volume 1 no. 1 may 1998
This paper is a survey of factors affecting Alzheimer’s. It discusses low cholesterol and low fat intake as possible contributing causes:
Barry Groves, “Alzheimer’s and Parkinson’s Diseases,” Second Opinions, 1 Aug 2008
A ketogenic diet (little or no carbs) has shown some effectiveness against Alzheimer’s:
Robert Krikorian et al., “Dietary ketosis enhances memory in mild cognitive impairment,” Neurobiol Aging. 2012 February
The following review article discusses the causes of Alzheimer’s. He notes that exercise and “cognitive stimulation” may reduce the risk:
Mark P. Mattson. “Pathways towards and away from Alzheimer’s disease,” Nature vol 430 |5 AUG 2004
Alzheimer’s is significantly reduced by a mediterranean Diet and by exercise:
Nikolaos Scarmeas et al., “Physical Activity, Diet, and Risk of Alzheimer Disease,” JAMA, August 12, 2009—Vol 302, No. 6
The ketogenic diet is again examined here. The author posits, “While the mechanisms through which the ketogenic diet works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism.” Let’s hear it for “normalization of aberrant energy metabolism,” the most oblique reference to “eating right” on record.
Carl E. Stafstrom and Jong M. Rho, “The ketogenic diet as a treatment paradigm for diverse neurological disorders,” Frontiers in Pharmacology | Neuropharmacology,April 2012 | Volume 3 | Article 59 | 2
The higher the total cholesterol, the better the cognition, in this paper from 2005. This is, by the way, the same cholesterol the medical profession has spent the last two decades trying to lower at all costs. Since statins lower cholesterol, the interesting experiment would be the effect of statins on cognition. Any volunteers?
Penelope k. Elias et al, “Serum Cholesterol and Cognitive Performance in the Framingham Heart Study,” Psychosomatic Medicine 67:24–30 2005
In this review article, the author suggests that Alzheimer’s should be called type 3 diabetes, as sugar/insulin is way out of regulation:
Suzanne M. de la Monte and Jack R. Wands, “Alzheimer’s Disease Is Type 3 Diabetes—Evidence Reviewed,” Journal of Diabetes Science and Technology IEW ARTICLE Volume 2, Issue 6, November 2008
These researchers also see Alzheimer’s as a metabolic disorder:
Sergio T. Ferreira et al., “Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease,” Alzheimer’s & Dementia 10 (2014) S76–S83
McNay is also supporting the metabolic syndrome hypothesis of Alzheimer’s:
Ewan McNay, “Your Brain on Insulin: From Heresy to Dogma,” Perspectives on Psychological Science 2014, Vol 9(1) 88–90
More research indicating glucose and insulin are at the root of the Alzheimer’s epidemic:
Enrique Blázquez et al., “Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer’s disease,” Frontiers of Endocrinology, October 2014 | Volume 5 | Article 161 | 1
Lipoprotein(a)
Also known as Lp(a), this variant form of the LDL lipoprotein particle significantly increases the risk of heart disease and clotting. The variation consists of the attachment of a protein string called apo(a). Lp(a)’s evolutionary benefit is unknown, but it may confer some resistance to cancer and adult onset diabetes. This review paper is an excellent overview. A molecular biology section that is a bit difficult follows the introduction. Then follows a very interesting review of known benefits and treatments.
Anti-sense therapy is proposed for high Lp(a). In this therapy, a molecule is introduced that binds to the specific RNA that initiates the Lp(a) apo(a) string. However, such drugs often bind to similar molecules and end up showing no benefit or even harm. Here are two recent papers:
Details of the attached apo(a) protein string are discussed here. The string comes in various lengths (isoforms), and the longer ones are significantly less harmful.
