6 Drivers of Chronic Low-Grade Inflammation

For years the honest objection to the inflammation story was that it might be correlational. Inflammatory markers rise with age and predict disease, but so does almost everything that tracks with ageing. Whether lowering them would change anything was unknown.

That question has now been answered, and the answer is what makes the rest of this worth reading.

Why this is a target and not just a signal

The CANTOS trial gave canakinumab, a monoclonal antibody against interleukin-1β, to patients with prior myocardial infarction and elevated hs-CRP. The 150 mg dose reduced the composite of myocardial infarction, stroke and cardiovascular death, with a hazard ratio of 0.85, and did so without lowering lipids. [1]

That is the result the field had been waiting for: an intervention that touched inflammation and nothing else, and changed hard outcomes.

Canakinumab was never approved for cardiovascular indications, because the same trial found more fatal infections in treated patients — 0.31 versus 0.18 events per 100 person-years. Blunting a core immune pathway costs something.

Colchicine has since produced the practical version. In COLCOT, 0.5 mg daily after myocardial infarction reduced the primary composite endpoint from 7.1% to 5.5%. [2] In LoDoCo2, in chronic coronary disease, the figures were 9.6% to 6.8%, a number needed to treat of 36. [3] In June 2023 the FDA approved low-dose colchicine to reduce cardiovascular risk in established atherosclerotic disease. [4]

1. Visceral adipose tissue

Visceral fat is not storage. It is an active endocrine and immune organ, infiltrated by macrophages and secreting interleukin-6, TNF-α and other mediators into the portal circulation. It is the largest single contributor to low-grade inflammation in most patients who have it, and it behaves quite differently from subcutaneous fat — which is why waist circumference tells you something that weight alone does not.

It is also the most modifiable item on this list, and the one where modest change produces disproportionate effect.

2. Cellular senescence

Senescent cells stop dividing but do not die, and many adopt a senescence-associated secretory phenotype: a sustained output of interleukin-6, interleukin-1, chemokines and matrix-degrading proteases. They accumulate with age, and they recruit inflammation to tissue that is not injured.

This is one of the twelve hallmarks of ageing, and it carries an important caveat. Senescence is also tumour-suppressive and contributes to wound healing, so the intuition that clearing these cells must be beneficial is not safe. The human evidence for senolytic intervention remains early.

3. Gut barrier dysfunction

When intestinal permeability increases, bacterial lipopolysaccharide translocates into the circulation and engages toll-like receptor 4, producing what is described as metabolic endotoxaemia. The mechanism is well characterised and the association with metabolic disease is consistent.

It deserves a caution. The consumer version of this idea — “leaky gut” as a diagnosis, assessed by panels sold direct to patients — runs far ahead of what can actually be measured. IgG food sensitivity testing in particular is not a validated method for identifying this or anything else. The biology is real; most of the testing marketed around it is not.

4. Persistent infection and oral disease

Chronic antigenic stimulation keeps the immune system engaged indefinitely. Latent viral carriage, particularly cytomegalovirus, is one contributor, and smouldering infections elsewhere are another.

The one worth asking about is periodontal disease. It is common, frequently undiagnosed, produces measurable systemic inflammatory signal, and is treatable — and it is almost never mentioned in longevity practice. A patient being worked up for unexplained raised CRP who has not seen a dentist in several years has an obvious next step that no laboratory panel will identify.

5. Sleep disturbance

Here the evidence is more specific than the popular version suggests.

A meta-analysis of 72 studies and more than 50,000 participants found that sleep disturbance — insomnia and poor sleep quality — was associated with higher CRP and IL-6, with effect sizes of 0.12 and 0.20 respectively. Long sleep duration, beyond eight hours, was also associated with higher markers. Short sleep duration had minimal inflammatory effect. [5]

That is not the message usually given to patients, and it points somewhere useful: disrupted, fragmented sleep matters more than short sleep, and long sleep is a signal rather than a solution. Undiagnosed obstructive sleep apnoea sits behind a substantial share of both, and screening for it is more productive than counselling someone to spend longer in bed.

6. Physical inactivity and low muscle mass

Skeletal muscle is itself an endocrine organ, releasing myokines during contraction that exert anti-inflammatory effects. Low muscle mass and sedentary behaviour remove that signal and tend to accompany the visceral adiposity in item one.

One point regularly confuses people, including clinicians. Acute exercise produces a sharp rise in interleukin-6 from contracting muscle, and that spike is anti-inflammatory — it drives IL-10 and IL-1 receptor antagonist production. Chronically elevated resting IL-6 from adipose tissue is a different thing entirely, despite being the same molecule. Measuring IL-6 the morning after a hard session will mislead you.

What does not belong on this list

Three things are marketed as inflammation drivers with far less support than the six above: unspecified “toxins,” IgG-based food sensitivity panels, and most of the anti-inflammatory supplement category. None has evidence approaching what exists for visceral adiposity or periodontal disease, and pursuing them tends to displace the things that would work.

It is also worth stating plainly that a raised CRP is not a diagnosis. It is a non-specific acute phase reactant, and an unexpectedly high value warrants thinking about infection, malignancy and autoimmune disease before it is attributed to lifestyle.

The practical consequence

These drivers are not independent. Visceral adiposity, inactivity, poor sleep and disrupted glucose handling cluster in the same patients and reinforce one another, which is discouraging to read and encouraging in practice: an intervention that addresses one commonly moves several.

It also means the sequence matters more than the completeness. Addressing sleep apnoea and visceral fat in a patient who has both will do more than any supplement protocol, and costs nothing beyond attention.

For the broader framework these drivers sit within, see Dr. Hassan Bennani’s The 12 hallmarks of aging. For why a falling marker is not by itself evidence of benefit, see Your biomarkers improved — did your healthspan?.