Category Archives: Nutrition

Nutrition is a key factor in maintaining good health throughout life.
Eating a balance diet, from birth with breastfeeding, and later during childhood, adolescence and adult life, is helpful in achieving and maintaining a good state of health and contributes, when associated with a healthy lifestyle, to the prevention of many chronic diseases such as cardiovascular diseases, osteoporosis, type II diabetes, and many types of cancers, conditions which are increasingly common nowadays.
And it is important to point out the relationship between nutrition and the intestinal microbiota, the community of microorganisms that colonize the gut: diet seems to be main factor in determining its composition, starting from breast milk.
Proper nutrition is essential even in the presence of allergic reactions to food components, as in the case of celiac disease, condition in which all food containing gluten must be avoided for life.
Proper nutrition is essential for athletes, and when combined with adequate training improves the performance in any sports.
And among the different types of diets, the Mediterranean diet is one of the healthiest. This dietary pattern was brought to the attention of the international scientific community in the 1950s by the work of Ancel Keys, an American physiologist. The Mediterranean diet, rich in plant products, such as extra virgin olive oil, vegetables, legumes, and whole grains, and low in red meats and derived products and high fat dairy products, ensures an good supply of fiber, compounds with anti-inflammatory and antioxidant actions, as well as a low intake of saturated fats.

Alkaline diet and health benefits

The acid-ash hypothesis posits that protein and grain foods, with a low potassium intake, produce a diet acid load, net acid excretion, increased urine calcium, and release of calcium from the skeleton, leading to osteoporosis.” (Fenton et al., 2009, see References).
Is it true?
Calcium, present in bones in form of carbonates and phosphates, represents a large reservoir of base in the body. In response to an acid load such as the high protein diets these salts are released into the circulation to bring about pH homeostasis. This calcium is lost in the urine and it has been estimated that the quantity lost with the such diet over time could be as high as almost 480 g over 20 years or almost half the skeletal mass of calcium!
Even these losses of calcium may be buffered by ingestion of foods that are alkali rich as fruit and vegetables, and on-line information promotes an alkaline diet for bone health as well as a number of books, a recent meta-analysis has shown that the causal association between osteoporotic bone disease and dietary acid load is not supported by evidence and there is no evidence that the alkaline diet is protective of bone health (but it is protective against the risk for kidney stones).

Note: it is possible that fruit and vegetables are beneficial to bone health through mechanisms other than via the acid-ash hypothesis.

And protein?
Excess dietary protein with high acid renal load may decrease bone density, if not buffered by ingestion of foods that are alkali rich, that is fruit and vegetables. However, an adequate protein intake is needed for the maintenance of bone integrity. Therefore, increasing the amount of fruit and vegetables may be necessary rather than reducing protein too much.
Therefore it is advisable to consume a normo-proteic diet rich in fruits and vegetables and poor in sodium, that is, a Mediterranean Diet-like eating patterns, eating foods with a negative acid load together with foods with a positive acid load. Example: pasta plus vegetables or meats plus vegetables and fruits (see figure below).

Alkaline Diet: Food and Acid Load
Food and Acid Load

Alkaline diet and muscle mass

As we age, there is a loss of muscle mass, which predispose to falls and fractures. A diet rich in potassium, obtained from fruits and vegetables, as well as a reduced acid load, results in preservation of muscle mass in older men and women.

Alkaline diet and growth hormone

In children, severe forms of metabolic acidosis are associated with low levels of growth hormone with resultant short stature; its correction with potassium or bicarbonate citrate increases growth hormone significantly and improves growth. In postmenopausal women, the use of enough potassium bicarbonate in the diet to neutralize the daily net acid load resulted in a significant increase in growth hormone and resultant osteocalcin.
Improving growth hormone levels may reduce cardiovascular risk factors, improve quality of life, body composition, and even memory and cognition.


Alkaline diet may result in a number of health benefits.

  • Increased fruits and vegetables would improve the K/Na ratio and may benefit bone health, reduce muscle wasting, as well as mitigate other chronic diseases such as hypertension and strokes.
  • The increase in growth hormone may improve many outcomes from cardiovascular health to memory and cognition.
  • The increase in intracellular magnesium is another added benefit of the alkaline diet (e.g. magnesium, required to activate vitamin D, would result in numerous added benefits in the vitamin D systems).

It should be noted that one of the first considerations in an alkaline diet, which includes more fruits and vegetables, is to know what type of soil they were grown in since this may significantly influence the mineral content and therefore their buffering capacity.


Fenton T.R., Lyon A.W., Eliasziw M., Tough S.C., Hanley D.A. Meta-analysis of the effect of the acid-ash hypothesis of osteoporosis on calcium balance. J Bone Miner Res 2009;24(11):1835-1840. doi:10.1359/jbmr.090515

Fenton T.R., Lyon A.W., Eliasziw M., Tough S.C., Hanley D.A. Phosphate decreases urine calcium and increases calcium balance: a meta-analysis of the osteoporosis acid-ash diet hypothesis. Nutr J 2009;8:41. doi:10.1186/1475-2891-8-41

Fenton T.R., Tough S.C., Lyon A.W., Eliasziw M., Hanley D.A. “Causal assessment of dietary acid load and bone disease: a systematic review and meta-analysis applying Hill’s epidemiologic criteria for causality.” Nutr J 2011;10:41. doi:10.1186/1475-2891-10-41

Schwalfenberg G.K. The alkaline diet: is there evidence that an alkaline pH diet benefits health? J Environ Public Health 2012; Article ID 727630. doi:10.1155/2012/727630

Metabolic acidosis and human diet

Life depends on appropriate pH levels around and in living organisms and cells.
We requires a tightly controlled pH level in our serum of about 7.4 (a slightly alkaline range of 7.35 to 7.45) to avoid metabolic acidosis and survive. As a comparison, in the past 100 years the pH of the ocean has dropped from 8.2 to 8.1 because of increasing carbon dioxide (CO2) deposition with a negative impact on life in the ocean (it may lead to the collapse of the coral reefs).

Metabolic Acidosis: The pH Scale
Fig. 1 – The pH Scale

Even the mineral content of the food we eat (minerals are used as buffers to maintain pH within the aforementioned range) is considerabled influence by the pH of the soil in which plants are grown. The ideal pH of soil for the best overall availability of essential nutrients is between 6 and 7: an acidic soil below pH of 6 may have reduced magnesium and calcium, and soil above pH 7 may result in chemically unavailable zinc, iron, copper and manganese.

Metabolic acidosis and agricultural and industrial revolutions

In the human diet, there has been considerable change from the hunter gather civilization to the present in the pH and net acid load. With the agricultural revolution (last 10,000 years) and even more recently with industrialization (last 200 years) it has been seen:

  • an increase in sodium compared to potassium (the ratio potassium/sodium has reversed from 10 to 1 to a ratio of 1 to 3 in the modern diet) and in chloride compared to bicarbonate in the diet,;
  • a poor intake of magnesium and fiber;
  • a large intake of simple carbohydrates and saturated fats.

This results in a diet that may induce metabolic acidosis which is mismatched to the genetically determined nutritional requirements.
Moreover, with aging, there is a gradual loss of renal acid-base regulatory function and a resultant increase in diet-induced metabolic acidosis.
Finally, a high protein low-carbohydrate diet with its increased acid load results in very little change in blood chemistry, and pH, but results in many changes in urinary chemistry: urinary calcium, undissociated uric acid, and phosphate are increased, while urinary magnesium, urinary citrate and pH are decreased.
All this increases the risk for kidney stones.

pH as a protective barrier

The human body has an amazing ability to maintain a steady pH in the blood with the main compensatory mechanisms being renal and respiratory.
The pH in the body vary considerably from one area to another. The highest acidity is found in the stomach (pH of 1.35 to 3.5) and it aids in digestion and protects against opportunistic microbial organisms. The skin is quite acidic (pH 4-6.5) and this provides an acid mantle as a protective barrier to the environment against microbial overgrowth (this is also seen in the vagina where a pH of less than 4.7 protects against microbial overgrowth).
The urine have a variable pH from acid to alkaline depending on the need for balancing the internal environment.

