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Hematopoietic aging is marked by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to impaired blood production. Signals from the bone marrow (BM) niche tailor blood production, but the contribution of the old niche to hematopoietic aging remains unclear. Here, we characterize the in ammatory milieu that drives both niche and hematopoietic remodeling. We nd decreased numbers and functionality of osteoprogenitors (OPr) and expansion of pro-in ammatory perisinusoidal mesenchymal stromal cells (MSC) with deterioration of the sinusoidal vasculature, which together create a degraded and in amed old BM niche. Niche in ammation, in turn, drives chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors (MPP), which promotes myeloid differentiation at the expense of lymphoid and erythroid commitment and hinders hematopoietic regeneration. Remarkably, niche deterioration, HSC dysfunction and defective hematopoietic regeneration can all be ameliorated by blocking IL-1 signaling. Our results demonstrate that targeting IL-1 as a key mediator of niche in ammation is a tractable strategy to improve blood production during aging. HighlightsBoth endosteal and central marrow niche populations are remodeled with age Old niche populations show disruption of cell identity and enrichment of in ammatory response genes Emergency myelopoiesis pathways are chronically activated in response to niche in ammation Targeting niche-mediated IL-1 signaling attenuates stromal and blood aging Etoc BlurbPassegué and colleagues examine the aged bone marrow niche microenvironment to understand its contribution to blood aging and identify targetable factor(s) for functional anti-aging interventions. They show that crosstalk between the in amed niche and the in amed hematopoietic system leads to degraded blood production both at steady state and during regeneration, and identify IL-1 as a major targetable driver of age-related niche and blood system deterioration.

While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.

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