Cossarizza surveys the state of inflammaging, the persistent low-grade sterile inflammation that accompanies aging in industrialized humans, and argues it is a modifiable driver of cardiovascular disease, neurodegeneration, metabolic dysfunction and frailty rather than an inevitable consequence of time. He assembles the mechanistic case from cellular senescence and the senescence-associated secretory phenotype, mitochondrial dysfunction and mitochondrial DNA release, NLRP3 inflammasome hyperactivation, immune senescence, and failed resolution of inflammation. He then reviews the therapeutic pipeline aimed at each node: senolytics that kill senescent cells, senomorphics that silence their secretions, metabolic modulators such as metformin and rapamycin, immune-directed approaches including CAR-T and NK cell therapy, and microbiome interventions. The most consequential single item he reports is not a drug. It is a cross-population comparison showing that the age-linked inflammatory signature seen in Italian and Singaporean cohorts is largely absent in the Tsimane of Bolivia and the Orang Asli of Malaysia, suggesting inflammaging is substantially a product of industrialized environments rather than universal biology.
For twenty-five years, the working assumption in geroscience has been that immune systems slowly catch fire as they age. Interleukin-6, TNF and C-reactive protein creep upward, and that smouldering fire drives the diseases of later life. Inflammaging became one of the field’s load-bearing concepts.
Cossarizza’s review keeps that concept but quietly undermines its universality. He points to a 2025 comparison of four cohorts totalling roughly 2,900 people. In the Italian InCHIANTI study and the Singapore Longitudinal Ageing Study, the familiar inflammatory axis behaves exactly as textbooks predict, rising with age and tracking disease. In the Tsimane, forager-horticulturalists in the Bolivian Amazon, and the Orang Asli of Peninsular Malaysia, it essentially does not. These populations carry heavy parasite and infection burdens, so they are not free of inflammation. Their inflammation simply does not organise itself into an age-linked axis, and it does not predict cardiovascular or metabolic disease. If this replicates, inflammaging is less a law of biology than a signature of the industrialised body.
The rest of the review is a tour of attempts to put the fire out pharmacologically, and here the honest reading is that the field is still at the starting line. Senolytics, drugs designed to kill senescent cells, have moved into humans. The first-in-human trial, in fourteen patients with pulmonary fibrosis, produced a 21.5 metre gain in six-minute walk distance with no control group. A pilot in twelve people with mild cognitive impairment produced a one-point gain on a thirty-point cognitive test, again with no control group. These are hypothesis-generating, nothing more.
The metabolic drugs have done worse. The MET-PREVENT trial randomised seventy-two frail older adults to metformin or placebo and found a treatment effect on walking speed of 0.001 metres per second, which is zero to three decimal places. An mTOR inhibitor that cut infection rates by 38 percent in a phase 2 trial failed to replicate in phase 3.
What the review does supply well is the mechanistic map, and its most underrated section concerns resolution. Switching inflammation off is an active process requiring specialised lipid mediators that decline with age. That reframes the problem: inflammaging may be less a stuck accelerator than a failing brake, which would mean suppressing cytokines treats the wrong end of it.
Cossarizza’s own conclusion is a call for combination therapy, better biomarkers and precision stratification. That is the correct scientific instinct. It is also what a field says when its single agents have not worked yet.
Actionable Insights
This is a review. The one finding with real practical weight is the population comparison. Age-linked inflammation appeared in industrialised Italian and Singaporean cohorts and was essentially absent in the Tsimane and Orang Asli, despite those groups carrying more infections. Diet, physical activity, sleep, pollution and psychosocial stress appear to be doing much of the work we have been attributing to time. Those are things you control.
For magnitude: across fifteen years in 1,843 older adults, each one standard deviation rise in log IL-6 carried a 48 percent higher risk of death from any cause (hazard ratio 1.48, 95% CI 1.33 to 1.64), independent of CRP, blood pressure, cholesterol, smoking, BMI and diabetes. Caveat that matters: this is an association. No trial has shown that pushing your own IL-6 down adds years.
On the drug side the measured effects are small or absent. Metformin changed walking speed by 0.001 metres per second versus placebo in frail elders, which is indistinguishable from nothing. Human senolytic gains come from uncontrolled pilots of twelve to fourteen people and sit inside the range of test practice effects. Track IL-6 and high-sensitivity CRP if you want a number to watch.
Context and Source
- Open Access Paper: Inflammaging: Experimental Insights and Translational Advances
- Institution: Chair of General Pathology and Immunology, University of Modena and Reggio Emilia School of Medicine, Modena, Italy
- *Country: Italy
- Journal: European Journal of Immunology (Wiley-VCH), 2026.
- Article type: Review, tagged “Highlights-Reviews”. 26 June 2026.
- Impact evaluation: The impact score of this journal is 4.1 (Journal Impact Factor; CiteScore 8.2), evaluated against a typical high-end range of 0 to 60+ for top general science, therefore this is a Low to Medium impact journal. In fairness to context: within its own discipline, European Journal of Immunology sits in Q1 of Immunology with an h-index above 200, so it is a respectable specialist venue. It is not Nature, Science, Cell, Nature Medicine or Immunity.