Hallmark 11 of 12

Chronic inflammation

With age, many people develop a persistently slightly elevated level of inflammation without any infection or rheumatic disease being present. Claudio Franceschi coined the term inflammaging for this. This hallmark was only added in its own right in 2023, although it belongs among the longest-described phenomena, and it is the one where measurability and interpretability diverge most.

Scientific term: Chronic inflammation
Group: Integrative consequences
Hallmarks of Aging: Added in 2023

The hallmarks of aging are a research framework, not a diagnostic tool. They describe processes that occur during ageing, but they do not prove causation and are not a basis for medical decisions.

What lies behind it

Chronic low-grade inflammation differs fundamentally from acute inflammation. Acute inflammation is time-limited, strongly upregulated and targeted, and it concludes with repair. Chronic means a weak constant signal without resolution that remodels tissue over years.

The sources are varied and point to other hallmarks. Senescent cells secrete pro-inflammatory messengers through their SASP. DNA leaking from damaged mitochondria is recognised as foreign by immune sensors in the cytoplasm. Bacterial components such as lipopolysaccharides enter the circulation from an increasingly permeable gut barrier. Visceral fat tissue is itself an endocrine organ that releases pro-inflammatory signals.

Two signalling pathways are central. The NLRP3 inflammasome detects danger signals and activates interleukin-1 beta. The transcription factor NF-kappa-B switches on a broad programme of inflammatory genes. Both systems respond more readily in the ageing organism and switch off less well.

At the same time the immune response changes overall. Fewer naive T cells are produced while the innate immune response remains persistently slightly activated. The result is a combination that seems contradictory at first: more background inflammation and yet weaker defence against new pathogens.

How robust is the evidence

Robust evidence

Consistent human data and mechanistic animal models point in the same direction.

The epidemiological evidence is extensive. Elevated interleukin-6 and elevated high-sensitivity CRP are associated in large cohorts with cardiovascular disease, diabetes, dementia, frailty and all-cause mortality. The associations mostly persist after accounting for classical risk factors, which argues for more than a by-product.

The decisive step beyond observation came from cardiology. The CANTOS trial studied the antibody canakinumab, which blocks interleukin-1 beta, in people after myocardial infarction with elevated CRP. The drug reduced cardiovascular events without affecting blood lipids. For the first time this showed that targeted anti-inflammation helps independently of cholesterol. At the same time more fatal infections occurred, which made the price of immune modulation visible.

A second strand of evidence comes from colchicine, an old anti-inflammatory compound. In randomised trials in coronary heart disease it reduced cardiovascular events. Here too the effect concerns people with existing disease, not healthy people with slightly elevated CRP.

In contrast stands the evidence on general anti-inflammation in healthy people. Results for prevention with low-dose acetylsalicylic acid in older people without cardiovascular disease were not favourable, with increased bleeding risk and no benefit for disability-free survival.

Findings in humans

Elevated interleukin-6 and high-sensitivity CRP are associated in large cohorts with cardiovascular disease, dementia and mortality.
In the CANTOS trial, blocking interleukin-1 beta reduced cardiovascular events without affecting blood lipids.
In the same trial, more fatal infections occurred under canakinumab.
Colchicine reduced cardiovascular events in randomised trials in coronary heart disease.
Low-dose acetylsalicylic acid showed no benefit for disability-free survival in older people without cardiovascular disease, with increased bleeding risk.

What of this is measurable at YEARS

Partly, via adjacent markers

This hallmark is the most directly accessible, because the key messengers are measurable in blood and established thresholds exist for some of them. That is precisely why the temptation is strong here to read more into the values than they support.

High-sensitivity CRP

The practically most useful value in this context and established as a cardiovascular risk marker. It does respond strongly to acute events, however: an infection, a dental inflammation or intense training in the preceding days can multiply the value. A single measurement without context is barely usable.

Interleukin-6

Mechanistically closer to the process than CRP, because it helps trigger CRP production in the liver. Binding clinical thresholds are lacking for interleukin-6, however, and values fluctuate over the day. The marker is informative over time, not as a single verdict.

Blood count with differential and lymphocyte subsets

The lymphocyte proportion and the neutrophil-to-lymphocyte ratio are simple measures with cohort-level significance. The lymphocyte proportion also feeds into PhenoAge.

