Inflammaging: How Chronic Low-Grade Inflammation Accelerates Aging (and What to Do About It)

At a Glance

Inflammaging is a portmanteau coined by the Italian immunologist Claudio Franceschi and colleagues in 2000 to describe the chronic, low-grade inflammation that accompanies aging, and its tie to the aging immune system (Franceschi 2000). Unlike the acute inflammation after a sprained ankle, which resolves in days, inflammaging persists for years without pain or fever.

It has since been linked to most major age-related diseases: cardiovascular disease, type 2 diabetes, dementia, sarcopenia and frailty (Franceschi 2018; Ferrucci 2018; Furman 2019). In older adults, higher IL-6 and CRP levels predicted higher mortality (Harris 1999). It is one of the twelve hallmarks of aging in the 2023 update (López-Otín 2023).

Claims below are labelled Established, Emerging, Tested in trials or Hypothesis.

The Biology of Inflammaging

Several processes feed it at once. Which one dominates differs between people, and in most cases it cannot be pinned down with a single test.

Senescent Cells and the SASP

As cells accumulate DNA damage, telomere shortening or oncogenic stress, some enter permanent growth arrest (senescence). Rather than dying, they persist and secrete inflammatory cytokines, chemokines and proteases, the senescence-associated secretory phenotype (SASP): IL-6, IL-8, IL-1β, MCP-1 and matrix metalloproteinases among them.

In young tissue, senescent cells help wound healing and tumour suppression. With age they accumulate. In mice, clearing senescent cells reduces several markers of age-related pathology (Kirkland 2017). Whether the same holds in people is still being tested (see senolytics below).

Mitochondrial Dysfunction and DAMPs

Damaged mitochondria release molecules such as mitochondrial DNA that resemble bacterial signals and can activate innate immune sensors (the cGAS-STING pathway and others), driving NF-κB-dependent inflammation. This is well described in cells and animals; how much it contributes to inflammaging in people is Emerging.

Gut Barrier Changes (“Inflammaging from Below”)

With age, the intestinal barrier can become more permeable and the microbial community shifts. Bacterial products such as lipopolysaccharide (LPS) reaching the circulation activate Toll-like receptor 4 on immune and endothelial cells. Mechanistically plausible and supported by animal data; clinical tests of “leaky gut” (zonulin, LPS-binding protein) are not standardised and do not guide treatment reliably (Emerging).

Visceral Fat

Visceral fat behaves like an inflammatory organ: enlarged fat cells and resident macrophages secrete TNF-α, IL-6 and IL-1β while adiponectin falls. Someone can have a normal BMI and still carry substantial visceral fat; waist circumference is a quick screen, imaging is more precise (Established as an association).

Immune Aging, CHIP and Persistent Infections

Three newer pieces belong in the picture:

• Immunosenescence. The thymus shrinks, fewer naive T cells are made and the immune repertoire narrows. Immune aging and inflammaging are intertwined and partly adaptive (Nikolich-Žugich 2018; Fulop 2017). Established.
• Clonal hematopoiesis (CHIP). Blood-cell clones with acquired mutations were found in 9.5% of people aged 70 to 79 and were associated with higher all-cause mortality and about double the coronary risk (Jaiswal 2014); mutant cells appear to promote inflammation in atherosclerosis (Jaiswal 2017; Polizio 2023). Emerging as a driver of inflammaging.
• Cytomegalovirus (CMV). CMV is one of the largest non-heritable influences on immune variation (Brodin 2015) and was associated with higher mortality in older adults (Savva 2013). Its link to inflammaging specifically is weaker than its link to T-cell changes (Gadoth 2024). Emerging.

The full picture, including EBV and shingles vaccination, is in infection, immunity and aging.

Key Biomarkers: How Inflammaging Is Measured

No single marker captures it, and most are non-specific: any infection, injury or flare raises them.

High-Sensitivity CRP (hsCRP)

The most accessible marker. The AHA/CDC cardiovascular risk strata are below 1 mg/L (lower risk), 1 to 3 mg/L (average) and above 3 mg/L (higher risk); values above 10 mg/L usually point to an acute process and should be repeated (Pearson 2003). CRP is produced by the liver in response to IL-6, so it is a downstream signal.

