This article provides a systematic analysis of the interplay between multimorbidity and immunosenescence, highlighting immunosenescence as a critical risk factor that contributes to the development of multimorbidity by impairing multiple organ functions through the mediation of chronic low-grade inflammation, termed "inflammatory senescence." Concurrently, certain diseases, including type 2 diabetes and cardiovascular conditions, may accelerate immunosenescence, thereby establishing a positive feedback loop and forming a complex pathological network that presents significant challenges for clinical prevention and treatment.
Drawing on research involving long-lived individuals, particularly centenarians, the article proposes utilizing these populations as natural models of immune homeostasis to investigate novel intervention strategies for multimorbidity. Centenarians typically exhibit delayed onset or avoidance of aging-related diseases and possess immune systems characterized by distinctive homeostatic regulatory capabilities. The author systematically delineates the immune homeostasis features of centenarians across three domains: the equilibrium of inflammatory mediators, immune cell remodeling, and the composition of the intestinal microbiota. Building upon this foundation, the article introduces the innovative concept of Immune Microenvironment Enhancement Therapy (IMET). This approach transcends traditional disease-centric diagnostic and therapeutic paradigms by implementing individualized interventions based on patients’ immunophenotypic classifications—such as aberrant inflammatory mediator profiles, immune cell abnormalities, intestinal flora imbalances, and complex immune dysregulation. Intervention modalities encompass lifestyle modifications, pharmacological treatments (e.g., metformin), immune cell therapies (e.g., CAR-T), and stem cell transplantation, aiming to comprehensively optimize the body's immune microenvironment.
The article also acknowledges current research limitations, including the absence of systematic quantitative comparisons of immune characteristics between centenarians and individuals with multimorbidity, insufficient causal evidence linking immune parameters to disease progression, and potential confounding effects of population and regional variability on the generalizability of findings. Consequently, future investigations should employ multi-omics approaches to quantitatively characterize the immune profiles of centenarians, identify key inflammatory mediators, and elucidate the molecular mechanisms underlying their immune responses to facilitate the effective clinical translation of IMET. Furthermore, at the clinical implementation level, several challenges must be addressed, such as establishing specialized outpatient clinics, reforming medical insurance reimbursement systems, fostering interdisciplinary collaboration, and securing policy support.
DOI: 10.1093/lifemedi/lnaf033.