Visceral fat mass on imaging

Visceral fat is a substantial source of pro-inflammatory signals and can be estimated on whole-body MRI. This finding links a measurable body characteristic to a mechanism, which makes it particularly usable in practice.

Context

A slightly elevated CRP is not a diagnosis and does not justify anti-inflammatory treatment. The trials showing benefit were conducted in people with existing cardiovascular disease, and the benefit came with increased infection risk. Before an elevated value is read as an ageing signal, the obvious causes belong on the list: infections, dental status, obesity, smoking, lack of sleep.

Limits of this hallmark

The direction of causality is unresolved and plausible both ways. Inflammation can drive tissue damage, and tissue damage triggers inflammation. Observational data cannot separate the two possibilities. The CANTOS trial provides the strongest argument for causal involvement, but only in people with a prior myocardial infarction and elevated CRP.

Anti-inflammation is not blanket good. The immune system needs the capacity for inflammatory responses in order to fight infections and degenerate cells. That precise price became visible in CANTOS: fewer cardiac events, more fatal infections. A concept that treats inflammation only as harm is misleading.

Practically problematic is the non-specificity of the markers. CRP and interleukin-6 rise with infections, after exercise, with obesity, with lack of sleep, with dental inflammation and in the context of autoimmune disease. A single value permits no attribution to inflammaging. Deriving a biological age or an inflammation profile from a CRP of 2.1 mg/l exceeds what the marker delivers.

Frequently asked questions

What is inflammaging?→

Inflammaging denotes a persistently slightly elevated level of inflammation that develops with age without any infection or rheumatic disease being present. The term goes back to Claudio Franceschi. Unlike acute inflammation, which is time-limited and concludes with repair, this signal remains weak and unresolved and remodels tissue over years. The sources are varied: senescent cells with their secretion profile, DNA leaking from mitochondria, bacterial components from a more permeable gut barrier, and visceral fat tissue that itself releases pro-inflammatory signals. At the same time fewer naive T cells are produced, so more background inflammation and weaker defence against new pathogens coincide.

What does a slightly elevated CRP indicate?→

On its own, little. High-sensitivity CRP is established as a cardiovascular risk marker and is associated in large cohorts with cardiovascular disease and mortality. The value is, however, distinctly non-specific. It rises with infections, after intense training, with obesity, with lack of sleep, with a dental inflammation and in the context of autoimmune disease. A single measurement without context therefore permits no attribution. The value is useful over time and after excluding obvious causes. A slightly elevated CRP is not a diagnosis and does not justify anti-inflammatory treatment.

Should inflammation be lowered with medication in older age?→

Only on a clear indication, not preventively in healthy people. The CANTOS trial showed that targeted blockade of interleukin-1 beta reduces cardiovascular events in people after myocardial infarction with elevated CRP, without affecting blood lipids. That was an important demonstration. At the same time more fatal infections occurred. Colchicine also reduced events in coronary heart disease. Both lines of evidence concern people with existing disease. For healthy individuals with slightly elevated CRP there is no demonstration of benefit, and for low-dose acetylsalicylic acid the balance was unfavourable in older people without cardiovascular disease.

What lowers chronic inflammation without medication?→

Best documented are measures that address the sources. Reducing visceral fat lowers pro-inflammatory signals, because this tissue itself acts as an endocrine organ. Regular physical activity is consistently associated with lower inflammatory values in observational studies, although a single intense session raises the value briefly. Adequate sleep is relevant, since sleep deprivation measurably raises inflammatory markers. Stopping smoking and treating gum inflammation act on concrete, often overlooked sources. For individual supplements as anti-inflammatories in healthy people, the evidence on clinical endpoints is thin.

Sources

Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology Series A. 2014;69(Suppl 1):S4–S9.
Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019;25(12):1822–1832.
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. New England Journal of Medicine. 2017;377(12):1119–1131.
Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. New England Journal of Medicine. 2020;383(19):1838–1847.
McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free survival in the healthy elderly. New England Journal of Medicine. 2018;379(16):1499–1508.
Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nature Reviews Cardiology. 2018;15(9):505–522.

Related hallmarks

Hallmark 8 of 12