Acid-Base Balance: Foods and Supplements

I previously wrote about the role lactic acid can play in disease.  This raised the question of whether foods and supplements can buffer metabolic acidity.  If so, which foods or supplements are most beneficial?  Does pH correlate to the effect on the acid-base balance of the body?

This is important because:

• Chronic acid load can deplete alkalinizing minerals, leading to e.g. calcium bone loss.
• Long Covid may be caused by metabolic acidosis: https://researchaidnetworks.org/hypothesis-summary/

After researching this, I concluded that a food's pH does not directly correlate with its impact on overall acid base balance.  Potential Renal Acid Load (PRAL) is determined by mineral and protein composition, not its inherent acidity.  

For example:

• Lemons taste acidic due to citric acid, but have a negative PRAL (alkaline-forming) because they're rich in potassium and other compounds that generate bicarbonate when metabolized
• Animal proteins may not taste acidic but have a high positive PRAL (acid-forming) due to sulfur-containing amino acids that get metabolized to sulfuric acid.

The key biochemical factors that determine a food's PRAL include:

1. Protein content (especially sulfur amino acids) - metabolized to produce acids
2. Mineral content: 
1. Potassium, calcium, magnesium - metabolized to produce bicarbonate (alkaline)
2. Phosphorus, chloride - contribute to acid load
3. Organic acid content - intermediates in the citric acid cycle (Krebs cycle), their oxidation generates bicarbonate. Each molecule of malate or citrate metabolized can generate multiple bicarbonate molecules.

Details

The pH of urine is influenced by the body's metabolic acid load and the kidney's ability to regulate hydrogen ion (H⁺) excretion.  The kidneys play a crucial role in maintaining acid-base balance by adjusting the amount of hydrogen ions eliminated or retained.  When the body experiences a metabolic acid load, the kidneys respond by increasing H⁺ excretion. This lowers urine pH, reflecting the increased acid load on the body.  However, positive cations can also stimulate renal acid-base regulation, leading to increased hydrogen ion excretion (and bicarbonate (HCO₃⁻) regeneration).  This results in a decrease in urine pH, even as the body experiences a reduced metabolic acid load.

Cations can also activate enzymes that convert metabolic acids to bicarbonate.  The more positively charged the cation, the more efficiently it can displace hydrogen ions.

Organic acid conjugation to cations enhances alkalinization.  For example, citrate enters the citric acid cycle directly and generates multiple bicarbonate (HCO₃⁻) upon oxidation.

Table of Common Supplements and Food Additives; their pH and effect on acid-base balance.  

This data shows how solution pH and PRAL effects don't always correlate. For example, while KCl has a neutral pH in solution, it has a slightly negative PRAL due to the potassium content. However, extreme pH (either acid or base) can correlate with PRAL effect.

Categories of Supplements

1. Neutral pH, Alkalizing Effect: 
1. Potassium citrate
2. Calcium lactate
3. Potassium gluconate
4. These demonstrate the pH vs. physiological effect paradox
2. Mineral-Organic Complexes: 
1. Magnesium citrate and malate show slightly acidic pH but strong alkalizing effects
2. Zinc citrate has less alkalizing effect despite similar pH
3. Simple Salts: 
1. KCl shows neutral pH with mild alkalizing effect
2. NaCl shows neutral pH and neutral physiological effect
4. Strong Acids/Bases: 
1. HCl, KOH, NaOH show correlation between pH and physiological effect
2. These are exceptions to the general trend of pH not predicting physiological impact

Alkalinizing Potential Ranking

The formula for PRAL (mEq/100g) is: PRAL = 0.49 × protein (g) + 0.037 × phosphorus (mg) - 0.021 × potassium (mg) - 0.026 × magnesium (mg) - 0.013 × calcium (mg).  

Negative PRAL indicates an alkalizing effect on the body.

Example:  mice

Mice diets were compared using Dietary Cation Anion Balance (DCAB), a similar metric to PRAL.  DCAB is calculated by adding the weighted amount of acidifying anions and alkalizing cations in the diet. 

