Skip to content

The Anabolic Role of Sodium

Facilitating Anabolism by Halting Catabolism

The physiological reason for why salt is both a keeper of peace and a cause of war


The post-neolithic era of human history is riddled with large-scale wars and conflicts, and in retrospect the reasons for some of them seem more trivial than others. Our appetite for sodium in the form of salt is usually brought up as such an example and people in civilised societies often have a difficult time understanding how or why it could possibly have provided our ancestors with the motivation for violence and tyranny as is evident from historical records.1)https://www.karger.com/Article/Abstract/168759

Even from a nutritional point of view it seems very puzzling at first glance since sodium-deficiency is extremely rare in omnivores consuming their standard diets and many indigenous human populations maintain sodium-balance without consuming any salt.2)https://pubmed.ncbi.nlm.nih.gov/1132118/ Also, about 93 % of the sodium ingested daily by modern men and women are excreted with urine the same day.3)https://onlinelibrary.wiley.com/doi/full/10.1111/jch.13353 In the lack of a proper explanation, our past battles for salt is hence often reductionistically attributed to things like the pursuit of hedonism and a uniquely human proclivity towards greed.

However, such beliefs does not square well with the fact that fierce conflicts over salt are observed even in other areas on nature as well, and that they also seem to be in disproportion to homeostatic needs of the organisms. Interestingly, both herbivores and omnivores have been shown to become more carnivorous, and even cannibalistic when they don’t get their salt-appetite satisfied.4)https://onlinelibrary.wiley.com/doi/abs/10.1111/ele.135175)https://doi.org/10.1111/1365-2656.12754

Image 1. Turns out we’re far from the only ones in nature who go on rampages if we cant salt our diet sufficiently. Interestingly it also seems to incite canibalism. Picture from Simpson et al., (2006).6)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1449662/

So why is this really, and could finding the answer to this question also give us a biological justification for our surprisingly salt-centered history as civilised humans? Let’s start from the beginning.

A Brief Review of Nutritional Hydrodynamics

The process of import, storage and utilisation of nutrients poses a problem to cells and organisms because it is inevitably associated with a constant change in fluid-dynamics and hydration. The mechanism by which this occurs is called osmosis, and although its precise workings are not yet fully understood by science, in practical terms it can be said to be the tendency of solutes to move across semipermeable membranes (such as those surrounding our cells) following the concentration-gradient of solvents. Osmosis is a passive phenomenon, and if unregulated it threatens to excessively concentrate or dilute the contents of intra- and extracellular fluids which can adversely affect nutrient-transport and cellular functions. It could also pose a physical threat to cells because of the pressures generated, which could easily reach atmospheric levels and above, and alone our average cell is only about as mechanically robust as a soap-bubble.

Figure 1. Concentration-differences between solutes across a semi-permeable membrane creates an osmotic gradient driving water-movement towards the side with the higher concentration of solvents (such as certain nutrients and electrolytes). This also affects and is affected by pressure-dynamics exerted on the membrane. Figure from Wikimedia Commons.7)https://commons.wikimedia.org/wiki/File:Osmotic_Processes_Diagram.jpg#/media/File:Osmotic_Processes_Diagram.jpg

Hence osmosis needs to be controlled by cells in order to allow transport and cross-passage of solvents in the form of nutrients and metabolites without compromising homeostasis. In mammalian cells this is chiefly done by proteins at the cellular membrane that import and export other osmotically active compounds which in this specific context serves to equalise the change in osmotic potential generated by the molecular flux associated with metabolism.8)https://www.pnas.org/content/100/10/6257