Metabolici Acidosis: pH of Selected Fluids, Organs, and Membranes
Fig. 2 – pH of Selected Fluids, Organs, and Membranes


Fenton T.R., Lyon A.W., Eliasziw M., Tough S.C., Hanley D.A. Meta-analysis of the effect of the acid-ash hypothesis of osteoporosis on calcium balance. J Bone Miner Res 2009;24(11):1835-1840. doi:10.1359/jbmr.090515

Fenton T.R., Lyon A.W., Eliasziw M., Tough S.C., Hanley D.A. Phosphate decreases urine calcium and increases calcium balance: a meta-analysis of the osteoporosis acid-ash diet hypothesis. Nutr J 2009;8:41. doi:10.1186/1475-2891-8-41

Fenton T.R., Tough S.C., Lyon A.W., Eliasziw M., Hanley D.A. Causal assessment of dietary acid load and bone disease: a systematic review and meta-analysis applying Hill’s epidemiologic criteria for causality. Nutr J 2011;10:41. doi:10.1186/1475-2891-10-41

Schwalfenberg G.K. The alkaline diet: is there evidence that an alkaline pH diet benefits health? J Environ Public Health 2012; Article ID 727630. doi:10.1155/2012/727630

Endurance sports and nutrition

In the last years endurance sports, defined in the PASSCLAIM document of the European Commission as those lasting 30 min or more, are increasing in popularity and competitions as half marathons, marathons, even ultramarathons, half Ironmans, or Ironman competitions attract more and more people.
Open water swimming, an endurance sportThey are competitions which can last hours, or days in the more extreme case of ultramarathons.
Athletes at all levels should take care of training and nutrition to optimize performance and to avoid potential health threats.
In endurance sports the most likely contributors to fatigue are dehydration and carbohydrate depletion (especially liver and muscle glycogen).

Dehydration and endurance sports

Dehydration is due to sweat losses needed to dissipate the heat that is generated during exercise. To prevent the onset of fatigue from this cause, the nutritional target is to reduce sweat losses to less than 2–3% of body weight; it is equally important to avoid drinking in excess of sweating rate, especially low sodium drinks, to prevent hyponatraemia (low serum sodium levels).

Glycogen depletion

Muscle glycogen and blood glucose are the most important substrates from which muscle obtains the energy needed for contraction.
Fatigue during prolonged exercise is often associated with reduced blood glucose levels and muscle glycogen depletion; therefore, it is essential starting exercise/competition with high pre-exercise muscle and liver glycogen concentrations, the last one for the maintaining of normal blood glucose levels.

Other problems which reduce performance and can be an health threat of the athlete, especially in long-distance races, are gastrointestinal problems, hyperthermia and hyponatraemia.
Hyponatraemia has occasionally been reported, especially among slower competitors with very high intakes of low sodium drinks.
Gastrointestinal problems occur frequently, especially in long-distance races; both genetic predisposition and the intake of highly concentrated carbohydrate solutions, hyperosmotic drinks, as well as the intake of fibre, fats, and proteins seem to be important in their occurrence.


Burke L.M., Hawley J.A., Wong S.H.S., & Jeukendrup A. Carbohydrates for training and competition. J Sport Sci 2011;29:Sup1,S17-S27. doi:10.1080/02640414.2011.585473

Saris W.H., Antoine J.M., Brouns F., Fogelholm M., Gleeson M., Hespel P., Jeukendrup A.E., Maughan R.J., Pannemans D., Stich V. PASSCLAIM – Physical performance and fitness. Eur J Nutr. 2003;42(Suppl 1):i50-i95. doi:10.1007/s00394-003-1104-0

Jeukendrup A.E. Carbohydrate feeding during exercise. Eur J Sport Sci 2008:2;77-86. doi:10.1080/17461390801918971

Jeukendrup A.E. Nutrition for endurance sports: marathon, triathlon, and road cycling. J Sport Sci 2011:29;sup1, S91-S99. doi:10.1080/02640414.2011.610348

Sawka M.N., Burke L.M., Eichner E.R., Maughan, R.J., Montain S.J., Stachenfeld N.S. American College of Sports Medicine position stand: exercise and fluid replacement. Med Sci Sport Exercise 2007;39:377-390. doi:10.1249/mss.0b013e31802ca597

Shirreffs S., Sawka M.N. Fluid and electrolyte needs for training, competition and recovery. J Sport Sci 2011;29:sup1, S39-S46. doi:10.1080/02640414.2011.614269

Fruits and vegetables in season

Numerous studies showed that seasonality plays a key role in optimizing the antioxidant properties of fruits and vegetables. For example, a recent Chinese study have investigated the influence of growing season (summer vs winter) on the synthesis and accumulation of phenolic compounds and antioxidant properties in five grape cultivars. The study showed that both phenolic compounds and antioxidant properties in the skin and seed of winter berries were significantly higher than those of summer berries for all of the cultivars investigated. Finally, to choose seasonal vegetables and fruits also ensures considerable saving of money.

List of vegetables and fruits in season

Fruits and Vegetables: Fruits in Season
Fig. 1 – Fruits in Season
Fruits and Vegetables: Vegetables in Season
Fig. 2 – Vegetables in Season


Xu C., Zhang Y., Zhu L., Huang Y., and Jiang Lu J. Influence of growing season on phenolic compounds and antioxidant properties of grape berries from vines Grown in Subtropical Climate. J Agric Food Chem 2011:59(4);1078-1086. doi:10.1021/jf104157z

Carbohydrate mouth rinse and endurance exercise performance

The importance of carbohydrates as an energy source for exercise is well known: one of the first study to hypothesize and recognize their importance was the study of Krogh and Lindhardt at the beginning of the 20th century (1920); later, in the mid ‘60’s, Bergstrom and Hultman discovered the crucial role of muscle glycogen on endurance capacity.
Nowdays, the ergogenic effects of carbohydrate supplementation on endurance performance are well known; they are mediated by mechanisms such as:

  • a sparing effect on liver glycogen;
  • the maintenance of glycemia and rates of carbohydrate oxidation;
  • the stimulation of glycogen synthesis during low-intensity exercise ;
  • a possible stimulatory effect on the central nervous system.

However, their supplementation, immediately before and during exercise, has an improving effect also during exercise (running or cycling) of a shorter and more intense nature: >75% VO2max (maximal oxygen consumption) and ≤1 hour, during which euglycaemia is rarely challenged and adequate muscle glycogen store remains at the cessation of the exercise.

Hypothesis for carbohydrate mouth rinse

In the absence of a clear metabolic explanation it was speculated that ingesting carbohydrate solutions may have a ‘non-metabolic’ or ‘central effect’ on endurance performance. To explore this hypothesis many studies have investigated the performance responses of subjects when carbohydrate solutions (about 6% carbohydrate, often maltodextrins) are mouth rinsed during exercise, expectorating the solution before ingestion.
By functional magnetic resonance imaging and transcranial stimulation it was shown that carbohydrates in the mouth stimulate reward centers in the brain and increases corticomotor excitability, through oropharyngeal receptors which signal their presence to the brain.
Probably salivary amylase releases very few glucose units from maltodextrins which is probably what is needed in order to activate the purported carbohydrate receptors in the oropharynx (no glucose transporters in the oropharynx are known).
However, the performance response appears to be dependent upon the pre-exercise nutritional status of the subject: most part of the studies showing an improving effect on performance was conducted in a fasted states (3- to 15-h fasting).
Only one study has shown improvements of endurance capacity; in both fed and fasted states by carbohydrate mouth rinse, but in non-athletic subjects.