It has been shown in many species that the dietary cation anion balance (DCAB) influences acid base homeostasis and urine pH.  With the DCAB, the resulting urinary pH can be predicted with species-specific equations. 

DCAB [mmol/kg DM] = 49.9 · Ca + 82.3 · Mg + 43.5 · Na + 25.6 · K − 59.0 · P − 62.4 · S − 28.2 · Cl; mineral content in g/kg DM.  (Negative DCAB indicates an acidifying effect on the body.)

The paper found that a negative DCAB results in metabolic acidosis, and "Fed long-term, this can contribute to the reduction of bone mineral density due to a PTH-mediated increase in renal calcium excretion. Metabolic acidosis also induces renal phosphorus excretion, resulting in hypophosphatemia."

Citation: https://www.mdpi.com/2076-2615/11/3/702 

Böswald, L.F.; Matzek, D.; Kienzle, E.; Popper, B. Influence of Strain and Diet on Urinary pH in Laboratory Mice. Animals 2021, 11, 702. https://doi.org/10.3390/ani11030702

Example:  human athletes

Alkaline water has demonstrated its effectiveness as an alkalizing agent in the treatment of metabolic acidosis in both animal and human research. Past studies have shown that daily intake of 2.5–4 L of alkaline water for 3~6 weeks has significant impacts on anaerobic performance and acid–base balance in athletes.  This study showed that alkaline water co-ingested with glutamine led to decreased stress markers in athletes.  Masterjohn hypothesizes that glutamine is converted to glutamate to buffer lactic acid in muscles, and that decreasing PRAL contributes to more available glutamine for other metabolic functions..  

Citation: https://www.mdpi.com/2072-6643/16/3/454

Lu, T.-L.; He, C.-S.; Suzuki, K.; Lu, C.-C.; Wang, C.-Y.; Fang, S.-H. Concurrent Ingestion of Alkaline Water and L-Glutamine Enhanced Salivary α-Amylase Activity and Testosterone Concentration in Boxing Athletes. Nutrients 2024, 16, 454. https://doi.org/10.3390/nu16030454

Thanks to Claude Sonnet for back-and-forth conversation, and for creating the table and figure above.  

Clues toward the Cause of Long COVID

I previously shared some of the amazing data from the paper "Muscle abnormalities worsen after post-exertional malaise in long COVID" by Appelman et al. 

The paper will undoubtable become a classic in the field of Long COVID, providing a fascinating series of clues that the researchers followed past several dead-ends to their interesting implications. 

First, and most importantly, the researchers confirmed beyond a shadow of doubt that Post-Exertional Malaise (PEM) is a real disease, with myriad muscle and metabolic abnormalities in the Long COVID patients following intense exercise.  Metabolomics provided additional key findings, including the first clue: a possible blockage of glycolysis in Long COVID (see diagrams in previous post).  

A Clue: Glycolysis Blockage

In the glycolysis pathway, the phosphoenolpyruvate (PEP) levels of Long COVID patients were increased, while pyruvate levels were decreased, indicating a disruption or imbalance in enzyme activities within the pathway.   This could be due to a decreased activity of the enzyme pyruvate kinase (PK), which converts PEP to pyruvate in the final step of glycolysis.  Reduced PK activity would result in a buildup of PEP.  With less PEP being converted to pyruvate, the downstream levels of pyruvate would be lower.  

There are several interconnected regulatory pathways that can reduce the activity of pyruvate kinase (PK), the two most relevant being Oxidative Stress and Hypoxia.  Increased levels of reactive oxygen species (ROS) or oxidative stress can lead to the oxidation and inactivation of PK.  Under hypoxic conditions (low oxygen levels), the transcription factor HIF-1 (Hypoxia-Inducible Factor 1) can be activated, which can lead to the downregulation of PK expression and activity.  This is part of the cellular adaptation to hypoxia, where glycolysis is regulated to favor the production of metabolic intermediates for other pathways.

Hypoxia?

In the context of Long Covid and post-exertional malaise (PEM), hypoxia from microclots has been suggested to increase lactic acid production. However, in this study the metabolomics showed decreased* lactic acid, because glycolysis was shut down at PEP by loss of PK activity, not at pyruvate by loss of pyruvate dehydrogenase (PDH).  

