Stem cell functions and ageing are deeply interconnected, continually influencing each other in multiple ways. Stem cells play a vital role in organ maintenance, regeneration, and homeostasis, all of which decline over time due to gradual reduction in their self-renewal, differentiation, and growth factor secretion potential. The functional decline is attributed to damaging extrinsic environmental factors and progressively worsening intrinsic genetic and biochemical processes. These ageing-associated deteriorative changes have been extensively documented, paving the way for the discovery of novel biomarkers of ageing for detection, diagnosis, and treatment of age-related diseases. Age-dependent changes in adult stem cells include numerical decline, loss of heterogeneity, and reduced self-renewal and differentiation, leading to a drastic reduction in regenerative potential and thereby driving the ageing process. Conversely, ageing also adversely alters the stem cell niche, disrupting the molecular pathways underlying stem cell homing, self-renewal, differentiation, and growth factor secretion, all of which are critical for tissue repair and regeneration. A holistic understanding of these molecular mechanisms, through empirical research and clinical trials, is essential for designing targeted therapies to modulate ageing and improve health parameters in older individuals.

Aging changes the protein activity status to affect the body's functions. However, how aging regulates protein posttranslational modifications (PTMs) to modulate the antiviral defense ability of the body remains unclear. Here, we found that aging promotes STAT1 β-hydroxybutyrylation (Kbhb) at Lys592, which inhibits the interaction between STAT1 and type-I interferon (IFN-I) receptor 2 (IFNAR2), thereby attenuating IFN-I-mediated antiviral defense activity. Additionally, we discovered that a small molecule from a plant source, hydroxy camptothecine, can effectively reduce the level of STAT1 Kbhb, thus increasing antiviral defense ability in vivo. Further studies revealed that STAT1 O-GlcNAc modifications at Thr699 block CBP-induced STAT1 Kbhb. Importantly, fructose can improve IFN-I antiviral defense activity by orchestrating STAT1 O-GlcNAc and Kbhb modifications. This study reveals the significance of the switch between STAT1 Kbhb and O-GlcNAc modifications in regulating IFN-I antiviral immunity during aging and provides potential strategies to improve the body's antiviral defense ability in elderly individuals.

Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now.

We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms.

We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging.

TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay.

TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.

Aging of hematopoietic stem cells (HSCs) is implicated in various aging phenotypes, including immune dysfunction, anemia, and malignancies. The role of HSC proliferation in driving these aging phenotypes, particularly under stress conditions, remains unclear. Therefore, we induced forced replications of HSCs in vivo by a cyclical treatment with low-dose fluorouracil (5FU) and examined the impact on HSC aging. Our findings show that proliferative stress induces several aging phenotypes, including altered leukocyte counts, decreased lymphoid progenitors, accumulation of HSCs with high expression of Slamf1, and reduced reconstitution potential, without affecting stem cell self-renewal capacity. The divisional history of HSCs was imprinted in the DNA methylome, consistent with functional decline. Specifically, DNA methylation changes included global hypermethylation in non-coding regions and similar frequencies of hypo- and hyper-methylation at promoter regions, particularly affecting genes targeted by the PRC2 complex. Importantly, initial forced replication promoted DNA damage repair accumulated with age, but continuous proliferative stress led to the accumulation of double-strand breaks, independent of functional decline. Overall, our results suggest that HSC proliferation can drive some aging phenotypes primarily through epigenetic mechanisms, including DNA methylation changes.

Hematopoietic stem cells (HSCs) ageing is a phenomenon described by reduction in self-renewal capacity, compromised homing, a bias towards myeloid differentiation, and defective reconstitution function. The molecular mechanisms of HSCs ageing have been investigated by several groups. In a broad classification, the underlying causes can be grouped into the intrinsic factors and those related to the microenvironment. Determination of the exact mechanism of HSCs ageing and detailed molecular events during its initiation and progression will help in the establishment of novel therapies for the treatment or prevention of ageing-related hematopoietic disorders. This review offers an overview of genetic and epigenetic causes of HSCs ageing. The findings of these investigations paved the way for design of novel strategies for rejuvenation of HSCs.

