Membrane-Mediated Inflammageing: TLR۴ and Extracellular Vesicles as a Self-Amplifying Loop in Age-Related Metabolic, Neurodegenerative, and Neoplastic Diseases

The chronic sterile inflammation that accompanies ageing is sustained in part by the progressive accumulation of senescent cells and their associated secretory phenotype (SASP). While much attention has focused on soluble cytokines, recent evidence points to extracellular vesicles (EVs) as equally critical, yet mechanistically less defined, mediators of this process. Concurrently, Toll-like receptor ۴ (TLR۴) has emerged as a principal innate immune sensor whose aberrant activation fuels age-related tissue dysfunction. This review synthesises these observations into a working hypothesis of membrane-mediated inflammageing, wherein EVs released from senescent cells act as membrane-bound inflammatory effectors that may perpetuate a feed-forward loop through TLR۴-dependent signalling. The proposition is that immunogenic cargo such as lipids and damage-associated proteins engages TLR۴ on recipient cells. Nucleic acids within these vesicles, by contrast, are more likely to exert their inflammatory effects through TLR۴-independent routes. This engagement drives NF-κB activation and secondary inflammatory responses that can reinforce senescence itself. The strength of this mechanism, however, appears highly context-dependent. Evidence is most compelling in metabolic disorders such as obesity, where lipid-enriched EVs directly provoke TLR۴-mediated insulin resistance; in neurodegenerative and neoplastic settings, the link remains largely inferential and requires further experimental testing. The inherent duality of senescence is also considered, including its protective roles in tissue repair and tumour suppression, alongside the likely involvement of other pattern-recognition pathways such as NLRP۳ and cGAS-STING that may compensate for or converge with TLR۴ signalling. Therapeutic implications, including senolytic and EV-targeted strategies, are discussed with appropriate caution, given the substantial gaps in in vivo validation and the heterogeneous nature of EV cargo. Rather than offering a settled mechanism, this framework is intended as a conceptually useful lens for interrogating how membrane-mediated intercellular communication contributes to age-related pathology and for identifying where the critical unknowns, particularly the direct demonstration of EV-TLR۴ engagement in living tissues, most urgently lie.

کلیدواژه ها:

Inflammageing ، cellular senescence ، extracellular vesicles ، Toll-like receptor ۴ ، diabetes ، cancer