Beelen M., Berghuis J., Bonaparte B., Ballak S.B., Jeukendrup A.E., van Loon J. Carbohydrate mouth rinsing in the fed state: lack of enhancement of time-trial performance. Int J Sport Nutr Exerc Metab 2009;19(4):400-409. doi:10.1123/ijsnem.19.4.400

Bergstrom J., Hultman E. A study of glycogen metabolism during exercise in man. Scand J Clin Invest 1967;19:218-228. doi:10.3109/00365516709090629

Bergstrom J., Hultman E. Muscle glycogen synthesis after exercise: an enhancing factor localized in muscle cells in man. Nature 1966;210:309-310. doi:10.1038/210309a0

de Salles Painelli V.S., Nicastro H., Lancha A. H.. Carbohydrate mouth rinse: does it improve endurance exercise performance? Nutrition Journal 2010;9:33. doi:10.1186/1475-2891-9-33

Fares E.J., Kayser B. Carbohydrate mouth rinse effects on exercise capacity in pre- and postprandial States. J Nutr Metab 2011, Article ID 385962. doi:10.1155/2011/385962

Krogh A., Lindhard J. The relative value of fat and carbohydrate as sources of muscular energy. Biochem J 1920;14:290-363. doi:10.1042/bj0140290

Rollo I. Williams C. Effect of mouth-rinsing carbohydrate solutions on endurance performance. Sports Med. 2011;41(6):449-461. doi:10.2165/11588730-000000000-00000

How to reduce body fat

The international scientific literature is unanimous in setting the lower limit for the daily caloric intake to 1200 kcal for women and 1500 kcal for men (adults).
To make negative the daily caloric intake, and therefore lose body weight, but expecially lose body fat, evaluation of actual caloric needs of the subject will be alongside:

  • the correct distribution of meals during the day;
  • an increased physical activity, by which the negative balance can be achieved without major sacrifices during meals.
Body Fat
Daily Caloric Balance

This will make weight loss easier and protect from subsequent weight gains and yo-yo effect.
Ultimately, there must be a change in lifestyle.


Body fat and “miracle diets”

So, the best strategy for losing body fat is not a drastic reduction in caloric intake, nor follow constrictive or “strange” diets, such as hcg diet plan, sacred heart diet, paleo diet, Master Cleanse diet (the diet that Beyonce did), etc., that require to eliminate or greatly reduce the intake of certain macronutrients, mostly carbohydrates.
Such conducts can be:

  • very stressful from psychological point of view;
  • not passable for long periods;
  • hazardous to health because of inevitable nutrient deficiencies.

Finally, they do not ensure that all the weight lost is only or almost only body fat and are often followed by substantial increases in body weight and/or by yo-yo effect.

Body fat and reduction of energy intake

An excessive reduction of energy intake means eating very little and this determines the risk, high, not to take adequate amounts of the various essential nutrients, that is, what we can’t synthesize, such as vitamins, certain amino acids, some fatty acids and minerals, including e.g. calcium, essential for bone metabolism at every stage of life, or iron, used in many body functions as the transport of oxygen to the tissues. This results in a depression of metabolism and hence a reduction in energy expenditure.
Whether the reduction in energy intake is excessive, or even there are periods of fasting, it adds insult to injury because a proportion of free fatty mass will be lost. How?

Reduction in energy intake and role of carbohydrates

Glucose is the only energy source for red blood cells and some brain areas, while other brain areas can also derive energy from ketone bodies, which are a product of fatty acid metabolism.
At rest, brain extracts 10% of the glucose from the bloodstream, a significant amount, about 75 mg/min., considering that its weight is about 1.5 kg. To maintain a constant glycemia, and thus ensure a constant supply of glucose to tissues, we needs to take carbohydrates or alternatively amino acids, both easily obtained from foods.
In the case of a low or absent dietary intake of carbohydrates, whereas after about 18 hours liver glycogen, which releases glucose into circulation, depletes, body synthesizes de novo glucose from certain amino acids through a process called gluconeogenesis (actually this metabolic pathway is active even after a normal meal but increases its importance in fasting).
But what’s the main source of amino acids in the body when their dietary intake is low or absent? Endogenous proteins, and there is a hierarchy in their use that is before we consume the less important and only after the most important ones. For the first digestive enzymes, pepsin, chymotrypsin, elastase, carboxypeptidase and aminopeptidase (around 35-40 g) will be used; successively liver and pancreas slow down their synthesis activities for export proteins and unused amino acids are directed to gluconeogenesis. It’s clear that these are quite modest reserves of amino acids and it is the muscle that will undertake to provide the required amounts of amino acids that is proteolysis of muscle proteins begins.
Note: Anyway, there is no absolute sequentiality in the degradation of several proteins, there is instead a plot in which, proceeding, some ways lose their importance and others will buy. So, to maintain constant glycemia the protein component of muscle is reduced, including skeletal muscle that is a tissue that represents a fairly good portion of the value of the basal metabolism and that, with exercise, can significantly increase its energy consumption: thus essential for weight loss and subsequent maintenance. It is as if the engine capacity was reduced.
One thing which we don’t think about is that heart is a muscle that may be subject to the same processes seen for skeletal muscle.
Ultimately make glucose from proteins, also food-borne, is like heat up the fire-place burning the furniture of the eighteenth century, amino acids, having available firewood, dietary carbohydrates.
Therefore, an adequate intake of carbohydrates with diet prevents excessive loss of proteins, namely, there is a saving effect of proteins played by carbohydrates.
Mammals, and therefore humans, can’t synthesize glucose from fats.

What goes in when carbohydrates goes out?

The elimination or substantial reduction in carbohydrate intake in the diet results in an increased intake of proteins, lipids, including cholesterol, because it will increase the intake of animal products, one of the main defects in hyperproteic diet.
In the body there are no amino acids reserves, thus they are metabolized and, as a byproduct of their use, ammonia is formed and it’ll be eliminated as toxic. For this reason high-protein diets imply an extra work for liver and kidneys and also for this they are not without potential health risks.
An increased fat intake often results into an increased intake of saturated fatty acids, trans fatty acids, and cholesterol, with all the consequences this may have on cardiovascular health.
What has been said so far should not induce to take large amounts of carbohydrates; this class of macronutrients should represent 55-60% of daily calories, fats 25-30% (primarily extra-virgin olive oil) and the remainder proteins: thus a composition in macronutrient that refers to prudent diet or Mediterranean Diet.

Body fat and the entry in a phase of famine/disease

A excessive reduction in caloric intake is registered by our defense mechanisms as an “entry” in a phase of famine/disease.
The abundance of food is a feature of our time, at least in industrialized countries, while our body evolved over hundreds of thousands of years during which there was no current abundance: so it’s been programmed to try to overcome with minimal damage periods of famine. If caloric intake is drastically reduced it mimics a famine: what body does is to lower consumption, lower the basal metabolism, that is, consumes less and therefore also not eating much we will not get great results. It is as if a machine is lowered the displacement, it’ll consume less (our body burns less body fat).

Yo-yo effect

Yo-yo effect or weight cycling, namely, repeated phases of loss and weight gain, appears related to excess weight and accumulation of fat in the abdomen.
Several studies suggest a link in women with:

  • increased blood pressure;
  • hypercholesterolemia;
  • gallbladder disease;
  • significant increase in binge eating disorder;
  • a sense of depression with regard to weight.

Lastly, yo-yo effect is related to a greater easy to gain weight than those who are not subject to it. In this regard there should be emphasized that the weight cycling occurs over years, during which, aging, the rate of metabolism inevitably tends to decrease: this could make more difficult the subsequent losses.


