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  • They are used to construct the cells and tissues that form our bodies, provide sources of energy to power metabolism (as well as provide a mechanism for storing energy between meals), and are used to form the countless enzymes that drive our metabolism. Unlike the micronutrients (vitamins and minerals) which are needed in small amounts and are generally reused, macronutrients undergo a constant flux in our body, necessitating a consistent intake to provide enough energy for our survival and enough building blocks for the growth, maintenance, and repair of our bodies.

    Each of the macronutrients is actually a complex of smaller building blocks with important nutritional roles. Proteins are constructed of amino acids, carbohydrates of sugars or monosaccharides, and fats of fatty acids. As macronutrients are absorbed from a meal, they are broken down into their individual constituents, which are used for the various purposes in metabolism. The great adaptability of our body chemistry gives us the ability to take these individual building blocks (amino acids, sugars, and fatty acids) and reassemble them or even interconvert them to satisfy our metabolic needs. This explains how an Innuit can consume a diet predominantly of fish protein and fat, yet still have enough carbohydrate (glucose) in their blood to fuel the demand of their brains. Or how someone can adopt a completely fat-free diet, yet still become obese through the conversion of excessive dietary carbohydrates into body fat. Because of their interconversion in the body, macronutrients themselves are not nutritionally essential, although some of their building blocks may be (nine of the amino acids and two of the fatty acids are considered essential). Evidence also suggests that although macronutrients can be readily interconverted in the body, each may have additional benefits when present in the diet as a particular percentage of total dietary intake.

    To gain an appreciation of the function of each of the macronutrients and ultimately understand how much we may need, it is really necessary to discuss each individually. In this first part of the series, we will examine the roles and requirements for dietary protein.

    Out of all the macronutrients, protein has the most diverse set of roles in metabolism. It forms the connective tissues that hold our organs together; it is a significant portion of our bones, and the predominant component of muscle fibers. Moreover, protein forms the thousands of enzymes which carry out critical chemical reactions, the various transporters that move nutrients in and out of cells and throughout the body, the antibodies of our immune system, and many of the hormones that direct our growth, energy utilization, and homeostasis. Due to its ubiquitous nature in the function of all living things, dietary protein occurs in most whole food sources. Muscle meats are the most concentrated sources (muscle fibers are constructed of protein filaments); milk and eggs are also good sources. Legumes, exotic grains, and many vegetables are good protein sources, such that a balanced vegetarian or vegan diet can provide adequate protein for the body’s needs. Once consumed, dietary protein is broken down by the action of stomach acid and several digestive enzymes secreted from the stomach and pancreas (called proteases). From here, the resulting individual amino acids or small protein fragments (called peptides) are absorbed from the small intestine, and distributed throughout the body to satisfy various roles. We generally don’t absorb enzymes or other proteins intact.

    Dietary protein has several fates in human metabolism:

    New Protein Synthesis. The amino acids liberated from dietary protein can be used to make other proteins in the body. While organisms can make amino acids from other sources (such as fats or carbohydrates), making new proteins from dietary amino acids is the quickest and most energetically economical way. This is especially important for sustaining periods of rapid growth, such as during childhood development or intense weight training. Perhaps more importantly, dietary protein is the only source of essential amino acids for metabolism. Of the twenty different amino acids used to make proteins, humans have lost the ability to produce nine of them on their own (methionine, lysine, valine, tryptophan, phenylalanine, isoleucine, leucine, threonine, and histidine). Therefore, a minimal amount of dietary protein is required to supply enough of these essentials to maintain protein synthesis in the body.

    Precursors to other biomolecules. Several of the essential amino acids from dietary protein are used to construct important “non-protein” chemicals for the body. For example, the hormones seratonin and melatonin, and vitamin B3 (niacin) are derived from the essential amino acid tryptophan; thyroxine (thyroid hormone), adrenaline, and the endorphins (natural analgesics) depend on intake of the essential amino acid phenylalanine. Thus, our ability to produce these hormones and neurotransmitters is heavily dependent on the presence of essential amino acids in the diet.

    Dietary protein is also the predominant sources of the elements nitrogen and sulfur, both essential to metabolism. Nitrogen from dietary amino acids is redistributed in the body to make other amino acids, nucleotides (the building blocks of DNA, as well as the energy molecule ATP), and glycosaminoglycans (components of connective tissues, such as chondroitin, keratan, and hyaluronic acid). Sulfur is also used in the construction of glycosaminoglycans, as well as several important antioxidants (such as glutathione and alpha lipoic acid).

    Fuel Source. Dietary protein can serve as an energy source. Following a meal, about 50 percent of the amino acids that have been released from dietary protein are metabolized by the liver into energy (ATP). Unlike carbohydrates or fats, excess amino acids from the diet are not stored in the body; if they are not immediately used to make new protein or energy, they are converted to carbohydrates or fats for storage. The liver can also metabolize most amino acids into glucose, to provide energy to the brain and other tissues. Proteins are less efficient at raising blood glucose than are carbohydrates; while they provide the same number of calories on a gram-for-gram basis (4 calories/gram), they only raise blood glucose 50–80 percent as much as an equivalent amount of carbohydrates.

    Skeletal muscles depend heavily on amino acids for energy. The essential amino acids leucine, isoleucine, and valine (called the branched chain amino acids or BCAAs) are preferentially taken up by muscle cells after a meal to be burned as fuel. Healthy individuals will metabolize upwards of 10 grams/ day of BCAAs in their muscles if they are available in the diet.

    In addition to their standard roles in metabolism, dietary protein has been associated with specific health effects, including:

    Weight Loss and Satiety. High protein diets have been associated with better glycemic control, and have been shown to promote greater fat reduction than high carbohydrate or high fat diets that provide the same number of calories. Dietary proteins are more difficult to convert into energy than the carbohydrates or fat; diets high in protein have been reported to have a greater thermogenic effect and expend more energy than lower protein diets. Randomized, controlled trials comparing low and high-protein diets studies have shown that diets higher in protein are more effective at preserving lean muscle, reducing body fat, and maintaining lower insulin levels after a meal.

    There is convincing evidence that proteins are more satiating than the other macronutrients, and that the satiating ability of proteins may be related to their amino acid composition and how quickly they are digested. Much of this effect has been attributed to the rapid appearance of the essential branched chain amino acids in the blood; leucine, one of the BCAAs, has been shown to influence the metabolic pathways in the brain that regulate food intake, at least in animal models. Evidence also suggests that higher protein intake at one meal may significantly decrease appetite at the next meal, although the studies in this area are not consistent.

