Inflammaging is the name given to the decline of the aging immune system into a state of constant, unresolved inflammation. Inflammatory signaling in the aged body arises in part because of an increased burden of senescent cells. These cells secrete a potent mix of pro-inflammatory signals, disrupting tissue function. This is one of the reasons why removal of lingering senescent cells produces such rapid rejuvenation, as these errant cells actively maintain a portion of the degradation of function and environment in aged tissues. Beyond senescent cells, the broad molecular damage and cellular dysfunction of aging produces circulating DNA debris, and similar outcomes, that are recognized by the innate immune system as indicative of infection or injury, leading to inflammatory behavior.
Beyond the removal of senescent cells, current approaches to suppression of inflammation, largely developed as treatments for autoimmune conditions, are crude and have significant long-term side-effects. Because they rely on suppression of specific signal molecules or their recognition, they inhibit not only excessive and inappropriate unresolved inflammation, but also the necessary short-term inflammation that is needed for regeneration, defense against pathogens, and elimination of damaged and potentially cancerous cells. More sophisticated approaches are needed, but given the overlap in signals and signal transduction between desirable and undesirable inflammation, it is unclear that anything will work really well other than removing the triggers that cause unresolved inflammation, as illustrated by the dramatic benefits observed in animal models following the removal of senescent cells.
Under physiological conditions, inflammation protects against external pathogens and intrinsic degenerative processes. Nevertheless, dysregulation of the immune system, as seen during aging, triggers a persistent state of low-grade inflammation, which has been recognized as an important driver for the development of age-related diseases. This phenomenon, referred to as inflamm-aging, has been linked to a higher risk of cardiovascular (CV) events and has been increasingly recognized as a determinant of CV outcomes. Since CV disorders are the leading cause of death in industrialized countries, improving the treatment of these diseases implies prolonging the average lifespan. Furthermore, acute CV events, particularly stroke, are associated with long-term disability, inevitably resulting in a worsening of quality of life. Long-term disability, dependence on daily living, and reduced quality of life are the most relevant backlashes of aging; thus, addressing those aspects is pivotal in promoting healthy aging. Finally, inflamm-aging is also involved in other age-related disorders, like sarcopenia, cancer, and neurocognitive impairment, all having a heavy impact on lifespan and quality of life of elderly people. Therefore, targeting inflamm-aging may prolong lifespan and promote successful aging by acting on multiple levels.
Inflamm-aging was firstly theorized in the 2000s as a phenomenon involved in the age-related deterioration of physiological processes. Defined as a chronic low-grade sterile inflammation, inflamm-aging was suggested to result from persistent antigenic load and stress. Since then, this concept has been intensively studied to identify its molecular mechanisms and how it contributes to age-dependent diseases. Even though the exact mechanisms of inflamm-aging are not yet fully elucidated, some pathologic features have been identified.
Inflamm-aging develops due to senescent cell accumulation, altered function of immune cells, and increased inflammasome activity due to incremented levels of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). To date, wide experimental evidence validated the importance of inflamm-aging in the pathophysiology of CV diseases and the potential of targeting inflammation as pharmacological therapy. Nevertheless, none of the tested anti-inflammatory agents has yet been implemented in everyday clinical cardiology; thus, more work remains to be done to optimize these promising interventions. Ultimately, future studies are encouraged to discover further potential therapeutic targets involved in the complex mechanism of inflamm-aging. Along with other treatment strategies against different age-related alterations in molecular pathways, inflamm-aging targeted approaches will intently endure the burden of CV disease in the growing aging population.