Cereda E., Malavazos A.E., Caccialanza R., Rondanelli M., Fatati G. and Barichella M. Weight cycling is associated with body weight excess and abdominal fat accumulation: a cross-sectional study. Clin Nutr 2011;30(6):718-723. doi:10.1016/j.clnu.2011.06.009

Montani J-P., Viecelli A.K., Prévot A. & Dulloo A.G. Weight cycling during growth and beyond as a risk factor for later cardiovascular diseases: the ‘repeated overshoot’ theory. Int J Obes (Lond) 2006;30:S58-S66. doi:10.1038/sj.ijo.0803520

Ravussin E., Lillioja S., Knowler W.C., Christin L., Freymond D., Abbott W.G.H., Boyce V., Howard B.V., and Bogardus C. Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med 1988;318:467-472. doi:10.1056/NEJM198802253180802

Sachiko T. St. Jeor S.T. St., Howard B.V., Prewitt T.E., Bovee V., Bazzarre T., Eckel T.H., for the AHA Nutrition Committee. Dietary Protein and Weight Reduction. A Statement for Healthcare Professionals From the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association. Circulation 2001;104:1869-1874. doi:10.1161/hc4001.096152

Strategies to maximize muscle glycogen resynthesis after exercise

Muscle glycogen is an important energy source for prolonged moderate to high intensity exercise, an importance that increases during high-intensity interval exercise, common in training session of swimmers, runners, rowers or in team-sport players, or during resistance exercise. For example, considering marathon, about 80% of energy needed comes from carbohydrate oxidation, for the most part skeletal muscle glycogen.
Fatigue and low muscle glycogen levels are closely correlated, but the underlying molecular mechanisms remain elusive. One hypothesis is that there is a minimum glycogen concentration that is “protected” and is not used during exercise, perhaps to ensure an energy reserve in case of need. Due to the closely relationship between skeletal muscle glycogen depletion and fatigue, its re-synthesis rate during post-exercise is one of the most important factors in determining necessary recovery time.
Finally, the highly trained athlete has muscle glycogen stores potentially higher and is also able to synthesize it faster due to more efficient enzymes.

The branched structure of glycogen molecule, the tiers and glycogeninTo synthesize glycogen it is necessary to ingest carbohydrates; but how many, which, when, and how often?


The two phases of muscle glycogen synthesis after exercise

In order to restore as quickly as possible muscle glycogen depots, it is useful to know that, as a result of training sessions that deplete muscle glycogen to values below 75% those at rest and not fasting, glycogen synthesis occurs in two phases.
To know and therefore take advantage of the biphasicity is important for those athletes who are engaged in more daily training sessions, or who otherwise have little time for recovery between a high intensity exercise and the subsequent one (less than 8 hours), in order to maximize glycogen synthesis and achieve the optimal performance during a second close exercise session.
The two phases are characterized by:

  • a different sensitivity to circulating insulin levels;
  • a different velocity.

The first phase

The first phase, immediately following the end of an activity and lasting 30-60 minutes, is insulin-independent, i.e. glucose uptake by muscle cell as glycogen synthesis are independent from hormone action.
This phase is characterized by an elevated rate of synthesis that however decreases rapidly if you do not take in carbohydrates: the maximum rate is in the first 30 minutes, then declines to about one fifth in 60 minutes, and to about one ninth in 120 minutes from the end of exercise.
How is it possible to take advantage of this first phase to replenish muscle glycogen stores as much as possible? By making sure that the greatest possible amount of glucose arrives to muscle in the phase immediately following to the end of exercise, best if done within the first 30 minutes.

  • What to ingest?
    High glycemic index, but easy to digest and absorb, carbohydrates.
    Therefore, it is advisable to replace foods, even though of high glycemic index, that need some time for digestion and the subsequent absorption, with solutions/gel containing for example glucose and/or sucrose. These solutions ensure the maximal possible absorption rate and resupply of glucose to muscle because of they contain only glucose and are without fiber or anything else that could slow their digestion and the following absorption of the monosaccharide, that is, they are capable of producing high blood glucose levels in a relatively short time.
    It is also possible to play on temperature and concentration of the solution to accelerate the gastric transit.
    It should be further underlined that the use of these carbohydrate solutions is recommended only when the recovery time from a training/competition session causing significant depletion of muscle glycogen and the following one is short, less than 8 hours.
  • How many carbohydrates do you need?
    Many studies has been conducted to find the ideal amount of carbohydrates to ingest.
    If in post-exercise the athlete does not eat, glycogen synthesis rate is very low, while if he ingests adequate amounts of carbohydrates immediately after cessation of exercise, synthesis rate can reach a value over 20 times higher.
    From the analysis of scientific literature it seems reasonable to state that, as a result of training sessions that deplete muscle glycogen stores as seen above (<75% of those at rest and not fasting), the maximum synthesis rate is obtained by carbohydrate intake, with high glycemic index and high digestion and absorption rates, equal to about 1.2 g/kg of body weight/h for the next 4-5 hours from the end of exercise.
    In this way, the amount of glycogen produced is higher than 150% compared to the ingestion of 0.8 g/kg/h.
    Because further increases, up to 1.6 g/kg/h, do not lead to further rise in glycogen synthesis rate, the carbohydrate amount equal to 1.2 g/kg/h can be considered optimum to maximize the resynthesis rate of muscle glycogen stores during post-exercise.
  • And the frequency of carbohydrate ingestion?
    It was observed that if carbohydrates are ingested frequently, every 15-30 minutes, it seems there is a further stimulation of muscle glucose uptake as of muscle glycogen replenishment compared with ingestion at 2-hours intervals. Particularly, ingestions in the first post-exercise hours seem to optimize glycogen levels.

The second phase

The second phase begins from the end of the first, lasts until the start of the last meal before the next exercise (hence, from several hours to days), and is insulin-dependent i.e. muscle glucose uptake and glycogen synthesis are sensitive to circulating hormone levels.
Moreover, you observe a significant reduction in muscle glycogen synthesis rate: with adequate carbohydrate intake the synthesis rate is at a value of about 10-30% lower than that observed during the first phase.
This phase can last for several hours, but tends to be shorter if:

  • carbohydrate intake is high;
  • glycogen synthesis is more active;
  • muscle glycogen levels are increased.

In order to optimize the resynthesis rate of glycogen, experimental data indicate that meals with high glycemic index carbohydrates are more effective than those with low glycemic index carbohydrates; but if between a training/competition session and the subsequent one days and not hours spend, the evidences do not favor high glycemic index carbohydrates as compared to low glycemic index ones as long as an adequate amount is taken in.

Muscle glycogen synthesis rate and ingestion of carbohydrates and proteins

The combined ingestion of carbohydrates and proteins (or free insulinotropic amino acids) allows to obtain post-exercise glycogen synthesis rate that does not significantly differ from that obtained with larger amounts of carbohydrates alone. This could be an advantage for the athlete who may ingest smaller amount of carbohydrates, therefore reducing possible gastrointestinal complications commons during training/competition afterward to their great consumption.
From the analysis of scientific literature it seems reasonable to affirm that, after an exercise that depletes at least 75% of muscle glycogen stores, you can obtain a glycogen synthesis rate similar to that reached with 1.2 g/kg/h of carbohydrates alone (the maximum obtainable) with the coingestion of 0.8 g/kg/h of carbohydrates and 0.4 g/kg /h of proteins, maintaining the same frequency of ingestion, therefore every 15-30 minutes during the first 4-5 hours of post-exercise.

The two phases: molecular mechanisms

The biphasicity is consequence, in both phases, of an increase in:

  • glucose transport rate into cell;
  • the activity of glycogen synthase, the enzyme that catalyzes glycogen synthesis.

However, the molecular mechanisms underlying these changes are different.
In the first phase, the increase in glucose transport rate, independent from insulin presence, is mediated by the translocation, induced by the contraction, of glucose transporters, called GLUT4, on the cytoplasmatic membrane of the muscle cell.
In addition, the low glycogen levels also stimulate glucose transport as it is believed that a large portion of transporter-containing vesicles are bound to glycogen, and therefore they may become available when its levels are depleted.
Finally, the low muscle glycogen levels stimulate glycogen synthase activity too: it has been demonstrated that these levels are a regulator of enzyme activity far more potent than insulin.
In the second phase, the increase in muscle glycogen synthesis is due to insulin action on glucose transporters and on glycogen synthase activity of muscle cell. This sensibility to the action of circulating insulin, that can persist up to 48 hours, depending on carbohydrate intake and the amount of resynthesized muscle glycogen, has attracted much attention: it is in fact possible, through appropriate nutritional intervention, to increase the secretion in order to improve glycogen synthesis itself, but also protein anabolism, reducing at the same time the protein-breakdown rate.

