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Deep Dive — Issue 05 Companion
Inflammageing: The Fire That Ages You
TL;DR:
Chronic, low-grade inflammation (“inflammageing”) is one of the central drivers of age-related disease. It’s fuelled by senescent cells secreting inflammatory signals (the SASP), an immune system that becomes simultaneously overactive and underperforming, and gut microbiome changes that leak inflammatory molecules into the bloodstream.
The most accessible biomarker is hs-CRP — cheap, widely available, worth tracking. Exercise is the single most effective intervention. Omega-3s (Grade A), sulforaphane (Grade B), and curcumin (Grade B) each target different points in the pathway.
Nobody has a pill that stops inflammageing, but movement, diet, and targeted compounds — applied consistently over years — are the best the evidence currently supports.
The Slow Burn
Here’s a question that should bother you: why does a 70-year-old heal more slowly, get sicker more easily, and accumulate chronic disease faster than a 30-year-old with essentially the same genetic blueprint?
Part of the answer is something immunologist Claudio Franceschi named “inflammageing” back in 2000 — a chronic, low-grade inflammation that builds with age in the absence of any obvious infection or injury. It’s not the dramatic, useful kind you get from a sprained ankle. It’s a quiet systemic smoulder: elevated inflammatory molecules circulating in the blood, nudging every organ toward dysfunction, decade after decade. You can’t feel it. Most GPs don’t test for it. But it’s there, and it’s doing damage.
Inflammageing now sits alongside genomic instability and mitochondrial dysfunction as one of the central hallmarks of ageing. A 2025 review in Cell Reports Medicine called it a “hub” — both a cause and a consequence of virtually every other hallmark. All three compounds we graded in Issue 05 (curcumin, resveratrol, sulforaphane) target it. Understanding the mechanism explains why some of them work, why one doesn’t, and where the real limits are.
How Inflammageing Works
The biology is a feedback loop. Once it starts, it tends to accelerate — which is partly why ageing feels slow at 40 and fast at 70. Three processes drive it.
Senescent cells and the SASP. When cells accumulate enough damage — from oxidative stress, DNA breaks, telomere shortening — some enter senescence. They stop dividing but refuse to die. In small numbers, that’s fine: senescent cells suppress tumours and assist wound healing. But with age, the immune system loses its ability to clear them, and they pile up. The real problem is what they secrete. Senescent cells pump out pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), chemokines, and matrix-degrading enzymes — collectively called the senescence-associated secretory phenotype, or SASP. NF-κB, the cell’s master inflammatory switch, controls more SASP genes than RB and p53 combined (Chien et al., Genes & Development, PMID: 22012621). Every senescent cell becomes a tiny inflammatory beacon, damaging surrounding tissue and — here’s the vicious part — pushing neighbouring cells toward senescence too.
An immune system at war with itself. Alongside the accumulation of senescent cells, the immune system undergoes its own decline. The thymus — which trains new T cells — shrinks dramatically with age. Naïve T cell production plummets. At the same time, the innate immune system (monocytes, macrophages) becomes chronically activated, pumping out inflammatory cytokines even without provocation. NF-κB stays switched on. Autophagy — the cell’s recycling system (our Issue 03 Deep Dive) — gets impaired, letting damaged mitochondria and protein junk accumulate. The result is an immune system that’s simultaneously overactive and underperforming: too much inflammation, too little pathogen clearance.
The gut connection. This one surprised me when I first read the literature. The gut microbiome shifts substantially with age — typically toward reduced diversity and more pro-inflammatory species. This increases intestinal permeability, allowing bacterial fragments like lipopolysaccharide (LPS) to leak into the bloodstream, where they trigger systemic inflammatory signalling. It’s a meaningful contributor to inflammageing, and it’s one reason dietary interventions keep showing up in the evidence.
Biomarkers: What to Actually Test
I get asked about this a lot, so let me be specific. There’s no single blood test that captures inflammageing — it’s a systemic state, not a single molecule. But several markers give you a useful window.
High-sensitivity CRP (hs-CRP) is where I’d start. It’s produced by the liver in response to IL-6 and serves as a reliable proxy for systemic inflammation. Below 1.0 mg/L is low risk. Between 1.0 and 3.0 is moderate. Above 3.0 suggests significant chronic inflammation worth investigating. It’s cheap (often under £20 privately), widely available, and I test mine every six months. If you track one inflammageing biomarker, make it this one.
Interleukin-6 (IL-6) is arguably the most important inflammageing cytokine — elevated plasma IL-6 predicts all-cause mortality in older adults (PMID: 10599621). It drives CRP production, promotes senescence, and contributes to sarcopenia. It’s not on standard NHS panels, but specialist blood services like Medichecks and Forth offer it.
TNF-α and GDF-15 (growth differentiation factor 15, a marker of mitochondrial stress and senescent cell burden) are worth knowing about but harder to access for routine tracking. Research tools for now; potentially clinical tools within five years.
What Targets What
This is where it gets practical — and where the newsletter’s evidence grades start to map onto biology.
