Inflammatory mechanism of aging

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Inflammatory mechanism of aging

Inflamm-aging, defined as the chronic low-grade inflammation typical of ageing, seems to be the common biological factor responsible for the decline and the onset of disease in the elderly. The major age-related diseases share a common inflammatory pathogenesis, giving rise to the so-called ‘diseasome of inflamm-aging’. Inflamm-aging is a multifactorial and systemic process, characterized by complex interactions of a plethora of molecular mediators, as exemplified by the nuclear factor (NF)-kB interactome. Concomitantly with the beneficial tumor suppression and tissue repair effects, senescent cells, accumulating with age, can determine the persistence of inflamm-aging, thus contributing to cancer growth.

Inflamm-aging refers to a low-grade pro-inflammatory phenotype, which accompanies aging in mammals. The aging process is associated with a decline in autophagic capacity, which impairs cellular housekeeping, leading to protein aggregation and accumulation of dysfunctional mitochondria, which provoke reactive oxygen species (ROS) production, and oxidative stress. The presence of a pro-inflammatory phenotype in aged mammals is evident by: i) increased expression of genes linked to inflammation and immune responses in the tissues of old humans and rodents; ii) higher level of cytokines in serum, e.g. IL-6 and TNF-α; iii) activation of NF-κB signaling which is the master regulator of inflammatory responses. There are tissue specific differences in the production of age-related inflammatory factors as well as in the onset and level of pathological changes.

The aging process jeopardizes the maintenance of cellular homeostasis leading to the activation of a variety of host defence systems. Inflammasomes are intracellular multiprotein sensors, which can recognize a large set of danger signals, induced by either pathogens or cellular stress, and once activated, they subsequently stimulate inflammatory responses. CASP-1 is the common effector molecule in inflammasomes, which cleaves the inactive precursors of two proinflammatory cytokines, i.e. IL-1β and IL-18, into their mature forms, which are then secreted from cells. Infections and tissue injuries can trigger an inflammatory reaction as a physiological host defence mechanism but in addition, cellular stress can also alert the immune system and induce adaptive responses. Macroautophagy, segregating organelles like mitochondria, is the major type of autophagy associated with innate immunity. In addition to the cleansing function, autophagy can regulate cellular energy balance, e.g. during starvation it can trigger energy production from its own components. Autophagy may also be involved in lipid metabolism by sequestering lipid droplets. In conjunction with this increased knowledge on inflammasomes, the role of autophagy in the regulation of inflammatory responses has started to emerge.