Inflammation

Inflammation is tissue defense and repair: heat, swelling, immune mediators, and a change in local blood flow. Acute, localized inflammation can clear injury. Chronic, systemic inflammation is a different process. It tracks low cellular energy, leaky vessels, excess estrogen, PUFA, and gut endotoxin, and it sits under aging, fibrosis, and many degenerative diseases.

Chronic inflammation

Before birth, injuries heal with less scarring. Two differences matter: high CO2, which limits lactate, and the absence of stored n-3 and n-6 polyunsaturated fats. In adulthood those fats accumulate. Prostaglandins and related agents rise. Cells shift toward lactic acid instead of carbon dioxide. Chronic systemic inflammation becomes the central factor in degenerative disease. A pooled analysis of 160,309 people across 54 prospective studies found each three-fold rise in baseline C-reactive protein predicted higher non-vascular mortality and a similarly elevated risk of vascular mortality and ischaemic stroke, tracking chronic low-grade inflammation across a wide range of degenerative outcomes rather than any single disease.

Before birth, injuries heal without inflammation and don't leave a scar. Two important causes for that difference are the high concentration of CO2, which limits lactic acid production, and the absence of the n-3 and n-6 polyunsaturated fatty acids. In adulthood, the tissues become progressively more loaded with fats of that type, leading to greater production of inflammatory agents such as prostaglandins, and an increasing tendency to produce lactic acid rather than carbon dioxide. Chronic systemic inflammation is the central factor in the various degenerative diseases.

— Ray Peat

Cellular energy metabolism is the basis for maintaining the barrier functions. Energy depletion causes the endothelial cells lining blood vessels to become excessively permeable.

— Ray Peat

Low energy opens barriers. Open barriers let endotoxin and inflammatory signals spread. Estrogen increases lipid peroxidation, free fatty acids, prostaglandins, and NF-κB-driven cytokines. Serotonin, histamine, and nitric oxide join the same field. See Tissue leakiness, Estrogen, Endotoxin, Serotonin.

One protective set

Prostaglandins form from linoleic and arachidonic acid, which the body cannot make, so adult exposure to them depends on diet; the fetus builds mostly saturated fats and Mead acid from glucose. Prostaglandin-forming polyunsaturated fats drive inflammation and vascular leakiness, and EPA and DHA form isoprostanes and neuroprostanes that act in many ways like prostaglandins. The same fats are toxic to mitochondria, suppress glucose oxidation, and inhibit thyroid function.

The same supports that restore oxidation lower chronic inflammation. Thyroid raises energy and barrier tone. Progesterone opposes unopposed estrogen. Gelatin and glycine, niacinamide, saturated fats, and vitamin E appear together in the leakiness essay as anti-inflammatory and barrier-protective.

Antioxidants, thyroid hormone, progesterone, and antiinflammatory agents, including glycine or gelatin, niacin, and saturated fats, can prevent, and in many cases reverse, these degenerative inflammatory processes.

— Ray Peat

Gamma-tocopherol, unlike alpha-tocopherol, significantly reduced PGE2 and inhibited leukotriene B4 in carrageenan pouch inflammation in rats, and at 100 mg/kg lowered TNF-alpha about 65% (see Vitamin E).

Aspirin blocks cyclooxygenase and cuts prostaglandin excess; its useful range is wider than a single enzyme story. Coffee and food energy support the same arc when the gut can handle them. Lower dietary PUFA and clear endotoxin so the fuel for inflammatory eicosanoids falls. See Aspirin, PUFA, Harm reduction.

Chronic inflammation is energy failure made public. Fix the field; do not only chase one cytokine.

Autoimmunity

Autoantibodies can mark damaged tissue for clearance and repair. Their presence identifies tissue under stress; it does not establish that the immune system caused the initial injury. PUFA, endotoxin, estrogen, cortisol, and low thyroid function can sustain tissue damage and keep the antibody response active. Lowering the antibody level without restoring tissue energy leaves the cause in place.

Pain: back pain

Chronic back pain has few dependable treatments, and two studies point at a hormonal and a stress-history side of it.