The most common of such proteins in mammals is Na/K-ATPase, which exports sodium-ions out of the cell while importing potassium at a ratio of about 3:2. As a result, sodium becomes our most common extracellular cation and it is estimated to contribute with about 88% of the total extracellular osmotic gradient which allows for reciprocal intracellular storage of nutrients and other important molecules without compromising hydration-status. Keeping osmotic balance is a very energy-demanding task and the regular activity of Na/K-ATPase (including its other functions) is estimated to constitute about 25-75% of total cellular energetics and it generates such an intense ionic traffic across the cellular membranes that it also makes a significant contribution to endothermy.9)https://doi.org/10.1007/s00424-012-1171-210)https://onlinelibrary.wiley.com/doi/abs/10.1111/ele.1351711)https://www.sciencedirect.com/science/article/pii/S0005272813001187

Even though osmosis is regulated in this manner, there are still changes in cellular hydration with different phases of metabolism. For example as is commonly known, for every gram of glucose stored in muscles and the liver as glycogen follows with it at least three grams of water, and the same thing in reverse that for every gram of glycogen used there is a reciprocal loss of water from the cell of three grams.12)https://pubmed.ncbi.nlm.nih.gov/25911631/ It is estimated that human storage-capacity for glycogen is about 15 g/kg of bodyweight, which means that someone who weighs 70 kg can store around 1050 g of glycogen, and assuming that about 50 % of this is used and re-supplied daily, that would create a water-flux of approximately 1,5 L.  13)https://pubmed.ncbi.nlm.nih.gov/3165600/ If this water were to be stored in the extracellular compartments of the tissues or in the blood this would severely compromise cellular metabolism, which is why the body needs to have mechanisms to evacuate water.

Such dispersal from the body occurs predominantly trough the kidneys (63 %), the skin (18 %), the lungs (12 %) and the gut (8 %), however the only way in which water is allowed to leave via these pathways is by osmosis, which then require the simultaneous export of solvents.14)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207053/15)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773238/16)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669342/ Fortunately, the body can reabsorb and recycle most of such solvents before they leave body-surfaces, but because of the “flushing-effect” there is still always an obligate percentage that is lost, and hence the greater the demand for water-expulsion, the greater such losses become.17)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773238/

Since the kidneys have the highest capacity for water-excretion it is also the place where most osmotic solvents are lost in this maner under normal conditions. However, the kidneys are not only tasked with excreting excess water, they also directly need water as a medium for excreting toxic wastes associated with cellular turnover and metabolism which is why even under prolonged starvation and water-deprivation there is an obligate loss of fluids through urine-production.18)https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.31.1_supplement.768.219)https://doi.org/10.1152/ajpregu.1983.245.3.r32920)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1358886/ However, the proportion of urine that is produced for this purpose is very small, which begs the question of what necessitates the excretion of the rest. Interestingly, according to calculated estimates in mice, total voluntary water intake seems to be in excess of the actual fluid-needs of the body by a factor of 1.2-2.1, when food-composition and the generation of metabolic water is also included in the equation.21)https://doi.org/10.1152/ajplegacy.1931.98.1.169 So why is this?

Fluid-Intake is Associated with Food-Intake

The osmolarity of the blood has a linear positive association with the sensation of thirst.22)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763530/ This means that thirst is not only stimulated by loss of water from the body and the blood, but also with the addition of osmotically active molecules and ions, such as what happens after ingestion of nutrients. This is why we, and most other animals need to co-ingest fluids with food (if the food itself does not contain sufficient moisture) as not to suffer dehydration, which is a behaviour that is automated in us as well as in many other species resulting in that about 60-70 % of daily fluid-intake co-occurs with food-intake.23)https://www.sciencedirect.com/science/article/abs/pii/0195666388900645

Image 2. The habit of co-ingesting fluids with meals is universal among animals because of the change in hydration required for metabolism. Picture taken by Radovan Zierik.24)https://pixabay.com/photos/ant-water-drop-nature-bug-insects-5094995/