CAUSES OF DISEASE – ADULT ONSET DIABETES
Insulin and Glucose
This paper is a transcript of a talk given in 1999. Though not at all kind to the medical establishment, it has a very broad range, and establishes the crucial importance of managing insulin:
Rosedale, Ron, “Insulin and Its Metabolic Effects,” Presented at Designs for Health Institute’s BoulderFest, August 1999 Seminar
Insulin resistance is a hallmark of type 2 (adult onset) diabetes. It is a syndrome wherein insulin is unable to clear blood glucose effectively. (The body becomes “resistant.”) One interpretation is that the various cells already have all the glucose that they want. This paper describes insulin resistance at the cellular level in some detail:
Schenk, M. Saberi, and J. Olefsky, “Insulin sensitivity: modulation by nutrients and inflammation,” J. Clin. Invest. 118:2992–3002 2008
This paper ties insulin resistance to inflammation:
Jerrold M. Olefsky and Christopher K. Glass, “Macrophages, Inflammation, and Insulin Resistance,” Annu. Rev. Physiol. 2010. 72:219–46
Is whole grain better for you? This paper looks at glucose and insulin after consumption of either whole or refined grain and finds no difference:
Katri S Juntunen et al., “Postprandial glucose, insulin, and incretin responses to grain products in healthy subjects,” Am J Clin Nutr 2002;75:254–62
Here is an important paper wherein adult onset diabetics were treated with insulin, rather than the standard, metformin. The insulin caused a significant increase of various cancers. Three conclusions here: 1) Thousands were treated with insulin. Where were the vaunted safety measures? This protocol went very wrong. 2) There is no logic here. If there is no demand for the excess glucose, the solution is to reduce the supply, not “force” an increased demand. 3) High insulin causes cancer.
J. Currie, C. D. Poole, and E. A. M. Gale, “The influence of glucose-lowering therapies on cancer risk in type 2 diabetes,” Diabetologia (2009) 52:1766–1777 DOI 10.1007/s00125-009-1440-6
Adult Onset Diabetes and Low-Carb Diet
A cohort of 28 diabetics undertook a low-carb diet, with very impressive results. Seven were able to stop taking their meds.
William S Yancy Jr. et al., “A Low-Carbohydrate, Ketogenic Diet To Treat Type 2 Diabetes,” Nutrition & Metabolism 2005, 2:34
Adult Onset Diabetes and Insulin
Insulin use in type 2 diabetics is associated with significant increase in cancer risk. It’s double the risk in this paper.
Samantha l. Bowker et al., “Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin,” Diabetes Care, Volume 29, Number 2, February 2006
Adult Onset Diabetes and Exercise
Interval training was associated with significant glucose improvement in a group of adult onset diabetics.
Jonathan P. Little et al., “Low-volume high-intensity interval training reduces hyperglycemia and increases muscle mitochondrial capacity in patients with type 2 diabetes,” J Appl Physiol 111: 1554–1560, 2011.
Adult Onset Diabetes and Glycation
Glycation is the attachment of a sugar molecule to some other molecule. The can be quite detrimental and is a factor in Alzheimer’s, atherosclerosis, and other diseases. Here glycated hemoglobin is identified in diabetes.
Kay-Tee Khaw et al.m “Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk),” BMJ Volume 322 6 January 2001
CAUSES OF DISEASE – OSTEOPOROSIS
Osteoporosis
This is an important paper. Those calcium supplements, which are almost universally recommended to treat osteoporosis, appear to increase the occurrence of heart attacks 25%, while having little effect on osteoporosis.
Mark J Bolland, “Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis,” BMJ 2011;342:d2040
Here is a paper showing the mild effect on bone from calcium/vitamin D supplementation. Basically calcium/vitamin D can only slow things down a bit.
Dawson-Hughes et al., “Effect Of Calcium And Vitamin D Supplementation On Bone Density In Men And Women 65 Years Of Age Or Older,” NEJM, September 4, 1997
And here is the cure. Note the date. The benefit of resistance exercise on osteoporosis is not a new story, yet it still is not mainstream medicine.