Glycogen synthesis rate and insulin

The coingestion of carbohydrates and proteins (or free amino acids) increases postprandial insulin secretion compared to carbohydrates alone (in some studies there was an increase in hormone secretion 2-3 times higher compared to carbohydrates alone).
It was speculated that, thanks to the higher circulating insulin concentrations, further increases in post-exercise glycogen synthesis rate could be obtained compared to those observed with carbohydrates alone, but in reality it does not seem so. In fact, if carbohydrate intake is increased to 1.2 g/kg/h plus 0.4 g/kg/h of proteins no further increases in glycogen synthesis rate are observed if compared to those obtained with the ingestion of carbohydrates alone in the same amount (1,2 g/kg/h, that, as mentioned above, like the coingestion of 0,8 g/kg/h of carbohydrates and 0,4 g/kg/h of proteins, allows to attain the maximum achievable rate in post-exercise) or in isoenergetic quantities, that is, 1.6 g/kg (proteins and carbohydrates contain the same calorie/g)

Insulin and preferential carbohydrate storage

The greater circulating insulin levels reached with the coingestion of carbohydrates and proteins (or free amino acids) might stimulate the accumulation of ingested carbohydrates in tissues most sensitive to its action, such as liver and previously worked muscle, thus resulting in a more efficient storage, for the purposes of sport activity, of the same carbohydrates.


Beelen M., Burke L.M., Gibala M.J., van Loon J.C. Nutritional strategies to promote postexercise recovery. Int J Sport Nutr Exerc Metab 2010:20(6);515-532. doi:10.1123/ijsnem.20.6.515

Berardi J.M., Noreen E.E., Lemon P.W.R. Recovery from a cycling time trial is enhanced with carbohydrate-protein supplementation vs. isoenergetic carbohydrate supplementation. J Intern Soc Sports Nutrition 2008;5:24. doi:10.1186/1550-2783-5-24

Betts J., Williams C., Duffy K., Gunner F. The influence of carbohydrate and protein ingestion during recovery from prolonged exercise on subsequent endurance performance. J Sports Sciences 2007;25(13):1449-1460. doi:10.1080/02640410701213459

Howarth K.R., Moreau N.A., Phillips S.M., and Gibala M.J. Coingestion of protein with carbohydrate during recovery from endurance exercise stimulates skeletal muscle protein synthesis in humans. J Appl Physiol 2009:106;1394–1402. doi:10.1152/japplphysiol.90333.2008

Jentjens R., Jeukendrup A. E. Determinants of post-exercise glycogen synthesis during short-term recovery. Sports Medicine 2003:33(2);117-144. doi:10.2165/00007256-200333020-00004

Millard-Stafford M., Childers W.L., Conger S.A., Kampfer A.J., Rahnert J.A. Recovery nutrition: timing and composition after endurance exercise. Curr Sports Med Rep 2008;7(4):193-201. doi:10.1249/JSR.0b013e31817fc0fd

Price T.B., Rothman D.L., Taylor R., Avison M.J., Shulman G.I., Shulman R.G. Human muscle glycogen resynthesis after exercise: insulin-dependent and –independent phases. J App Physiol 1994:76(1);104–111. doi:10.1152/jappl.1994.76.1.104

van Loon L.J.C., Saris W.H.M., Kruijshoop M., Wagenmakers A.J.M. Maximizing postexercise muscle glycogen synthesis: carbohydrate supplementation and the application of amino acid or protein hydrolysate mixtures. Am J Clin Nutr 2000;72: 106-111. doi:10.1093/ajcn/72.1.106

Daily protein requirements for athletes

It is now accepted by athletes, coaches and athletic trainers that proper diet is one of the cornerstones for achieving better athletic performance. Despite this widely spread assumption, many, even at the highest levels, still believe that an high protein intake is fundamental in the athlete’s diet. This opinion is not new and is deeply rooted in the imaginary of many people almost as if, eating meat, even of big and strong animals, we were able to gain their strength and vitality too.
Foods high in proteins and protein requirements of athletes
The function of proteins as energy-supplier for working muscle was hypothesized for the first time by von Liebig in ‘800 and it is because of his studies if, even today, animal proteins, and therefore meats, are often believed having great importance in the energy balance in the athlete’s diet, despite nearly two centuries in which biochemistry and sports medicine have made enormous progress.
Really, by the end of ‘800 von Pettenkofer and Voit and, at the beginning of ‘900, Christensen and Hansen retrenched their importance for energy purposes, also for the muscle engaged in sport performance, instead bringing out the prominent role played by carbohydrates and lipids.
Of course we shouldn’t think that proteins are not useful for the athlete or sedentary people. The question we need to answer is how many proteins a competitive athlete, engaged in intense and daily workouts, often two daily sessions (for 3-6 hours), 7/7, for more than 10 months a year, needs per day. We can immediately say that, compared to the general population, and with the exception of some sports, (see below) the recommended amount of protein is greater.

Metabolic fate of proteins at rest and during exercise

In a healthy adult subject engaged in a non-competitive physical activity, the daily protein requirements is about 0.85 g/kg desirable body weight, as shown by WHO.
Proteins turnover in healthy adults, about 3-4 g/kg body weight/day (or 210-280 g for a 70 kg adult), is slower for the muscle than the other tissues and decreasing with age, and is related to the amount of amino acids in the diet and protein catabolism.
At rest the anabolic process, especially of synthesis, uses about 75% amino acids while the remaining 25% undergoes oxidative process, that will lead to CO2 and urea release (for the removal of ammonia).
During physical activity, as result of the decreased availability of sugars, i.e. muscle glycogen and blood glucose used for energy purposes, as well as the intervention of cortisol, the percentage of amino acids destinated to anabolic processes is reduced while it increases that of amino acids diverted to catabolic processes, that is, it occurs an increase in the destruction of tissue proteins.
At the end of physical activity, for about two hours, anabolic processes remain low whereupon it occurs their sharp increase that brings them to values higher than basal ones, so, training induces an increase in protein synthesis even in the absence of an increase in proteins intake.

What determines the daily protein requirements?

There are many factors to be taken into account in the calculation of the daily protein requirements.

  • The age of the subject (if, for example, he/she is in the age of development).
  • Gender: female athletes may require higher levels as their energy intake is lower.
  • An adequate carbohydrate intake reduces their consumption.
    During physical activity, glucogenic amino acids may be used as energy source directly in the muscle, after their conversion to glucose in the liver through gluconeogenesis.
    An adequate carbohydrate intake before and during prolonged exercise lowers the use of body proteins.
  • The amount of carbohydrates stored in muscles and liver (glycogen) (see above).
  • The energy intake of the diet.
    A reduced energy intake increases protein requirements; conversely, the higher energy intake, the lower the amount of protein required to achieve nitrogen balance; usually there is a nitrogen retention of 1-2 mg per kcal introduced.
    If the athlete is engaged in very hard competition/workouts, or if he requires an increase in muscle masses (e.g. strength sports) nitrogen balance must be positive; a negative balance indicates a loss of muscle mass.
    The nitrogen balance is calculated as difference between the nitrogen taken with proteins (equal to: g. proteins/6.25) and the lost one (equal to: urinary urea in 24 hours, in g., x0.56]; in formula:

Nb (nitrogen balance) = (g. protein/6.25) – [urinary urea in 24 hours, in g., x 0.56)]

  • The type of competition/workouts that the athlete is doing, either resistance or endurance, as well as the duration and intensity of the exercise itself.
    Resistance training leads to an increase in protein turnover in muscle, stimulating protein synthesis to a greater extent than protein degradation; both processes are influenced by the recovery between a training and the next one as well as by the degree of training (more training less loss).
    In the resistance and endurance performances the optimal protein requirements in younger people as for those who train less time are estimated at 1.3 to 1.5 g protein/kg body weight, while in adult athletes who train more time is slightly lower, about 1-1.2 g/Kg of body weight.
    In subjects engaged in a hard physical activity, proteins are used not only for plastic purposes, which are incremented, but also for energy purposes being able to satisfy in some cases up to 10-15% of the total energy demand.
    Indeed, intense aerobic performances, longer than 60 minutes, obtain about 3-5% of the consumed energy by the oxidation of protein substrates; if we add to this the proteins required for the repair of damaged tissue protein structures, it results a daily protein demand about 1.2 to 1.4 g/kg body weight.
    If the effort is intense and longer than 90 minutes (as it may occur in road cycling, running, swimming, or cross-country skiing), also in relation to the amount of available glycogen in muscle and liver (see above), the amount of proteins used for energy purposes can get to satisfy, in the latter stages of a prolonged endurance exercise, 15% of the energy needs of the athlete.
  • The physical condition.
  • When needed, the desired weight.
    Athletes attempting to lose weight or maintain a low weight may need more proteins.

