Inflammaging

During ageing, a chronic, sterile, low-grade inflammation called inflammaging develops, which contributes to the pathogenesis of age-related diseases. ^[1] Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging that occurs despite the absence of overt stimuli such as bacterial or microbial invasion, distinguishing it from classical inflammation activated in response to such stimuli. ^[2] The inflammaging concept was introduced in 2000 by Prof. Franceschi as an evolutionary conceptualization of the immune changes in response to a lifelong stress. ^[3]

A variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self), and nutrients and gut microbiota (quasi-self), which are sensed by a limited number of receptors that activate innate immune responses. ^[1] Factors secreted by senescent cells, known as the senescence-associated secretory phenotype (SASP), promote chronic inflammation and can induce senescence in normal cells, while chronic inflammation in turn accelerates the senescence of immune cells, creating a vicious cycle of inflammation and senescence. ^[4] The chronic inflammation of inflammaging is underpinned mechanistically by persistent activation of the immune system, with a central role for NF-κB. ^[5]

The low-grade chronic inflammation during aging without overt infection, defined as inflammaging, is associated with increased morbidity and mortality in the aging population. ^[6] Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions such as cardiovascular diseases, neurodegeneration, cancer, and frailty. ^[6] Like aging, inflammaging is associated with increased risk of many age-related pathologies and disabilities, as well as frailty and death, and may be viewed both as a biomarker of the failure of resilience mechanisms and as a causal factor in the rising burden of disease with aging. ^[5]

Non-pharmacological intervention strategies targeting inflammaging, including diet, nutraceutical supplements, phytochemicals, physical activity and microbiome-based therapies, are being explored to restore health in older adults, alongside pharmacological approaches such as caloric restriction mimetics, p38 MAPK inhibitors, and senolytics. ^[7] Healthy diets including the Mediterranean diet are associated with lower concentrations of inflammatory mediators such as C-reactive protein and Tumor Necrosis Factor-α that are hallmarks of inflammaging. ^[8] The fact that inflammation can be reduced through non-pharmacological interventions such as diet and exercise suggests that a life course approach may be a successful strategy to increase healthspan with few adverse consequences. ^[5]