Immunosenescence in older adults with sepsis: immune dysregulation, recovery trajectories, and translational therapeutic perspectives—a narrative review

Background and Objective: Older adults bear a disproportionate burden of sepsis, yet chronological age does not capture the biological heterogeneity that shapes immune dysfunction and recovery. This structured narrative review examines how immunosenescence and inflammaging influence immune reserve and resilience in older adults with sepsis. It also evaluates how these concepts may inform longitudinal phenotyping and precision therapeutic research. Methods: PubMed and the Web of Science Core Collection were searched on 27 July 2026 for literature published from 1 January 2001. Reference lists and citing articles were also examined. Direct studies in older adults were prioritized, while general adult, healthy-aging, animal and ex vivo evidence was retained when needed for mechanistic or translational context. Key Content and Findings: Age-associated hematopoietic remodeling, reduced adaptive diversity, impaired neutrophil targeting, defective antigen presentation, lymphocyte loss, metabolic inflexibility, and endothelial injury reshape septic immunity. Rather than following a fixed transition from hyperinflammation to immune suppression, older adults may exhibit heterogeneous recovery patterns shaped by pre-infection reserve, inflammatory burden, and resilience. Persistent failure to recover may be associated with secondary infection, chronic critical illness, functional decline, and loss of healthspan. Biomarkers, omics signatures, and candidate immune endotypes are most informative when tied to a defined clinical purpose, serial sampling and staged validation. Most immunomodulatory and geroscience interventions remain investigational and require phenotype-enriched trials with explicit timing, reversibility and safety criteria. Conclusions: Immunosenescence in sepsis reflects a dynamic interaction between baseline reserve, inflammatory burden, acute perturbation and recovery capacity. Progress toward precision therapy will require geriatric-aware longitudinal cohorts, harmonized functional assays, validated trajectories and biomarker-enriched trials that measure secondary infection, cognition, function, independence and survival.