2022 – AGING HEMATOPOIESIS: BEYOND THE DETERMINISTIC DOGMA OF HEMATOPOIETIC STEM CELL DYSFUNCTION

Organismal aging is thought to be mediated by the interaction of multiple genetic and environmental variables acting cumulatively over long periods of time, confounding mechanistic insights into this process. In this study, we measured a wide range of hematologic variables (cell counts, histology, flow cytometry, HSC transplantation, scRNA and scATAC-seq) from hematopoietic tissues across a large cohort (>100 individuals) of young (8 weeks), middle aged (18 months) and old (>24 months) female C57BL/6J mice housed in the same controlled environment. Surprisingly, the aged phenotypes across the cohort were highly variable, with some 24-month-old mice displaying parameters in line with 8-week-old controls while others demonstrating extreme aged outcomes, despite the minimal variance in genotype and environment. This suggests a dominant stochastic basis to hematopoietic aging that is rarely considered in the literature. Importantly, canonical age-associated phenotypes that are thought to have a causal relationship (HSC functional potential, HSC expansion, myeloid bias, anemia) poorly correlated across the cohort, challenging the concept that HSC dysfunction drives the evolution of aged hematopoiesis. scRNAseq of bone marrow HSCs, progenitors, mature hematopoietic and niche cells identified a new population of inflammatory adipocytes precursors exclusive to, but heterogenous across aged individuals. Interaction analysis suggests that these cells receive inflammatory signals from neutrophils (Il1b and Tnf), and downregulate ligands (Kitl, Vcam1, and Angpt2) that typically signal to HSCs, potentially mediating HSC decline during aging. Taken together, these findings challenge the notion of a uniform hematological aging process stemming from compromised HSCs, but rather indicate a stochastic process, which extends to a heterogenous niche composition.