Anti-Aging

The Link Between Uric Acid & Inflammation

What is Uric Acid?

Uric acid is a waste product resulting from the breakdown of purines, which are substances naturally found in our bodies and present in foods like red meat, seafood, and alcoholic beverages. In medieval times, gout was called the “disease of royalty” since the wealthy typically indulged in a “rich” diet. Emerging research suggests a link between high and even what is considered normal uric acid levels and increased inflammation in the body. When we talk about inflammation, we now see the connection to regenerative medicine. We must remember that aging and inflammation go hand in hand to form the process known as “inflammaging.” 

Most people associate uric acid with gout, but this is only partially true and somewhat misleading. Uric acid is taking on a new importance that will change the landscape in regenerative medicine. Some studies say that high uric acid can harm one’s health, but the newest thinking suggests that even “normal levels” of uric acid, even normal physiological levels, can cause many health problems and contribute to inflammation or inflammatory conditions. 

Several studies have found that uric acid, even at levels considered within the normal range, is positively associated with increased levels of inflammatory markers like C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). A closer look at these studies revealed that a large population of patients showed serum uric acid levels correlated positively with CRP, TNF-α, and IL-6 levels, even after adjusting for factors like body mass index. Another study found that uric acid directly stimulates the production of inflammatory cytokines like TNF-α in human macrophages in vitro, suggesting a pro-inflammatory role even at normal levels. Higher uric acid levels, even within the normal range, were associated with progressively higher prevalence of elevated inflammatory markers like IL-6 and CRP. 

The mechanisms by which uric acid may promote inflammation at normal levels are unclear, but proposed pathways include activation of the NLRP3 inflammasome, induction of oxidative stress, and stimulation of inflammatory cytokine production.

Inflammation is the immune system’s natural response to irritants, pathogens, and damaged cells. It’s a protective mechanism that allows the body to remove harmful stimuli and initiate healing. However, chronic, low-grade inflammation with no apparent external cause has been associated with numerous health conditions, including obesity, diabetes, cancer, cardiovascular disease, and, ultimately, aging. So, how does uric acid contribute to this inflammatory state? Let’s take a closer look at some of the mechanisms.

Crystallization and “Normal Levels of Uric Acid” 

When uric acid levels are excessively high, needle-like monosodium urate crystals can form in the joints and surrounding tissues. These crystals act as irritants, triggering an inflammatory response as the immune system mobilizes to attack the perceived threat. This is not surprising since it occurs at high levels, which is not a problem for most people. However, even with lower blood levels, non-crystallized uric acid can stimulate the NLRP3 inflammasome, leading to an inflammatory response. The concept of an inflammasome is a fundamental aspect of the immune system. Think of your body as a castle with a defense system against intruders (pathogens or harmful substances). The NLRP3 inflammasome is a watchman that constantly monitors for signs of danger or trespassers. When the NLRP3 inflammasome detects something harmful, like a virus, bacteria, or even moderately elevated uric acid levels in the body, it raises the alarm. 

This alarm system comprises different proteins that form the “inflammasome complex.” The main protein in this complex is NLRP3. When NLRP3 spots danger, it recruits another protein called ASC, which acts as a messenger. Together, they form the inflammasome complex. This complex then activates an enzyme called caspase-1, which acts like molecular scissors. Caspase-1 cuts and activates two critical proteins, IL-1β and IL-18. These are two potent inflammatory cytokine growth factors. These proteins act as warning signals released from the cell to alert the body’s immune system. When the immune system receives these warning signals (IL-1β and IL-18), it triggers an inflammatory response. This response is designed to fight off the intruders or harmful substances detected by the NLRP3 inflammasome. However, if the NLRP3 inflammasome becomes overactive or is triggered unnecessarily, it can lead to excessive inflammation, which can contribute to various diseases like gout, diabetes, cancers, and even neurodegenerative disorders. 

Uric acid crystals are well-known activators of the NLPR3 inflammasome. Recent studies have shown that soluble (non-crystalline) uric acid can also activate this inflammatory pathway. The mechanism by which soluble uric acid activates the NLRP3 inflammasome has not been fully understood, but several potential pathways have been proposed.

  1. Uric acid uptake and intracellular crystallization: Soluble uric acid can enter cells, and once inside, it may form microcrystals or undergo phase transitions recognized by the NLRP3 inflammasome.
  1. Alteration of cellular homeostasis: High levels of soluble uric acid can disrupt cellular homeostasis, producing reactive oxygen species (ROS) or other cellular stress signals that can indirectly activate the NLRP3 inflammasome. The toll-like receptors are located on the cell membrane and take clues from the surrounding environment. There are receptors on the cell. If inflammation is sensed, it makes the cell more inflammatory.
  1. Interference with autophagy: Uric acid may inhibit autophagy, a cellular mechanism for removing damaged organelles or harmful molecules. This disruption can lead to the accumulation of cellular debris activating the NLRP3 inflammasome.

The concentration of soluble uric acid required to activate the NLRP3 inflammasome is unknown. It may be higher than the levels typically seen in healthy individuals. However, in conditions associated with hyperuricemia, such as gout, metabolic syndrome, or chronic kidney disease, elevated levels of soluble uric acid can contribute to the inflammatory response mediated by the NLRP3 inflammasome. But now we think that even smaller amounts of uric acid can stimulate the NLRP3 inflammasome. 

What Are Some Other Aspects of Uric Acid and Inflammation?

Promoters of Oxidative Stress 

Oxidative stress occurs when the body’s free radicals and antioxidants are imbalanced. Studies show that soluble uric acid can induce oxidative stress, which drives up inflammatory markers like C-reactive protein.