Pregnenolone

In a randomized, double-blind trial of Iraq- and Afghanistan-era veterans with chronic low back pain, pregnenolone was added for 4 weeks after a 1-week placebo lead-in, at 100 mg for 1 week, 300 mg for 1 week and 500 mg for 2 weeks. Of 94 veterans analyzed, mean pain diary ratings fell from 5.24 to 4.19 on pregnenolone and from 4.83 to 4.74 on placebo. The adjusted difference was 0.56 points on the 0-10 scale, and pain interference with work and activity also improvedand 0.03). Pregnenolone was well tolerated.

Childhood stress

In a prospective Canadian cohort, chronic back pain risk rose with the number of stressful childhood experiences. Two or more such events raised the risk by about half. A single event did not raise it significantly. The pattern held across gender, socioeconomic status and health status. Fearful experiences, prolonged hospitalization and parental unemployment were the specific events linked to higher risk.

Curcumin

Curcumin molecular structure

Curcumin is a turmeric pigment sold in high-dose extracts for inflammation claims. Absorption is poor without special formulations.

Extracts and food amounts

Food spice amounts differ from gram extracts. Upstream PUFA and endotoxin still dominate inflammatory load. Treat extracts as drugs.

Pain: fibromyalgia

Fibromyalgia is chronic widespread muscle pain and fatigue with no single confirmed structural cause on standard testing. Ray Peat connected it to prolactin elevation and thyroid status rather than treating it as a diagnosis of exclusion with no metabolic thread.

Prolactin and the old "rheumatism" label

The same symptom picture doctors once called rheumatism is now often labeled fibromyalgia, and elevated prolactin's link to this muscle disorder is mainstream-recognized, even though thyroid treatment is rarely offered for it:

Later, in a more mature person, chronically fatigued and painful muscles that at one time would have been diagnosed as rheumatism, may be diagnosed as fibromyalgia. Most doctors are reluctant to prescribe thyroid supplements for the problem, but the association of elevated prolactin with the muscle disorder is now generally recognized.

— Ray Peat

Separately, serotonin excess interfering with muscle mitochondria has been proposed as a contributing mechanism.

A study of 40 women with fibromyalgia and 30 matched healthy controls found higher G-protein coupled estrogen receptor (GPER) levels in patients, with GPER negatively correlated with prolactin.

Growing pains in children reflect the same waterlogging process as cardiac muscle during congestive heart failure. The same changes occur in skeletal muscle and heart muscle alike, and thyroid hormone corrects both, which puts growing pains, heart failure, and fibromyalgia under low thyroid function.

Serotonin and muscle

Raising serotonin with tryptophan is sometimes promoted for fibromyalgia, but the evidence increasingly points to excess serotonin, interfering with muscle mitochondria, as a major factor in the syndrome. Fibromyalgia is one variation of hypothyroid myopathy, in which enzymes leak from the skeletal muscles and also from the heart. Chronic fatigue and fibromyalgia are closely tied to nutrition and hormones, and mysterious infections are over-diagnosed as their cause.

Practice

Because prolactin tracks thyroid status and serotonin/estrogen pressure, this framework treats investigating and supporting thyroid function as a relevant angle, even though this is not the standard first-line approach to a fibromyalgia diagnosis. See Prolactin, Thyroid, Serotonin, Muscle.

Fibrosis

Fibrosis is excess scar collagen that stiffens organs: liver, lung, heart, skin. Chronic inflammation, serotonin, TSH, and low energy drive it. Estrogen and stress chemistry add to the load.

Fibrosis and aging

Peat listed fibrosis as an outstanding feature of aging affecting skin, joints, liver, kidneys, heart, blood vessels, and even the brain, driven by excitotoxins, estrogen, lactate, edema, and inflammation, while saturated fats, antihistamines, and thyroid hormone prevent or reverse it.

Glycine in experimental fibrosis

Glycine is repeatedly listed among antistress factors that can limit fibrotic injury in the Peat corpus (see Gelatin). In rats with alcoholic liver injury, glycine reduced hepatic hydroxyproline/total collagen and cross-link markers. In a rat myocardial infarction model, glycine attenuated myocardial fibrosis with down-regulation of STAT3/NF-κB/TGF-β-axis signals.