Hematopoietic stem cells (HSCs) sustain blood cell production throughout the mammalian life span. However, it has become clear that at the single cell level a subset of HSCs is stably biased in their lineage output, and that such heterogeneity may play a key role in physiological processes including aging and adaptive immunity. Analysis of chromatin accessibility, DNA methylation, and histone modifications has revealed that HSCs with different lineage bias exhibit distinct epigenetic traits inscribed at poised, lineage-specific enhancers. This allows for lineage priming without initiating lineage-specific gene expression in HSCs, controlling lineage bias while preserving self-renewal and multipotency. Here, we review our current understanding of epigenetic regulation in the establishment and maintenance of HSC fate decisions under different physiological conditions.

Cultured human embryonic stem cells (hESCs) can develop genetic anomalies that increase their susceptibility to transformation. In this study, we characterized a variant hESC (vhESC) line and investigated the molecular mechanisms leading to the drift towards a transformed state. Our findings revealed that vhESCs up-regulate EMT-specific markers, accelerate wound healing, exhibit compromised lineage differentiation, and retain pluripotency gene expression in teratomas. Furthermore, we discovered an altered epigenomic landscape and overexpression of the lysine methyltransferases EHMT1, EHMT2, and NSD group of proteins in vhESCs. Remarkably, depleting NSD3 oncogene reversed the molecular and phenotypic changes in vhESCs. We identified a detailed mechanism where EHMT2 interacts and methylates NSD3 at lysine 477, stabilizing its protein levels in vhESCs. In addition, we showed that NSD3 levels are regulated by protein degradation in hESCs, and its stabilization leads to the emergence of the variant state. Overall, our study identify that misregulation of NSD3 in pluripotent stem cells, through methylation-mediated abrogation of its protein degradation, drives hESCs towards oncogenic transformation.

Hematopoietic stem cells (HSCs) are central to blood formation and play a pivotal role in hematopoietic and systemic aging. With aging, HSCs undergo significant functional changes, such as an increased stem cell pool, declined homing and reconstitution capacity, and skewed differentiation toward myeloid and megakaryocyte/platelet progenitors. These phenotypic alterations are likely due to the expansion of certain clones, known as clonal hematopoiesis (CH), which leads to disrupted hematopoietic homeostasis, including anemia, impaired immunity, higher risks of hematological malignancies, and even associations with cardiovascular disease, highlighting the broader impact of HSC aging on overall health. HSC aging is driven by a range of mechanisms involving both intrinsic and extrinsic factors, such as DNA damage accumulation, epigenetic remodeling, inflammaging and metabolic regulation. In this review, we summarize the updated understanding of age-related changes in hematopoietic stem and progenitor cells (HSPCs) and the mechanisms underlying the aging process in mammalian models, especially in human study. Additionally, we provide insights into potential therapeutic strategies to counteract aging process and enhance HSC regenerative capacity, which will support therapeutic interventions and promote healthy aging.

Deep learning (DL) and explainable artificial intelligence (XAI) have emerged as powerful machine-learning tools to identify complex predictive data patterns in a spatial or temporal domain. Here, we consider the application of DL and XAI to large omic datasets, in order to study biological aging at the molecular level. We develop an advanced multi-view graph-level representation learning (MGRL) framework that integrates prior biological network information, to build molecular aging clocks at cell-type resolution, which we subsequently interpret using XAI. We apply this framework to one of the largest single-cell transcriptomic datasets encompassing over a million immune cells from 981 donors, revealing a ribosomal gene subnetwork, whose expression correlates with age independently of cell-type. Application of the same DL-XAI framework to DNA methylation data of sorted monocytes reveals an epigenetically deregulated inflammatory response pathway whose activity increases with age. We show that the ribosomal module and inflammatory pathways would not have been discovered had we used more standard machine-learning methods. In summary, the computational deep learning framework presented here illustrates how deep learning when combined with explainable AI tools, can reveal novel biological insights into the complex process of aging.

