The same mechanism that leaves you drained and feverish during a cold can work quietly for entire decades, long before any diagnosis appears. In both cases the key role is played by the same molecules: cytokines. They differ mainly in the timing and the force of their action. During an infection they raise a violent alarm lasting a few days. In aging they produce a barely audible hum that builds up over years, and which today sits at the very centre of longevity research.
What Are Cytokines?
Cytokines are small proteins that cells secrete in order to communicate with one another – something like the text messages of the immune system. One cell releases a cytokine, another cell reads it using a matching receptor on its surface and changes its behaviour: it starts to divide, it matures, it moves towards the site of an infection, it intensifies inflammation or it quiets it down.
The main source of cytokines is immune cells (macrophages, T and B lymphocytes and dendritic cells). They are also secreted, however, by tissues outside that system – the vascular endothelium, fibroblasts and fat cells. This largely explains why an excess of deep (visceral) fat tissue sustains inflammation throughout the body.
The most important families of cytokines include:
- Interleukins – the largest group, coordinating the work of white blood cells (for example IL-1, IL-6, IL-10).
- Interferons – indispensable in fighting viruses and in regulating immunity.
- Tumour necrosis factors (TNF) – powerful inflammatory mediators, led by TNF-α.
- Chemokines – they act as navigation, directing immune cells to the site of injury or infection.
- Growth factors (for example TGF-β) – they govern tissue rebuilding and quiet excessive inflammatory reactions.
From a practical point of view we divide them into pro-inflammatory (for example IL-1, IL-6, TNF-α) and anti-inflammatory (for example IL-10, TGF-β). The key is maintaining the right proportion between them.
A cytokine signal reaches the inside of the cell along a particular biochemical route – one of the key ones is the JAK-STAT pathway, which activates whole packages of genes like a single switch. That is why even one molecule can set off a chain reaction: instead of a single gene it activates an entire cellular programme at once.
Inflammaging: When the Alarm Will Not Switch Off
The concept of inflammaging (a combination of the words inflammation and aging) was introduced at the turn of the century by the Italian immunologist Claudio Franceschi. He used it to describe the latent, chronic inflammation that develops in the body with age – even when we have no infection at all. Instead of a short, intense alarm, the body maintains a permanently elevated level of pro-inflammatory cytokines (mainly IL-6, TNF-α and IL-1), which slowly burdens the blood vessels, the joints and the brain.
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Read moreThe main source of this process is what are known as senescent cells (often called “zombie cells”). They have stopped dividing but do not die – instead they secrete into their surroundings an inflammatory set of substances called SASP (the senescence-associated secretory phenotype), rich in IL-6 and IL-1. The more such cells accumulate in the body, the stronger and more persistent the inflammatory signal becomes².
Chronic inflammation is today recognised as one of the official pillars of aging (the Hallmarks of Aging). You can read more about this mechanism and its effect on the body in our earlier articles.
IL-6 and CRP: The Cytokines That Best Predict Risk
Of the dozens of cytokines, it is interleukin 6 that has earned the nickname “the gerontologists’ cytokine”. Its concentration in the blood rises with the years and is directly linked to a decline in physical form, loss of independence and a higher risk of death. In a now classic study of older people, elevated levels of IL-6 and of CRP (produced by the liver largely in response to IL-6 itself) were associated with higher mortality in the following years of observation, independently of the coexisting conditions present at the start of the study³.
IL-6 is not unambiguously “bad”, however. This molecule also enters the blood from working muscles during exercise, and such a brief spike produces an anti-inflammatory effect in the body. The problem is therefore not the existence of IL-6 as such, but its chronically elevated baseline value, sustained for months without clear peaks and troughs. This is exactly the same pattern that in other biological contexts (in the rhythm of cortisol, for example) also turns out to be more harmful than a single, transient spike.
How Can You Check Your Own Level of Chronic Inflammation?
Unlike many markers of aging, this one is easily accessible. The high-sensitivity CRP test (hs-CRP) is a routine, inexpensive blood test which – unlike the ordinary CRP used when an acute infection is suspected – can pick up the subtle, chronic elevation associated with inflammaging, and not only the pronounced inflammation that accompanies illness. Values below 1 mg/l are usually considered low cardiovascular risk related to inflammation, and above 3 mg/l elevated, although the precise interpretation belongs to a doctor, not to reading the result on your own.
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Read moreA single measurement, as with many other biomarkers of aging, means less than a trend observed over time. Acute inflammation – a cold, a cut, an intense workout the day before – can temporarily inflate the result, regardless of the baseline level of inflammaging. Hs-CRP is therefore best treated above all as a reference point for the future.
What Quiets Chronic Inflammation?
The effectiveness of a few simple habits is now very well documented by research:
- Movement: Regular training lowers resting concentrations of CRP and IL-6.
- The Mediterranean diet: A menu based on fibre and polyphenols favours lower levels of inflammatory markers compared with a highly processed diet.
- Reducing visceral fat: Getting rid of excess deep fat tissue eliminates one of the main sources of continuously secreted cytokines.
None of these approaches will switch off inflammation as if by magic. Good habits do, however, help to take control of a process that the body handles less and less well with age.
Senolytics and Experimental Therapies Targeting Cytokines
Since latent inflammation is fuelled by senescent cells, researchers set out to look for ways of eliminating them. This gave rise to senolytics – substances (for example the combination of dasatinib with quercetin) which in laboratory studies on mice clear tissues of old cells. This translated not only into better physical performance in the animals but also into longer lives⁴. It has to be remembered, though, that this is still the experimental phase and the data do not yet amount to ready treatments for humans.
The breakthrough in humans, by contrast, came with the CANTOS trial. In this large clinical study, patients who had suffered a heart attack were given an antibody blocking IL-1β. The drug reduced the risk of further cardiac events, and did so entirely independently of cholesterol levels⁵. This is one of the most important pieces of evidence that inflammation is a direct cause, and not merely a side symptom, of cardiovascular disease.
Conclusions
A chronically elevated level of pro-inflammatory cytokines (mainly IL-6 and IL-1) indicates an ongoing process of inflammaging in the body. Over time these protein signalling molecules burden the blood vessels and tissues, accelerating biological age. Measuring hs-CRP regularly makes it possible to catch this hidden inflammation at an early stage, which gives a clear starting point for lifestyle changes.
Sources
1. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
2. https://doi.org/10.1038/s41569-018-0064-2
3. https://doi.org/10.1016/s0002-9343(99)00066-2
4. https://doi.org/10.1038/s41591-018-0092-9
5. https://doi.org/10.1056/NEJMoa1707914
