Interleukin-6 in Ageing and Disease

IL-6 is a pro-inflammatory cytokine produced by macrophages, T cells, endothelium, adipocytes and skeletal muscle — a central component of the innate immune cascade along with IL-1, TNF-alpha, complement proteins and immunoglobulins.

Increased IL-6 is one of the defining age-related changes of the immune system (Table 2.3), alongside decreased IL-2 and IL-2 responsiveness, thymic atrophy, decreased cell-mediated immunity, accumulation of memory T cells, increased autoantibodies, impaired macrophage function, and increased NK cell number with decreased cytotoxicity.

Plasma IL-6 rises as a function of normal ageing — not merely a marker of disease. It is the best-characterised molecular marker of "inflammageing".

KEY EXAM POINT: plasma IL-6 correlates INVERSELY with functional ability in older people. The higher the IL-6, the poorer the function.

Higher circulating CRP and cytokine receptor levels are independently associated with physical dysfunction and disability.

Ageing behaves like a chronic stress state — with increased cortisol and catecholamines and decreased sex hormones and growth hormone.

Cortisol and catecholamines stimulate IL-6 and TNF-alpha release, whereas sex hormones inhibit IL-6. The fall in oestrogen and testosterone with age therefore disinhibits IL-6 — the core mechanism to quote.

Other drivers feeding into IL-6: mitochondrial dysfunction, cellular senescence (SASP), loss of proteostasis, epigenetic alterations, plus extrinsic factors such as chronic infection (especially CMV) and altered microbiota.

Senescent cells secrete IL-6 as part of the SASP, spreading senescence to neighbouring cells.

The ageing innate immune system shows basal immune stimulation but immune paralysis when a specific response is required — this paradox is inflammageing.

Clinically: baseline alveolar IL-6 and TNF-alpha are higher in aged lungs, yet toll-like receptor activation is blunted, so the acute response to a real pathogen is dampened. High baseline levels indicate a dysregulated, not a better, immune response. Systemic Consequences — Where IL-6 Shows Up Clinically

Anorexia of ageing — IL-1, IL-6 and TNF-alpha are satiating cytokines that reduce food intake and body weight centrally and peripherally. IL-1 and IL-6 are elevated in older people with cachexia.

Sarcopenia and frailty — inflammation drives age-related loss of muscle mass and strength. Frail patients have higher CRP, fibrinogen, factor VIII, D-dimer, leukocytes and glucose, with low vitamin D and low haemoglobin.

The overlap of frailty and cardiovascular biomarkers suggests a common biological pathway linking frailty and CVD.

Anaemia of chronic disease — the classic IL-6 story. IL-6 mediates the hypoferraemia of inflammation by inducing hepatic synthesis of hepcidin.

Hepcidin blocks the ferroportin transporter, blocking duodenal iron absorption and iron release from macrophages, so iron is locked in ferritin stores — a functional iron deficiency.

Laboratory picture of ACD: normocytic anaemia; haemoglobin low; serum iron low-to-normal, transferrin low-to-normal, transferrin saturation low, ferritin normal-to-high, soluble transferrin receptor NORMAL (this last distinguishes it from iron deficiency, where sTfR is high).

Pro-inflammatory cytokines also lower erythropoietin production, damage EPO-producing renal cells, downregulate EPO receptors, and directly damage erythroid precursors by cytokine-mediated apoptosis.

Atherosclerosis and endothelial dysfunction — TNF-alpha, IL-1beta and IL-6 released from ageing endothelium activate NF-kappaB and AP-1, inducing COX-2 and iNOS, generating superoxide and peroxynitrite (Figure 36.1).

Depression in older adults is associated with raised IL-6, along with vitamin D deficiency and white-matter hyperintensities.

COVID-19 — the "cytokine storm" of dysregulated host immune response underlies complications, and IL-6 is one such target. Tocilizumab and sarilumab were studied; a systematic review of observational data suggested tocilizumab reduced complication rate and illness duration.

Proof of principle for anti-cytokine therapy: IL-1beta inhibition with canakinumab (CANTOS) reduced the incidence of age-related diseases in humans.

ZEUS trial — IL-6 inhibition fails in cardiovascular disease (July 2026). ZEUS was a multinational double-blind placebo-controlled trial of 6,376 participants with ASCVD, CKD and hsCRP ≥2 mg/L, randomised to ziltivekimab 15 mg subcutaneously monthly or placebo. Mean age 69.5 years, 65.7% diabetes, 41.3% heart failure, mean eGFR 44.5 mL/min/1.73 m2, median hsCRP 4.5 mg/L, median IL-6 4.9 pg/mL. Although ziltivekimab demonstrated target engagement with expected reductions in free IL-6 and hsCRP, this did not translate into any MACE reduction (HR 0.99; 95% CI 0.88–1.11). Overall adverse event rates were similar, but a higher proportion of ziltivekimab-treated participants had a serious infection. HERMES (heart failure) and ARTEMIS (post-MI) continue. Exam message: this demonstrates biomarker–outcome dissociation. (JAMA Cardiology 2026)

Sarilumab — first biologic approved for polymyalgia rheumatica (2023). On 28 February 2023 the FDA approved sarilumab, an IL-6 receptor antagonist, for adults with PMR in whom glucocorticoids proved inadequate or who cannot tolerate a taper. Approval was based on the phase 3 SAPHYR trial in steroid-resistant active PMR: sarilumab 200 mg every two weeks with a 14-week steroid taper versus placebo with a 52-week taper, achieving sustained remission in 28% versus 10% at 52 weeks (p = 0.0193). Tocilizumab, though beneficial in PMR studies, is not FDA-approved for PMR; it is approved for giant cell arteritis, which overlaps with PMR in about half of cases. This is the first steroid-sparing biologic option for an almost exclusively geriatric disease.

IL-6 blockade in giant cell arteritis. Tocilizumab showed beneficial effects in GCA leading to its approval; a phase 3 trial of sarilumab in GCA was conducted but recruitment difficulties exacerbated by the COVID-19 pandemic led to premature discontinuation by the sponsor. (Arthritis Research & Therapy 2023)

IL-6 in contemporary frailty biomarker panels. IL-6 is no longer used alone. Current work combines IL-6 with GDF-15, FGF-21, sRAGE and neurofilament light to identify frailty in community-dwelling older adults, with GDF-15 emerging as the strongest single predictor of incident frailty, malnutrition and falls.

"Plasma IL-6 rises with normal ageing and correlates inversely with functional ability."

"IL-6 induces hepcidin, which blocks ferroportin, producing the functional iron deficiency of anaemia of chronic disease."