# Toll-like receptors (TLRs)

Toll-like receptors (TLRs) are ten receptors, on the cell surface and inside endosomes, that form a primary sensing layer of your innate immunity. The surface TLRs (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10) detect bacterial parts: lipoproteins, lipopolysaccharide, and flagellin. (TLR6 pairs with TLR2 to sense diacylated lipopeptides.) The endosomal TLRs (TLR3, TLR7, TLR8, TLR9) recognize microbial nucleic acids. Each TLR has a leucine-rich outer domain and a cytoplasmic 'TIR' domain. The TIR domain recruits MyD88 or TRIF, which switch on NF-κB, IRF3/7, and MAP kinases. That drives output of TNF-α, IL-1β, IL-6, and type I interferons. TLRs do not just sense germs (PAMPs). They also respond to your own damage signals (DAMPs), like HMGB1, oxidized lipids, heat-shock proteins, and misplaced self-DNA, released by stressed or dying cells. This sterile, DAMP-driven activation is central to inflammaging: the chronic, low-grade inflammation tied to heart disease, neurodegeneration, and higher all-cause death in older adults. TLR2 directly governs the SASP. Hari et al. (2019, Science Advances) showed TLR2 jumps during oncogene-driven senescence, and that knocking it down strongly cut IL-1β, IL-6, IL-8, and CCL20, affecting over 1,000 downstream genes. TLR4 expression rises in aged innate immune cells. And extracellular HSP70/HSP90 acts as a self-made TLR4 trigger, sustaining NF-κB even without infection. A miR-146a feedback loop normally restrains TLR/NF-κB output. Olivieri et al. (2013) showed that, in aged macrophages, this brake fails. Human intervention trial evidence is absent as of 2026.

## Sources

- Akira S, Uematsu S, Takeuchi O. (2006). Pathogen recognition and innate immunity. Cell. https://doi.org/10.1016/j.cell.2006.02.015
- Olivieri F, Rippo MR, Prattichizzo F, Babini L, Graciotti L, Recchioni R, Procopio AD. (2013). Toll like receptor signaling in 'inflammaging': microRNA as new players. Immunity & Ageing. https://doi.org/10.1186/1742-4933-10-11
- Hari P, Millar FR, Tarrats N, Birch J, Quintanilla A, Rink CJ, Fernández-Duran I, Muir M, Finch AJ, Brunton VG, Passos JF, Morton JP, Boulter L, Acosta JC. (2019). The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Science Advances. https://doi.org/10.1126/sciadv.aaw0254
- Kim HJ, Kim H, Lee JH, Hwangbo C. (2023). Toll-like receptor 4 (TLR4): new insight immune and aging. Immunity & Ageing. https://doi.org/10.1186/s12979-023-00383-3

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_Canonical: https://longevity-switzerland.com/en/glossary/toll-like-receptors · Part of Longevity Cities · Updated 2026-06-22_