From the above, protein requirements don’t exceed 1.5 g/kg body weight, also for an adult athlete engaged in intense and protracted workouts, while if you consider the amount of protein used for energy purposes, you do not go over 15% of the daily energy needs.
So, it’s clear that diets which supply higher amounts (sometimes much higher) of proteins aren’t of any use, stimulate the loss of calcium in bones and overload of work liver and kidney. Moreover, excess proteins don’t accumulate but are used to fat synthesis.

How to meet the increased protein requirements of athletes

A diet that provides 12 to 15% of its calories from protein will be quite sufficient to satisfy the needs of almost all of the athletes, also those engaged in exhausting workouts.
In fact, with the exception of some sports whose energy expenditure is low, close to that of sedentary subject (for example: shooting, or artistic and rhythmic gymnastics), athletes need a high amount of calories and, for some sports such as road cycling, swimming or cross-country skiing, it may be double/triple than that of a sedentary subject.
The increase in food intake is accompanied by a parallel increase in protein intake, because only a few foods such as honey, maltodextrin, fructose, sucrose and vegetable oils are protein-free, or nearly protein-free.

Calculation of protein requirements of athletes

If you consider an energy demand of 3500 kcal/die, with a protein intake equal to 15% of total daily calories, you have:

3500 x 0.15 = 525 Kcal

As 1 gram of protein contains 4 calories, you obtain:

525/4 = 131 g of proteins

Dividing the number found by the highest protein requirements seen above (1.5 g/kg body weight/day), you obtain:

131/1.5 = 87 kg

that is, the energy needs of a 87 kg athlete engaged in intense workouts are satisfied.
Repeating the same calculations for a caloric intake of 5000 , you obtain 187 g of protein; dividing it by 1.5 the result is 125 kg, that is, the energy needs of a 125 kg athlete are satisfied.
These protein intakes can be met by a Mediterranean-type diet, without protein or amino acids supplements.


Protein and amino acid requirements in human nutrition. Report of a joint FAO/WHO/UNU expert consultation. 2002 (WHO technical report series ; no. 935).

Stipanuk M.H., Caudill M.A. Biochemical, physiological, and molecular aspects of human nutrition. 3rd Edition. Elsevier health sciences, 2012

Omega-6 polyunsaturated fatty acids

Omega-6 polyunsaturated fatty acids are the major polyunsaturated fatty acids (PUFA) in the Western diet (about 90% of all of them in the diet), being components of most animal and vegetable fats.


The synthesis of ω-6 polyunsaturated fatty acids

Within the omega-6 (ω-6) family, linoleic acid is one of the most important and widespread fatty acids and the precursor of all omega-6 polyunsaturated fatty acids. It is produced de novo from oleic acid (an omega-9 fatty acid) only by plant in a reaction catalyzed by Δ12-desaturase, i.e. the enzyme that forms the omega-6 polyunsaturated fatty acid family from omega-9 one.
Δ12-desaturase catalyzes the insertion of the double bond between carbon atoms 6 and 7, numbered from the methyl end of the molecule.
Linoleic acid, together with alpha-linolenic acid, is a primary product of plant polyunsaturated fatty acids synthesis.

Biosynthesis and metabolism of omega-6 polyunsaturated fatty acids
Omega-6 Polyunsaturated Fatty Acid Metabolism

Animals, lacking Δ12-desaturase, can’t synthesize it, and all the omega-6 polyunsaturated fatty acid family de novo, and they are obliged to obtain it from plant foodstuff and/or from animals that eat them; for this reason omega-6 polyunsaturated fatty acid are considered essential fatty acids, so called EFA (the essentiality of omega-6 polyunsaturated fatty acids, in particular just the essentiality of linoleic acid, was first reported in 1929 by Burr and Burr).

ω-6 PUFA: from linoleic acid to arachidonic acid

Animals are able to elongate and desaturase dietary linoleic acid in a cascade of reactions to form very omega-6 polyunsaturated fatty acids.
Linoleic acid is first desaturated to gamma-linolenic acid, another important ω-6 fatty acid with significant physiologic effects, in the reaction catalyzed by Δ6-desaturase. It is thought that the rate of this reaction is limiting in certain conditions like in the elderly, under certain disease states and in premature infants; for this reason, and because it is found in relatively small amounts in the diet, few oils containing it (black currant, evening primrose, and borage oils) have attracted attention.
In turn gamma-linolenic acid may be elongated to dihomo-gamma-linolenic acid by an elongase (it catalyzes the addition of two carbon atoms from glucose metabolism to lengthen the fatty acid chain) that may be further desaturated in a very limited amount to arachidonic acid, in a reaction catalyzed by another rate limiting enzyme, Δ5-desaturase.
Arachidonic acid can be elongated and desaturated to adrenic acid.

It should be noted that polyunsaturated fatty acids in the omega-6 family, and in any other n-families, can be interconverted by enzymatic processes only within the same family, not among families.

C-20 polyunsaturated fatty acids belonging to omega-6 and omega-3 polyunsaturated fatty acids are the precursors of eicosanoids (prostaglandins, prostacyclin, thromboxanes, and leukotrienes), powerful, short-acting, local hormones.

While the deprivation of omega-3 polyunsaturated fatty acids causes dysfunction in a wide range of behavioral and physiological modalities, the omission in the diet of omega-6 polyunsaturated fatty acids results in manifest systemic dysfunction.

In plant seed oils omega-6 fatty acids with chain length longer than 18 carbons are present only in trace while arachidonic acid is found in all animal tissues and animal-based food products.


Akoh C.C. and Min D.B. “Food lipids: chemistry, nutrition, and biotechnology” 3th ed. 2008

Aron H. Uber den Nahvert (On the nutritional value). Biochem Z. 1918;92:211–233 (German)

Bender D.A. “Benders’ dictionary of nutrition and food technology”. 2006, 8th Edition. Woodhead Publishing. Oxford

Bergstroem S., Danielsson H., Klenberg D. and Samuelsson B. The enzymatic conversion of essential fatty acids into prostaglandins. J Biol Chem 1964;239:PC4006-PC4008.

Burr G.O. and Burr M.M. A new deficiency disease produced by the rigid exclusion of fat from the diet. Nutr Rev 1973;31(8):148-149. doi:10.1111/j.1753-4887.1973.tb06008.x

Chow Ching K. “Fatty acids in foods and their health implication” 3th ed. 2008

Rosenthal M.D., Glew R.H. Mediacal biochemistry. Human metabolism in health and disease. John Wiley & Sons, Inc. 2009

Stipanuk M.H., Caudill M.A. Biochemical, physiological, and molecular aspects of human nutrition. 3rd Edition. Elsevier health sciences, 2012

Van D., Beerthuis R.K., Nugteren D.H. and Vonkeman H. Enzymatic conversion of all-cis-polyunsaturated fatty acids into prostaglandins. Nature 1964;203:839-841

Omega-3 fatty acids: synthesis, mechanism of action, health benefits, and foods

Omega-3 polyunsaturated fatty acids or omega-3 PUFAs or omega-3 fatty acids are unsaturated fatty acids that have a double bond three carbons from the methyl end of the carbon chain. For humans, the most important omega-3 PUFAs are:

  • alpha-linolenic acid or ALA or 18:3n-3, with 18 carbon atoms and 3 double bonds;
  • eicosapentaenoic acid or EPA or 20:5n-3, with 20 carbon atoms and 5 double bonds;
  • docosahexaenoic acid or DHA or 22:6n-3, that, with 22 carbon atoms and 6 double bonds, is the most complex.

