An aging-related immune landscape in the hematopoietic immune system

Abstract

Background Aging is a holistic change that has a major impact on the immune system, and immunosenescence contributes to the overall progression of aging. The bone marrow is the most important hematopoietic immune organ, while the spleen, as the most important extramedullary hematopoietic immune organ, maintains homeostasis of the human hematopoietic immune system (HIS) in cooperation with the bone marrow. However, the overall changes in the HIS during aging have not been described. Here, we describe a hematopoietic immune map of the spleen and bone marrow of young and old mice using single-cell sequencing and flow cytometry techniques. Results We observed extensive, complex changes in the HIS during aging. Compared with young mice, the immune cells of aged mice showed a marked tendency toward myeloid differentiation, with the neutrophil population accounting for a significant proportion of this response. In this change, hypoxia-inducible factor 1-alpha (Hif1α) was significantly overexpressed, and this enhanced the immune efficacy and inflammatory response of neutrophils. Our research revealed that during the aging process, hematopoietic stem cells undergo significant changes in function and composition, and their polymorphism and differentiation abilities are downregulated. Moreover, we found that the highly responsive CD62L + HSCs were obviously downregulated in aging, suggesting that they may play an important role in the aging process. Conclusions Overall, aging extensively alters the cellular composition and function of the HIS. These findings could potentially give high-dimensional insights and enable more accurate functional and developmental analyses as well as immune monitoring in HIS aging.

Aging brain: exploring the interplay between bone marrow aging, immunosenescence, and neuroinflammation

“…With advancing age, the bone marrow microenvironment undergoes remarkable alterations that profoundly influence hematopoiesis and immune cell function ( Figure 1A ). These changes encompass a spectrum of cellular and molecular modifications within the bone marrow niche, including shifts in stromal cell composition, increased adiposity, and dysregulated signaling pathways ( 4 , 34 ). Age-related alterations in stromal cell populations, such as mesenchymal stromal cells (MSCs) and osteoblasts, modulation of fibroblastic reticular cell populations, changes in the extracellular matrix composition and organization disrupt the supportive microenvironment necessary for HSC maintenance and differentiation.…”

“…Hematopoietic stem cell dysfunction represents a critical component of bone marrow aging, significantly impacting immune cell production and overall hematopoietic activity ( 4 , 12 , 34 , 38 ). As individuals age, HSCs undergo alterations in their self-renewal capacity and differentiation potential, leading to a decline in the generation of diverse immune cell lineages ( Figure 1A ).…”

“…In general, bone marrow aging exerts a significant impact on the aging of the adaptive immune system, leading to alterations in T- and B- cell development, function, and homeostasis ( 34 ). Immunosenescence ( Figure 1B ) is characterized by an accumulation of memory T cells, particularly effector memory T cells (TEM) and terminally differentiated memory T cells (TEMRA).…”

“…Age-related changes in the bone marrow microenvironment can skew the differentiation of precursor cells towards a pro-inflammatory phenotype, contributing to chronic inflammation, tissue damage, and impaired immune responses ( 11 , 33 , 36 ). The development and function of natural killer (NK) cells are also compromised, leading to alterations in their cytotoxic activity and cytokine production as well as in their ability to eliminate infected or transformed cells and to contribute to immune surveillance ( 4 , 13 , 34 , 60 ). Aged bone marrow microenvironment can lead to alterations in granulocyte production, differentiation, and migration, affecting their ability to respond to pathogens and contribute to inflammatory processes ( 4 , 13 ).…”

“…Age-related alterations in stromal cell populations, such as mesenchymal stromal cells (MSCs) and osteoblasts, modulation of fibroblastic reticular cell populations, changes in the extracellular matrix composition and organization disrupt the supportive microenvironment necessary for HSC maintenance and differentiation. Moreover, an accumulation of adipocytes within the bone marrow, known as adipogenesis, displaces hematopoietic and stromal cells, leading to diminished hematopoietic activity and impaired immune cell production (11,13,(33)(34)(35). Dysregulated signaling pathways, including increased production of pro-inflammatory cytokines and altered expression of niche factors, further contribute to the disruption of hematopoiesis and immune cell homeostasis in the aging bone marrow microenvironment.…”