During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driven by a proinflammatory milieu in mice. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with highly abundant P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation capacity upon regenerative stress. Ectopic expression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and impair erythropoiesis. Mechanistically, we uncovered that P-selectin receptor activation by its primary ligand, P-selectin glycoprotein ligand-1, suppressed aging-associated gene expression, and, reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.

Inflammation is a driving force of hematopoietic stem cells (HSCs) aging, causing irreversible exhaustion of functional HSCs. However, the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understood. Here, we find that transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal, leading to depletion of HSCs. Meanwhile, the central regulator nuclear factor kappa B (NF-κB) mediating functional impairment by inflammation insult induces differential transcriptional response in aged HSCs compared with young HSCs, with precocious activation of myeloid lineage genes. Altered compartmentalization and chromatin loop formation are associated with aging-related differential transcriptional response in HSCs upon lipopolysaccharide (LPS) stimulation. Mechanistically, enhancer and promoter regions of myeloid lineage genes in aged HSCs are more accessible and display more rapid and prominent CTCF occupancy upon LPS stimulation. Our study provides comprehensive resources for the three-dimensional (3D) genome structure of HSCs and sheds light into the ordered genome organization and the associated transcriptome signature underlying HSCs aging.

Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.

Aging is a key risk factor for many diseases, including cancer, and a better understanding of its underlying molecular mechanisms may help to prevent, delay, or treat age-related pathologies. Epigenetic alterations such as DNA methylation (DNAme) changes are a hallmark of aging and form the basis of so-called epigenetic clocks, yet their functional relevance and directionality in different organs during disease development is often unclear.

Here, we link cell-specific age-related DNAme changes with three key hallmarks of aging and cancer (senescence, promoter methylation in genes associated with stem cell fate, and dysregulated proliferation) to comprehensively dissect their association with current and future cancer development, carcinogen exposure or preventive measures, and mortality using data in different organs from over 12,510 human and 105 mouse samples, benchmarking against existing epigenetic clocks.

Our findings offer insights into the association of functionally enriched groups of age-related DNAme changes with cancer, identify sites perturbed earliest during carcinogenesis, as well as those distinct between cancer and reprogramming that could inform strategies to prevent teratoma formation upon in vivo reprogramming. Surprisingly, both mouse and human data reveal accelerated aging in breast cancer tissue but decelerated epigenetic aging in some non-cancer surrogate samples from breast cancer patients, in particular cervical samples.

This work provides evidence for discordant systemic tissue aging in breast cancer.

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.

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.

Immunosenescence, a systematic reduction in the immune system connected with age, profoundly affects the health and well-being of elderly individuals. This review outlines the hallmark features of immunosenescence, including thymic involution, inflammaging, cellular metabolic adaptations, and hematopoietic changes, and their impact on immune cells such as macrophages, neutrophils, T cells, dendritic cells, B cells, and natural killer (NK) cells. Thymic involution impairs the immune system's capacity to react to novel antigens by reducing thymopoiesis and shifting toward memory T cells. Inflammaging, characterized by chronic systemic inflammation, further impairs immune function. Cellular metabolic adaptations and hematopoietic changes alter immune cell function, contributing to a diminished immune response. Developing ways to reduce immunosenescence and enhance immunological function in the elderly population requires an understanding of these mechanisms.

How organisms age is a question with broad implications for human health. In mammals, DNA methylation is a biomarker for biological age, which may predict age more accurately than date of birth. However, limitations in mammalian models make it difficult to identify mechanisms underpinning age-related DNA methylation changes. Here, we show that the short-lived model plant Arabidopsis thaliana exhibits a loss of epigenetic integrity during aging, causing heterochromatin DNA methylation decay and the expression of transposable elements. We show that the rate of epigenetic aging can be manipulated by extending or curtailing lifespan, and that shoot apical meristems are protected from this aging process. We demonstrate that a program of transcriptional repression suppresses DNA methylation maintenance pathways during aging, and that mutants of this mechanism display a complete absence of epigenetic decay. This presents a new paradigm in which a gene regulatory program sets the rate of epigenomic information loss during aging.