Cis-regulatory elements (CREs) control gene expression and are dynamic in their structure and function, reflecting changes in the composition of diverse effector proteins over time1. However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA-protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size. Using these multiscale footprints, we created the seq2PRINT framework, which uses deep learning to allow precise inference of transcription factor and nucleosome binding and interprets regulatory logic at CREs. Applying seq2PRINT to single-cell chromatin accessibility data from human bone marrow, we observe sequential establishment and widening of CREs centred on pioneer factors across haematopoiesis. We further discover age-associated alterations in the structure of CREs in murine haematopoietic stem cells, including widespread reduction of nucleosome footprints and gain of de novo identified Ets composite motifs. Collectively, we establish a method for obtaining rich insights into DNA-binding protein dynamics from chromatin accessibility data, and reveal the architecture of regulatory elements across differentiation and ageing.

The developmental competence and epigenetic progression of oocytes gradually become dysregulated with increasing maternal age. However, the mechanisms underlying age-related epigenetic regulation in oocytes remain poorly understood. Zygote arrest proteins 1 and 2 (ZAR1/2) are two maternal factors with partially redundant roles in maintaining oocyte quality, mainly known by regulating mRNA stability. In addition to this known function, it is found that ZAR1/2 is required for oocyte epigenetic maturation and zygotic reprogramming. Zar1/2-deleted oocytes exhibited reduced levels of multiple histone modifications and of the expression of corresponding histone modifiers, along with over-condensed chromatin, leading to compromised minor zygotic genome activation and deficient embryo development following fertilization. Cytoplasmic ZAR1/2 participated in intranuclear epigenetic maturation by binding the transcripts encoding histone modifiers and regulating their stability and translational activity. Moreover, oocytes from aged mice exhibited similar histone-modification deficiencies as the Zar1/2-deleted oocytes. ZAR1/2 mRNA and protein levels are downregulated in oocytes from mice and women with advanced ages, suggesting ZAR1/2 as regulators of epigenetic changes with reproductive aging. This study presents a new nucleo-cytoplasmic interaction mechanism that is involved in preventing oocyte epigenetic aging. Further, ZAR1/2 represents potential gene targets for diagnosis and clinical interventions in age-associated deficiencies in oocyte and embryo development.

Bone marrow hematopoietic injury encompasses a range of pathological conditions that disrupt the normal function of the hematopoietic system, primarily through the impaired production and differentiation of bone marrow hematopoietic cells. Key pathogenic mechanisms include aging, radiation damage, chemical induction, infection and inflammation, and cross-talk with non-hematopoietic diseases. These pathological factors often lead to myelosuppression and myeloid skewing. Furthermore, we explored the potential and application prospects of natural products in the treatment of bone marrow hematopoietic injury. Natural products, particularly those derived from Chinese herbal medicines and other natural sources, have emerged as promising therapeutic options due to their distinctive mechanisms and minimal side effects. A deeper understanding of the underlying mechanisms of bone marrow hematopoietic injury could illuminate how natural products exert their effects, thereby optimizing treatment strategies and offering safer, more effective options for patients. Future research should leverage emerging technologies to further elucidate the composition and interactions within the bone marrow microenvironment, as well as the specific pathways through which natural products modulate hematopoietic dysfunction.

Cardiovascular and cardiometabolic diseases are leading causes of morbidity and mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or marrow niche, plays a critical role in both immune system regulation and disease progression. The bone marrow niche is essential for maintaining hematopoietic stem cells (HSCs) and orchestrating hematopoiesis. Under normal conditions, this niche ensures a return to immune homeostasis after acute stress. However, in the setting of inflammatory conditions such as those seen in cardiometabolic diseases, it becomes dysregulated, leading to enhanced myelopoiesis and immune activation. This review explores the reciprocal relationship between the bone marrow niche and cardiometabolic diseases, highlighting how alterations in the niche contribute to disease development and progression. The niche regulates HSCs through complex interactions with stromal cells, endothelial cells, and signaling molecules. However, in the setting of chronic diseases such as hypertension, atherosclerosis, and diabetes, inflammatory signals disrupt the balance between HSC self-renewal and differentiation, promoting the excessive production of proinflammatory myeloid cells that exacerbate the disease. Key mechanisms discussed include the effects of hyperlipidemia, hyperglycemia, and sympathetic nervous system activation on HSC proliferation and differentiation. Furthermore, the review emphasizes the role of epigenetic modifications and metabolic reprogramming in creating trained immunity, a phenomenon whereby HSCs acquire long-term proinflammatory characteristics that sustain disease states. Finally, we explore therapeutic strategies aimed at targeting the bone marrow niche to mitigate chronic inflammation and its sequelae. Novel interventions that modulate hematopoiesis and restore niche homeostasis hold promise for the treatment of cardiometabolic diseases. By interrupting the vicious cycle of inflammation and marrow dysregulation, such therapies may offer new avenues for reducing cardiovascular risk and improving patient outcomes.

