Pro-Resolving Mediators: An Antidote for Inflammation

Readers of this magazine know by now that chronic inflammation is a major driver of nearly all diseases of aging.

Anti-inflammatories can help reduce existing inflammation. But that may not be enough.

To more fully undo the damage that chronic inflammation can cause, we need to also resolve the inflammation. Resolution stops the inflammation at the source and helps return inflamed tissues to their healthy, normal state.

Specialized pro-resolving mediators (PRMs) are compounds produced in the body that are the key players in the resolution of inflammation.

PRMs may play a vital role in helping to ward off many diseases of aging, including atherosclerosis and neurological disorders.

The Dangers of Inflammation

Early inflammation in response to an injury or infection is important in healing and protecting the body.

But when that inflammation continues and becomes chronic or unresolved, it drives the progression of numerous disorders,¹ including:^2,3

• Cardiovascular,
• Type II diabetes,
• Alzheimer's,
• Parkinson's,
• Osteoporosis, and
• Arthritis.

Many of these conditions are considered age-associated diseases. Because of the role unresolved inflammation plays, the term "inflammaging" is sometimes used to describe the hand-in-hand relationship between inflammation and accelerated aging.^4-6

Many nutrients exert anti-inflammatory effects, which are extremely beneficial.^7-9 But to truly counter inflammaging and restore health, the inflammation also needs to be resolved.

What Are Pro-Resolving Mediators?

Resolving inflammation is a coordinated and active process guided by specific signaling compounds produced in the body.^10-12

The compounds that are most responsible for the resolution of inflammation are called specialized pro-resolving mediators (PRMs). PRMs are derived from EPA and DHA, the omega-3 fatty acids found in fish oil, and from the omega-6 fats found in certain vegetable oils.^13,14

In response to inflammation, omega-3s can be converted to several classes of PRMs: resolvins, protectins, and maresins. Omega-6s can be converted to PRMs called lipoxins.^15-18

To raise PRM levels in the body high enough to have a significant effect, direct oral intake of PRMs and precursors may be necessary.^19,20 These include:

• 18-HEPE (18-hydroxyeicosapentaenoic acid),
• 17-HDHA (17-hydroxydocosahexaenoic acid), and
• 14-HDHA (14-hydroxydocosahexaenoic acid).

How PRMs Resolve Inflammation

While each type of PRM has slightly different actions, they complement each other and collectively coordinate the processes involved in inflammation resolution.

PRMs resolve inflammation in several important ways. Among others, they:^21-23

• Inhibit the further migration of immune cells that were recruited to damaged tissue during the acute inflammatory phase,
• Inhibit the release of pro-inflammatory mediators from other immune cells,
• Help clear away microorganisms, tissue debris, and dead cells, and
• Stimulate cellular regeneration and tissue repair in damaged tissue.

Together, these actions can help counter diseases driven by inflammation.

Metabolic Diseases

Atherosclerosis, the buildup of plaque in artery walls, is driven in part by inflammation and by a deficiency of inflammation-resolution signals in the arteries.²⁴ It is the major cause of heart disease, heart attacks, and strokes.

In preclinical studies, specialized pro-resolving mediators can help prevent atherosclerosis by initiating the removal of dead cells and cholesterol-rich foam cells in a process called efferocytosis. If these cells are not removed, they contribute to plaque progression.^24,25

Obesity and fat tissue are tied to chronic inflammation.  Genetic and dietary studies show that obesity is associated with low levels of PRMs in fat tissue.^17,26

Non-obese patients with chronic conditions such as type II diabetes also show signs of systemic inflammation,¹⁷ and deficiencies in the production of PRMs have been associated with defective resolution of inflammation that underlies chronic diabetic wounds.²⁷

In animal models of obesity and diabetes, administration of resolvins was able to improve glucose tolerance, reduce fasting blood sugar, and enhance the clearance of dead and damaged tissue.²⁸ This indicates that PRMs may improve metabolism and wound repair in these conditions.^27,29

Preclinical studies show that, in obese animals, taking omega-3 fatty acids can increase levels of resolvins.²⁶ This is an instance when taking PRM precursors may help raise levels more.

Brain Diseases

Prolonged and unresolved inflammation in the brain contributes to neuronal death in Alzheimer's disease. In patients with Alzheimer's, low levels of lipoxins (PRMs derived from omega-6s) have been found after death compared to patients without Alzheimer's.³⁰

In addition, animal studies found that treatment with aspirin, triggered lipoxin, reduced inflammation, and facilitated the clearance of beta-amyloid plaques in the brain,³¹ which are seen in human patients with Alzheimer's disease.

Other preclinical studies show that PRM administration can reduce inflammation and functional deficits in models of age-associated Parkinson's disease.^32,33

PRMs have been shown in preclinical and experimental models to improve other neurological conditions as well, including postoperative cognitive impairment,³⁴ stroke,^35-41 and depression.⁴²

Other Disorders

There is an inflammatory component to many other chronic age-related conditions. For example, PRM production is lower in osteoarthritis⁴³. In a preclinical model of obesity-associated osteoarthritis, treatment with resolvins slowed its progression in the knee joint.⁴⁴

Boosting pro-resolving mediators has also been effective in models of inflammatory liver disease,^45,46 and there is evidence that PRMs can reduce fibrosis (scarring) in chronic kidney disease.⁴⁷

The benefits of PRMs are also being studied in conditions as far-ranging as dry eyes, periodontitis (a serious gum infection), the digestive disease colitis, lung disease, and inflammatory pain,^16,48,49 highlighting the growing attention to the role these compounds play in resolving inflammation.

Clinical Study

An open-label pilot study published in 2022 demonstrates that taking PRM precursors along with bioavailable curcumin delivers significant relief of pain and discomfort.¹⁸ The study recruited 29 healthy males and females with mild to moderate pain. Participants received 500 mg of marine oil enriched with PRM pre-cursors, and 500 mg of highly bioavailable (absorbable) curcumin. To measure pain, quality of life, and overall health, participants completed three questionnaires.

In just 30 days, the combination significantly reduced:

• Total pain,
• Pain intensity, and
• Pain severity.

An impressive 62% of participants had an improved total pain score at 30 days, and after 60 days, a remarkable 79% of participants had an improvement in total pain.

No adverse events were reported.

This suggests that taking PRM precursors with a bioavailable form of curcumin delivers significant relief of pain and discomfort associated with inflammation.

Summary

Without adequate levels of specialized pro-resolving mediators (PRMs) in the body, inflammation can persist and do great harm.

Chronic inflammation that underlies so many age-related diseases has been associated with lower levels of PRMs in the body.

Adequate intake of omega-3 fatty acids from fish oil can increase bodily production of PRMs.

Direct oral intake of PRM (pro-resolving mediator) precursors can boost levels higher.

Emerging evidence suggests that maintaining PRM levels may help fight a variety of inflammatory conditions, from atherosclerosis and degenerative brain diseases to osteoarthritis.

If you have any questions on the scientific content of this article, please call a Life Extension Wellness Specialist at 1-866-864-3027.

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