    Promoting Healthy Levels of Blood Lipids. Dietary protein, particularly dietary soy protein, has been studied for its ability to lower cholesterol levels by either increasing the removal of low-density lipoprotein cholesterol (LDL or “bad” cholesterol) from the blood, or as a replacement for other high fat/ high cholesterol protein sources. Over 60 controlled trials of soy protein consumption in humans have been performed, many in hypercholesterolemic patients. Taken together, these studies revealed that an average intake of 47 g/day of soy protein resulted in significant improvements in blood lipid/lipoprotein parameters, with average reductions in total cholesterol of 9 percent and LDL cholesterol of 12.9 percent. These data were the foundation for the FDA approved health claim for soy protein in the prevention of cardiovascular disease.

    Promoting Healthy Blood Pressure. Several human trials and epidemiological studies have indicated an inverse associate between dietary protein intake and blood pressure. Forty-six human studies of protein intake and blood pressure (20 clinical trials, 15 observational studies and 13 biomarker studies) have demonstrated a clear, beneficial effect for plant protein on reductions in blood pressure. The reductions averaged up to a 1.4 mm Hg reduction in systolic blood pressure and a 1 mm Hg reduction in diastolic blood pressure for every 11 g of plant protein consumed per day, based on observational studies. The mechanism by which protein may reduce blood pressure is unclear; it may be helping to rid the body of sodium, it may increase insulin sensitivity, or it may increase the blood concentration of the amino acid arginine, the precursor to the blood-pressure lowering hormone nitric oxide.

    As with most macronutrients, the required amount of dietary protein depends on individual needs. Discussion of the research regarding the merits of diets differing in the relative ratios of protein, carbohydrate, and fats will be the subject of a future article, but some general considerations on dietary protein content bear mentioning here.

    The Food and Nutrition Board of the National Institute of Medicine has established a dietary reference intake of 56 g/day for adult men, 46 g/day for adult women, based on metabolic studies. These figures are based on a reference (“average”) body weight; a more individualized assessment of daily protein requirements for a healthy individual would be 0.8 g/kg (about 0.36 g/lb) body weight. Under circumstances of increased metabolic demand, higher protein intakes may be warranted. In pregnant and lactating women, for example, daily protein requirements increase to approximately 1.1 g/kg of body weight, or 71 g/day for the “average” woman. The dietary protein requirements of athletic individuals who wish to increase their lean body mass has been the subject of considerable debate, but is generally believed to exceed the reference values. Studies have suggested protein requirements of 1.1 g/ kg per day for endurance athletes and 1.3 g/kg per day in strength-trained athletes.

    There are some circumstances where reduced protein intake may be warranted. Since excess dietary protein is not stored in the body, it must be immediately used up (to make new proteins), converted into energy, or converted to carbohydrates or fat for storage. In the latter two cases, amino acids are broken down, and the nitrogen they carry is eliminated from the body (as urea). The breakdown of amino acids and excretion of nitrogen are fundamental functions of the liver and kidneys, but for individuals with kidney or liver disease, excessive protein consumption can be problematic. Low-protein diets (below 0.8 g/kg per day) may be beneficial in these cases. Dietary protein requirements should also be carefully considered in individuals with hyperuricemia, a condition of excessive uric acid in the blood. Hyperuricemia affects an estimated 21 percent of Americans, and is a primary risk factor for gout, a type of arthritis typified by a rapid onset of inflammation, usually in the joints of the extremities. Elevated blood uric acid is also a risk for kidney and cardiovascular diseases, and diabetes. While dietary protein itself does not elevate blood uric acid, compounds found in some sources of animal protein (called purines) do increase hyperuricemia risk. Therefore, individuals with elevated blood uric acid should limit their intake of protein from meats (other animal proteins, such from milk or eggs, as well as vegetable protein, do not appear to be associated with hyperuricemia risk and may actually reduce it).

    To read the series on Macronutrients:

  • Carbohydrates are the most abundant biomolecules on our planet and in our food supply. They exhibit some of the largest differences in their metabolism by different members of the animal kingdom. At one extreme, herbivores can almost completely break down dietary plant material with the help of beneficial bacteria that dwell within their gastrointestinal tract; at the other extreme, true carnivores can’t process most dietary carbohydrates. Humans fall somewhere in between; we derive a great deal of nutrition out of some dietary carbohydrates, but are unable to process others.

    In our diets, digestible carbohydrates consist of sugars and starches, while the indigestible carbohydrates are the fibers and resistant starches1. Dietary sugars are predominantly monosaccharides (sugars consisting of a single unit, such as glucose and fructose) or disaccharides (sugars consisting of two monosaccharides linked together, such as sucrose and lactose). Starches are long chains (polymers) of many linked monosaccharide molecules, usually glucose.

    Monosaccharides are the preferred form by which sugars are absorbed from the intestines, therefore, starches and disaccharide sugars (sucrose, lactose) must be broken down by digestive enzymes before assimilation. Starches are fairly easily digested by the action of pancreatic enzymes, while disaccharide sugars are degraded by enzymes that dwell on the surface of the small intestines. The familiar lactose maldigestion (“lactose intolerance”) experienced by many individuals actually results from the lack of one of these intestinal enzymes (lactase, the enzyme that breaks down lactose into glucose and galactose).

    Fibers and resistant starches are carbohydrates as well. Like starches, fiber is composed of polymers of linked monosaccharide sugars. Unlike starches, however, fibers and resistant starches are not used as a source of calories; humans lack the necessary enzymes to break down resistant starches and fibers, therefore, they are not absorbed. Some soluble fiber and resistant starch is broken down by intestinal bacteria, the rest passes through the gastrointestinal tract intact.

    The majority of dietary carbohydrates are obtained from plant sources (fruits, vegetables, grains). In contrast to animal tissues, which are held together by mostly proteins, plants cells are held together by cellulose and lignin, two types of dietary fiber. The edible portions of plants are usually those that contain large amounts of storage carbohydrates, such as the kernels of grains (which store starches) or fruits (which store sugars). Smaller amounts of carbohydrates are found in animal products; carbohydrates constitute only about one percent of the mammalian body2.

    Although they do not have the diversity in human metabolism as do proteins, dietary carbohydrates and fibers still have a number of fates:
    Fuel Source and Fuel Storage.

