The aging of the immune system is of great importance to aging more generally, likely a major contributing factor in the onset and progression of age-related dysfunction and disease. Researchers tend to draw a distinction between two forms of immune aging: (a) loss of the capacity of the immune system to destroy pathogens and errant cells, known as immunosenescence, and (b) overactivation of the immune system in the form of constant, unresolved inflammatory signaling in the absence of pathogens, known as inflammaging. Both of these forms of immune aging are serious issues.
In today’s open access review paper, the authors start with immunosenescence and inflammaging before moving on to the topic of immune resilience, which we might define as an older individual exhibiting lesser degrees of both immunosenescence and inflammation. The paper points out that despite a general acceptance of immune aging as consisting of some combination of immunosenescence and inflammaging, there is little unity when it comes to how to define and assess immune resilience. Lack of a consensus on measurement is a hindrance when it comes to developing approaches to improve immune resilience by reducing immunosenescence and inflammaging.
The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience
As we age, our immune system’s ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases.
Chronic stress and accumulated damage, whether occurring naturally or from acute and chronic infections, can lead to persistent inflammation, a precursor to altered cellular states known as the hallmarks of aging. As we age, our immune systems can aberrantly produce persistent low-grade, chronic, and systemic inflammation in non-pathogenic or “sterile” conditions referred to as “inflammaging”. Aged individuals frequently exhibit this pro-inflammatory state characterized by elevated levels of pro-inflammatory markers within cells and tissues. Inflammaging can affect both the innate and adaptive immune responses and multiple molecular mechanisms can drive this inflammation, including cellular senescence, mitochondrial dysfunction, defective autophagy, inflammasome activation, DNA damage, and changes in the microbiome. Inflammaging is theorized to contribute to the development of chronic age-related conditions such as cancer, cardiovascular disease, diabetes, frailty, neurodegeneration, and osteoarthritis.
Immune resilience (IR) is a critical component of fully understanding immunosenescence. Immune resilience refers to the ability of the immune system to maintain or quickly restore its functions, thus promoting disease resistance and controlling inflammation during infectious diseases and other inflammatory stressors. Individuals with immune resilience are likely to have high immunocompetence and functionality, along with minimal background inflammation, which can potentially help buffer against the immune and systemic effects of harmful stimuli. However, reliably capturing this remains elusive. Much of the knowledge in this area is derived from disparate animal studies that lack standardized models, cross-sectional or short-term longitudinal analyses, and have limited endpoints. While previous studies suggest that immune variation is largely driven by non-heritable factors, investigating heritable influences on immunity is still worthwhile and presents an opportunity to identify novel therapeutic targets.
Current studies on immune resilience have been largely limited to basic immunophenotyping of common immune populations, cytokine analyses, or transcriptomic studies on leukocytes. Although cytokine analysis can provide information on the inflammatory background and immunophenotyping can describe population shifts, additional functional studies are needed to properly assess immunocompetence and how it changes in response to age, immune challenges, or other forms of stress. Furthermore, these endpoints need to be accessible, practical, and cost-effective for widespread clinical deployment. These steps are critical for identifying and benchmarking biomarkers or surrogate endpoints for immune resilience that can: 1) be translated back to pre-clinical animal models to generate standardized models with translational potential, and 2) be used to more reliably assess interventions that promote immune resilience and allow for comparisons between them.
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