The article examines the close relationship between multimorbidity, defined as the coexistence of multiple chronic diseases, and immunosenescence, the gradual decline of immune function with ageing. Rather than being a passive outcome of ageing, immunosenescence is presented as a central driver of multimorbidity. As immune regulation weakens, the body enters a state of persistent, low-grade inflammation known as inflammatory senescence. This chronic inflammatory environment disrupts the normal functioning of multiple organs, increasing vulnerability to a wide range of chronic conditions. In parallel, diseases such as type 2 diabetes and cardiovascular disorders can further accelerate immune ageing. These reciprocal effects create a positive feedback loop in which immune dysfunction and disease progression reinforce one another, forming a complex pathological network that poses significant challenges for prevention and treatment in clinical practice.
To address these challenges, the article draws on evidence from studies of long-lived individuals, particularly centenarians. Despite their advanced age, centenarians often experience a delayed onset of age-related diseases or avoid them altogether. The article proposes that these individuals can serve as natural models of immune homeostasis, offering valuable insights into how immune balance can be maintained over a long lifespan. Compared with individuals suffering from multimorbidity, centenarians tend to preserve immune stability and functional adaptability, suggesting that their immune systems age differently rather than simply declining.
The immune characteristics of centenarians are described across three key domains. First, they maintain a balanced regulation of inflammatory mediators, limiting harmful chronic inflammation while retaining effective immune responses. Second, their immune systems undergo adaptive remodelling of immune cell populations, which supports sustained immune competence rather than uniform deterioration. Third, centenarians often exhibit a distinct and relatively stable intestinal microbiota, which plays a vital role in regulating immunity and controlling inflammation. Together, these features reflect a state of immune equilibrium that may protect against the accumulation of multiple chronic diseases.
Building on these observations, the article introduces Immune Microenvironment Enhancement Therapy (IMET) as a novel conceptual approach to managing multimorbidity. Unlike traditional disease-centred models that target individual conditions separately, IMET focuses on improving the overall immune microenvironment. This approach relies on classifying patients according to their immunophenotypic profiles, including abnormal inflammatory signalling, immune cell dysfunction, gut microbiota imbalance, or complex immune dysregulation. Interventions are then tailored accordingly and may include lifestyle modification, pharmacological treatments such as metformin, immune-based therapies such as CAR-T cells, or stem cell transplantation. The aim is to restore immune balance in a comprehensive and personalised manner.
The article also highlights several limitations in current research. There is a lack of systematic, quantitative comparisons between the immune profiles of centenarians and individuals with multimorbidity, as well as insufficient causal evidence linking immune alterations to disease progression. Population and regional differences may further limit generalisability. Future studies should therefore use multi-omics approaches to characterise immune features in greater depth, identify key regulatory mediators, and clarify underlying molecular mechanisms. At the same time, parallel efforts are needed to address clinical and policy barriers to implementing IMET in practice.
More information: Xiaolin Ni et al, Centenarians: a model of immune resilience against multimorbidity, Life Medicine. DOI: 10.1093/lifemedi/lnaf033
Journal information: Life Medicine Provided by Higher Education Press