    As versatile as humans are in obtaining energy from a variety of macronutrients, the preferred energy source in our metabolism is the carbohydrate glucose. Under normal conditions, the brain uses glucose as an energy source almost exclusively, and most other tissues rely heavily on it. To accommodate the body’s need for glucose, most sugars and starches can be converted into glucose as they are absorbed and distributed amongst various tissue following a meal. Additionally, some amino acids from digested protein can also be converted into glucose (in true carnivores like cats, this is where most glucose comes from).

    Unlike other cellular energy sources (amino acids and fatty acids), glucose can be converted into energy in the absence of oxygen (anaerobic glycolysis). This makes glucose a critical source of quick energy during times when oxygen is scarce, such as during intense exercise.

    Glucose can also be stored for later usage, in the form of glycogen (“animal starch”). Glycogen is abundant in the liver, which stores about a day’s worth of glucose in order to provide enough energy to fuel the brain during periods between meals. Glycogen is also used to store glucose for use in muscles, which rely on it for quickly generating energy. If the dietary intake of carbohydrates exceeds what is needed for immediate energy and glycogen reserves, then the excess is converted to fat for long-term storage.

    Precursors to other biomolecules. Carbohydrates are used to make other important biomolecules. These include: glycosaminoglycans (such as chondroitin, keratin, and hyaluronic acid), important constituents of joints and connective tissues; nucleic acids (DNA and RNA are partially constructed from the sugar ribose); as well as other amino acids and fatty acids for making new cellular proteins and cell membranes.

    Stimulation of digestion. Fiber, despite its non-nutritive value, still has evolved important roles in human physiology. The bulk of insoluble fibers helps digested food to move more easily through the intestines and be readily eliminated from the body. Soluble fibers and resistant starches can provide a source of energy for intestinal bacteria, which themselves provide a number of health benefits, including the stimulation of immunity, protection from pathogenic bacteria, and enhanced absorption of minerals from the diet. Prebiotics, a subset of soluble fiber, have gained attention in recent years in their ability to be selectively fermented by gut flora for a diversity of potential health-promoting benefits3.

    Many of the health benefits realized by modifying carbohydrate intake involve altering patterns of consumption: reducing intake of sugars, and increasing intake of fiber. For example, recent emphasis on increased intake of whole grains (which contain significantly more fiber, phytonutrients, and protein than do refined cereal flours) has resulted from several studies which suggest that its consumption may reduce the risk of certain cancers, diabetes, and cardiovascular disease4. Fiber intake, in particular, has been the subject of thousands of studies in humans and animals, in part for its ability to successfully reduce the risk of several diseases by different mechanisms:

    Reducing Chronic Low-level Inflammation. In contrast to the conspicuous inflammation that is characteristic of an injury or infection, chronic low-level inflammation can progress unnoticed. This potentially silent affliction has been associated with the progression of several diseases, including cancer, diabetes, cardiovascular, and kidney diseases. In an analysis of 7 studies on the relationship between weight loss and inflammation, increased fiber consumption correlated with significantly greater reductions in C-reactive protein (CRP), one indicator of low-level inflammation5. In these studies, daily fiber intakes ranging from 3.3 to 7.8 g/MJ (equivalent to about 27 to 64 g/day for a standard 2000 kcal diet) reduced CRP from 25–54 percent in a dose-dependent fashion. The Women’s Health Initiative Study also found significant inverse relationships with dietary soluble and insoluble fiber (over 24 g/day) and certain markers of chronic inflammation6.

    Promoting Healthy Blood Pressure. It is not clear how dietary fiber reduces blood pressure, but many studies have observed this trend. Fiber, when taken with a meal, may by reducing the glycemic index of foods and lowering the response of insulin following a meal (insulin may play a role in blood pressure regulation). Soluble fibers may also increase mineral absorption (such as calcium, magnesium, and potassium; all important for healthy blood pressure) by feeding intestinal flora, which lowers intestinal pH and establish a favorable acidic environment for mineral absorption7. Whatever the cause, at least thirty randomized, controlled clinical trials examined the effects of fiber in both hypertensive and normotensive patients. Across all participants, increased fiber intake demonstrated modest average reductions in systolic (1.13–1.15 mm Hg), and diastolic (1.26–1.65 mm Hg) blood pressure89. Amongst hypertensive patients, the average blood pressure reductions were much larger: A significant average reduction in both systolic (-5.95 mm Hg) and diastolic (-4.20 mm Hg) blood pressure was observed over 8 weeks in trials where hypertensive participants increased their daily fiber intake9.

    Promoting Healthy Levels of Blood Lipids. High-fiber diets have been associated with lower prevalence of cardiovascular disease (10). When included as part of a low-saturated fat/low cholesterol diet, dietary fiber can lower low-density lipoprotein cholesterol (LDL-C) by 5–10 percent in persons with high cholesterol, and may reduce LDL-C in healthy individuals as well10. Dozens of controlled clinical trials have shown the cholesterol-lowering potential of dietary fibers including soluble oat fiber, psyllium, pectin, guar gum, b-glucans from barley, and chitosan3,12,13.

    Soluble fibers lower cholesterol by several potential mechanisms (3). They may directly bind cholesterol in the gut, preventing its absorption. The high viscosity of soluble fiber and its ability to slow intestinal motility may help to limit cholesterol and fat uptake as well. Fiber can also increase satiety, which can limit overall energy intake14,15. Lowering Uric Acid. Elevated blood uric acid (hyperuricemia) is a risk factor for kidney disease, cardiovascular diseases, and diabetes; it is also a primary cause for gout16. Fiber intake may lower blood uric acid levels. A significant inverse relationship between fiber intake and hyperuricemia risk was established by analyzing dietary fiber intake data from over 9000 otherwise healthy adults participating in the National Health and Nutrition Examination Survey (NHANES) from 1999–2004. Based on these data, participants with high fiber diets (over about 19 grams fiber/day for the average 2000 kcal diet) had a 55 percent reduction in hyperuricemia risk compared to those on lower fiber diets (<9.2 g fiber/day)17. While these mechanisms for this reduction is unknown, dietary fiber may reduce the absorption of purines from the diet, one of the inciting factors for hyperuricemia.