Interleukin-6 (IL-6)

IL-6 is central to inflammaging and predicts mortality in older adults (Harris 1999). Assays and reference ranges differ between laboratories, and there is no agreed “optimal” value; it is mostly a research marker.

TNF-α and GDF-15

TNF-α is involved in insulin resistance and muscle loss. GDF-15 rises with mitochondrial stress, inflammation and cancer, and tracks mortality in cohorts. Both are research markers; neither has a validated treatment target.

Other Markers Often Ordered

Fibrinogen, ferritin and homocysteine can be raised in chronic inflammation, but each has many other causes and needs interpretation in context. Treat any single abnormal value as a reason to look further, not as a diagnosis of inflammaging.

What Lowers Inflammaging: The Evidence

The aim is to address drivers rather than suppress inflammation wholesale. Inflammation is part of defence; the anti-inflammatory drug trials below show what suppressing it can cost.

Physical Activity and Weight

Established. More daily activity and less sitting go with lower all-cause mortality in a dose-response way (Ekelund 2019). Regular exercise lowers visceral fat and inflammatory markers over time, even though a single hard session is briefly pro-inflammatory. Resistance training protects against sarcopenia, and wasting muscle is itself an inflammatory source. See zone 2 training and sarcopenia prevention.

Diet

Established / Emerging.

• Mediterranean-style diet. In a meta-analysis of 17 randomised trials (about 2,300 participants), Mediterranean diets lowered hsCRP by about 1 mg/L and improved endothelial function compared with control diets, with large differences between trials (Schwingshackl 2014). In PREDIMED, a Mediterranean diet supplemented with olive oil or nuts reduced major cardiovascular events in people at high risk (Estruch 2018).
• Calorie restriction. In CALERIE, two years of moderate calorie restriction in healthy non-obese adults was feasible (Ravussin 2015) and lowered CRP by about 40% and TNF-α by about 50% compared with an unrestricted diet, without impairing cell-mediated immunity (Meydani 2016). Sustained calorie restriction is hard to keep up, and it is not advisable for everyone (for example older adults at risk of muscle loss).
• Ultra-processed food. Lower intake is sensible for many reasons; direct evidence on inflammaging markers is limited.

Sleep

Established as an association. In a meta-analysis of cohort and experimental studies, sleep disturbance and long sleep duration were associated with higher CRP and IL-6 (Irwin 2016). See sleep architecture and longevity.

Omega-3 Fatty Acids

Emerging. EPA and DHA are precursors of pro-resolving mediators and compete with arachidonic acid in eicosanoid pathways (Calder 2017). Effects on inflammatory markers in trials are modest and inconsistent.

For informational purposes only — this summarises doses used in research and practice; it is not a prescription or individual medical advice.

Clinical dosing: 2–4 g/day of combined EPA+DHA, ideally with a meal. At the higher end of this range, triglyceride reduction (25–30%) is an additional benefit. Monitoring omega-6:omega-3 ratio is preferable to guessing at dose sufficiency. Check interactions (for example with anticoagulants) with your physician. See omega-3 and inflammation.

Senolytics

Emerging, trial-only. Senolytics aim to clear senescent cells. Human data so far: small open-label studies of dasatinib plus quercetin showed feasibility and lower senescence markers (Justice 2019; Hickson 2019), and a phase 2 randomised trial in postmenopausal women did not reduce bone resorption (Farr 2024). Human trials of fisetin are registered, but I have not found peer-reviewed efficacy results. Dasatinib is a prescription cancer drug with real side effects.

For informational purposes only — this summarises doses used in research and practice; it is not a prescription or individual medical advice.

Typical protocols use intermittent pulsing — e.g., 2–3 consecutive days per month — rather than daily dosing: quercetin 500–1,000 mg (combined with dasatinib in D+Q protocols) or fisetin at 20 mg/kg/day on the pulse days. See senolytics.