Fate decisions during immune cell development require temporally precise changes in gene expression. Evidence suggests that the dynamic modulation of these changes is associated with the formation of diverse, membrane-less nucleoprotein assemblies that are termed biomolecular condensates. These condensates are thought to orchestrate fate-determining transcriptional and post-transcriptional processes by locally and transiently concentrating DNA or RNA molecules alongside their regulatory proteins. Findings have established a link between condensate formation and the gene regulatory networks that ensure the proper development of immune cells. Conversely, condensate dysregulation has been linked to impaired immune cell fates, including ageing and malignant transformation. This Review explores the putative mechanistic links between condensate assembly and the gene regulatory frameworks that govern normal and pathological development in the immune system.

To identify the differences between aged and young human hematopoiesis, we performed a direct comparison of aged and young human hematopoietic stem and progenitor cells (HSPCs). Alterations in transcriptome profiles upon aging between humans and mice were then compared. Human specimens consist of CD34+ cells from bone marrow, and mouse specimens of hematopoietic stem cells (HSCs; Lin- Kit+ Sca1+ CD150+). Single-cell transcriptomic studies, functional clustering, and developmental trajectory analyses were performed. A significant increase in multipotent progenitor 2A (MPP2A) cluster is found in the early HSC trajectory in old human subjects. This cluster is enriched in senescence signatures (increased telomere attrition, DNA damage, activation of P53 pathway). In mouse models, the accumulation of an analogous subset was confirmed in the aged LT-HSC population. Elimination of this subset has been shown to rejuvenate hematopoiesis in mice. A significant activation of the P53-P21WAF1/CIP1 pathway was found in the MPP2A population in humans. In contrast, the senescent HSCs in mice are characterized by activation of the p16Ink4a pathway. Aging in the human HSC compartment is mainly caused by the clonal evolution and accumulation of a senescent cell cluster. A population with a similar senescence signature in the aged LT-HSCs was confirmed in the murine aging model. Clearance of this senescent population with senotherapy in humans is feasible and potentially beneficial.

Human hematopoietic stem cells (HSCs) have traditionally been viewed as self-renewing, multipotent cells with enormous potential in sustaining essential steady state blood and immune cell production throughout life. Indeed, around 86% (1011-1012) of new cells generated daily in a healthy young human adult are of hematopoietic origin. Therapeutically, human HSCs have contributed to over 1.5 million hematopoietic cell transplants (HCTs) globally, making this the most successful regenerative therapy to date. We will commence this review by briefly highlighting selected key achievements (from 1868 to the end of the 20th century) that have contributed to this accomplishment. Much of our knowledge of hematopoiesis is based on small animal models that, despite their enormous importance, do not always recapitulate human hematopoiesis. Given this, we will critically review the progress and challenges faced in identifying adult human HSCs and tracing their lineage differentiation trajectories, referring to murine studies as needed. Moving forward and given that human hematopoiesis is dynamic and can readily adjust to a variety of stressors, we will then discuss recent research advances contributing to understanding (i) which HSPCs maintain daily steady state human hematopoiesis, (ii) where these are located, and (iii) which mechanisms come into play when homeostatic hematopoiesis switches to stress-induced or emergency hematopoiesis.

Chronic low-grade inflammation observed in older adults, termed inflammaging, is a common feature underlying a multitude of aging-associated maladies including a decline in hematopoietic activity. However, whether suppression of inflammaging can preserve hematopoietic health span remains unclear, in part because of a lack of tools to measure inflammaging within hematopoietic stem cells (HSCs). Here, we identify thrombospondin-1 (Thbs1) as an essential regulator of inflammaging within HSCs. We describe a transcriptomics-based approach for measuring inflammaging within stem cells and demonstrate that deletion of Thbs1 is sufficient to prevent HSC inflammaging. Our results demonstrate that suppression of HSC inflammaging prevents aging-associated defects in hematopoietic activity including loss of HSC self-renewal, myeloid-biased HSC differentiation, and anemia. Our findings indicate that suppression of HSC inflammaging may also prolong overall systemic health span.

Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored.

The mitotic inheritability of DNA methylation as an epigenetic marker in higher-order eukaryotes has been established for >40 years. The DNA methylome and mitotic division interplay is now considered bidirectional and highly intertwined. Various epigenetic writers, erasers, and modulators shape the perceived replicative methylation dynamics. This Review surveys the principles and complexity of mitotic transmission of DNA methylation, emphasizing the awareness of mitotic aging in analyzing DNA methylation dynamics in development and disease. We reviewed how DNA methylation changes alter mitotic proliferation capacity, implicating age-related diseases like cancer. We link replicative epimutation to stem cell dysfunction, inflammatory response, cancer risks, and epigenetic clocks, discussing the causative role of DNA methylation in health and disease.

The microbiome is a highly complex and diverse symbiotic component that undergoes dynamic changes with the organismal aging. Microbial perturbations, termed dysbiosis, exert strong influence on dysregulating the bone marrow niche and subsequently promoting the aging of hematopoietic and immune system. Accumulating studies have revealed the substantial impact of intestinal microbiome on the initiation and progression of age-related hematologic alteration and diseases, such as clonal hematopoiesis and blood cancers. Current therapeutic approaches to restore the altered microbiome diversity target specific pathobionts and are demonstrated to improve clinical outcomes of antihematologic malignancy treatments. In this review, we discuss the interplay between the microbiome and the hemato-immune system during aging process. We also shed light on the emerging therapeutic strategies to tackle the dysbiosis for amelioration of aging and disease progression.

Fanconi anemia (FA) is generally classified as a DNA repair disorder, conferring a genetic predisposition to cancer and prominent bone marrow failure (BMF) in early childhood. Corroborative human and murine studies point to a fetal origin of hematopoietic stem cell (HSC) attrition under replicative stress. Along with intriguing recent insights into non-canonical roles and domain-specific functions of FA proteins, these studies have raised the possibility of a DNA repair-independent BMF etiology. However, deeper mechanistic insight is critical as current curative options of allogeneic stem cell transplantation and emerging gene therapy have limited eligibility, carry significant side effects, and involve complex procedures restricted to resource-rich environments. To develop rational and broadly accessible therapies for FA patients, the field will need more faithful disease models that overcome the scarcity of patient samples, leverage technological advances, and adopt investigational clinical trial designs tailored for rare diseases.

Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit "younger" molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of "younger" HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.

In a Science paper, Park et al. identified interleukin (IL)-1α as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1α production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice.

Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and long interspersed nuclear elements. Retrotransposon transcription activates the innate immune sensors cyclic guanosine 3',5'-monophosphate-adenosine 5'-monophosphate synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in nonpregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN-regulated genes were also induced in mouse HSCs after serial bleeding and, in human HSCs, during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant but not in nonpregnant people, suggesting conservation of these mechanisms from mice to humans.

Hematopoiesis within the bone marrow (BM) is a complex and tightly regulated process predominantly influenced by immune factors. Aging, diabetes, and obesity are significant contributors to BM niche damage, which can alter hematopoiesis and lead to the development of clonal hematopoiesis of intermediate potential (CHIP). Genetic/epigenetic alterations during aging could influence BM niche reorganization for hematopoiesis or clonal hematopoiesis. CHIP is driven by mutations in genes such as Tet2, Dnmt3a, Asxl1, and Jak2, which are associated with age-related hematological malignancies.

This literature review aims to provide an updated exploration of the functional aspects of BM niche cells within the hematopoietic microenvironment in the context of age-related hematological malignancies. The review specifically focuses on how immunological stressors modulate different signaling pathways that impact hematopoiesis.

An extensive review of recent studies was conducted, examining the roles of various BM niche cells in hematopoietic stem cell (HSC) trafficking and the development of age-related hematological malignancies. Emphasis was placed on understanding the influence of immunological stressors on these processes.