Think of inflammageing as a river. You can try to stop it at the source (preventing cells from becoming senescent), dam the flow in the middle (blocking the inflammatory signalling), or clean up downstream (clearing senescent cells after they’ve formed). Different interventions sit at different points.
Upstream — preventing senescence. Sulforaphane (Issue 05, Grade B) activates Nrf2, which upregulates over 200 cytoprotective genes. By reducing the oxidative stress that pushes cells into senescence, it acts before the SASP even starts. Its 80% bioavailability means it actually reaches tissue at meaningful concentrations.
Mid-stream — blocking inflammatory signalling. Curcumin (Issue 05, Grade B) directly inhibits NF-κB, the master regulator of the SASP. Omega-3 fatty acids (Issue 04, Grade A) reduce cytokine production and resolve chronic inflammation through specialised pro-resolving mediators. Omega-3s remain the best-supported anti-inflammatory supplement for mortality reduction — they’re the intervention I’d choose if I could only take one.
Downstream — clearing senescent cells. Fisetin (Issue 05 Spotlight, ⏳ Watch this space) works as a senolytic, selectively killing the senescent cells that produce the SASP. If the human data matches the preclinical results, senolytics could address the source rather than the symptoms. But we’re not there yet.
And then there’s exercise, which is annoyingly effective at every level. It reduces CRP and IL-6, improves immune function, promotes autophagy, and improves gut microbiome diversity. No pill matches its breadth. I know that’s not what the supplement-curious reader wants to hear, but the evidence is unambiguous.
The Frontier
Inflammatory clocks. The iAge clock (Sayed et al., 2021, Nature Aging, PMID: 37117524) uses circulating immune proteins to estimate inflammatory age independently of chronological age. Unlike the Horvath clock we dissected in this week’s Hype Check, iAge specifically measures inflammageing and predicts cardiovascular risk and frailty. When these tools become commercially available — likely within two to three years — they could enable genuinely personalised anti-inflammatory protocols.
Senomorphics. Rather than killing senescent cells (the senolytic approach), senomorphics aim to suppress the SASP while leaving cells intact. This matters because senescent cells do useful things — wound healing, tumour suppression. Silencing their inflammatory output while preserving their protective functions is a more elegant solution, and several candidates are in preclinical development.
The exposome question. A provocative 2025 review (Franck et al., Ageing Research Reviews) argues that inflammageing may not be universal at all — but rather a mismatch between evolved human biology and industrialised environments. Studies of non-industrialised populations show strikingly different inflammatory trajectories. If that’s right, then much of what we call inflammageing is environmental — and potentially preventable. It’s an idea that reframes the entire field.
What This Means for You
You can’t eliminate inflammageing entirely — some chronic inflammation seems intrinsic to how the immune system ages. But you can slow it, manage it, and track it. Here’s what I’d do — and largely what I am doing:
Get your hs-CRP tested. If it’s above 1.0, you have room to work with. Retest every six to twelve months.
Move your body. Thirty minutes of moderate activity most days. Zone 2 cardio and resistance training both contribute. This one intervention does more than any supplement.
Eat to reduce inflammation. Mediterranean-pattern eating — omega-3-rich fish, polyphenols, fibre, turmeric, cruciferous vegetables — consistently reduces inflammatory biomarkers in RCTs.
Supplement strategically. Omega-3s first (Grade A). Bioavailability-enhanced curcumin and sulforaphane are reasonable additions if diet and exercise are already dialled in. Resveratrol at Grade C is hard to justify at current prices.
Stay informed on senolytics. Fisetin is the natural compound to watch. The human trial pipeline will tell us within the next few years whether clearing senescent cells delivers on its extraordinary preclinical promise.
The honest bottom line: nobody has a pill that stops inflammageing. But exercise, diet, and targeted anti-inflammatory compounds — applied consistently over years, not weeks — are the closest thing the evidence supports. It’s not dramatic. It’s not expensive. And that’s precisely why it works.
Sources and Further Reading
Franceschi C, et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-254. PMID: 10911963
López-Otín C, et al. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243-278. PMID: 36599349
Chien Y, et al. Control of the SASP by NF-κB. Genes Dev. 2011;25(20):2125-2136. PMID: 22012621
Sayed N, et al. An inflammatory aging clock (iAge). Nat Aging. 2021;1:598-615. PMID: 37117524
Franck M, et al. Inflamm-aging as a diverse and context-dependent process. Ageing Res Rev. 2025.
Cardiovascular inflammaging: mechanisms and therapeutic perspectives. Cell Rep Med. 2025.
Jafari S, et al. Curcumin and human health: systematic review of 103 RCTs (n=7,216). Phytother Res. 2024.
Saito A, et al. Sulforaphane: comprehensive analysis of clinical trials. J Nutr Sci. 2025;14:e65.
Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28. PMID: 30279143
This article is part of Longevity Latest’s Deep Dive series — long-form explorations of the biological mechanisms that drive ageing.
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