The researchers looked for but did not find decreased muscle oxygen perfusion or any differences in microvasculature.  The researchers noted decreased oxygen utilization, but this could be due to anything that disrupts metabolism and does not indicate hypoxia as a specific issue.  

They noted amyloid plaques in the extracellular matrix; the plaques were not blocking the microcapillaries and it is unclear what role they play in the pathophysiology of Long COVID: are they a cause of PEM, or a consequence?  

Their observation that Long COVID patients' muscle force was not dependent on The Citric Acid (TCA) cycle enzyme succinate dehydrogenase (SDH) can also be explained by impaired metabolism upstream of TCA Cycle, i.e. in glycolysis.

Oxidative Stress

Therefore, it seems likely that the regulatory pathway most likely to contribute to reduced pyruvate kinase (PK) expression and activity is the oxidative stress pathway.  

Long Covid patients have been reported to exhibit higher levels of oxidative stress markers, such as lipid peroxidation products and decreased antioxidant levels, compared to healthy individuals or those who have recovered from acute COVID-19 infection.  Physical exertion and exercise can lead to an acute increase in reactive oxygen species (ROS) production, potentially exacerbating oxidative stress in individuals with Long Covid and triggering PEM symptoms.

Some studies have suggested that Long Covid patients may experience mitochondrial dysfunction, which can further contribute to increased ROS generation and oxidative stress.

Next Steps

The paper concluded with these results, but the logical next step would be to use metabolomics to assess free radical concentrations.  One theory is that COVID spike proteins form "pores", or holes in the mitochondrial membranes, disrupting the mitochondria and releasing free radicals into the cell.  

The researchers did look at COVID nucleocapsid protein, but found it in both the control and Long COVID groups in equal concentrations, suggesting that remnant viral protein doesn't explain the pathophysiology of Long COVID.  But maybe remnant virus affects the Long COVID patients differently?  

The researchers noted immune cell infiltration into muscle tissue, which could be in response to a signal from excess free radicals, or could be due to some other reason like persistent COVID infection/expression.  

Lactate?

This study seems to indicate the lactate is not an important variable for the pathophysiology of Long COVID.  However, the details about how lactate was measured limit these conclusions. The researchers measured lactate from three different sources:  metabolomic blood (venous) and muscle lactate measured before and after PEM, and capillary (i.e. finger prick) lactate measured during exercise.  Venous lactate measured one week after PEM induction showed a slightly increased level in Long COVID patients, but none of the other metabolomic lactate measurements showed any difference.  The capillary lactate also showed a slightly elevated blood lactate level before exercise in the Long COVID patients, but the difference was not significantly different.  

However, the baseline measurements were not taken in a fasted condition, and because eating normally raises resting lactate it cannot be determined from this study if fasted lactate might show other differences that are important to Long COVID.

Post Exertional Malaise in Long Covid

 Severe exercise-induced myopathy has been found in long COVID post-exertional malaise (PEM).  

Just look at these long COVID patients (in red) pushing close to 20 mmol/L lactate on the exercise bike!  That is serious dedication for a group of patients who know what the consequences will be.

After the exercise test, blood metabolomics show elevated glycolysis, but decreased pyruvate and TCA cycle metabolites.

Muscle biopsy metabolomics show decreased purine synthesis and TCA cycle.

Key:

Appelman, B., Charlton, B.T., Goulding, R.P. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 15, 17 (2024). https://doi.org/10.1038/s41467-023-44432-3

Lactic Acid in Health and Disease

 Introduction

Lactic acid is produced for energy when mitochondria can't use oxygen for aerobic respiration. 

Lactic acidosis develops when you have too much lactic acid in your body. Athletes monitor their blood lactate levels as a way to pace their training.  Chronic resting lactate levels greater than 2 mmol/L represent hyperlactatemia, whereas lactic acidosis is generally defined as a serum lactate concentration above 4 mmol/L.   High levels of lactic acid can cause muscle soreness, fibromyalgia-like symptoms, and anxiety.

Overproduction or Under-removal?