EPA and DHA are termed long-chain polyunsaturated fatty acids or LC-PUFAs.
Animals cannot synthesize linoleic acid or LA and alpha-linolenic acid, the precursors to omega-6 polyunsaturated fatty acids and omega-3 PUFAs, respectively, due to the lack of two desaturases: delta-12 desaturase (EC and delta-15 desaturase (EC 1-14.19.13). Such desaturases insert double bonds at positions 6 and 3 from the methyl end of the molecule, respectively. Linoleic acid and alpha-linolenic acid are therefore essential fatty acids. Humans and many other animals can produce, from dietary ALA, all the other omega-3 polyunsaturated fatty acids. Then, such omega-3 PUFAs become essential in the absence of dietary ALA, and for this reason they are termed conditionally essential fatty acids.
EPA and DHA are important structural components of cell membranes, where they are mainly found, especially in muscle and nerve tissues. Conversely, many other fatty acids are stored mainly in adipose tissue triglycerides.
DHA is the main component of cell membrane phospholipids of neural tissues of vertebrates, including photoreceptor of the retina, where it performs important functions. In addition to their structural functions, omega-3 PUFAs are substrates for the production of bioactive lipid mediators with anti-inflammatory action, such as eicosanoids, maresins, resolvins, and protectins.
Omega-3 polyunsaturated fatty acids are essential in neurological development of the fetus, and their intake during pregnancy is especially important in the third trimester of pregnancy, when significant brain growth occurs. In the course of life their intake has been associated with a reduction in the risk of developing many chronic diseases, particularly cardiovascular diseases.
The major dietary sources for humans are fishery products, especially those obtained from cold waters.


Synthesis of omega-3 polyunsaturated fatty acids

Alpha-linolenic acid, the precursors to omega-3 polyunsaturated fatty acids, is produced from linoleic acid, an omega-6 PUFAs, only in the plastids of phytoplankton and vascular terrestrial plants, where delta-15 desaturase inserts a double bond between carbon 3 and 4 from the methyl end of LA. In turn, ALA undergoes desaturation reactions, catalyzed by delta-5 desaturase (EC and delta-6 desaturase (EC, elongation reactions, catalyzed by elongase 5 (EC and elongase 5 and/or by elongase 2 (EC, and a limited beta-oxidation in peroxisomes, to produce DHA. For more details see the article on DHA.

Synthesis and metabolism of omega-3 polyunsaturated fatty acids
Omega-3 Fatty Acid Metabolism

The enzymes that catalyze the conversion of ALA to DHA are shared with the synthetic pathways leading to the synthesis of omega-6, omega-7 and omega-9 PUFAs. Omega-3 PUFAs appear to be the preferred substrates for delta-5 desaturase and delta-6 desaturase. However, because in many Western diets there is a high intake of linoleic acid relative to alpha-linolenic acid intake, the omega-6 pathway would be preferred over the other pathways. This could be one of the explanations for the low conversion rate of alpha-linolenic acid into the other omega-3 PUFAs, although the synthesis of arachidonic acid or ARA from linoleic acid seems to be very low, too. Note that both the omega-3 and omega-6 families inhibit the synthesis of omega-9 polyunsaturated fatty acids.

Omega-3 PUFA synthesis in humans

Humans, like many other animals, can convert alpha-linolenic acid to docosahexaenoic acid, a metabolic pathway found mainly in the liver and cerebral microcirculation of the hematoencephalic barrier, but also in the cerebral endothelium and astrocytes. It is common opinion that humans, like other terrestrial animals, have a limited capacity to synthesize LC-PUFAs, and therefore need an adequate intake of EPA and DHA from food.
It has been shown that the yield of the synthesis decreases along the pathway: the rate of conversion of alpha-linolenic acid to eicosapentaenoic acid is low, and the limiting factor seems to be the activity of delta-6 desaturase, and the rate of conversion to docosahexaenoic acid is extremely low. However recent studies have demonstrated the existence of a marked polymorphism in the fatty acid desaturase (FADS) gene cluster, especially for the contiguous genes FADS1 and FADS2 coding for delta-5 desaturase and delta-6 desaturase, respectively, which are present on chromosome 11q12.2. By analyzing genome-wide sequencing data from Bronze Age individuals and present-day Europeans, a  comprehensive overview was obtained of the changes in allele frequency of FADS genes. In European populations, the transition from a hunter-gatherer society to an agricultural society would have resulted in an increase in the intake of linoleic acid and alpha-linolenic acid, and a reduction in the intake of EPA and ARA. Natural selection would then have favored the haplotype associated with the increase in the expression of FADS1 and the decrease in the expression of FADS2. This pattern is opposite to that found in the Greenlander Inuit, where it is hypothesized that natural selection would have favored alleles associated with a decrease in the rate of conversion of linoleic acid and alpha-linolenic acid into LC-PUFAs, in order to compensate for their relatively high dietary intake in such population.

Do other animals need EPA and DHA?

Organisms lacking delta-15 desaturase cannot synthesize alpha-linolenic acid and hence the other omega-3 PUFAs, and, if needed, must obtain it from dietary sources. However, many animals do not need to get EPA and DHA from diet.
Terrestrial herbivorous vertebrates satisfy their need for long chain omega-3 polyunsaturated fatty acids by synthesizing them from alpha-linolenic acid obtained from the green parts of plants.
And there are animals that do not need EPA and DHA, and practically do not have them. These include terrestrial insects, that have very low levels of EPA. In such animals, EPA is synthesized from dietary alpha-linolenic acid and used for eicosanoid production.
Conversely, aquatic insects have high levels of EPA, whereas DHA is practically absent.
Some classes of phytoplankton, such as Cryptophyceae and Dinophyceae, are very rich in EPA and DHA, whereas Bacillariophyceae or diatoms are very rich in EPA. In general, microalgae are the primary producers of EPA and DHA, and then, aquatic ecosystems are the main source of omega-3 LC-PUFAs in the biosphere. EPA and DHA are then transferred from these microalgae along the food chain, from invertebrates to fish, and from fish to terrestrial animals, including humans. So, from microalgae to humans.

Benefits of omega-3 polyunsaturated fatty acids for humans

Omega-3 polyunsaturated fatty acids are essential components of a healthy and balanced diet. They are needed throughout development, starting from fetal life, and are associated with health improvements and reduced risk of disease. Indeed, many epidemiological studies have associated high intake of EPA and DHA with a lower cardiovascular mortality, especially for cardiac diseases, than predicted, probably due to the improvements in many risk factors such as plasma levels of triglycerides, HDL-cholesterol, C-reactive protein, blood pressure, both systolic and diastolic, and heart rate.
EPA and DHA have also been shown to be useful in the treatment of diseases such as rheumatoid arthritis, and could be useful in the treatment of other inflammatory conditions such as asthma, psoriasis or inflammatory bowel disease, due to their ability to modulate many aspects of the inflammatory processes.
Conversely, LC-PUFAs seem to have little or no effects on measures of glucose metabolism, such as insulin, insulin resistance, fasting glucose, and  glycated haemoglobin, or on type 2 diabetes.