Vincent, K. R., and R. W. Braith, “Resistance Exercise And Bone Turnover In Elderly Men And Women,” Med. Sci. Sports Exerc.,Vol. 34, No. 1, 2002, pp. 17–23.
CAUSES OF DISEASE – AGING
Free radicals were the new bad boy 15 years ago, launching an antioxidant industry featuring all sorts of supplements designed to gobble them up. Things are a bit more settled now. Like everything else, free radicals have a purpose and are regulated. This paper broadly reviews research on the free radical theory of aging. Nothing definite can be concluded.
Kenneth B. Beckman And Bruce N. Ames, “The Free Radical Theory of Aging Matures,” Physiological Reviews Vol. 78, No. 2, April 1998.
Mitochondria
The mitochondrial theory of aging holds that mitochondrial DNA, which indeed hasn’t the precision of repair and maintenance of our regular cellular DNA, degrades with time, causing the mitochondria to perform less efficiently, thus contributing to accelerated aging and degenerative disease. This is somewhat controversial, though it undoubtedly is a significant factor, perhaps the most significant factor. This entire book is available online, is very well written, and gives a great overview.
Aubrey D.N.J. de Grey, “The Mitochondrial Free Radical Theory of Aging,” 1999 R.G. Landes Company (ENTIRE BOOK)
Numerous aspects of the mitochondria theory have been examined since de Grey’s publication. Some have survived and others have not. The following paper gives a good overview of this14 years later.
Gustavo Barja, “Updating the Mitochondrial Free Radical Theory of Aging: An Integrated View, Key Aspects, and Confounding Concepts,” Antioxidants & Redox Signaling. October 20, 2013, 19(12): 1420-1445
The cause of insulin resistance is somewhat controversial. It is known that the muscles either won’t or can’t take up the glucose. This paper argues that excess fat in the cell interferes with insulin signaling and that is the cause. This could be interpreted as “the cell is full and doesn’t want any more stuff.”
Timothy R. Koves et al., “Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance,” Cell Metabolism 7, 45–56, January 2008
EFFECTS OF LIFESTYLE
Cancer and Lifestyle
The number of people in this study was a bit small, but the results were quite stunning. Around 200 people with high blood pressure (around 140 mm Hg) either meditated or received “standard” health instruction. They were followed for some years. The meditators had a 23% decrease in all-cause mortality, a 30% decrease in mortality from heart disease, and a huge 50% decrease in cancer mortality.
Schneider, et al., “Long-Term Effects of Stress Reduction on Mortality in Persons ≥55 Years of Age With Systemic Hypertension,” Am J Cardiol. 2005 May 1
This paper represents the other side of the coin: depression, which could likely be alleviated by meditation. Chronic depression increased cancer risk 88%.
Brenda W. J. H. Penninx, et al., “Chronically Depressed Mood and Cancer Risk in Older Persons,” Journal of the National Cancer Institute, Vol. 90, No. 24, December 16, 1998
These papers examines the incidence of cancer in night and shift workers. Megdal et al. find a 50% increase in breast cancer.
Bhatti, D. Mirick, S. Davis, “Invited Commentary: Shift Work and Cancer.,” Am J Epidemiol. 2012;
Megdal et al., “Night work and breast cancer risk: A systematic review and meta-analysis,” European Journal of Cancer 41 (2005)
Cancer incidence in the Nurses’ Health Study is computed for many lifestyle choices, including smoking, drinking, and nut consumption.
Baer et al., “Risk Factors for Mortality in the Nurses’ Health Study: A Competing Risks Analysis,” Am J Epidemiology 2011
EATING
Gluttony
In an experiment likely to never be repeated, we have two charmingly titled papers wherein subjects consumed enormous amounts of fat, some as much as 6,000 calories/day. To the astonishment of the researchers, they essentially did not gain weight. There were hot and sweaty all the time. If you want proof positive that fat doesn’t make you fat, here it is.