The necessity of fluid-ingestion for the absorption, transport and storage of nutrients becomes evident when studying experiments of water-limitation and -deprivation in both humans and animals. These studies consistently show that when water-intake is restricted there is a reciprocal voluntary decrease in food intake that is almost directly proportional, and if water is eliminated from the diet food-intake drops to starvation-levels or equal to zero in long-term scenarios 25)https://www.sciencedirect.com/science/article/abs/pii/019566638890064526)https://doi.org/10.1152/ajplegacy.1931.98.1.169 The level of water-intake also varies considerably with the osmolarity of ingested nutrients in animal-studies, and intake of meals rich in carbohydrates and/or protein (which are mostly polar molecules) drives thirst significantly more than meals with higher proportion of fatty acids (which are mostly non-polar).27)https://doi.org/10.1152/ajplegacy.1931.98.1.16928)https://doi.org/10.1016/j.physbeh.2020.112910 Animals also adjust their macro-nutrient intake according to water-availability, and migratory birds are seen to abandon their normal carbohydrate-rich diets (more polar) for a more protein-based (less polar) one when water is restricted, while food-intake and weight-gain stalls if such an option isn’t available.29)https://pubmed.ncbi.nlm.nih.gov/18278515/

Cardiovascular Adaptations to Postprandial Changes in Hydration

The water that moves into the cardiovascular system as a consequence of the osmolar pull of absorbed nutrients cause an expansion of blood-volume. This could be a reason for the increase in cardiac-output that occurs postprandially, which has been shown to vary with meal-size and nutrient-composition being significantly larger with large and carbohydrate rich meals.30)https://pubmed.ncbi.nlm.nih.gov/1877363/31)https://doi.org/10.1111/j.1748-1716.1992.tb09426.x This effect is also observed with endogenous release of nutrients such as glucose.32)https://pubmed.ncbi.nlm.nih.gov/22206473/ An expansion of the fluid-volume inside the cardiovascular system also necessitates a reciprocal radial expansion of the vasculature which is accomplished through a drop in vascular tonicity in order not to increase blood-pressure, which remains stable in most healthy individuals. However, if the vascular walls are hardened and/or thickened, vascular relaxation may fail to accommodate the increased postprandial blood-volume, which is perhaps why a postprandial increase in blood-pressure has been shown to be associated with atherosclerosis.33)https://pubmed.ncbi.nlm.nih.gov/22867753/ Contrastingly, elderly and diabetic patients commonly show a drop in their blood-pressure postprandially, which could be caused by a lesser ability to clear the vascular system of ingested nutrients (and hence also water), necessitating a more pronounced drop in vascular tonicity occurring at a compromise with the maintenance of normal blood-pressure.34)https://pubmed.ncbi.nlm.nih.gov/2856754/35)https://pubmed.ncbi.nlm.nih.gov/8783777/36)https://pubmed.ncbi.nlm.nih.gov/17726508/

The Costs of Fluid-Excretion

When ingested nutrients have reached their target destination and either turned to energy or biomass, the excess water that is left in the system needs to go, and because of the large flux in body-water that is necessary for metabolism we then need to make good use our most efficient organ for water-elimination, the kidneys. However, as mentioned before this process is not without significant costs partly because of the “flushing-effect” and fluid-excretion hence taxes our body in osmolar currency. The chief urinary solvents that constitutes this currency and mediate the osmolar pull required for urine-production are sodium, ketones, ammonia and urea.37)https://core.ac.uk/download/pdf/82587016.pdf What then quickly becomes evident is that all of these solvents except sodium are derived from organic compounds that serve as energy-substrates and/or building-blocks for the organism. Hence the loss of such substrates is an expensive cost, that is then added to the cost of kidney energetics (which is estimated to be about 7 % of whole-body oxygen-metabolism) and the metabolic costs involved in the process of priming organic substrates for excretion (which is far from free).38)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951849/39)https://www.kidney-international.org/article/S0085-2538(15)59526-4/pdf But what about sodium then? Since sodium is not an essential part of organic compounds in the body it could potentially act as an osmolar solvent that would then spare the loss of such anabolically and catabolically useful molecules.