Priming of Inflammatory Cells

Excess uric acid is thought to “prime” innate immune cells like neutrophils, monocytes, and macrophages, making them more prone to releasing inflammatory proteins and reactive oxygen species when activated by a secondary stimulus. It can also affect their cell membrane, where the toll-like receptors come into play.

Endothelial Dysfunction

The endothelial cells that line our blood vessels play an important role in regulating inflammation. Uric acid may impair endothelial function, disrupting this inflammatory control process.

While the mechanism is not fully understood, a substantial body of evidence links chronically elevated uric acid levels to increased systemic inflammation, even without conditions like gout. This low-grade “metainflammation” may contribute to the development and progression of various chronic diseases and, as previously stated, inflammaging.

What Can We Do About This?

Having blood uric acid levels checked is a good idea. We hope to have test strips available at PUR-FORM shortly to assess uric acid ranges. The strip goes on the tongue and gives a range of uric acid levels, from healthy to problematic. We will not be getting an exact number, but we will get a range.

The newest thinking suggests that optimal uric acid levels for overall health are below 5.5 mg/dL, which is lower than the traditional “normal” range of up to 7 mg/dL used to assess gout risk. Uric acid levels above 5.5 mg/dL are linked to an increased risk of metabolic diseases like obesity, diabetes, heart disease, and neurological conditions such as dementia. However, some studies indicate that moderately elevated uric acid within the normal range (e.g., 6-6.8 mg/dL) may protect cognition in older adults over 70. While high uric acid levels above 7 mg/dL are detrimental, the ideal range is below 5.5 mg/dL for metabolic health. However, according to some studies, allowing slightly higher levels, around 6-6.8 mg/dL in older adults, may provide cognitive benefits. I disagree with this concept and would instead recommend lowering uric acid levels and using other methods to prevent cognitive declines, such as exercise, supplements, and other modalities for reducing inflammaging. The key is avoiding very high levels above 7 mg/dL and deficient levels below 2 mg/dL, which have also been linked to neurological disorders and kidney issues. Overall, the latest evidence points to an optimal uric acid level below 5.5 mg/dL for most people but allows a slightly higher level of around 6-6.8 mg/dL, specifically for cognitive protection in older people.

Lifestyle Changes 

Here are some fundamental lifestyle changes that can help lower uric acid levels:

Dietary Changes

Limit intake of purine-rich foods like red meat, organ meats, seafood (especially shellfish), and alcohol, as they increase uric acid production. Increase consumption of low-fat dairy products, vegetables, fruits, whole grains, and plant-based protein sources, which are low in purines. Drink plenty of water to help flush out uric acid. Limit or avoid sugary beverages and foods with high-fructose corn syrup, as they increase uric acid levels.

Weight Management

Lose weight if overweight or obese, as excess weight increases uric acid levels. Even modest weight loss can provide benefits.

Exercise

Engage in regular low-impact exercise, such as walking, swimming, or cycling, for at least 150 minutes per week. Exercise can help reduce uric acid levels.

Limit Alcohol

Avoid heavy alcohol consumption, especially beer, as it provides purines and can trigger gout attacks.

The key is adopting a healthy lifestyle focused on a well-rounded diet, achieving a healthy body weight, staying hydrated, limiting purine sources, and getting regular exercise. Medications are often still needed to get uric acid into the optimal range below 5.5-6 mg/dL for preventing gout attacks. 

What About Supplements? 

Some of you may know that I am a member of the scientific board of the company HumanN. They have developed a new product called “Uric Acid Balance.” I believe this is an excellent product that addresses the uric acid problem. The product contains vitamin C, quercetin, green tea extract, and tart cherry extract. All these compounds help support normal uric acid levels already in the normal range through the following mechanisms:

  1. Vitamin C: Vitamin C is a potent antioxidant that can help increase the excretion of uric acid through the kidneys. It can also reduce the production of uric acid by inhibiting the enzyme xanthine oxidase, which is involved in the breakdown of purines into uric acid. Here at PUR-FORM we offer a high-dose vitamin C IV drip.
  1. Quercetin: Quercetin is a flavonoid compound with antioxidant and anti-inflammatory properties. It can inhibit the activity of xanthine oxidase, thereby reducing the production of uric acid from purines. Quercetin may also promote the excretion of uric acid through the kidneys. Here at PUR-FORM we offer intravenous quercetin.
  1. Green tea extract: Green tea is rich in polyphenolic compounds, such as epigallocatechin gallate (EGCG), which have antioxidant benefits and support a healthy inflammatory response. EGCG can inhibit the activity of xanthine oxidase, reducing the production of uric acid. Green tea extract may also enhance the excretion of uric acid through the kidneys. Intravenous EGCG is our latest IV drip offering at PUR-FORM. Check out my recent blog on green tea extract to learn more about this powerful compound. 
  1. Tart cherry extract: Tart cherries are rich in anthocyanins, which are potent antioxidants. Anthocyanins have been shown to inhibit xanthine oxidase activity, thereby reducing uric acid production. Tart cherry extract also supports a healthy inflammatory response and helps reduce inflammation associated with overuse or exercise. This can help alleviate symptoms related to high uric acid levels. HumanN has also developed Tart Cherry Gummies.

The combination of these compounds can have a synergistic effect in promoting normal uric acid levels. They can inhibit xanthine oxidase, a key enzyme in the production of uric acid from purines. They can promote the excretion of uric acid through the kidneys and provide antioxidant and anti-inflammatory effects, which can help mitigate the adverse effects of high uric acid levels. It’s important to note that while these compounds may be beneficial, they should be consumed as part of a balanced diet and lifestyle. Remember that what was once thought to be healthy uric acid levels is changing. One must keep up with these new changes.

– Dr. P

*These statements have not been evaluated by the FDA

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