Miller and P. Mumford, “Gluttony 1. An Experimental Study of Overeating Low or High Protein Diets,” The American Journal of Clinical Nutrition, Vol. 20, No. 11, November 1967.
Miller and P. Mumford, “Gluttony 2. Thermogenesis in Overeating Man,” The American Journal of Clinical Nutrition, Vol. 20, No. 11, November 1967.
Another “gluttony” experiment. These people either took excess olive oil (they gained some weight) or corn oil (they lost weight).
H Kasper, H Thiel, M Ehl, “Response of body weight to a low carbohydrate, high-fat diet in normal and obese subjects,” The American journal of clinical Nutririon, 1973 – Am Soc Nutrition
Low-Carb Diets
Here’s a marvelous paper from Stanford where a group was given a very high-fat diet for several weeks, then a high-carbohydrate diet for several more. As we would expect in light of today’s knowledge, cholesterol and triglycerides were stable on the high-fat diet, but soared on the high-carb one. What’s remarkable is the date of the study—1966—after which followed 50 years of high-carb, low-fat diet recommendations, with endless wonderment all the while as to why everyone was getting so fat.
Farquhar, A. Frank, R. Gross, and G. Reaven, “Glucose, Insulin, and Triglyceride Responses to High and Low Carbohydrate Diets in Man,” Journal of Clinical Investigation Vol. 45, No. 10, 1966
The following papers discuss low-carb diets, such as the Atkins Diet. Invariably, LDL, HDL, and triglycerides show marked improvement.
Richard J. Wood et al., “Carbohydrate Restriction Alters Lipoprotein Metabolism by Modifying VLDL, LDL, and HDL Subfraction Distribution and Size in Overweight Men,” J. Nutr. February 2006 vol. 136 no. 2 384-389
This review article examines the very strong association of high carbohydrate consumption and high triglycerides. Its conclusion is that “the American public has increased its consumption of carbohydrate, either through the consumption of more food per day or through replacement of fats with carbohydrates. At the same time, the incidence of obesity in this country is rising. Whether these 2 trends are linked is unknown.” Aren’t we ignoring an elephant in the room here?
Elizabeth J Parks and Marc K Hellerstein, “Carbohydrate-Induced Hypertriacylglycerolemia: Historical Perspective And Review Of Biological Mechanisms,” Am J Clin Nutr February 2000 vol. 71 no. 2 412-433
Here is a paper astonishing for its prescience in 2004. Specifically we have this: “In postmenopausal women with relatively low total fat intake, a greater saturated fat intake is associated with less progression of coronary atherosclerosis, whereas carbohydrate intake is associated with a greater progression.” Translation: “saturated fat good—carbs bad.” Ten years later, the medical world has grasped about half of this: carbs are bad. Saturated fat is still in nutritional limbo.
Mozaffarian, E. Rimm, and D. Herrington, “Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women,” Am J Clin Nutr 2004;80:1175–84
A survey paper summarizing the huge shift in attitude concerning saturated fat.
Arne Astrup, “A Changing View On SFAs and Dairy: From Enemy To Friend,” Am J Clin Nutr doi: 10.3945/ajcn.114.099986.
Yet another paper indicating that high-carb diets cause heart disease. This one dates from 1997.
Jeppesen J et al., “Effects of low-fat, high-carbohydrate diets on risk factors for ischemic heart disease in postmenopausal women,” Am J Clin Nutr. 1997 Apr;65(4):1027-33.
This huge meta-analysis concludes there is no association of saturated fat with heart disease. These were highest to lowest quintile comparisons, which would mean that one group that consumed a lot of saturated fat was compared to another that consumed very little. Saturated fat was mildly protective for heart attack, and neutral for strokes and atherosclerosis.
Siri-Tarino, Q. Sun, F. Hu, and R. Krauss, “Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease,” Am J Clin Nutr 2010;91:535–46.
The Mediterranean diet shows a 30% reduction in heart disease.