Omega-3/omega-6 ratio

Epidemiological studies suggest that the consumption of a diet with a low omega-3/omega-6 ratio has had a negative impact on human health, contributing to the development, together with other risk factors such as sedentary life and smoking, of the main classes of diseases. Indeed, a lower incidence of cancer, autoimmunity and coronary heart disease has been observed in populations whose diet has a high omega-3/omega-6 ratio, such as Eskimos and Japanese, populations with a high fish consumption.
Despite these evidences, Western diet has become rich in saturated fatty acids and omega-6 polyunsaturated fatty acids, and poor in omega-3 polyunsaturated fatty acids, with an omega-3/omega-6 ratio between 1:10 and 1:20, then, far from the recommended ratio of 1:5.
The low value of the omega-3/omega-6 ratio is due to several factors, some of which are listed below.

  • Although wild plant foods are generally high in omega-3 PUFAs, crops high in omega-6 PUFAs have been much more successful in industrial agriculture than those high in omega-3 PUFAs.
  • Low consumption of fishery products and fish oils.
  • The high consumption of animals raised on corn-based feed, such as chickens, cattle, and pigs. Added to this is the fact that the omega-3 PUFA content of some farmed fish species is lower than that of  their wild counterparts.
  • The high consumption of oils rich in omega-6 PUFAs and poor in omega-3 PUFAs, such as safflower, sunflower, soybeans and corn oils.

Note: there is no evidence that the omega-3/omega-6 ratio is important for prevention and treatment of type 2
diabetes mellitus.

Effects at the molecular level of EPA and DHA

In recent years, the molecular mechanisms underlying the functional effects attributed to omega-3 polyunsaturated fatty acids, especially to EPA and DHA, are being clarified, and most of these require their incorporation into membrane phospholipids.
Omega-3 PUFAs are structural components of cell membranes where they play an essential role in regulating fluidity. Due to this effect, omega-3, especially EPA and DHA, can modulate cellular responses that depend upon membrane protein functions. This is particularly important in the eye, where DHA allows for optimal activity of rhodopsin, a photoreceptor protein. The effect on membrane fluidity is essential for animals living in cold water, as EPA and DHA also have an antifreeze function.
EPA and DHA can modify the formation of lipid raft, microdomains with a specific lipid composition that act as platforms for receptor activities and the initiation of intracellular signaling pathways. By modifying lipid raft formation, they affect intracellular signaling pathways in different cell types, such as neurons, immune system cells, and cancer cells. In this way, EPA and DHA can modulate the activation of transcription factors, such as NF-κB, PPARs and SREBPs, and so the corresponding gene expression patterns. This is  central to their role in controlling adipocyte differentiation, the metabolism of fatty acids and triacylglycerols, and inflammation.
EPA, DHA, and ARA are substrates for the synthesis of bioactive lipid mediators, such as eicosanoids, that are involved in the regulation of inflammation, immunity, platelet aggregation, renal function, and smooth muscle contraction. Eicosanoids produced from arachidonic acid, that is the major substrate for their synthesis, have important physiological roles, but an excessive production has been associated with numerous disease processes. The increase in EPA and DHA content in membrane phospholipids is paralleled by a reduction in ARA content and associated with a decreased production of lipid mediators form ARA and an increased production of lipid mediators from the two omega-3. Moreover, among the molecules derived from EPA and DHA, there are eicosanoids analogous to those produced from ARA, but with lower activity, resolvins, and, from DHA, protectins and maresins. These molecules appear to be responsible for many of the immune-modulating and anti-inflammatory actions attributed to the omega-3 polyunsaturated fatty acids EPA and DHA.
EPA and DHA can also play a role in the non-esterified form, acting directly through receptors coupled to G proteins, modulating their activity.
Finally, they can reduce the intestinal absorption of omega-6 PUFAs, and, at the enzymatic level, competitively inhibit cyclooxygenase-1 or COX-1 (EC and lipoxygenases, and compete with omega-6 PUFAs for acyltransferases.

Major sources of EPA and DHA for humans

In general, fish and aquatic invertebrates, such as molluscs and crustaceans, are the major sources of EPA and DHA for humans. These animals can get EPA and DHA from food, namely, from phytoplankton, or synthesize them from alpha-linolenic acid. Moreover, DHA is present in high concentrations in many fish oils, too, especially those from coldwater fish. However, it should be underscored that such oils are also high in saturated fatty acids. For those who do not eat fishery products, good sources of omega-3 LC-PUFAs are the liver of terrestrial animals and several birds of the order Passeriformes.
Regarding the recommended intake of omega-3 polyunsaturated fatty acids, it is not yet clear what it is. The following table shows the values suggested by Food and Agriculture Organization (FAO) of the United Nations and the European Food Safety Authority (EFSA).

Omega-3 polyunsaturated fatty acids and culinary treatments

As omega-3 polyunsaturated fatty acids are particularly susceptible to oxidation due to heating, cooking and other culinary treatments could reduce their content. However, this is only partially true. In food, EPA and DHA are not in free form but mainly esterified into membrane phospholipids and, in such form, are much less susceptible to oxidation.
Considering the content of EPA and DHA, to express it as a percentage of the total fatty acids instead of as absolute content, namely, mg/g wet weight, leads to erroneous conclusions. For example, a fatty fish like salmon has a high EPA + DHA content, ~8 mg/g wet weight, and expressed as a percentage of the total fatty acids ~20%; conversely Atlantic code has a low EPA + DHA content, ~3 mg/g of wet weight, but, if expressed as a percentage of the total fatty acids ~40%. Atlantic code has a high percentage of EPA + DHA because is a lean fish, whereas in fatty fish EPA + DHA content is diluted by the high fatty acid content of the adipose tissue of the animal.
And when EPA + DHA content is expressed in mg/g of product, no decrease in LC-PUFAs content is observed following most common culinary treatments.


AbuMweis S., Jew S., Tayyem R. Agraib L. Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo-control human clinical. J Hum Nutr Diet 2018 31(1):67-84.  doi:10.1111/jhn.12493

Akoh C.C. and Min D.B. “Food lipids: chemistry, nutrition, and biotechnology” 3th ed. 2008

Aron H. Uber den Nahvert (On the nutritional value). Biochem Z. 1918;92:211-233 (German)

Bergstroem S., Danielsson H., Klenberg D. and Samuelsson B. The enzymatic conversion of essential fatty acids into prostaglandins. J Biol Chem 1964;239:PC4006-PC4008.

Brown T.J., Brainard J., Song F., Wang X., Abdelhamid A., Hooper L. Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials. BMJ 2019;366:l4697. doi:10.1136/bmj.l4697

Buckley M.T., Racimo F., Allentoft M.E., et al. Selection in Europeans on fatty acid desaturases associated with dietary changes. Mol Biol Evol 2017;34(6):1307-1318. doi:10.1093/molbev/msx103

Calder P.C. Very long-chain n-3 fatty acids and human health: fact, fiction and the future. Proc Nutr Soc 2018 77(1):52-72. doi:10.1017/S0029665117003950

Chow Ching K. “Fatty acids in foods and their health implication” 3th ed. 2008

De Meester F., Watson R.R.,Zibadi S. Omega-6/3 fatty acids: functions, sustainability strategies and perspectives. Springer Science & Business Media, 2012

EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific opinion on dietary reference values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol. 2010. doi:10.2903/j.efsa.2010.1461

FAO. Global Recommendations for EPA and DHA Intake (As of 30 June 2014)

Gladyshev M.I.  and Sushchik N.N. Long-chain omega-3 polyunsaturated fatty acids in natural ecosystems and the human diet: assumptions and challenges. Biomolecules 2019;9(9):485. doi:10.3390/biom9090485

Oh D.Y., Talukdar S., Bae E.J., Imamura T., Morinaga H., Fan WQ, Li P., Lu W.J., Watkins S.M., Olefsky J.M. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010 142(5):687-698. doi:10.1016/j.cell.2010.07.041

Simopoulos A.P. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med 2008;233(6):6746-88. doi:10.1016/S0753-3322(02)00253-6

Van D., Beerthuis R.K., Nugteren D.H. and Vonkeman H. Enzymatic conversion of all-cis-polyunsaturated fatty acids into prostaglandins. Nature 1964;203:839-841