Pattern recognition receptors and aging

Abstract

Pattern recognition receptors (PRRs), such as the toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors (NLRs), and the more recently discovered cytosolic RNA- and DNA-sensing receptors, are a crucial element of the innate immune system owing to their function of enabling immune cells to detect macromolecules of foreign and potentially harmful origin, such as those of infectious agents, and instructing appropriate protective inflammatory and adaptive immune responses. However, PRRs and their signaling components are expressed on not only innate immune cells but various other immune and structural cells of the body including endothelial, epithelial, muscle, and stromal cells, as well as fibroblasts, adipocytes, and cells of the nervous system, and are increasingly being shown to play an active and diverse role in the regulation of cellular senescence and tissue homeostasis. For instance, PRRs maintain balanced immunity towards nonpathogenic commensals at host-environment interfaces such as the gut and skin, detect danger signals released during cell stress or injury, and interact with physiological processes such as autophagy, DNA repair, and cellular apoptosis. The regulation of many of these processes and PRR families is altered in the course of ageing, and the mechanisms underlying this dysregulation are discussed in this chapter. We also review the extensive evidence from gene association or functional studies indicating that loss or gain of PRR expression or activity is pertinent to the increased susceptibility to infection and poor responsiveness to vaccination of aged individuals and, furthermore, is implicated in numerous age-related diseases such as metabolic syndrome, cardiovascular and neurodegenerative diseases, and cancer. The hyperactivation of PRR pathways, to which both infectious agents and endogenous sources of ligands have been shown to contribute, may promote a state of persistent low-grade inflammation in elderly individuals, referred to as inflammageing, which in turn may also facilitate the emergence of chronic age-related diseases. Most notably, deficiency in TLR activity may be responsible for the impaired immunity to infection observed in ageing, whereas hyperactivation of TLRs and inflammasomes has been frequently associated with chronic age-related diseases, suggesting that these PRR families may be particularly amenable to therapies aimed at enhancing immunity in the elderly or treating age-related disorders.