Ramón Estruch et al., “Primary Prevention of Cardiovascular Disease with a Mediterranean Diet,” n engl j med 368;14
The Omega-6 – Omega-3 Controversy
There is abundant popular literature suggesting that we reduce omega-6 oils or maintain some ration of omega-6 to omega-3. This paper dives into that controversy and finds that omega-6 oil is beneficial, particularly for reduction of heart disease risk, and further that excess omega-6 is not harmful and may have additional benefit.
William S. Harris et al., “Omega-6 Fatty Acids and Risk for Cardiovascular Disease,” Circulation. 2009;119:902-907.
Nuts
Here heart disease is reduced around 30% for people who eat nuts five times a week or more. Ischemic heart disease is cut in half and all-cause mortality is also reduced around 30%.
Joan Sabaté, “Nut consumption, vegetarian diets, ischemic heart disease risk, and all-cause mortality: evidence from epidemiologic studies,” Am J Clin Nutr 1999;70(suppl):500S–3S
Also see this one for nuts versus cancer.
Baer, et al., “Risk Factors for Mortality in the Nurses’ Health Study: A Competing Risks Analysis,” Am. J. Epidemiol. (2011) 173 (3): 319-329.
Trans fat
By the mid-’90s, trans fat had been nailed as a really bad actor. Ascherio and Willett conclude that it caused 30,000 premature deaths annually in the United States alone. Sixteen years later, the FDA decided to start looking at it, and is currently (2016) considering measures to further reduce it. If you are wondering why there wasn’t an outright ban two decades ago, you are not alone.
A Ascherio, WC Willett, “Health effects of trans fatty acids,” Am J Clin Nutr October 1997vol. 66 no. 4 1006S-1010S
Fructose
We do not appear to be well adapted to deal with the unnaturally large amounts of fructose present in the Western diet. The effects are summarized in this short editorial. Apparently curtailing fructose in processed food has a deleterious effect on profits, as there is significant industry pushback. Will the FDA ban added fructose anytime soon? Perhaps they should be encouraged to require the industry to prove s high-fructose corn syrup is good for you before they allow its use—as they do with drugs.
George A Bray. “How bad is fructose?” Am J Clin Nutr 2007;86:895–6.
EXERCISE
Interval Versus Aerobic Exercise
This is about as close as you can come to a free lunch or magic pill. Here one group cycled at 65% maximum heart rate for 4 ½ hours per week, and another group did high-intensity exercise for 10 minutes per week. That’s 10 minutes spent doing the actual exercises, which typically involve a 30-second all-out effort and a 30-second rest. So the actual time involved may be 20 minutes. In spite of spending less than a tenth of the time as the bikers, the interval people had significantly greater improvement in VO2Max and also in a measure of mitochondrial function.
Gibala, J. Little, M. MacDonald and J. Hawley, “Physiological adaptations to low-volume, high-intensity interval training in health and disease,” Physiol 590.5 (2012) pp 1077–1084
Here the same experiment was done, except this time both groups had heart issues. Again, the interval group did better.
Darren E.R. Warburton et al., “Effectiveness of High-Intensity Interval Training for the Rehabilitation of Patients With Coronary Artery Disease,” The American Journal of Cardiology Vol. 95 May 1, 2005
Finally, here is a broad review of results of interval training. There seems to be no downside to interval training.
Paul B. Laursen and David G. Jenkins, “The Scientific Basis for High-Intensity Interval Training,” Sports Med 2002; 32 (1)
Your Wate and Fate
Here’s one of the articles that identifies the healthiest body mass index as “overweight.”
Flegal, B. Kit, H. Orpana, B. Graubard, “Association of All-Cause Mortality With Overweight and Obesity Using Standard Body Mass Index CategoriesA Systematic Review and Meta-analysis,” JAMA. 2013;309(1):71-82.
Here’s the paper about the 450-pound Scotsman who fasted for over a year.