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.

Nutrient-sensing pathways undergo deregulation in aged animals, exerting a pivotal role in regulating the cell cycle and subsequent stem cell division. Nevertheless, their precise functions in governing pluripotent stem cell differentiation remain largely elusive. Here, we uncovered a significant alteration in the cellular constituents of the intestinal epithelium in aged humans and mice. Employing Drosophila midgut and mouse organoid culture models, we made an observation regarding the altered trajectory of differentiation in intestinal stem cells (ISC) during overnutrition or aging, which stems from the erroneous activation of the insulin receptor signaling pathway. Through genetic analyses, we ascertained that the nutrient-sensing pathway regulated the direction of ISC differentiation by modulating the maturation of endosomes and SOX21A transcription factor. This study elucidates a nutrient-sensing pathway-mediated mechanism underlying stem cell differentiation, offering insights into the etiology of stem cell dysfunction in aged animals, including humans.

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.

Inborn errors of immunity (IEIs) are a group of typically monogenic disorders characterized by dysfunction in the immune system. Individuals with these disorders experience increased susceptibility to infections, autoimmunity and malignancies due to abnormal immune responses. Epigenetic modifications, including DNA methylation, histone modifications and chromatin remodeling, have been well explored in the regulation of immune cell development and effector function. Aberrant epigenetic modifications can disrupt gene expression profiles crucial for immune responses, resulting in impaired immune cell differentiation and function. Dysregulation of these processes caused by mutations in genes involving in epigenetic modifications has been associated with various IEIs. In this review article, we focus on IEIs that are caused by mutations in 13 genes involved in the regulation of DNA methylation, histone modification and chromatin remodeling.

Polyphenols are organic compounds with diverse biological activities such as anti-inflammatory and antioxidant effects, making them important candidates for the development of anti-aging drugs. In this systematic review, we aimed to answer the question: can plant-derived polyphenols have an immunomodulatory effect in experimental models of aging?

We systematically searched Web of Science, MEDLINE/Pubmed, and Embase to select articles using the following combinations of terms and synonyms: polyphenols, phenols, senescence, aging, and immune. The selected articles were evaluated for reporting quality and risk-of-bias according to standard guidelines.

The most used polyphenol was resveratrol, followed by curcumin, salidroside, and gallic acid. These molecules demonstrated an ability to restore immune function both in vitro and in vivo. The mechanism of action was not completely elucidated in these studies, but inhibition of NF-kB signaling, and antioxidant properties seemed to account for the anti-aging effects. All articles included in the review had good quality of reporting but failed to describe an adequate sample size, criteria for inclusion/exclusion, randomization, and blinding.

We conclude that polyphenols are promising immunomodulatory substances for use in anti-aging therapies. However, more research with standardized analysis is needed to understand the role of these molecules in the prevention or reduction of damage associated with the aging process, as well as to determine the safety profile and consequences of systemic action.

Chemokine like factor 1 (CKLF1) is a novel atypical chemokine, playing a crucial role in cardiovascular and cerebrovascular diseases (CCVDs) demonstrated by a growing body of works. In cardiovascular diseases including atherosclerosis and myocardial infarction, meanwhile in cerebrovascular diseases such as ischemic stroke and hemorrhagic stroke, the expression levels of CKLF1 change markedly, which triggers downstream signaling pathways by binding with its functional receptors, and then exerts multiple effects to participate in the occurrence and development of these CCVDs. The functional roles of CKLF1 are dynamic and CKLF1 may act as a double-edged sword. The CCVDs-promoting role is related to recruiting inflammatory cells, enhancing the proliferation of vascular smooth muscle cells and endothelial cells, while the CCVDs-suppressing role may correlate with migration of nerve cells and promotion of hematopoietic stem cell proliferation which contributes to disease recovery. Based on this, the paper intends to review expression shifts, potential roles, and molecular mechanisms of CKLF1 in CCVDs, and the current status of CKLF1 targeted therapeutic strategies is also included. We hope this review may provide a valuable reference for using CKLF1 as a diagnostic and prognostic biomarker for CCVDs or developing novel treatments.

