IL-6 and TGFβ1 Upregulation with Age Cause Detrimental Changes in Hematopoiesis

Researchers here show that blocking the age-related upregulation of inflammatory signal molecules IL-6 and TGFβ1 can reverse some of the deterimental changes in the function of hematopoiesis. Hematopoiesis is the process by which hematopoietic stem cells and related progenitor cell populations generate immune cells and red blood cells. With age, the production of lymphoid immune cells declines, and this is an important component of the aging of the immune system.

It is interesting to note that both IL-6 and TGFβ1 are generated by senescent cells as a part of the senescence-associated secretory phenotype. Senescent cells accumulate with age throughout the body, and contribute to chronic inflammation, as well as to the progression of near all age-related conditions. Given this, we should perhaps expect senolytic treatments that selectively destroy senescent cells in old tissues to be capable of reversing those aspects of immune aging investigated here.

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFβ signalling-induced gene expression in aged bone marrow stroma.

Inhibition of TGFβ signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFβ-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and HSC-extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.

Link: https://doi.org/10.1038/s41467-020-17942-7