A Ascherio, WC Willett, “Health effects of trans fatty acids,” ;2DW. K. Stewart, Laura W. Fleming, “Features of a successful therapeutic fast of 382 days’ duration,” Postgrad Med J 1973;49:203-209
How would you measure jollity? Find out here.
A H Crisp and B McGuiness, “Jolly fat: relation between obesity and psychoneurosis in general population,” Br Med J. Jan 3, 1976; 1(6000): 7–9.
SLEEP AND MEDITATION
There is little research on meditation, but in all cases where it was measured, meditation caused a significant reduction in cortisol. As cortisol is a launch pad for both cancer and adult onset diabetes, keeping it under control merits attention.
There is far more research on sleep. Poor sleep patterns are so strongly associated with cancer that it could be said to be causative. Shift work and irregular sleep derail the melatonin cycle, which sets off a whole series of subsequent problems.
Sleep and low stress are far more important than generally recognized. This 50-year-old article established that Human Growth Hormone only comes out at night, effectively being zero during the day. This hormone triggers a number of renew and repair hormones, including IGF-1:
Takahashi, et al., “Growth Hormone Secretion during Sleep,” The Journal of Clinical Investigation Volume 47 1968
Young and Taylor argue that meditation has survival roots, and was a form of hibernation.
John Ding-E Young and Eugene Taylor, “Meditation as a Voluntary Hypometabolic State of Biological Estivation,” News Physiol. Sci. Volume 13 June 1998
A course of transcendental meditation lowers cortisol.
Christopher R. K. et al., “Effects Of The Transcendental Meditation Program On Adaptive Mechanisms: Changes In Hormone Levels And Responses To Stress After 4 Months Of Practice,” Psychoneuroendocrinology, Vol. 22, No. 4, pp. 277-295, 1997
In this meta-analysis, night work, primarily airline work, led to a 50% higher risk of breast cancer.
Sarah P. Megdal et al., “Night work and breast cancer risk: A systematic review and meta-analysis,” European Journal of Cancer 41 (2005) 2023–2032
This paper tends to close the loop on the preceding one. Melatonin is substantially disrupted if sleep is disturbed. Here it is shown to have direct breast-cancer-fighting properties.
J. Sánchez-Barceló et al., “Melatonin: An Endogenous Antiestrogen with Oncostatic Properties,” Melatonin: From Molecules to Therapy- Chapter XV
These researchers find that poor sleep patterns in the elderly are strongly associated with all-cause mortality. Of course, terminal diseases are likely to cause poor sleep. These researchers studied healthy people and found that poor sleep doubled the risk of death.
Mary Amanda Dew et al., “Healthy Older Adults’ Sleep Predicts All-Cause Mortality at 4 to 19 Years of Follow-Up,” Psychosomatic Medicine 65:63–73 (2003) (ABSTRACT ONLY)
Kreuger and Friedman did a large meta-analysis and concluded that the average amount of sleep in the U.S. is between seven and eight hours, and that those sleeping seven hours had the lowest mortality.
Patrick M. Krueger and Elliot M. Friedman, “Sleep Duration in the United States: A Cross-sectional Population-based Study,” 1052 Am J Epidemiol 2009;169:1052–1063
These researchers found essentially the same result.
Kripke er al., “Mortality Associated With Sleep Duration and Insomnia,” Arch Gen Psychiatriatry Vol 50, Feb 2002
EVERYTHING ELSE
Hunter-Gatherer Health and Lifestyle
This article, dating from 1937, identifies cancer among various societies. It does not indicate the cause for the cancer.
Bonne, “Cancer and Human Races,” Am J Cancer 1937;30:435-454.
Gurven and Kaplan study mortality patterns of 14 different hunter-gatherer tribes—very thorough and analytical. They develop expected longevity given current age and have various other analyses. Pertinent to our endeavor are causes of death. For the elderly, degenerative disease appears to cause it 20% to 25% of the time.
Gurven and H. Kaplan, “Longevity Among Hunter-Gatherers: A Cross-Cultural Examination,” Population and Development Review 33(2): 321–365 (June 2007)
Milton offers interesting comments on the diversity of hunter-gatherer diets.