    The amount and composition of carbohydrates in the “ideal” diet is amongst the most heavily debated topics in nutrition. There are scientifically-substantiated merits to both the “low-carb” and “low-fat, high-carb” diets in terms of reducing disease risk and maintaining a healthy body mass index (these will be discussed in greater detail in a future article). The common ground between the two schools of thought is that the average Western diet probably contains too little fiber, and too much refined grains and added sugar. A low-fiber/high-sugar diet, when coupled with excessive caloric intake, has been associated with significant increases in the risk for a number of ailments, including obesity, insulin resistance/type II diabetes, and cardiovascular disease.

    As mentioned previously, the benefits of dietary fiber are numerous. The average daily fiber intake in the American diet, based on data from 2007–2008 NHANEs survey, is about half of the 28 grams/day recommendation by the Institute of Medicine (IOM). Significant numbers of people consume even less than the national average. The highest intakes of dietary fiber are associated with the lowest disease risks; for several observational studies, the greatest risk reductions required intakes exceeding the IOM recommendations.

    In contrast, the American diet contains no shortage of refined grains or sugars. The U.S. Department of Agriculture estimates average grain consumption at about 33 percent more than 6 oz./day recommended in its Dietary Guidelines for Americans. Most of this grain is refined; the same group estimates Americans consume only one-third of the recommended 3 oz./day of whole grains18,19.

    Analysis of data from the last NHANEs survey (2007–2008) determined that Americans consume an average of 120 grams/day of total sugars (about 30 teaspoons), most of which are added sugars. This amounts to approximately 480 kilocalories of energy per day. Most of these sugars come from sweetened carbonated beverages (~37 percent); other top sources include desserts and fruit drinks (fruitades and fruit punches). While arguments can be made that it is the added fructose or corn syrup are particularly dangerous to health (there is evidence that supports and refutes this hypothesis), or that sugar is additive and contributes to overeating (animal models may support this claim), added sugar clearly contributes a significant amount of calories to the average diet, and in many cases displaces essential nutrients20,21.

    To read the series on Macronutrients:


    1. Fardet A. New hypotheses for the health-protective mechanisms of whole-grain cereals: what is beyond fibre? Nutr Res Rev 2010 Jun.;23(1):65–134.
    2. Engelking L. Textbook of Veterinary Physiological Chemistry. Updated 2nd ed. Burlington, MA: Academic Press; 2011.
    3. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999 Jan.;69(1):30–42.
    4. Higgins JA. Whole grains, legumes, and the subsequent meal effect: implications for blood glucose control and the role of fermentation. J Nutr Metab 2012;2012:829238.
    5. North CJ, Venter CS, Jerling JC. The effects of dietary fibre on C-reactive protein, an inflammation marker predicting cardiovascular disease. Eur J Clin Nutr 2009 Aug.;63(8):921–33.
    6. Ma Y, Hébert J, Li W, Bertone-Johnson E. Association between dietary fiber and markers of systemic inflammation in the Women’s Health Initiative Observational Study. Nutrition 2008;
    7. Greger J. Nondigestible carbohydrates and mineral bioavailability. J Nutr 1999.
    8. Streppel MT, Arends LR, van t Veer P, Grobbee DE, Geleijnse JM. Dietary fiber and blood pressure: a meta-analysis of randomized placebo-controlled trials. Arch Intern Med 2005 Jan.;165(2):150–6.
    9. Whelton SP, Hyre AD, Pedersen B, Yi Y, Whelton PK, He J. Effect of dietary fiber intake on blood pressure: a meta-analysis of randomized, controlled clinical trials. J. Hypertens 2005 Mar.;23(3):475–81.
    10. Badimon L, Vilahur G, Padro T. Nutraceuticals and atherosclerosis: human trials. Cardiovasc Ther 2010 Aug.;28(4):202–15.
    11. Anderson J, Randles K. Carbohydrate and fiber recommendations for individuals with diabetes: a quantitative assessment and meta-analysis of the evidence. J Am Coll Nutr 2004.
    12. AbuMweis SS, Jew S, Ames NP. -glucan from barley and its lipid-lowering capacity: a meta-analysis of randomized, controlled trials. Eur J Clin Nutr 2010 Dec.;64(12):1472–80.
    13. Baker WL, Tercius A, Anglade M, White CM, Coleman CI. A meta-analysis evaluating the impact of chitosan on serum lipids in hypercholesterolemic patients. Ann Nutr Metab 2009;55(4):368–74.
    14. Brighenti F, Casiraghi M, Canzi E. Effect of consumption of a ready-to-eat breakfast cereal containing inulin on the intestinal milieu and blood lipids in healthy male volunteers. Eur J Clin Nutr 1999; Pages 726–33.
    15. Li S, Guerin-Deremaux L, Pochat M, Wils D, Reifer C, Miller LE. NUTRIOSE dietary fiber supplementation improves insulin resistance and determinants of metabolic syndrome in overweight men: a double-blind, randomized, placebo-controlled study. Appl Physiol Nutr Metab 2010 Dec.;35(6):773–82.
    16. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: The National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum 2011 Oct.;63(10):3136–41.
    17. Sun SZ, Flickinger BD, Williamson-Hughes PS, Empie MW. Lack of association between dietary fructose and hyperuricemia risk in adults. Nutr Metab 2010;7(1):16.
    18. Grotto D, Zied E. The Standard American Diet and its relationship to the health status of Americans. Nutr Clin Pract 2010 Dec.;25(6):603–12.
    19. U. S. Department of Agricuture USDOHAHS. Dietary Guidelines for Americans 2010. 2011 Jan.;:1–112.
    20. Avena NM, Rada P, Hoebel BG. Sugar and fat bingeing have notable differences in addictive-like behavior. Journal of Nutrition 2009 Mar.;139(3):623–8.
    21. Berner LA, Avena NM, Hoebel BG. Bingeing, self-restriction, and increased body weight in rats with limited access to a sweet-fat diet. Obesity (Silver Spring) 2008 Sep.;16(9):1998–2002.

  • The lipids are the third class of macronutrient. They are as ubiquitous in the diet as proteins and carbohydrates, where they occur predominantly as storage lipids called triglycerides(formed from fatty acids), and cholesterol, a lipid with roles in both cell structural and communication.