Practice (fibrosis)

Lower inflammatory drivers; support thyroid and progesterone context. Medical care by organ. See Serotonin, Inflammation, Thyroid, Estrogen, Heart, Liver.

Nitric oxide

Nitric oxide molecular structure

Nitric oxide (NO) is a signaling gas that dilates blood vessels. It has established roles in blood pressure and immunity.

Ray Peat is critical of chronic excess NO. Sustained overproduction ties to Inflammation, Estrogen effects, PUFA peroxidation, and inhibition of mitochondrial cytochrome oxidase. Acute NO is physiological; the concern is sustained output under Stress, Endotoxin, and Estrogen dominance.

Mitochondrial inhibition

In rat aortic smooth muscle cells, interferon-gamma and TNF-alpha together induced NO production that inhibited Complexes I and II of the respiratory chain.

Peat lists nitric oxide among inhibitors of cytochrome c oxidase (complex IV), the thyroid-sensitive bottleneck of respiration:

This enzyme is dependent upon the thyroid hormone and is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin.

— Ray Peat (via FunctionalPS)

TNF (raised by endotoxin and estrogen) increases carbon monoxide formation, further blocking respiration.

Estrogen, endotoxin, and NO

Estrogen increases production of nitric oxide systemically, and nitric oxide can stimulate TNF formation.

— Ray Peat (via FunctionalPS)

In mice, lipopolysaccharide increases nitric oxide and inflammatory mediators; niacinamide blocks some of these effects. Oral nicotinamide at 62.5 mg/kg or more significantly suppressed LPS-induced TNF-alpha production in Balb/c mice, and the same compound inhibited inducible nitric oxide synthase directly, the enzyme responsible for the NO surge this section describes.

Breath analysis in stress shows elevated NO among inflammatory volatiles in Peat's leakiness article.

The nitric oxide hypothesis of aging

In one review, recurrent infections over a lifetime drive much of aging through the same endotoxin/iNOS pathway: bacterial endotoxin induces inducible nitric oxide synthase (iNOS), producing NO in quantities toxic to host cells, not just invading microbes. The review links this to age-related decline in pituitary and pineal hormone output (including growth hormone, prolactin, and melatonin), loss of the febrile response, Parkinsonism, and Alzheimer's-associated plaques, and note melatonin, vitamin C, and vitamin E as antioxidants that counter the damage. This is the same infection/endotoxin-driven mechanism Ray Peat describes elsewhere on this wiki, from a mainstream gerontology angle rather than a bioenergetic one. Danny Roddy connects the same paper to hair loss, framing pattern baldness as one more tissue accelerated by chronic intracellular calcium turning on NO and suppressing local energy metabolism. Danny and Georgi Dinkov also discuss the same paper directly.

Lowering excess NO

Raising NO metabolites with potassium nitrate for 6 weeks did not improve aerobic capacity, total work, or quality of life in a randomized crossover trial in heart failure with preserved ejection fraction.

CO₂ retention, Progesterone, niacinamide, lower PUFA, and reduced gut Endotoxin are the usual approach to excess NO. Fitness-industry NO boosters are viewed skeptically. See Harm reduction.

Acetylcholine triggers NO synthesis in blood vessels, inhibiting mitochondrial respiration; this is a proposed mechanism connecting chronic cholinergic dominance to learned helplessness and its associated neurodegeneration.

Pain

Pain has several separate drivers, and the wiki covers them on their own pages. This page collects the ones with evidence.

Anesthetic steroids

A 1986 patent by Ray Peat describes DHEA and other "anesthetic steroids" dissolved in an oily vehicle and applied topically or taken orally for rheumatoid arthritis, osteoarthritis, and non-specific joint pain linked to stress. In one case history, a 78-year-old man with mild knee osteoarthritis coated his knees with a solution of 2.5% DHEA and 2.5% progesterone in tocopherols and olive oil, and within 30 minutes he walked more normally. Pregnenolone also cut chronic low back pain in a randomized trial; see Back pain.

Serotonin and mast cells

After skin injury, mast cells were the main source of serotonin, and mice lacking mast cells or their serotonin synthesis had drastically less postoperative pain. See Mast cells.

Conditions

• Back pain
• Osteoarthritis
• Arthritis
• Migraine
• Fibromyalgia
• IBS