The body naturally produces and consumes lactate: although anaerobic exercise can raise blood lactate levels over 10 mmol/L, resting lactate in health adults is usually between 1 and 2 mmol/liter and is constantly produced and consumed.  High levels of lactic acid can be caused by overproduction or under-removal of lactate.

Resting lactate is usually between 0.5-1.5 in a large (10,000 participant) study of healthy adults.  More info.

Although many organs consume lactate, the liver and the kidney represent the major sites of lactate uptake and clearance as they metabolize approximately 53% and 30% of daily lactate production, respectively. Lactate is metabolized by two main mechanisms: First, lactate can be used as a substrate to regenerate glucose by gluconeogenesis, a process that is exclusive to liver and the kidney. Second, at least 50% of circulating lactate is removed and metabolized by means of oxidation during resting conditions. Unlike gluconeogenesis, which is restricted to liver and kidney, oxidation can take place in many organs, including the heart, brain, and skeletal muscle.

Supplements that affect Lactic Acid

Biotin (B7) is a cofactor required for gluconeogensis.  Aspirin can increase lactate levels by interfering with LDH lactate dehydrogenase, the enzyme responsible for turning lactate into pyruvate for gluconeogensis.   B1 deficiency impairs Citric Acid cycle and leads to accumulation of pyruvate and lactate.  Organic acids involved in the Citric Acid cycle may may provide substrates to better metabolize lactate and may reduce the acidifying side effects of elevated lactate (i.e. reduce Potential Renal Acid Load (NRAL)).  Nutrient deficiencies of CoQ10 and lipoic acid have also been associated with elevated lactic acid levels in both urine and blood.   Magnesium in muscles helps to decrease contractions and lactate buildup.  

Exercise

Slow exercise (i.e. HR below 100) can lower blood lactate and blood glucose levels in healthy adults.

Mitochondrial Dysfunction in Disease

Many diseases, included Type-2 diabetes, Chronic Fatigue Syndrome, and Long Covid, are associated with mitochondrial dysfunction and increased resting lactate levels.  Post-exertional malaise (PEM) is a major symptom of ME/CFS and Long Covid and may be caused by elevated lactate levels.  Although we don’t know the cure, #StopRestPace is the best treatment because only resting and then reducing/pacing activity can lower lactate levels.  

Lactic acid is being investigated as a possible metric of Long Covid and PEM severity.  If it plays a causal role in these diseases, methods that reduce lactic acid buildup may be promising treatments.  

Research

Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome. https://www.nature.com/articles/s41598-019-55473-4

-Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group. The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group.

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndroms.  https://www.atsjournals.org/doi/full/10.1164/rccm.202108-1903LE

-The transition from fat oxidation to glucose oxidation occurs prematurely, suggesting metabolic reprogramming and dysfunctional mitochondria.

Figure 1 from paper.  Long Covid patients show greater increases in lactic acid at low intensity exercise compared to controls.  Blue and purple are Long Covid patients (with and without comorbidities (like diabetes), respectively) and grey and black are matched controls (with and without comorbidities, respectively).

Metabolic Pathways

Say you want to know what the possible effects of taking a supplement might be.  You could research the supplement on the two high-quality websites that report supplement interactions based on human trials:

Examine.com

The Mayo Clinic - not as many supplements covered.

It would be great if there were reliable "trip reports" from patients on the effects and side-effects of drugs, but unfortunately side-effects are not reliably reported.

If you wanted more basic information, you could consult a metabolic pathway interaction diagram.  Note that the study of genetics and proteomics still has a long way to go:  we don't know what most of the essential genes even do, nor do we know the function of xx% of all genes.  No network diagram is complete....

SigmaAldrich offers a searchable poster:



According to this, NAC can increase glutathione, but also homocysteine. Important information from the network!




Biochemical-pathways.com has even more information.  Note that because the network diagram is again a poster, single compounds (e.g. cysteine) can occur in different places on the diagram.




Metacyc is the most detailed, but only shows one "pathway" at a time.


KEGG is another very good resource with drop-down menus to explore individual pathways.

A long list of other resources.

What is the Microbiome Good for?