    Fatty acids are the building blocks of most lipids. These energy-rich molecules come in a variety of configurations, each with different chemical and physical properties to serve a diversity of functions. The long, straight, tightly stacked molecules of saturated fatty acids predominate in the rigid solid fat deposits in animals; the loose associations of the molecularly kinked unsaturated fatty acids allows them to stay liquid and form the oils of vegetables, seeds, and fish. The kinks in unsaturated fatty acids are a result of the type of chemical bonds between atoms within the fatty acid (double bonds for the chemically-inclined). Fatty acids can vary in length, and amount of saturation (monounsaturated fatty acids have one double bond, polyunsaturated can have several). Unsaturated fatty acids can also be in cis- or trans- configurations, which refers to the nature of the double bonds within the acid. Trans-fatty acids produced by the chemical hydrogenation of oils have gained particular notoriety for their potential to increase the risk of heart disease, while naturally-occurring trans fats (such as conjugated linoleic acid from milk products) can be beneficial.

    Although fatty acids can be taken up from the diet, the body is well equipped to synthesize its own for energy storage or structural purposes. The exception is the two essential fatty acids which cannot be synthesized by mammals and must be obtained through the diet: alpha-linolenic acid, an omega-3 fatty acid; and linoleic acid, an omega-6 fatty acid. Given adequate amounts of these two compounds, and the body’s enzymatic machinery, the entire repertoire of fatty acids can be constructed.

    Much of the fats and oils in the diet are in the form of triglycerides, which are storage lipids formed of a molecular complex of glycerol and three fatty acids (unsaturated, saturated, or mixtures of the two). Other sources of dietary fatty acids include phospholipids (which form cell membranes), mono- and di-glycerides. Whatever the source, dietary fats and oils are broken down by the action of digestive enzymes secreted from the pancreas and intestines (called lipases) to release individual fatty acids, which are absorbed from the small intestine, packaged into new triglycerides or phospholipids, and distributed throughout the body to serve their various roles.

    Cholesterol is a type of lipid distinct from the fatty acids, triglycerides, or phospholipids. It is a waxy, steroid compound that has critical roles in metabolism. The human body makes the majority of its own cholesterol, although some is obtained through the diet: dietary sources of cholesterol are exclusively animal products (plant sources of cholesterol are extremely rare and appear to be limited to certain types of algae).1 To partition cholesterol into “good” and “bad” varieties is a bit misleading; there is only a single type of cholesterol in nature. Elevated levels of blood cholesterol (or more accurately, elevated levels of cholesterol that are contained in specific types of lipid particles called low density lipoproteins) have been implicated in the progression of atherosclerosis, the progressive accumulation of fatty deposits in arteries that can lead to serious cardiovascular consequences. However, cholesterol’s association with heart disease risk obscures its many critical roles in metabolism, from serving as a building block to many hormones, to ensuring the proper firing of nerve impulses.

    Roles of Fats and Cholesterol in Normal Metabolism Dietary lipids have several potential fates in human metabolism:

    Fuel Source and Fuel Storage. Triglycerides, and the fatty acids they contain, are a rich source of cellular energy. While glucose is the preferred energy source for most cells, glucose is a bulky molecule that contains little energy for the amount of space it occupies (glucose is stored in the liver and muscles as glycogen, which is used to power the brain and muscles between meals). Not only are fatty acids better sources of energy on a per-weight basis (one gram of carbohydrate contains 4 kilo-calories of energy, compared to 9 kilo-calories/gram for triglyceride), but they are denser, giving them the ability to store massive amounts of energy in fat deposits. The average human, for example, can only store enough glucose as glycogen in the liver for about 12 hours worth of energy, but can store enough fat to power the body for significantly longer (up to several days during starvation).

    Because fatty acids are superior for storing excess energy, excess dietary carbohydrates are converted into fatty acids and packaged into triglycerides for long-term storage. However, this conversion is one-way; fatty acids cannot be converted back to glucose. This presents a problem for some cells (like neurons in the brain), which do not metabolize fatty acids, and do not have access to the vast energy stores of adipose tissue. In times of carbohydrate deficit (such as during starvation or low-carbohydrate dieting), fatty acids are converted into ketone bodies, an alternate source of fuel for brain cells.

    Building blocks of cell membranes. Lipids form the bulk of the membranes which surround each cell in the body; these lipids are predominantly formed of phospholipids and cholesterol. It is here that the importance of cholesterol becomes apparent; its “waxy” nature helps to keep the membranes around cells fluid, so that cells are viable at a wider range of temperatures. Some cells have a particularly heavy reliance on cholesterol for proper function: The membranes surrounding healthy liver cells, for example, are almost one-third cholesterol,2 and cholesterol is a major component of the myelin sheath that surrounds neurons and allows for these cells to transmit electrical impulses rapidly over long distances.3 Mitochondria, the centers of energy generation in most cells, also rely heavily on cholesterol to insulate against the loss of electrolytes during their generation of ATP.4

    Precursors to hormones. Cholesterol is used as the starting material in the synthesis of all of the bodies steroid hormones, which include the sex hormones (testosterone, progesterone, and the estrogens), mineralcorticoids (which control the balance of water and minerals in the kidney) glucocorticoids (which control protein and carbohydrate metabolism, immune suppression, and inflammation), and vitamin D (which controls calcium and phosphate balance). Omega-3 and omega-6 fatty acids from the diet are used to synthesize eicosanoids, a set of hormone-like molecules that are important for a diverse set of metabolic functions, including inflammation/anti-inflammation, blood clotting, immune function, response to allergens, protection from stomach acid, and parturition (labor).

    Digestion and Absorption of Fats. Cholesterol is the starting material for bile acids, a group of detergent-like molecules that are synthesized in the liver, and used to emulsify/solubilized many dietary fats and cholesterol. This facilitates the absorption of dietary lipids in the intestines.

