How the aging immune system fuels neurodegeneration: the role of immune cell exhaustion and immunosenescence

Abstract Age-related neurodegenerative diseases (ARNDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are increasingly recognized as disorders involving systemic immune dysfunction in addition to central nervous system pathology. While chronic neuroinflammation is a well-established hallmark of both diseases, emerging evidence suggests that aging and chronic systemic inflammation may ultimately drive immune cell exhaustion and immunosenescence, which may in turn impair immune surveillance and protein clearance, contributing to progressive neurodegeneration. Here, we review clinical and preclinical evidence supporting exhaustion- and senescence-associated phenotypes across peripheral and central immune compartments in AD and PD. We first outline the spectrum of immune activation states and describe how aging and chronic systemic inflammation remodel immune function toward exhausted and senescent states. We then examine evidence linking these processes to disease progression, highlighting mechanisms involving impaired adaptive and innate immune responses, metabolic dysfunction, and neuroimmune crosstalk. Finally, we contrast these findings with observations from cognitively healthy centenarians, whose preserved immune competence suggests that maintenance of immune fitness may promote resilience against neurodegeneration. Collectively, the available evidence supports a conceptual shift from viewing ARNDs solely as diseases of excessive inflammation toward recognizing progressive loss of immunocompetence as a key contributor to pathogenesis, with important implications for the development of therapies that restore, rather than suppress, immune function.