NAD+ Precursors

Hypothesis / Emerging. NAD+ declines with age in several tissues, and oral precursors (NMN, NR) raise blood NAD+ levels in humans. Mechanistic links to sirtuins and mitochondrial quality control are plausible, but consistent effects on inflammatory markers or clinical outcomes have not been shown. See NAD+ precursors compared.

Nutraceuticals

Hypothesis to Emerging, compound by compound. Curcumin, resveratrol, berberine, sulforaphane and boswellia act on inflammatory pathways in the lab. Human trials are mostly small, short and on surrogate markers, with variable product quality. They are not substitutes for the measures above.

For informational purposes only — this summarises doses used in research and practice; it is not a prescription or individual medical advice.

• Curcumin (liposomal or BCM-95 formulation): inhibits NF-κB and COX-2; 1–2 g/day
• Resveratrol: activates SIRT1, reduces NF-κB signaling; best evidence at 150–500 mg/day
• Berberine: activates AMPK (mimicking caloric restriction), reduces IL-6 and TNF-α, improves insulin sensitivity; 500 mg 2–3× daily
• Magnesium: deficiency drives NF-κB activation; optimal serum levels >0.85 mmol/L; 300–400 mg/day supplementation widely indicated
• Sulforaphane (from broccoli sprout extract): activates Nrf2, the master antioxidant transcription factor
• Boswellia serrata (AKBA): inhibits 5-lipoxygenase (5-LOX), complementing curcumin’s COX-2 activity. See boswellia serrata.

Anti-Inflammatory Drugs: The Outcome Trials

Tested in trials. Two randomised trials showed that lowering inflammation, independent of cholesterol, reduces cardiovascular events:

• CANTOS: canakinumab, an IL-1β antibody, reduced recurrent cardiovascular events in people after a heart attack with raised hsCRP, and increased fatal infections (Ridker 2017).
• LoDoCo2: low-dose colchicine reduced cardiovascular events in chronic coronary disease; non-cardiovascular deaths were higher in the colchicine group (Nidorf 2020).

These trials prove inflammation is a modifiable cause of heart disease in these patients. They did not test aging, and they show why suppressing inflammation broadly is not a free lunch.

My Clinical Protocol for Inflammaging

For informational purposes only — this summarises doses used in research and practice; it is not a prescription or individual medical advice.

When hsCRP, IL-6 or GDF-15 are elevated in the absence of acute illness or active cancer, my starting framework is:

1. Confirm it: repeat the test when well; a single high CRP often reflects a passing infection.
2. Identify drivers: active infection, inflammatory or autoimmune disease, dental or gum disease, gut panel (GI-MAP or equivalent), organic acids test, heavy metal screen, visceral fat quantification, insulin resistance, sleep quality assessment
3. Fix the gut first: targeted dysbiosis treatment and probiotics selected for IL-10–inducing strains. Gut-healing peptides such as KPV or BPC-157 are an option some patients ask about; I help them weigh the evidence and risks to make an informed decision.
4. Layer anti-inflammatory nutrition: Mediterranean framework, eliminate ultra-processed foods, optimize omega-6:omega-3 ratio
5. Add evidence-based nutraceuticals: Omega-3 (3–4 g EPA+DHA), curcumin (1.5 g BCM-95), magnesium (400 mg glycinate), sulforaphane
6. Consider senolytic pulsing in patients >50 with high SASP markers: quercetin + fisetin for 2–3 consecutive days monthly
7. Address mitochondrial dysfunction: NAD+ repletion strategy individualized to response
8. Optimize sleep and exercise: Zone 2 training 3–4×/week minimum, plus resistance training; treat cardiovascular risk factors to guideline targets and keep vaccinations current
9. Re-check biomarkers at 12 weeks: IL-6, hsCRP, GDF-15 minimum panel

The goal is not zero inflammation. The immune system needs the capacity to respond. The goal is less of the chronic background signal.

Related Articles

• Infection, immunity and aging
• The 12 hallmarks of aging
• Senolytics: clearing senescent cells
• Omega-3 fatty acids and inflammation
• Quercetin as a senolytic