Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases

Abstract

The immune system is the central regulator of tissue homeostasis, ensuring tissue regeneration and protection against both pathogens and the neoformation of cancer cells. Its proper functioning requires homeostatic properties, which are maintained by an adequate balance of myeloid and lymphoid responses. Aging progressively undermines this ability and compromises the correct activation of immune responses, as well as the resolution of the inflammatory response. A subclinical syndrome of "homeostatic frailty" appears as a distinctive trait of the elderly, which predisposes to immune debilitation and chronic low-grade inflammation (inflammaging), causing the uncontrolled development of chronic and degenerative diseases. The innate immune compartment, in particular, undergoes to a sequela of age-dependent functional alterations, encompassing steps of myeloid progenitor differentiation and altered responses to endogenous and exogenous threats. Here, we will review the age-dependent evolution of myeloid populations, as well as their impact on frailty and diseases of the elderly.

Keywords: Age-related disease; Frailty; Immunosenescence; Inflammaging; Myeloid cells.

Fig. 1

Schematic network connecting senescence/immunosenescence, inflammaging, frailty, and age-related diseases. The physiological cellular and tissue senescence, which occurs during aging, contributes to inflammaging through the disruption of tissue barriers. This event increases the release of PAMPs mediated by the entry of pathogens, via the production of SASP factors, and the release of cellular debris (DAMPs and/or GARBage). PAMPs, DAMPs, and GARBage elements are recognized by myeloid cells (neutrophils, macrophages, dendritic cells) via their PRRs, thus enhancing the production of pro-inflammatory mediators (i.e., IL-6, TNFα, IL-1β). These last exacerbate the inflammaging process. In addition, senescence of HSCs leads to their reduced renewal and to a biased differentiation of hematopoietic progenitors toward myelopoiesis, rather than lymphopoiesis. Inflammaging appears increasingly responsible for the onset and progression of the most common diseases in the elderly. Among them, atherosclerosis, obesity, diabetes, neurodegenerative and musculoskeletal (e.g., sarcopenia) diseases, cancer, and infections (e.g., COVID-19) are well characterized for their inflammatory facet and/or etiology. These pathologies meet the definition of age-related disease, also in terms of clinical management among frail elderly subjects. PAMP, pathogen-associated molecular patterns, SASP, senescence-associated secretory phenotype, DAMP, damage-associated molecular patterns, PRR, pattern recognition receptor, HSC, hematopoietic stem cell. For details, see the text