Inflammaging

Inflammaging is the chronic, low-grade, systemic inflammation that develops with age without an identifiable infection. It is measured by modestly elevated circulating interleukin-6, C-reactive protein and tumour necrosis factor, levels far below those of acute illness but persistently above those of young adults. Claudio Franceschi introduced the term in 2000 as part of an evolutionary argument: the immune responses that protect against pathogens in early life become maladaptive when sustained across decades.¹ Chronic inflammation was added as a distinct entry to the Hallmarks of aging in 2023.

§The observation

Inflammatory markers rise with age in essentially every population studied, and their level predicts outcomes. Interleukin-6 concentration in older adults is associated with subsequent disability, frailty, cognitive decline and all-cause mortality, robustly enough that it is sometimes described as the single most informative blood measure in geriatric epidemiology.² Elevated C-reactive protein carries similar predictive weight for cardiovascular events.

The elevation is small in absolute terms. It is chronic, not episodic; sterile, in that no pathogen is present; and heterogeneous, in that individuals of the same age differ widely. Some very old people show inflammatory profiles resembling those of middle-aged adults, and centenarian cohorts have been reported to combine high pro-inflammatory markers with high anti-inflammatory ones, which Franceschi interpreted as successful counter-regulation rather than absent inflammation.

§Where it comes from

No single source accounts for it. The candidates below are all supported by mechanistic work in animals and by correlational work in humans, and they interact.

Senescent cells. The senescence-associated secretory phenotype is an inflammatory programme by construction, and senescent cells accumulate in aged tissue. Transplanting them into young mice raises systemic inflammatory markers, which makes senescence the most directly demonstrated source.

Cytosolic DNA sensing. DNA that escapes the nucleus as chromatin fragments, or leaks from damaged mitochondria, is detected in the cytoplasm by cGAS, which activates STING and drives type I interferon and inflammatory cytokine production. This pathway evolved to detect viruses; in aged cells it is triggered by the cell's own genome, connecting mitochondrial damage and genome instability to a specific inflammatory output.³

Retrotransposons. LINE-1 elements, silenced by heterochromatin in young cells, become de-repressed in senescent and aged cells. Their reverse-transcribed cDNA is a cGAS substrate, and inhibiting reverse transcription reduces interferon signalling and age-associated inflammation in mice.⁴

The gut. Intestinal permeability increases with age in model organisms and, by indirect measures, in humans, allowing bacterial products such as lipopolysaccharide into the circulation. Microbiome composition shifts with age, though whether the shift causes inflammation or reflects it is unresolved — the same ambiguity that makes dysbiosis the least secure of the twelve hallmarks.

Immunosenescence. The thymus involutes from childhood, shrinking the naive T-cell pool. Lifelong cytomegalovirus infection drives large expansions of memory T cells in most of the world's population. The remodelled immune system responds poorly to new antigens while maintaining chronic activation against old ones. Failing clearance of debris by aged macrophages compounds the effect, as does the clonal expansion of mutant blood stem cells described under stem cell exhaustion.

Body composition and lifestyle. Visceral adipose tissue is an endocrine organ that secretes IL-6 and recruits inflammatory macrophages, and adiposity increases with age in most populations. Physical inactivity, short or disrupted sleep and periodontal disease all raise inflammatory markers independently of age.

Cause or consequence

The mechanistic case for inflammaging as a driver is strong in mice. In humans it rests largely on association, and inflammatory markers are downstream of nearly everything that goes wrong with an aging body. Sceptics argue that IL-6 is an excellent prognostic indicator precisely because it integrates many forms of damage, which is a different claim from saying that lowering it would help.

§Evidence that it is causal

The best human evidence comes from cardiovascular medicine rather than from geroscience. Genetic studies of variants in the interleukin-6 receptor that mimic pharmacological blockade find lower coronary heart disease risk, supporting a causal role for IL-6 signalling in atherosclerosis. The CANTOS trial then tested this directly: canakinumab, an antibody against interleukin-1β, reduced recurrent cardiovascular events in patients with prior myocardial infarction and elevated CRP, without changing lipid levels.⁵ The same trial recorded an increase in fatal infection, which is the expected cost of suppressing innate immunity in an older population. Low-dose colchicine has since shown cardiovascular benefit in two large trials and has entered clinical use for that purpose.

