Inflammation and immunity: hsCRP, IL-6, the thymus, the gut, and what actually lowers it

Inflammageing

Acute inflammation is the immune system doing its job: a cut swells, a virus produces a fever, and the response switches off when the threat is gone. Inflammageing — the term was coined by Claudio Franceschi in 2000 — is the low-grade, sterile, persistent version that rises with age even in people with no infection: a slow drip of interleukin-6, tumour necrosis factor and C-reactive protein from senescent cells, visceral fat, a leakier gut and an immune system that has lost its brakes. It is a driver, not a bystander: it accelerates atherosclerosis, insulin resistance, muscle loss, bone loss and neurodegeneration, which is why the 2023 update of the hallmarks of ageing gave it a line of its own.

What the markers predict

High-sensitivity CRP is the practical measure. The American Heart Association bands are below 1 mg/L low risk, 1–3 average, above 3 high. In the Women's Health Study (Ridker 2000, 28,000 women) hsCRP predicted cardiovascular events better than LDL cholesterol, and the two were largely independent — a low LDL with a high CRP was not safe. IL-6 is the upstream cytokine that drives CRP production in the liver; in the InCHIANTI and Health ABC cohorts it was the single inflammatory marker most strongly associated with loss of muscle, mobility and life in older adults.

Two trials settled whether inflammation is a cause or a marker:

The lesson for a healthy adult is not to take an antibody. It is that an hsCRP above 2 is a number worth taking seriously even when everything else on the panel is in range — and that ferritin, which is also an acute-phase protein, needs to be read next to it.

What the immune system loses

The thymus, where T cells are trained, is the clearest case of programmed ageing in the body: it begins to shrink after puberty and by fifty is mostly fat, producing a trickle of the new "naive" T cells a twenty-year-old makes in abundance. The result is an immune system that remembers old threats well and learns new ones badly — the reason vaccine responses weaken, shingles reactivates and new infections hit harder after sixty. Alongside it, immunosenescence fills the body with exhausted memory T cells and leaves fewer, slower neutrophils and natural-killer cells.

The best-known attempt to reverse this is TRIIM (Fahy 2019, Aging Cell): nine men aged 51–65 took growth hormone, DHEA and metformin for a year. Thymic fat was replaced by tissue on MRI in most of them, naive T cells rose, and four epigenetic clocks read about 2.5 years younger. It is a striking result with nine participants and no control group; a larger controlled trial (TRIIM-X) is running. Treat it as the most interesting pilot in the field, not as a protocol.

The gut

About 70% of immune tissue sits in the gut wall, and the gut lining is the body's largest interface with the outside world. With age and a poor diet the lining becomes more permeable and bacterial fragments (lipopolysaccharide) leak into the circulation, where they are a direct, measurable source of IL-6 and CRP. The microbiome also loses diversity and the species that make butyrate, the short-chain fatty acid that feeds the gut lining and dampens inflammation.

The evidence for what fixes this is strongest for the boring interventions: fibre (30 g or more a day, from a wide range of plants — the American Gut Project tied diversity to the number of plant species eaten per week, with 30 as the threshold), fermented foods (a 2021 Stanford trial found ten weeks of them raised microbiome diversity and lowered 19 inflammatory markers, where a high-fibre diet alone did not), fewer ultra-processed foods and less alcohol. Probiotic capsules, by contrast, have thin and strain-specific evidence; most do not colonise.

What lowers inflammation — ranked

What to measure

• hsCRP at baseline and every six months; always with ferritin, because both rise with inflammation and a high ferritin with a high CRP is a different problem from a high ferritin alone.
• IL-6 is worth one baseline in anyone over sixty or with a CRP above 2; it is not a routine repeat.
• Full blood count with differential: the neutrophil-to-lymphocyte ratio is a free inflammation marker; above 3 is worth a look.
• Fasting insulin and HbA1c, because insulin resistance and inflammation are the same process seen from two sides.
• Visceral fat on DEXA, the usual source.
• Not a food-sensitivity IgG panel: it measures exposure, not intolerance, and has no validated use.

Draw it 48 hours after the last hard session — a marathon raises CRP ten-fold for two days — and not during or just after a cold.

Where peptides and therapies fit

The immune and inflammation goal page describes the protocol built around this article, with the levers above as the base. Two compounds in the research library are studied in this territory: thymosin alpha-1, a thymic peptide that is a licensed medicine in several countries for hepatitis B and as a vaccine adjuvant and is studied for restoring T-cell function, and KPV, the anti-inflammatory fragment of alpha-MSH studied for gut inflammation. Both are gated on a baseline that includes hsCRP and ferritin. Among therapies, sauna has the best cohort data; the sleep article covers the lever most people with a raised CRP are actually missing.

Common mistakes

• Reading a raised ferritin as "good iron stores" without a CRP next to it.
• An anti-inflammatory supplement stack on top of five hours of sleep and a 105 cm waist.
• Testing CRP the day after a hard session or during a cold, and panicking.
• Probiotic capsules instead of plants. Thirty species a week does what the capsule claims.
• Ignoring the teeth. Gum disease is one of the commonest hidden CRP sources in people over fifty.
• Treating TRIIM as a recipe. Nine men, no control; growth hormone has its own risks.