Katharine Milton, “Hunter-gatherer diets—a different perspective,” Am J Clin Nutr 2000;71:665–7.
Here’s a cure to degenerative disease that appears to work. O’Dea follows 10 middle-aged Australian aboriginal hunter-gatherers who returned to the bush after attempting to acclimate to city life, noting: “In conclusion, the major metabolic abnormalities of type 2 diabetes were either greatly improved or completely normalized in this group of Aborigines by relatively short reversal of the urbanization process.” Blood test measurements were done before the reintroduction and seven weeks later. The group’s sugar numbers improved dramatically in these seven weeks.
Kerin O’Dea, “Marked Improvement in Carbohydrate and Lipid Metabolism in Diabetic Australian Aborigines After Temporary Reversion to Traditional Lifestyle,” Diabetes, vol. 33, June 1984
Weston Price was a dentist as well as a university anthropologist who traveled worldwide in the 1920s and 1930s examining the health of various isolated people, particularly their dental health. This is reinforced with numerous dental photos. There is detailed information on diet. Weston-Price attributes the near absence of dental problems among isolated people and hunter-gatherers to their traditional diet.
Weston A. Price, “Nutrition and Physical Degeneration: A Comparison of Primitive and Modern Diets and Their Effects,” Harper & Brothers New York London, 1939 (ENTIRE BOOK)
A variety of health observations of various hunter-gatherers can be found here.
Zac Goldsmith, “Cancer: A Disease of Industrialization,” Pharmaceutical Research, Vol. 25, No. 9, September 2008
The wide variety of Paleolithic fare is quite thoroughly described.
Eaton, M. Konner, “Paleolithic Nutrition: A consideration of it Nature and Current Implications,” NEJM, Jan 31, 1985
The authors of the previous paper re-examine the Discordance Hypothesis. Oddly, they rehash paleo dietary items in the context of conventional wisdom (saturated fat and cholesterol are bad), almost as though setting out to “prove” this by hunter-gatherer behavior. They then conclude that hunter-gatherers ate little saturated fat, but a lot of cholesterol, and then conclude that the lesser amount of saturated fat counteracts the excess cholesterol. Quite a lot of logical gymnastics to go through to protect the party line. Then they start in on salt.
Melvin Konner, and S. Boyd Eaton, “Paleolithic Nutrition Twenty-Five Years Later,” Nutrition in Clinical Practice Vol. 25, No. 6, December 2010
Again the same authors with a general discussion of degenerative disease.
Eaton, M. Konner, M. Shostak, “Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective,” The American Journal of Medicine Volume 84, 1988
These people conclude that hunter-gatherer societies will eat meat when they can and 73% get over half their energy from meat.
Cordain, J. Miller, S., N. Mann, S. Holt, and J. Speth, “Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets,” Am J Clin Nutr 2000;71:682–92
These hunter-gatherers in India appear to frequently live to 100, and easily outlive the people in the surrounding areas.
R.K. Anuradha et al., “Cultural and Nutritional Perspective of Indian Hunter-Gatherers (Kurichia Tribe),” American Medical Journal 3 (1): 1-7, 2012
Here, a 1974 paper concluding that beyond a certain age, hunter-gatherers outlive others.
Alexander R. P. Walker, “Survival rate at middle age in developing and western populations,” Postgraduate Medical Journal (January 1974) 50, 29-32.
An excellent book on hunter-gatherer lifestyles would be:
McMichael, AJ, “Human Frontiers, Environments and Disease: Past Patterns, Uncertain Futures,” 250–282 (Cambridge Univ. Press, Cambridge, 2001) (BOOK-VARIOUS PARTS AVAILABLE ONLINE)
Pathogens and the Immune System
Here is a fascinating paper describing the various tricks bacteria and viruses use to fool the immune system.
