Cold‐inflammaging: When a state of homeostatic‐imbalance associated with aging precedes the low‐grade pro‐inflammatory‐state (inflammaging): Meaning, evolution, inflammaging phenotypes.

The age‐related pro‐inflammatory state, discovered and called 'inflammaging' by Franceschi et al. (2000) plays an important role in the pathogenesis of age‐related chronic diseases. A substantial body of data established that inflammaging is accompanied by a '2‐fold to 4‐fold' increase in plasma levels of pro‐inflammatory mediators in healthy elderly people, when compared to the healthy adult population. This review focuses on the pre‐inflammaging phase, here we reported as 'cold‐inflammaging', a state where plasma levels of cytokines are slightly increased, but below the lower limit of 2‐fold increase established for inflammaging. Slightly altered cytokine levels by innate immunity are known to be associated with homeostasis imbalances, this functional pleiotropy of cytokines as signal transducers, have a physiological counterpart, representing an adaptive process aimed at restoring (or achieving a new) homeostatic stability. If a dyshomeostatic state persists, the cytokine response by innate immunity increases and becomes a driver of inflammaging. A scenario where cytokines are characterised as major players in homeostasis imbalances at the beginning (cold‐inflammaging) and then in chronic low‐grade pro‐inflammatory‐state (inflammaging). Other important drivers of inflammaging are cellular senescence with its senescence‐associated secretory phenotype, the altered gut microbiota, and the age‐related dysregulation in the production of endogenous molecular waste (Garb‐aging). The main purpose of this review being to thoroughly investigate each step of the pathway from cold‐inflammaging to overt‐inflammaging, because aging, cold‐inflammaging, overt‐inflammaging and the pathogenesis of age‐related diseases have been shown to share some established basic pillars of geroscience that largely converge on inflammaging. [ABSTRACT FROM AUTHOR]