    Many of the health benefits realized by modifying lipid intake involve altering patterns of consumption: reducing intake of saturated, trans-fats, and cholesterol, and increasing intake of mono- and polyunsaturated fats. Omega-3 intake, in particular, has been the subject of hundreds of studies in humans and animals, in part for its ability to successfully reduce the risk of several diseases by different mechanisms:

    Reducing Chronic Low-level Inflammation. Diets high in saturated fats have been associated with an increase in proinflammatory markers in some studies, particularly in diabetic or overweight individuals.5, 6 The intake of synthetic trans-fats has also been associated with increases in markers of inflammation in some studies,7, 8 although this data is conflicting and may be more pronounced in individuals that are also overweight.9, 10 Omega-3 fatty acids have been studied for their prevention of cardiovascular disease and mortality in tens of thousands of patients; the anti-inflammatory effects of omega-3’s are thought to contribute to this activity.11 Several small studies of omega-3 fatty acid consumption have demonstrated their beneficial effects against other inflammatory diseases, particularly asthma, IBD, and rheumatoid arthritis.12, 13 These clinical trials are supported by several large observational trials encompassing thousands of patients, which have revealed inverse relationships between fish oil/omega-3 consumption and markers of systemic inflammation within diverse populations.14-17

    Promoting Healthy Blood Pressure. Omega-3 fatty acids consumption has led to significant reductions in blood pressure across several clinical trials. In a survey of 36 clinical trials on the effects of omega-3 supplementation in over 2000 individuals, a median intake of 3.7 g/day of fish oil demonstrated an average reduction of blood pressure of 2.1 mm Hg (systolic) and 1.6 mm Hg (diastolic).18 In hypertensive individuals, the average reductions in blood pressure were much greater, amounting to -4 mm Hg (systolic) and -2.73 mm Hg (diastolic). When compared to low-fat diets, Mediterranean diets (moderate fat diets characterized by high intakes of monounsaturated fats from nuts and olives, and polyunsaturated fats from fish) demonstrated average reductions of 1.7 mm Hg (systolic) and 1.5 mm Hg (diastolic) over six studies including more than 2600 individuals.19 While these reductions may seem very small, it is important to remember that even modest reductions in blood pressure can have significant effects on cardiovascular health; for example, lowering diastolic blood pressure by 5 mm Hg has been estimated to lower the risk of stroke death by 40 percent and the risk of death by heart disease or other vascular causes by 30 percent.20

    Promoting Healthy Levels of Blood Lipids. The effects of fish oil fatty acids on the reduction of serum triglycerides (a cardiovascular risk factor) are well established. Forty-seven studies with over 15,000 patients, have demonstrated an average triglyceride reduction of 30 mg/dL, at an average intake of 3.35 g fish oil over 24 weeks.21 The effects of fish oil fatty acids on LDL and HDL cholesterol are equivocal.22 (Prescription fish oil uses a highly concentrated esterified fatty acids that provides a dosage of 3.36 g of omega-3 in 4 capsules; its degree of triglyceride reduction—up to 45 percent—is similar to non-prescription fish oil at a similar dose, but requires less capsules.23) High monounsaturated and polyunsaturated fatty acid intake typical of Mediterranean diets have demonstrated reductions in serum triglycerides and total cholesterol, when compared to low-fat diets.19

    As with the case of carbohydrates, there are opposing opinions on the optimal amount and composition of lipid for a healthy diet. There is general agreement that synthetic trans-fats should be avoided. The majority of expert opinions suggest that cholesterol and saturated fat intake (particularly from animal sources) be minimized; the USDA RDIs suggest these values at < 300 mg/day and < 20 grams/day (~10 percent of total calories in a 2000 calorie diet) respectively. The National Cholesterol Education Program’s Therapeutic Lifestyle Changes (TLC) diet suggests more conservative daily intakes of < 200 mg/ day cholesterol and < 7 percent of total calories from saturated fats.24 Beyond these recommendations, however, is a substantial schism between proponents of low-fat/higher carb and low-carb/ higher fat diets. There is evidence that both diets can reduce disease risk and maintain a healthy body mass index.25

    As for the benefits of omega-3 fatty acids in particular, the majority of clinical studies on the effects of fish oil for cardiovascular health and inflammation looked at intakes of 3–4 grams of omega-3 fatty acids per day, which is a considerable amount to consume from fish alone (200 –400 grams of fatty fish per week provides between 500 and 800 mg of omega-3’s per day).26 Significant health benefits have been observed at these lower levels of fish oil consumption in some observational studies.16, 26

    To read the series on Macronutrients:

    References download:

  • A common nutritional complaint regarding American eating habits is that the culture tends toward a mono-diet, meaning that only a handful of foods account for most of the diet. Favored foods typically include, either directly or in derived and hidden forms, corn, wheat, soy, potatoes, canola oil and a few other items along with foods based on these as feed, such as the meat, fish and fowl raised on them. There are a number of reasons for the narrowness of this range, one of the most powerful being subsidies to agriculture. Staple crops and foods are subsidized and relatively inexpensive whereas fresh fruit and vegetables along with most foods not on the favored lists of subsidies are expensive. One result is what economists term "externalities," in this case costs borne by individuals and society, such as poor health, higher medical and medical insurance costs along with shorter life spans. In contrast to the results of typical American eating habits, experience commonly demonstrates that merely increasing the range of food choices with an emphasis on fresh as opposed to canned, frozen and preserved foods can introduce considerable benefits. Similar benefits sometimes can be achieved through the proper use of dietary supplements with the catch, however, that not all supplements match the purposes for which they are being taken. (Note: some foods do well frozen, such as corn, peas and many fruits, especially berries; canning is more limited, but includes, for example, tomatoes. However, most vegetables need to start off fresh!)

    Foods Rescue the Prostate

    It is not necessary to consume large amounts of exotic nutrients to obtain significant benefits. In 2013 a group of British researchers performed a six month long experiment in which 203 adult males with prostate cancer consumed either a placebo or a simple supplement mixture consisting of powdered pomegranate, turmeric, green tea and broccoli.1 Only the green tea was an extract, and even then providing roughly the same amount of actives as found in a cup or two of brewed green tea. Consumed three times a day, the active arm was comprised of:

    • broccoli powder (Brassica oleracea) 100 mg
    • turmeric powder (Curcuma longa) 100 mg
    • pomegranate whole fruit powder (Punica granatum) 100 mg
    • green tea 5:1 extract (Camellia sinensis) 20 mg, equivalent to 100 mg of crude green tea

    After six months, the researchers found that prostate-specific antigen (PSA) levels, a possible marker for prostate cancer, were 63 percent lower among those taking the supplement than among those taking the placebo. This significant result was achieved with really quite tiny amounts of everyday foods and, except in the case of the green tea, these were not even extracts.

    A number of studies have demonstrated that quite a range of compounds found in everyday foods are protective not just against prostate cancer, but also against many other cancers, as well. As another example, ursolic acid (found in apple peels and rosemary herb) in combination with turmeric’s ingredient curcumin or resveratrol (found in grapes and berries) blocks the uptake of glutamine by cancer cells yet do not interfere with the metabolism of normal cells—glutamine is a nutrient cancer cells need in order to grow.

