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. We seek to understand the causes of these age-related and deleterious alterations in immune responsiveness. Our recent studies have highlighted the remarkable and profound inflammatory and immunological consequences of the clearance of dead cells accomplished by macrophages and other phagocytic cells. The process of specific apoptotic cell recognition represents a ubiquitous and unconventional innate immunity that discriminates effete from viable cells and that potently modulates inflammation. 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 responding cell, and is exerted upon binding, independent of subsequent engulfment. Our new data demonstrate a striking aging-associated decline in this innate immune responsiveness. Significantly, this aging-associated effect reflects a quantitative, and not an absolute, alteration in apoptotic modulation. We hypothesize that the aging-associated diminution in immune modulation exerted by apoptotic cells may underlie and exacerbate the paradoxical and pathological alterations of immunosenescence. The work outlined in this proposal focuses on the mechanistic characterization of the aging-associated alterations in innate apoptotic recognition and response. We will evaluate directly whether the abilities of macrophages and other professional and non-professional phagocytes to interact with and engulf apoptotic cells and consequently to signal and modulate their inflammatory responses are altered in an aging-associated manner, employing a variety of functional molecular criteria reflective of this specific response pathway. 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. PUBLIC HEALTH RELEVANCE: Cells die normally throughout the life of an organism, and those dead ("apoptotic") cells are recognized by phagocytes and cleared. We find that dead cells exert potent anti-inflammatory and other effects on the phagocytes that recognize them, exerted through a characteristic repertoire of signaling events. We also find that responsiveness to dead cells is diminished with increasing age, and we hypothesize that this may be casually linked to the pathologies that arise as a consequence of aging-associated immune dysregulation ("immunosenescence"). We will study the regulatory mechanism by which dead cells exert their effects, and examine the molecular nature of aging-associated defects in this response pathway. These studies will reveal new aspects of inflammatory regulation. A deeper understanding of the inflammatory (and immune) modulation exerted physiologically by apoptotic cells and of the molecular events involved may reveal new targets for inflammatory control, with great potential for intervention in cases of pathological inflammation, including inflammatory responses that underlie and exacerbate immunosenescence.