Ecological Distribution of Sodium

The availability of sodium varies largely both geographically and within different ecosystems, and although sodium is estimated to constitute about 3 % of the earths crust most of this is not bio-available, and therefore most enters the food-chain from the second most abundant source in nature, seawater, containing a concentration of about 1-2 % in the form of sodium-chloride.40)https://onlinelibrary.wiley.com/doi/full/10.1111/ele.1351741)https://www.sciencedaily.com/terms/seawater.htm Because of this the distribution of bio-available sodium in land-masses concentrates around the shorelines through precipitation and hence the further in-land that organisms live, the the harder it is for them to acquire it.42)https://onlinelibrary.wiley.com/doi/full/10.1111/ele.13517 Sodium also accumulates up the food-chain in ecosystems, on land starting with plants and fungi who concentrate sodium available in the ground and the aerosol which are in turn eaten by herbivores and fungivores who are then eaten by carnivores. So the higher up in the food-chain and the closer to the sea that an organism lives, the more it can rely on sodium for its metabolic functions.

Sodium Availability Governs the Relative Role of Urea in Urine-Production

Returning to the question of urine-production this would mean that organisms that have frequent access to sodium could potentially use it more to this end while saving up organic compounds such as proteins and ketones for anabolism and energetics. Indeed, the levels of sodium found in urine collected from wild animals and humans seems to vary in accordance with the principles stated in the above paragraph. Studies have shown that animals living in-land excrete virtually no sodium at all in their urine while animals of the same species living near the sea excrete urine with a sodium-concentration in the range of 100 to >300 mmol/L which is equivalent to values of people in western cultures consuming diets high in salt.43)https://doi.org/10.1038/217922a044)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1834069/ The same pattern is seen in indigenous human populations that vary in their proximity to the sea.45)https://pubmed.ncbi.nlm.nih.gov/12856272/ Although much smaller in absolute terms, there is also a significant difference in urinary sodium between herbivores and carnivores both living in-land, with herbivores excreting urine with a sodium-concentration between 0.05 (winter) and 1,5 mmol/L (summer) while carnivores excreted sodium with a concentration of 18,8 mmol/L.46)https://doi.org/10.2307/138040847)https://doi.org/10.2307/3801620 Taken together, these findings seems to suggests that the contribution of sodium-excretion to urine-production is governed by its availability to the organism rather than it being an obligate requirement.

Sodium-Mediated Nitrogen-Conservation

About 84 % of the total amount of nitrogen that leaves the body each day leaves through urine, and most of it is in the form of urea which is also the chief solvent present in urine that creates the necessary osmotic pull for urine-production.48)https://academic.oup.com/jn/article/130/7/1868S/4686204 Hence when investigating the potential role of sodium in conserving organic compounds, its greatest potential in this regard is for the conservation of nitrogenous molecules that are catabolised to urea, such as proteins. An interesting observation that seems to support such a role of sodium is that in ant-colonies, which are omnivorous by nature, declining availability of sodium in the environment cause them to turn increasingly carnivorous.49)https://besjournals.onlinelibrary.wiley.com/doi/full/10.1111/1365-2656.12754 Similar results has also been shown for crickets.50)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1449662/

Figure 2. Diagrams showing how deprivation of either salt or protein increase the tendency towards canibalism in crickets. Modified from Simpson et al., (2006).51)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1449662/

This could simply be a strategy to access sodium that has accumulated further up the food-chain, however an intriguing thought is that a declining sodium-intake could also possibly be physiologically met by increasing the intake of nitrogen (from flesh) in order to maintain essential excretory functions.

Interchangeability of Sodium and Nitrogenous Compounds

Starting by looking at renal physiology, there is evidens to suggest that when sodium intake increases there is a reciprocal increase in urea-reabsorption by the kidneys causing less of it to be excreted.52)https://www.ajkd.org/article/S0272-6386(17)30851-X/pdf53)https://pubmed.ncbi.nlm.nih.gov/23737200/ The reverse also seems to be true, as when reabsorption of urea is pharmacologically inhibited, this has been shown to conserve sodium.54)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523423/ This clearly shows that sodium can mimic the role of urea in urine-production and vice-versa.