These results establish that a specific inflammatory pathway causes a specific age-related disease. They do not establish that inflammation drives aging in general. The counter-example is instructive: low-dose aspirin given to healthy older adults for primary prevention did not extend disability-free survival and increased major bleeding.⁶ Broad anti-inflammatory prophylaxis in the well elderly has not been shown to help.

Animal work continues to produce larger effects than human work. Antibody blockade of interleukin-11 started in already-old mice extended median lifespan and improved several functional measures in a 2024 report — a substantial mouse result with no human counterpart, and one whose translation should be assumed uncertain until tested.⁷

§Measurement

Inflammatory markers have been assembled into composite scores intended as aging biomarkers. An immune-age metric derived from longitudinal high-dimensional immune monitoring predicted cardiovascular outcomes and mortality beyond chronological age, and a separate inflammatory clock built from circulating protein data identified the chemokine CXCL9 as a major contributor to age-related dysfunction.⁸ These are promising as research tools. None is a validated surrogate endpoint, and none is comparable in predictive performance to a well-constructed methylation clock across all outcomes.

Population comparisons complicate interpretation. Tsimane forager-horticulturalists in the Bolivian Amazon carry heavy parasite and infection burdens and correspondingly high inflammatory markers, yet have among the lowest levels of coronary artery calcification ever measured in adults.⁹ Whatever inflammaging is in an industrialized population, it is not simply "high CRP".

§Interventions

Exercise lowers IL-6 and CRP modestly and reliably, and is the only intervention with strong human evidence on both inflammation and function. Caloric restriction lowers inflammatory markers in the human trials that have measured them. Senolytic drugs reduce inflammatory markers in mice and in small uncontrolled human studies. Rapamycin and Metformin and the TAME trial both have anti-inflammatory effects among their many actions.

The design problem for all of them is that inflammation is not optional. It clears pathogens, resolves tissue damage, and supports repair; the CANTOS infection signal shows what happens when it is suppressed in an older population. Any intervention aimed at inflammaging must therefore target a specific source — senescent cells, cytosolic DNA sensing, a single cytokine — rather than inflammation as such. Which source dominates in an individual older human is, as of 2026, not measurable, and that is the practical obstacle to acting on the geroscience version of the argument.

§See also

• Hallmarks of aging
• Cellular senescence
• Senolytics
• Aging biomarkers
• Stem cell exhaustion
• Exercise as a geroprotector

§References

Footnotes

1. paperFranceschi, C. et al. "Inflamm-aging: An evolutionary perspective on immunosenescence." Annals of the New York Academy of Sciences, 2000. ↩

2. paperFerrucci, L., Fabbri, E. "Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty." Nature Reviews Cardiology, 2018. ↩

3. paperDou, Z. et al. "Cytoplasmic chromatin triggers inflammation in senescence and cancer." Nature, 2017. ↩

4. paperDe Cecco, M. et al. "L1 drives IFN in senescent cells and promotes age-associated inflammation." Nature, 2019. ↩

5. paperRidker, P. M. et al. "Antiinflammatory therapy with canakinumab for atherosclerotic disease." New England Journal of Medicine, 2017.↩Participants had a previous heart attack and elevated CRP, so the result concerns secondary prevention in an already inflamed population.

6. paperMcNeil, J. J. et al. "Effect of aspirin on disability-free survival in the healthy elderly." New England Journal of Medicine, 2018.↩A primary-prevention trial in community-dwelling older adults, a different population from the CANTOS one.

7. paperWidjaja, A. A. et al. "Inhibition of IL-11 signalling extends mammalian healthspan and lifespan." Nature, 2024.↩The lifespan and healthspan measurements are in mice dosed from old age; the paper reports no human data.

8. paperSayed, N. et al. "An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging." Nature Aging, 2021. ↩

9. paperKaplan, H. et al. "Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study." The Lancet, 2017. ↩