Recent findings reveal a significant microheterogeneity and temporal stochasticity of niche cells across the BM during hematopoiesis. These studies demonstrate that niche cells, including mesenchymal stem cells, osteoblasts, and endothelial cells, exhibit dynamic interactions with HSCs, significantly influenced by the BM microenvironment as the age increases. Immunosurveillance plays a crucial role in maintaining hematopoietic homeostasis, with alterations in immune signaling pathways contributing to the onset of hematological malignancies. Novel insights into the interaction between niche cells and HSCs under stress/aging conditions highlight the importance of niche plasticity and adaptability.

The involvement of age-induced genetic/epigenetic alterations in BM niche cells and immunological stressors in hematopoiesis is crucial for understanding the development of age-related hematological malignancies. This comprehensive review provides new insights into the complex interplay between niche cells and HSCs, emphasizing the potential for novel therapeutic approaches that target niche cell functionality and resilience to improve hematopoietic outcomes in the context of aging and metabolic disorders.

This review introduces novel concepts regarding the plasticity and adaptability of BM niche cells in response to immunological stressors and epigenetics. It proposes that targeted therapeutic strategies aimed at enhancing niche cell resilience could mitigate the adverse effects of aging, diabetes, and obesity on hematopoiesis and clonal hematopoiesis. Additionally, the review suggests that understanding the precise temporal and spatial dynamics of niche-HSC interactions and epigenetics influence may lead to innovative treatments for age-related hematological malignancies.

Globally, the human population is aging, with an increased proportion of people in "old age" (over 60 years). This trend leads to a growing demand in aging research, stimulating studies in animal models such as mice, fish, and invertebrates. Recently, we published a research summary on the aging of hematopoietic stem cells (HSCs) in C57BL/6 mice based on 12 gene expression datasets. Here, I discuss in greater detail the added value of taking an integrated view, rather than considering each publication separately, to determine genes involved in aging. Considerable variation exists between lists of differentially expressed (DE) genes in HSCs, comparing young and old mice. This variation can result from factors such as inconsistent definitions of "young" and "old", technical variations and variations between laboratory mouse strains. We previously demonstrated that the variation between gene lists could be circumvented by forming a unified list of DE genes-the "aging list"-with citation indexes attached. The most frequently detected DE genes [approximately 200 most cited, which we named the "aging signature" (AS)] were highly consistent across publications. Gene Ontology classification of the AS list identified additional sources of variation between studies: one comes from the specifics of how the data are collected and analyzed; another comes from inconsistencies between how we define the gene categories. As discussed, overcoming these variations is the next challenge toward an integral approach to our systematic knowledge of the aging process.

Hematopoietic stem cell (HSC) fate decisions are dictated by epigenetic landscapes. The Polycomb Repressive Complex 1 (PRC1) represses genes that induce differentiation, thereby maintaining HSC self-renewal. Depending on which chromobox (CBX) protein (CBX2, CBX4, CBX6, CBX7, or CBX8) is part of the PRC1 complex, HSC fate decisions differ. Here, we review how this occurs. We describe how CBX proteins dictate age-related changes in HSCs and stimulate oncogenic HSC fate decisions, either as canonical PRC1 members or by alternative interactions, including non-epigenetic regulation. CBX2, CBX7, and CBX8 enhance leukemia progression. To target, reprogram, and kill leukemic cells, we suggest and describe multiple therapeutic strategies to interfere with the epigenetic functions of oncogenic CBX proteins. Future studies should clarify to what extent the non-epigenetic function of cytoplasmic CBX proteins is important for normal, aged, and leukemic blood cells.

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

Cellular plasticity in adult multicellular organisms is a protective mechanism that allows certain tissues to regenerate in response to injury. Considering that aging involves exposure to repeated injuries over a lifetime, it is conceivable that cell identity itself is more malleable-and potentially erroneous-with age. In this review, we summarize and critically discuss the available evidence that cells undergo age-related shifts in identity, with an emphasis on those that contribute to age-associated pathologies, including neurodegeneration and cancer. Specifically, we focus on reported instances of programs associated with dedifferentiation, biased differentiation, acquisition of features from alternative lineages, and entry into a preneoplastic state. As some of the most promising approaches to rejuvenate cells reportedly also elicit transient changes to cell identity, we further discuss whether cell state change and rejuvenation can be uncoupled to yield more tractable therapeutic strategies.

How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.