Figure 3. Flow-chart displaying how urine is concentrated by using both sodium-chloride and urea as primary solvents in interchangeable quantities. Reproduced from Chang et al., (2020).55)https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-020-02536-0

A Potential Explanation for The “Natriuresis of Starvation”

The conservational function of sodium with regards to nitrogen-metabolism could explain a strange phenomenon that is observed in early starvation which is that the rate of sodium-excretion often increase dramatically during the first few days, before it gradually drops down to levels below baseline.56)https://doi.org/10.1016/0026-0495(73)90239-4 This is often referred to as the “natriuresis of starvation” as starving individuals have been shown to suffer a negative sodium-balance of about 350 mmol/day and in some cases it can reach over 1000 mmol/day which is significant in relation to the fed-state in which it averages at 150 mmol/day and also to the total amount stored in the body which is about 4000 mmol.57)https://pubmed.ncbi.nlm.nih.gov/29516104/58)https://core.ac.uk/download/pdf/82587016.pdf This means that some proportion of the bodys sodium stores can act as a physiological buffer that it is perhaps preferentially used instead of nitrogenous compounds for urine-production in order to conserve protein in the early phase of food-deprivation.

Studies on the Effects of Sodium on Nitrogen-Balance

The fact that the addition of sodium to animal diets seems to be anabolically beneficial has been known by farmers, industries, hunters and wildlife-managers for decades, but the mechanism as to why is not commonly known. There are several studies that have investigated the effects of different levels of added sodium to diets, and unsurprisingly most of them have been done on livestock. In chickens it has been established that increasing contents of dietary sodium increases both food-intake, feed conversion-efficiency, nitrogen-assimilation, body-mass and egg-production, and that the effect plateaus at a concentration of about 0.1 % sodium-chloride per kilo of food but that it still produces a positive effect at four times this concentration.59)https://pubmed.ncbi.nlm.nih.gov/30940270/60)https://www.sciencedirect.com/science/article/pii/S003257911954847761)https://doi.org/10.3382/ps.029048062)https://doi.org/10.22358/jafs/66285/201063)https://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-635X2004000300002 The effect-sizes observed at this interval are extremely impressive and are in excess of the effects on feed-intake.

Table 1. In chickens only 0.1% of added sodium to the diet gives an almost 3-fold improvement in feed conversion-rate (FCR) resulting in double the body-weight (BW) of controls in only 20 days with only about 70% increase in average daily feed-intake (ADFI). From Jiang et al., (2019).64)https://doi.org/10.1017/S1751731119000594

The same trend is observed in cattle, with effects peaking for growth at a sodium-chloride concentration of about 0.2 % of feed-weight.65)https://doi.org/10.17226/9825 If sodium-intake is increased further it causes no further increase in growth, only larger daily urine-volumes, and although this increase in urine output was shown to increase urinary nitrogen loss by about 9 % when the concentration of sodium-chloride in the feed increased from 0.8 % to 4.8 % of feed-weight, this did not show a linear negative correlation with nitrogen balance in the total sample.66)https://www.sciencedirect.com/science/article/pii/S0022030212007564 This might be because of an increased efficiency of nitrogen-assimilation from the rumen since there was a reciprocal decrease in fecal nitrogen, and that most ruminal microbes that mediate this process thrive in sodium-rich environments.67)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC380082/

