Immunosenescence is characterized by paradoxical alterations in adaptive and innate immune responsiveness. Striking increases in the inflammatory status of many individuals with age - even in the absence of overt infection - and the diminished ability to modulate those responses have been implicated causally in the pathogenesis of a variety of aging-associated disorders, and may be involved centrally in all aspects of aging-associated immune dysfunction. In this context, potential changes with age in the anti-inflammatory effects of apoptotic cells have not been considered previously. Our recent studies have demonstrated the profound ability of apoptotic cells to modulate the pro-inflammatory responses of macrophages with which they interact. The modulatory activity of the apoptotic corpse, representing a gain-of-function acquired during the physiological cell death process, is manifest as an immediate-early inhibition of pro-inflammatory cytokine gene transcription within the engulfing macrophage, and is exerted upon binding to the macrophage, independent of subsequent engulfment. Recognition and inflammatory modulation represent key elements of an innate immune response, independent of Toll-like receptor signaling, that discriminates live from effete cells. We hypothesize that the extent of immune modulation exerted by apoptotic cells may be altered in an aging-associated manner, and that these changes underlie and exacerbate the paradoxical and pathological alterations of immunosenescence. The exploratory experiments proposed in this application will test this novel hypothesis by examining, as a function of animal age, the interactions in vivo of macrophages with apoptotic cells, as well as the consequences of those interactions with respect to a variety of innate macrophage immune responses, employing rigorous quantitative approaches. We will evaluate directly whether the abilities of macrophages to interact with and engulf apoptotic cells and consequently to modulate their inflammatory and other immune responses are altered in an aging-associated manner. We will test as well the ability of exogenous apoptotic modulators to attenuate inflammatory responses in vivo as a function of animal age. A fuller understanding of the process of immune modulation exerted physiologically by apoptotic cells has enormous significance for efforts to intervene in cases of deleterious and pathological inflammatory responses that underlie and exacerbate immunosenescence. ? ? ?