    Plant Colors, Plant Nutrients and Nutritional Synergy
    red beetsCurrent government health recommendations include five servings per day of fruit and vegetables along with the suggestion that nine servings would be better. Unfortunately, this type of recommendation tends to be a bit misleading in that some fruits and vegetables are vastly more nutritious than others. For instance, cabbages in general are sources of compounds including isothiocyanates and indoles. However, cabbage-family members such as bok choy are comparatively light in nutrition compared with purple cabbage, which is rich in anthocyanidins as well as the expected precursors of sulforaphane. Similarly, leaf lettuces tend to be much more nutrient rich than is head lettuce. Below is a rough overview of some of the phytonutrients matched to associated colors in plants. There is a large degree of overlap and many phytonutrient polyphenols are almost colorless in the amounts found in foods. We tend to not associate black tea and coffee with nutrition, but the former is a source of theaflavin and the latter, if not overly roasted and freshly brewed, is a good source of chlorogenic acids.

    Red—lycopene, associated with tomatoes, pink grapefruit and watermelon; anthocyanidins (cyanidin literally meaning "red color") associated with berries, other highly colored fruit, beets

    Red/Purple—anthocyanidins, resveratrol and related compounds found in berries, other highly colored fruit, beets and eggplant, also found in black and other beans, black rice

    Yellow/Orangealpha- and beta-carotene, beta-cryptoxanthin; sources include carrots, citrus fruit, squashes, sweet potatoes, cantaloupes; hesperidin and diosmin are found in citrus fruit; rutin, related to hesperidin, is found in buckwheat

    Yellow/Green—lutein, zeaxanthin, quercetin, catechin, epicatechins, ellagic acid, isothiocyanates and indoles found in peppers, kale, cabbage, many other green vegetables, green tea; the best single source of highly bioavailable lutein and zeaxanthin is the yolk of eggs from hens allowed to eat grass and insects

    White/Green—allicin and related compounds, rutin in garlic and onions; isothiocyanates and indoles are found in cabbage family members, including cauliflower; many flavonoids; quercetin glycosides, phloretin glycoside (apple skin), chlorogenic acid and epicatechin found in "white" fruits (apples, pears), eggplant, green tea, freshly brewed coffee (chlorgenic acid)

    Various polyphenols and other phytonutrients provide benefits, many of which overlap, but some of which are special to one or another family of compounds. One huge payoff from variety is that there can be unexpected synergisms. This is an issue dealt with in these pages several years ago in the article, "Beyond Synergy—the Entourage Effect in Nutrition and Herbalism." (Total Health, September 2015) It is worth repeating here a key example described in that essay.

    At the 219th American Chemical Society National Meeting held in San Francisco on March 26–30, 2000 researchers associated with the company Polyphenolics presented studies that supported supplementing the diet with special plant-derived nutrients and consuming more whole fruits and vegetables. One of my associates pointed out that antioxidant vitamins are present in the human body at levels typically twenty to several hundred times the level of plant polyphenols. This is one reason that so much less research has focused on the antioxidant vitamins in foods and relatively little research has been done on the antioxidant roles of the other compounds present. By 2000, however, it already was becoming clear that these non-vitamin plant antioxidants have an impact on the antioxidant status of the body that is much beyond their representation in the blood and tissues. For instance, at the conference it was explained that an extract from grape seeds given to human volunteers led to a much greater increase in the antioxidant capacity of the subjects’ blood than was theoretically possible based on the compound alone. This was a finding that called for explanation. A second set of tests helped to clarify the result of the first—the same grape seed extract demonstrated significant synergism when tested in vitro with the antioxidant vitamins C and E, either alone or in combination.

    To establish a quantitative baseline for the antioxidant power of each of the compounds, tests used the standard cupric ion generation of oxidation to look at the impact of combining our grape seed extract (Vixox Gold™) with vitamins C and E to gauge the synergy of the combinations. Vitamin C, vitamin E and grape seed extract were each tested individually to determine their effects at several concentrations. These baselines were added to yield the "Sum of Individual Inhibitions" which then was compared with the "Actual Inhibitions When Tested Together." The Actual Inhibitions minus the Sum of Individual Inhibitions times 100 yielded the percent of Synergism. This series of in vitro tests thus allowed the investigator to elegantly demonstrate the concentrations of maximal synergism amongst the three antioxidants. Strong synergism was shown for Vinox Gold™ plus vitamin C, for Vinox Gold™ plus vitamin E, and, finally, for Vinox Gold™ plus vitamin C and vitamin E.

    Synergisms in the ranges shown here are good examples of why it is that consuming a diet rich in fruit and vegetables is so much more successful in terms of health than is eating a diet based on refined carbohydrates, protein and fats.

    Cautionary Tales Regarding Supplements

    Refining the "big three" macronutrients and then "adding back" nutrients/micronutrients loses the benefits of the plant compounds that otherwise are present in the original sources of carbohydrates and in partially refined oils, such as olive and sesame oils. Supplements are useful, but they do not take the place of fresh food properly prepared in a diet emphasizing adequate variety. Moreover, there are other reasons for being careful about the use of non-food interventions.

    Synergistic Ratios of Antioxidants

    A good example, one that shows the overlap of how we sometimes use over-the-counter drugs and nutrients, is drawn from sports. Almost all of us, whether inclined towards athletics or not, have experience with soreness from exercise beyond our current level of physical preparation. "Weekend warriors" are familiar with this and so are high school, college and professional athletes. To overcome soreness from exertion beyond our capacity, it is common to take pain relievers. Hard physical training even in healthy you individuals, of course, is itself associated with post-exercise soreness.

    To prevent this, researchers at various centers have explored whether taking aspirin or similar compounds can prevent the development of post-exercise soreness. The findings of these experiments were that taking aspirin or some other non-steroidal anti-inflammatory can, in fact, mitigate the development of soreness. That was the positive finding. The not-so-positive finding was that this approach also prevented improvements based on training or overload effects! It turned out that a certain amount of local damage to the tissues caused by overload is required to induce improvements in exercise capacity based on training.

    That was a bit of a surprise even if, in scientific terms, it also was a very interesting and useful finding. More surprising still were the results of a variation on the theme of using NSAIDs prophylactically to prevent muscle pain. Researchers reasoned that tissue damage was due to, among other things, localized oxidative challenge associated with tissue damage. Instead of NSAIDs, classic powerful antioxidant vitamins and compounds were provided: vitamin C, E and N-acetyl cysteine (NAC). As was the case with the pre-workout use of NSAIDs, these antioxidants taken in quantity before training sessions did reduce soreness. Just as in the case of the NSAIDs, they also reduced the benefits of training.