The Secondary Effect of Fluid-Intake on Nitrogen-Balance

In the before-mentioned study, there was a linear positive correlation between sodium-intake and water-intake, and with every gram of additional sodium ingested there was an increase in urine-output by 0.14 liters, amounting to a total difference of about 50 liters of urine between cows that consumed a diet containing 0.3 % sodium with those consuming a diet containing 1.9 %. Because of effective nitrogen conservation-mechanisms in the gut and that sodium is very potent in terms of osmoles, this massive difference in urine-output occurred without significantly affecting nitrogen balance, and this suggests that ingestion of large amounts of salt is in fact not catabolic through increased urine-output, and this has also been confirmed in a similar study on humans.68)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278848/ However, when sodium is not abundantly available, an intake of fluids that surpass absolute physiological needs may cause a significant negative effect on nitrogen-balance, and this have been shown in a study on cattle subjected to supra-physiological water-loading which caused them to show signs of negative nitrogen-balance.69)https://doi.org/10.1017/S0021859600069483 Interestingly, there are also studies showing that restricting animal water-intake to half or a third of ad-libitum levels significantly improves nitrogen-assimilation, however this could just simply be a physiologic response to dehydration by the animals increasing serum-concentrations of urea as to conserve water.70)http://www.bioline.org.br/pdf?md0603671)https://www.sasas.co.za/wp-content/uploads/2012/09/van-der-walt29issue3_0.pdf

An Alternative Explanation for the Anabolic or Anti-Catabolic Effect of Dietary Sodium

The above findings suggest that urine-production might provide a significant leak for organic compounds and that this can be prevented by ingestion of additional sodium causing the anabolic or anti-catabolic net-effect on the organism that is commonly observed. However, there are other possible explanations for this phenomenon, for example one study suggests that protein-metabolism is positively regulated by an increasing level of cellular hydration, perhaps because it creates a fluid-pressure similar to “turgor” which is observed in the growth of plant-cells, and this in turn could perhaps be a side-effect of increased levels of intracellular sodium.72)https://www.nature.com/articles/1601894 Another possible explanation is that sodium-intake could decrease the metabolic cost of digestion and absorption of nutrients, which is supported by the fact that it has been associated with a significant decrease in intestinal Na/K-ATPase activity, which is up-regulated with the process of absorbing glucose and amino-acids.73)https://doi.org/10.1017/S1751731119000594

Table 2. Sodium-intake dose-dependently lowers the metabolic cost of nutrient-absorption associated with Na/K-ATPase activity such as that of glucose and amino-acids. Table modified from Jiang et al., (2019).74)https://doi.org/10.1017/S1751731119000594

Summary

In adult humans and animals, the minimal required intake of sodium is rendered impressively low because of effective conservational mechanisms that evolved in order for them to be able to cope with periods of scarcity of sodium and water, and allow them to exist in such environments. However, because of the unique electrochemical properties of sodium, consumption at levels that surpasses the minimal needs to sustain homeostasis is still desirable because the excess can act as a substitute to the metabolites of anabolically or energetically important organic compounds in the expensive process of urine-production that is necessitated by the water-flux needed for nutrient- and waste-handling. This hence makes sodium an important nutrient (or a pseudo-macronutrient) that can sustain organisms and enable growth at lower levels of food-consumption. However, since the sodium-intake of the average person greatly exceed the levels seen to promote such effects, most of us are blissfully unaware of the critical role that dietary sodium could once have played in the parts of our history characterised by less abundance and where effective population-growth was also more desirable. So to our ancestors the salt-shaker must have been one of the greatest “bio-hacks” ever discovered for survival and reproduction, whereas now it only makes us pee more.

With all this taken together, a clearer picture emerges of why sodium has been such a significant source of conflict in human history, and also why it was an important factor in the advancement of early human civilisations (for better and for worse). However, there are many other effects of sodium on human health and the health of other organisms, and in a coming section we’ll discuss more what the potential downsides of excess dietary sodium might be, both in a physiological and ecological context.

Disclaimer and clarification: because of the reasons stated above, for the average individual increasing sodium-intake will probably NOT have an anabolic effect, however for people who consume no or very little added salt, or for those doing different fasting-protocols it could perhaps be of benefit through the mechanisms discussed.

 

Image by Quang Nguyen vinh from Pixabay

References   [ + ]

We use cookies in order to give you the best possible experience on our website. By continuing to use this site, you agree to our use of cookies.
Accept
Reject
Privacy Policy