How Inhibit Ammonia Production in Large Intestines?
"In general, the treatment of [excess ammonia] has as common elements the reduction of protein in the diet, removal of excess ammonia and replacement of intermediates missing from the urea cycle."

Eating large amounts of protein feeds harmful bacteria: "Protein fermentation by human faecal bacteria in the absence of sugars not only leads to the formation of hazardous metabolic products, but also to the possible proliferation of harmful bacteria [such as Clostridium, Enterococcus, Shigella and Escherichia coli]."

--
text below from:

Increasing the amounts of alimentary proteins results in a spectacular increase of the luminal and faecal ammonia [92]. In humans, the ammonia luminal concentration progressively increases from the ascending to the descending colon [93] in accordance with a higher rate of protein fermentation in
the distal than in the proximal colon. The two environmental characteristics of the proximal colon (low pH and high carbohydrate) explain the reduced net production of ammonia. [13]

Large amounts of ammonia can be absorbed through the large intestine mucosa [96]. Ammonia has been considered as a metabolic troublemaker since this compound is able to inhibit in a dose-dependent manner the mitochondrial oxygen consumption [104]. In addition, high millimolar concentrations of ammonia inhibit short-chain fatty acid oxidation [105,106] in colonic epithelial
cells.

Also of concern is H2S:  H2S is a bacterial metabolite produced through fermentation of sulfur containing amino acids (methionine and cysteine). Interestingly, there is a correlation between the level of meat intake and the level of faecal excretion of sulfide. [110]  H2S at excessive concentrations inhibits colonic epithelial cell respiration [120] and provokes genomic DNA damage [121], [122].

What to do?
inhibit large intestine production of ammonia!
Lactulose (comalose) would help acidify colon, feed good bacteria: http://www.lactulose.eu/97.htm

Don't Spike Your Blood Sugar

There have been a number of scientific papers in the last couple years, and now a number of high-profile articles (like last week's Time Magazine article "Ending the War on Fat") that have found no correlation between fat -- even saturated fat -- and Alzheimer's, diabetes, cancer, or heart disease. The idea that cholesterol and saturated fat are the cause of heart disease is no longer supported by the best available science.

However, there is still broad consensus among health professionals that we need to avoid processed, sugary, and high-glycemic foods. High-glycemic foods are energizing for an hour or two but then cause sleepiness and craving for more (usually high-glycemic) snack foods. These foods are dangerous because they raise blood sugar, leading to a crash afterwards, a "roller-coaster" blood sugar dynamic that promotes over-eating and a variety of diseases.

Gary Taubes, in Good Caloreis Bad Calories, explains how sugar metabolism makes you fat:

"Glycerol phosphate is produced from glucose when it is used for fuel in the fat calls and the liver, and it, too, can be burned as fuel in the cells. But glycerol phosphate is also an essential component of the process that binds three fatty acids into a triglyceride. It provides the glycerol molecule that links the fatty acids together. In other words, a product of carbohydrate metabolism --i.e. burning glucose for fuel-- is an essential component in the regulation of fat metabolism: storing fat in the fat tissue. In fact, the rate at which fatty acids are assembled into triglycerides, and so the rate at which fat accumulates in the fat tissue, depend primarily on the availability of glycerol phosphate. The more glucose that is transported into the fat cells and used to generate energy, the more glycerol phosphate will be produced. The the more glycerol phosphate produced, the more fatty acids will be assembled into triglycerides. Thus, anything that works to transport more glucose in the fat cells -- insulin, for example or rising blood sugar, will lead to the conversion of more fatty acids into triglycerides, and the storage of more calories as fat."

"So yes, dietary fat is responsible for fat accumulation, but it is carbohydrates that mediate the accumulation, and the energy balance of the body as a whole. Don't spike your blood sugar, and your body will continue burning fat, not storing it."

Metabolic profiling

http://www.nature.com/news/2010/100526/full/news.2010.266.html

I don't understand this and can't access the original article, but wanted to mention it, nonetheless, because some of the compounds in this list are the same mentioned in Dr. Watson's pioneering work on metablic imbalances:

Watson, G.: Differences in Intermediary

Metabolism in Mental Illness, Psychol. Rep., 17:563-582, Oct., 1965