The decline in immune function with aging, known as immunosenescence, has been implicated in evolutionarily diverse species, but the underlying molecular mechanisms are not understood. During aging in Caenorhabditis elegans , intestinal tissue deterioration and the increased intestinal proliferation of bacteria are observed, but how innate immunity changes during C. elegans aging has not been defined. Here we show that C. elegans exhibits increased susceptibility to bacterial infection with age, and we establish that aging is associated with a decline in the activity of the conserved PMK-1 p38 mitogen-activated protein kinase pathway, which regulates innate immunity in C. elegans . Our data define the phenomenon of innate immunosenescence in C. elegans in terms of the age-dependent dynamics of the PMK-1 innate immune signaling pathway, and they suggest that a cycle of intestinal tissue aging, immunosenescence, and bacterial proliferation leads to death in aging C. elegans . Author Summary Aging is associated with a diminished capacity to resist infection in evolutionarily diverse species including humans, mice, and fruit flies. Few studies have addressed the underlying genetic and molecular basis of this phenomenon. Here we examined immune function during aging in the nematode Caenorhabditis elegans , which we demonstrate exhibits a progressive age-dependent increase in susceptibility to the human pathogen Pseudomonas aeruginosa . Our studies suggest that, during aging in C. elegans , the activity of the PMK-1 p38 mitogen-activated protein kinase pathway, a conserved pathway involved in pathogen defense, sharply declines. We propose a model in which age-related damage to intestinal tissue impairs immune function and therefore promotes infection, which in turn amplifies tissue damage, thus setting in motion a self-perpetuating cycle that gradually erodes host defense.
【초록키워드】 Innate immunity, aging, susceptibility, Genetic, Infection, molecular mechanism, Protein, Deterioration, immunosenescence, pathogen, mice, humans, death, pathway, Bacterial infection, immune function, age, Bacteria, signaling pathway, change, Bacterial, innate immune, Pseudomonas aeruginosa, host defense, MAPK, regulate, Decline, proliferation, protein kinase, leads, Caenorhabditis elegans, mitogen-activated protein kinase, tissue damage, cycle, phenomenon, Author, motion, molecular basis, human pathogen, declines, Defense, mitogen, intestinal tissue, PMK-1, Host, intestinal, defined, examined, conserved, involved, amplify, promote, increase in, implicated, addressed, turn, exhibit, impair, Caenorhabditis, elegan, Caenorhabditis elegan,