    More recently still, reports have emerged showing that very high dose resveratrol (250 mg) interferes with the benefits of exercise training.2 This finding is not limited to resveratrol and potentially extends to quite a number of nutrients:

    "support for beneficial effects of resveratrol in human [sic] is weak and studies even show that resveratrol supplementation, similarly to supplementation with other antioxidants, can counteract the positive effects of physical activity. Regular physical activity remains the most effective way of maintaining and improving vascular health status and caution should be taken regarding potential interference of supplements on training adaptations."3

    It should be pointed out that such negative findings are balanced by other positive findings. In another study with older individuals 65–80 years of age, 500 mg per day resveratrol, although it did not improve cardiovascular risks compared to exercise alone, did improve the number of functional mitochondria in muscle and "subjects that [sic] were treated with RSV had an increase in knee extensor muscle peak torque (8 percent), average peak torque (14 percent), and power (14 percent) after training, whereas exercise did not increase these parameters in the placebotreated older subjects."4,5

    These findings can be reconciled in a variety of ways. For instance, one implication is that high dose resveratrol might be cycled to improve muscle quality and function, then removed from the cycle to allow for the emergence of other benefits. Those readers interested in further exploring the use of antioxidants in exercise and aging might do well to consult "Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging."6

    A second and more serious type of caveat emptor case involves taking a cocktail of supplements and finding that one of these undoes the benefits of the others. Several years back, a group of researchers at Georgetown University Medical Center, of whom I was one, examined whether avoiding insulin resistance, which is associated with aging, might lengthen life span in rodents as indicated by previous studies using caloric-restricted animals. We assessed whether consuming niacin-bound chromium (NBC) alone or in a formula containing other so-called "insulin sensitizers" would overcome various manifestations of aging and extend life span in Zucker Fatty Rats (ZFR).7 As we report in the abstract of our research, we "compared many metabolic parameters of ZFR fed NBC alone (n=12) or NBC in a unique formula (n=10) to a control group (n=10). In addition to NBC, the formula contained Allium sativum, Momordica charantia, Trigonella foenum-graecum and Gymnema sylvestre. The formula group received roughly ½ as much NBC daily as the NBC group. At week 44, all rats still lived, and no abnormalities in blood count (CBC), renal, or liver functions were found. In the two treatment groups compared to control, circulating glucose levels were significantly lower, with a trend toward lower HbA1C. Relatively elevated cholesterol and triglyceride concentrations occurred in the formula group. Compared to control, the NBC group had increased average lifespan (21.8%), median lifespan (14.1%), 30th percentile survival (19.6%), and maximum lifespan (22%). Despite similar beneficial effects on the glucose and blood pressure systems, a difference in aging was also found when the NBC group was compared to the formula group. When all rats in the other two groups had died, four in the NBC group continued to live at least a month longer."

    The fact that the life extension benefits of supplementation with chromium were undone by the inclusion of the other ingredients despite similar improvements in markers, such as blood glucose and blood pressure, was the source of considerable discussion in our group. My position at the time was and remains that the "insulin sensitizer" approach is beneficial. However, one of the ingredients in the formula, Gymnema sylvestre, is not an insulin sensitizer; instead, it is an inducer of insulin release from the pancreas, thus can elevate insulin levels or prevent a lowering of such levels even in conjunction with better insulin sensitivity. Elevated levels of circulating insulin are damaging the arteries and to many systems of the body regardless of any apparent benefit in terms of lowering circulating glucose and HbA1C. Adding this inappropriate ingredient to the mix negated benefits in terms of actual final endpoints, in this case extended lifespan, as opposed to improving mere markers.

    The American diet notoriously tends to be restricted in terms of the range and types of foods included. Surprisingly small changes in the diet that increase the variety of polyphenols and other nutrients, mostly plant-derived, can lead to quite outsized effects in terms of benefits. As described above in one example, plant nutrients equal to a small portion of a well-designed curry plus a cup of green tea yielded significant returns in terms of prostate health. Dietary supplements can be useful aids to enlarging the range of nutrients consumed each day, but supplements do not take the place of fresh food properly prepared and eaten in variety. Moreover, supplement interactions are not always obvious and need to be observed carefully.

    1. van Die MD, Williams SG, Emery J, Bone KM, Taylor JM, Lusk E, Pirotta MV. A Placebo-Controlled Double-Blinded Randomized Pilot Study of Combination Phytotherapy in Biochemically Recurrent Prostate Cancer. Prostate. 2017 May;77(7):765 –75.
    2. Gliemann L, Schmidt JF, Olesen J, Biensø RS, Peronard SL, Grandjean SU, Mortensen SP, Nyberg M, Bangsbo J, Pilegaard H, Hellsten Y. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol. 2013 Oct 15;591(20):5047–59.
    3. Gliemann L, Nyberg M, Hellsten Y. Effects of exercise training and resveratrol on vascular health in aging. Free Radic Biol Med. 2016 Sep;98:165–76.
    4. Alway SE, McCrory JL, Kearcher K, Vickers A, Frear B, Gilleland DL, Bonner DE, Thomas JM, Donley DA, Lively MW, Mohamed JS. Resveratrol Enhances Exercise-Induced Cellular and Functional Adaptations of Skeletal Muscle in Older Men and Women. J Gerontol A Biol Sci Med Sci. 2017 Nov 9;72(12):1595 –1606.
    5. Pollack RM, Barzilai N, Anghel V, Kulkarni AS, Golden A, O’Broin P, Sinclair DA, Bonkowski MS, Coleville AJ, Powell D, Kim S, Moaddel R, Stein D, Zhang K, Hawkins M, Crandall JP. Resveratrol Improves Vascular Function and Mitochondrial Number but Not Glucose Metabolism in Older Adults. J Gerontol A Biol Sci Med Sci. 2017 Nov 9;72(12):1703 – 09.
    6. Simioni C, Zauli G, Martelli AM, Vitale M, Sacchetti G, Gonelli A, Neri LM. Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging. Oncotarget. 2018 Mar 30;9(24):17181– 98.
    7. Preuss HG, Echard B, Clouatre D, Bagchi D, Perricone NV. Niacin-bound chromium increases life span in Zucker Fatty Rats. J Inorg Biochem. 2011 Oct;105(10):1344 – 9.