Immunosenescence and the Geriatric Giants: Molecular Insights into Aging and Healthspan

Aging is associated with complex immune dysfunction that contributes to the onset and progression of the "geriatric giants", including frailty, sarcopenia, cognitive decline, falls, and incontinence. Central to these conditions is immunosenescence, marked by thymic involution, the loss of naïve T cells, T-cell exhaustion, impaired B-cell class switch recombination, and increased autoreactivity. Concurrently, innate immunity deteriorates due to macrophage, neutrophil, and NK cell dysfunction, while chronic low-grade inflammation-or "inflammaging"-amplifies systemic decline. Key molecular pathways such as NF-κB, mTOR, and the NLRP3 inflammasome mediate immune aging, interacting with oxidative stress, mitochondrial dysfunction, and epigenetic modifications. These processes not only impair infection control and vaccine responsiveness but also promote tissue degeneration and multimorbidity. This review explores emerging interventions-ranging from senolytics and immunonutrition to microbiome-targeted therapies and exercise-that may restore immune homeostasis and extend healthspan. Despite advances, challenges remain in translating immunological insights into clinical strategies tailored to older adults. Standardization in microbiome trials and safety optimization in senolytic therapies are critical next steps. Integrating geroscience into clinical care could help to mitigate the burden of aging-related diseases by targeting fundamental drivers of immune dysfunction.