The immune system declines with age for a range of reasons. The thymus atrophies, reducing the supply of new T cells; persistent infection by cytomegalovirus causes cells to become uselessly specialized rather than ready to tackle new threats; and the hematopoietic stem cells responsible for generating immune cells become damaged, inactive, and dysfunctional. One of these forms of dysfunction is that hematopoietic stem cells begin to generate too many myeloid cells and too few lymphoid cells, the so-called myeloid skew.
The cause of this skewing in cell production is much debated, but researchers have found that chronic inflammation plays a role. Naturally, nowadays whenever inflammation appears to be an important aspect of any age-related dysfunction, attention turns towards senescent cells. Lingering senescent cells accumulate with age in all tissues, and secrete a potent mix of signals that rouses the immune system into an inflammatory state. It seems likely that they are an important part of the problem when it comes to the myloid skew in the hematopoietic stem cell population.
Why do senescent cells accumulate with age? Cells become senescent in great numbers throughout life, but only later do they linger to a significant degree. Near all are destroyed, either by their own programmed cell death processes, or by the immune system, called into action by the inflammatory signaling of the senescent cells. One reason for a greater number of lingering senescent cells in later life is that the immune system declines and falters in destroying errant cells. Thus, like many issues in aging, the relationship between cellular senescence and immune decline is a circular one; these two processes start off very slowly, but feed one other and accelerate as time passes and damage mounts.
Dysfunction of the human hematopoietic system with age includes diminished immune response, marrow failure, and clonal selection. Aging is also associated with a general increase in tissue inflammation that remains largely unexplained. The mechanisms driving these characteristics of aged hematopoiesis have, to date, primarily been attributed to intrinsic hematopoietic stem cell (HSC) changes. With age, in both humans and mice, the phenotypic long-term HSC (LT-HSC) pool is expanded and globally LT-HSCs differentiate preferentially towards the myeloid lineage.
Multipotent HSCs with platelet bias were recently identified by a number of investigators describing their increased expression of von Willebrand Factor (vWF) and of the Integrin αIIb (CD41). Recent data demonstrate that aged murine HSCs also have increased cell-surface expression of CD41 and vWF. Notably, human aged HSCs display platelet (or megakaryocytic) bias, suggesting that insights in mechanisms determining murine HSC platelet bias will not only improve our understanding of diseases attributed to the aging hematopoietic system, but also provide novel therapeutic approaches to hematopoietic dysfunction associated with advanced age.
Since the bone marrow microenvironment (BMME) critically regulates HSCs, whether it be considered instructive or enabling distinct HSC fates, unique characteristics of the aged BMME could contribute to HSC changes associated with age. In fact, in the Drosophila gonad, extrinsic signals from the niche contribute to stem cell aging, and mathematical models have suggested that non-cell-autonomous changes could drive this process in mammalian HSCs. While data have suggested that aged endothelial and mesenchymal BMME populations are abnormal and may participate in HSC aging, microenvironmental signals governing the megakaryocytic bias of aged HSCs remain unclear. Thus, we hypothesized that defects in critical BMME populations caused by age could lead to the expansion of platelet-biased HSCs.
We found that macrophages (Mφs) within the aged BMME could impose the megakaryocytic bias characteristic of aging in HSCs. Aged human and murine marrow Mφs had distinct transcriptional profiles compared to young Mφs, including an increased inflammatory activation signature. We identified increased interleukin 1B (IL1B) mRNA in aged marrow Mφs and elevated caspase 1 activity in Mφs and neutrophils from aged bone marrow. Moreover, IL1B signaling was necessary and sufficient to induce HSC bias and drive young HSPCs to adopt an aged phenotype.
While investigating the cause of this increase, we made the novel observation that aged marrow Mφs had a defect in efferocytosis - their ability to clear apoptotic cells. Clearance of apoptotic cells is a critical function of Mφs that prevents necrosis of dead cells and associated local inflammation and also triggers anti-inflammatory responses in phagocytes. In young mice, removal of phagocytic cells or genetic loss of the efferocytic receptor Axl increased HSCs with megakaryocytic bias, suggesting that the efferocytic defect in aged marrow Mφs leads to the increase in IL1B activation and signaling. Together these data define a novel mechanism within the aged BMME that enables a specific HSC fate.