Leigh A. Knodler, Jean Celli And B. Brett Finlay, “Pathogenic Trickery: Deception Of Host Cell Processes,” Nature Reviews | Molecular Cell Biology Volume 2 | August 2001
Stem Cells
Here is a very readable paper on intestinal stem cells.
Barker, Wetering, and Clevers, “The intestinal stem cell,” Genes & Development 22:1856–1864 2008
More on stem cells.
Petersen and Polyak, “Stem Cells in the Human Breast,” Cold Spring Harbor Perspect Biol 2010;2:a003160
Statins
The title of this paper says it all. ENHANCE was a trial that tested statins used alone or in combination with another drug, ezetimibe, which also lowered cholesterol. The trial was a flop. People taking both the drugs got worse even though their cholesterol was further reduced. Now statins do, in fact, lower cholesterol, but they are also anti-inflammatory, like aspirin, and may suppress the immune system. The ENHANCE result would tend to indicate that cholesterol reduction is not doing the heavy lifting.
Greg Brown, M.D., Ph.D., and Allen J. Taylor, “Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe?” NEJM 358;14, April 3, 2008
This is a bizarre paper of the relation between ezetimibe and cancer. In the abstract, results are stated as “Assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites.” and “Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer.” Yet the conclusion was, “The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer.” What—50% more cancer is not credible? Go reread your abstract, docs.
Richard Peto et al., “Analyses of Cancer Data from Three Ezetimibe Trials,” NEJM 359;13 September 25, 2008
This is a 10-year-old result on the benefits of statins on women of all ages. With no heart disease, statins had no effect on heart disease mortality (and a negative effect otherwise). For women with heart disease, statins did reduce heart disease mortality, but not overall mortality. Conclusion: no women get any benefit from statins. This 10-year-old result is from the prestigious Journal of the American Medical Association (JAMA), and you would think this would not be taken lightly. Do you suppose statin prescriptions are still being written to women 10 years later? Remember the takeaway: Statins+Women=no benefit. How did this ever get to be a blockbuster drug?
Judith M. E. Walsh, Michael Pignone, “Drug Treatment of Hyperlipidemia in Women,” JAMA, May 12, 2004—Vol 291, No. 18
A study to determine if statins reduce heart calcium. They didn’t.
Arad, L. Spadaro, M. Roth, D. Newstein, A. Guerci, “Treatment of Asymptomatic Adults With Elevated Coronary Calcium Scores With Atorvastatin, Vitamin C, and Vitamin E,” Journal of the American College of Cardiology, Vol. 46, No. 1, 2005 ISSN 0735-1097/05/$30.00 doi:10.1016/j.jacc.2005.02.089
The statin results reported here were for people over 55 with moderate heart disease risk. Statins did not lower all-cause mortality or cardiac heart disease in this group.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, “Major Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual Care,” JAMA, December 18, 2002—Vol 288, No. 23
This paper is a meta-study, which concluded statins showed no all-cause mortality benefit even with a high-risk group. The study covers 244,000 person-years.
For those at low risk, this paper finds that statins increase all-cause mortality with no benefit for heart disease:
What is amazing is that this was even still being discussed in 2013.
Abramson lecturer, H. Rosenberg, N. Jewell, and J. Wright, “Should people at low risk of cardiovascular disease take a statin?” BMJ 2013;347:f6123
This almost completely covers it. So far, the only data we don’t have is the effect on men under 55 who are neither low risk nor high risk. Will this group rescue statins from the jaws of complete uselessness? These men are the last hope: if they fail to cooperate and get some sort of overall benefit from statins, it will mean that the only benefit of the drug is to the pharmaceutical industry bottom line.
So what do statins do? Besides providing no overall benefit, they do at least three things we definitely do not want. First, they lower LDL particle size. This would tend to increase atherosclerosis. Here is this onerous result:
Statins increase the risk of adult onset diabetes almost 50% according to this paper:
Finally, it seems statins lower the efficacy of the immune system, the last thing we want: