Modulation of Toll-like Receptors with Natural Compounds: A Therapeutic Avenue Against Inflammaging?

Chronic low-grade inflammation, or “inflammaging,” is a defining feature of aging and a key driver of functional decline. Among innate immune sensors, Toll-like receptors (TLRs) are central mediators linking cellular stress to sterile inflammation, yet their modulation in physiological aging remains largely overlooked. This review bridges that gap by integrating molecular and clinical evidence on age-associated TLR remodeling and summarizing preclinical data on natural compounds that suppress TLR signaling. Across diverse inflammatory models, phytochemicals such as curcumin, quercetin, resveratrol, baicalin, and glycyrrhizin consistently downregulate Toll-like receptor 2- (TLR2-), Toll-like receptor 4- (TLR4-), and Toll-like receptor 9- (TLR9-) dependent myeloid differentiation primary response 88 (MyD88)/ nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/ mitogen-activated protein kinase (MAPK) pathways, lowering interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF-α) while enhancing IL-10. These mechanisms mirror the molecular signature of inflammaging, supporting TLRs as actionable targets for restoring immune balance. Collectively, the evidence positions natural TLR modulators as a promising, yet untapped, avenue for promoting healthy aging and extending healthspan.