Age-Related Inflammation and its Effects on the Generation of Immune Cells
With age, the immune system falls into a state of ever increasing chronic inflammation, a process known as inflammaging: the immune system is overactive, but nonetheless declines in effectiveness at the same time. Researchers here consider how inflammaging can damage the bone marrow stem cell populations responsible for generating immune cells, possibly the basis for a vicious cycle in which the failures of the immune system feed upon themselves to accelerate age-related damage and dysfunction.
Hematopoiesis is an active, continuous process involving the production and consumption of mature blood cells that constitute the hemato-lymphoid system. All blood cells arise from a small population of hematopoietic stem cells (HSCs) in the bone marrow (BM) that have two unique properties: self-renewing capacity, the ability to generate themselves, and multi-lineage differentiation capacity, the ability to produce all blood cell types. Since, in the steady state, most adult HSCs are in the G0 phase of the cell cycle, i.e., they are quiescent and are estimated to turnover slowly on a monthly time scale, daily hematopoietic production is mainly sustained by highly proliferative downstream hematopoietic progenitor cells (HPCs).
Aging of the hematopoietic system is represented by functional declines in both the adaptive and the innate immune system, an immunosenescence that leads to high susceptibility to infections, low efficacy of vaccinations, and increased vulnerability to the development of autoimmunity and hematologic malignancies. It has been show that (a) B cell production decreases significantly with advancing age, i.e., the naïve B cell pool diminishes, while the memory B cell pool expands. Diversity of the B cell repertoire also decreases in association with lowered antibody affinity and impaired class switching. B cells are prone to produce auto-antibodies increasing the incidence of spontaneous autoimmunity; (b) de novo T cell production also declines with aging partially due to thymic involution. CD8+ T cells undergo oligoclonal expansion and their repertoire is skewed toward previously encountered antigens, as niches for naïve T cells in peripheral lymphoid tissues become occupied by terminally differentiated cells; (c) NK cells show diminished cytotoxicity and cytokine secretion; (d) although myeloid cells increase in number, their functionality is decreased, e.g., neutrophils migrate less in response to stimuli, and macrophages have reduced phagocytic activity and decreased oxidative burst; and (e) erythropoiesis also declines in elderly people causing frequent anemia, while the thrombocytic lineage has not, to date, been reported to be significantly affected by aging.
There are similarities between hematopoietic alterations during inflammation and those that occur with aging. In response to aging and bacterial infection, myelopoiesis becomes dominant over lymphopoiesis in relation to immunosenescence. Most notably, B-lymphopoiesis is impaired due to a decreased level of E47, a transcription factor essential for B cell development, in aged mice. The aging-associated myeloid dominance and/or adipogenesis in BM might be triggered by increased basal levels of pro-inflammatory cytokines even in the absence of infection. Indeed, levels of circulating pro-inflammatory cytokines, such as IL-6, TNF-α, IL-1Rα, and C-reactive protein, are reportedly upregulated in healthy elderly populations. These observations allow us to hypothesize that "inflammaging" represents a subclinical grade of chronic inflammation possibly contributing to the initiation and/or acceleration of hematopoietic aging.
Since numerous inflammatory factors are increased in aged hematopoietic tissues, and inflammation- and aging-associated hematopoietic changes share common cellular and molecular alterations, it is reasonable to speculate that low-grade inflammation might be involved in hematopoietic aging with reduced fitness of both adaptive and innate immune cells. Given that some hematopoietic phenotypes during inflammation and aging arise from functional alterations in HSCs and progenitor cells (HSPCs), it would be worthwhile to elucidate the underlying common mechanisms. Future research could yield meaningful insights into cell-intrinsic changes in HSPC quantity and quality, e.g., how aspects of HSPC population dynamics such as functional heterogeneity and population size change, whether all subsets of HSCs with a distinct lineage output respond equally to inflammatory stimuli or only the minor fraction is responsive, how the self-renewal and differentiation capacities of HSC are altered on a per-cell basis, and molecular changes in cellular signaling, such as alterations in cellular metabolism, transcriptional networks, epigenetic modifications, and genomic instability. It is also essential to understand to what extent inflammaging-associated cell-extrinsic factors influence HSPC biology, including signals derived from the BM niche, tissue damage/repair, infection, obesity, or the microbiome. In addition, the fundamental task that remains is identification of the factors initially triggering the process of hematopoietic inflammaging. Inflammation- or aging-related external stimuli appear to force quiescent HSCs to proliferate and impair their self-renewal and differentiation capacities, as suggested by evidence that HSC cycling in response to chemotherapy administration or hematopoietic stress accelerates the manifestation of aging phenotypes. These data suggest that the central features of HSCs aging might be attributable to accumulation of a proliferative history that is closely associated with perturbed self-renewal and differentiation.
Inflammation and aging have thus far been seen as two independent pathophysiological processes. However, a growing body of evidence has highlighted biological changes in hematopoiesis and HSCs that are common to both inflammation and aging. Thus, it is likely that sustained inflammatory stimuli contribute to hematopoietic aging and possibly leukemogenesis, supporting the inflammaging concept. Since inflammation and aging might both be involved in increased risk for leukemogenesis, eliminating unwanted inflammaging factors is a potential approach to preserving both HSC and immune functions, and thereby preventing a functional decline in hematopoiesis and the emergence of malignant clones. Future investigation is required to better characterize hematopoietic inflammaging processes at the tissue, cellular, and molecular levels.