As the demographic structure shifts towards an aging society, strategies aimed at slowing down or reversing the aging process become increasingly essential. Aging is a major predisposing factor for many chronic diseases in humans. The hematopoietic system, comprising blood cells and their associated bone marrow microenvironment, intricately participates in hematopoiesis, coagulation, immune regulation and other physiological phenomena. The aging process triggers various alterations within the hematopoietic system, serving as a spectrum of risk factors for hematopoietic disorders, including clonal hematopoiesis, immune senescence, myeloproliferative neoplasms and leukemia. The emerging single-cell technologies provide novel insights into age-related changes in the hematopoietic system. In this review, we summarize recent studies dissecting hematopoietic system aging using single-cell technologies. We discuss cellular changes occurring during aging in the hematopoietic system at the levels of the genomics, transcriptomics, epigenomics, proteomics, metabolomics and spatial multi-omics. Finally, we contemplate the future prospects of single-cell technologies, emphasizing the impact they may bring to the field of hematopoietic system aging research.

Epigenetic clocks, built on DNA methylation patterns of bulk tissues, are powerful age predictors, but their biological basis remains incompletely understood. Here, we conducted a comparative analysis of epigenetic age in murine muscle, epithelial, and blood cell types across lifespan. Strikingly, our results show that cellular subpopulations within these tissues, including adult stem and progenitor cells as well as their differentiated progeny, exhibit different epigenetic ages. Accordingly, we experimentally demonstrate that clocks can be skewed by age-associated changes in tissue composition. Mechanistically, we provide evidence that the observed variation in epigenetic age among adult stem cells correlates with their proliferative state, and, fittingly, forced proliferation of stem cells leads to increases in epigenetic age. Collectively, our analyses elucidate the impact of cell type composition, differentiation state, and replicative potential on epigenetic age, which has implications for the interpretation of existing clocks and should inform the development of more sensitive clocks.

The aging process has been one of the most necessary research fields in the current century, and knowing different theories of aging and the role of different genetic, epigenetic, molecular, and environmental modulating factors in increasing the knowledge of aging mechanisms and developing appropriate diagnostic, therapeutic, and preventive ways would be helpful. One of the most conserved signs of aging is epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, noncoding RNAs, and extracellular RNAs. Numerous biological processes and hallmarks are vital in aging development, but epigenomic alterations are especially notable because of their importance in gene regulation and cellular identity. The mounting evidence points to a possible interaction between age-related epigenomic alterations and other aging hallmarks, like genome instability. To extend a healthy lifespan and possibly reverse some facets of aging and aging-related diseases, it will be crucial to comprehend global and locus-specific epigenomic modifications and recognize corresponding regulators of health and longevity. In the current study, we will aim to discuss the role of epigenomic mechanisms in aging and the most recent developments in epigenetic diagnostic biomarkers, which have the potential to focus efforts on reversing the destructive signs of aging and extending the lifespan.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared 'young' regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.

Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.

DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.

Neurodegenerative diseases are increasing in prevalence and comprise a large socioeconomic burden on patients and their caretakers. The need for effective therapies and avenues for disease prevention and monitoring is of paramount importance. Fluid biomarkers for neurodegenerative diseases have gained a variety of uses, including informing participant selection for clinical trials, lending confidence to clinical diagnosis and disease staging, determining prognosis, and monitoring therapeutic response. Their role is expected to grow as disease-modifying therapies start to be available to a broader range of patients and as prevention strategies become established. Many of the underlying molecular mechanisms of currently used biomarkers are incompletely understood. Animal models and in vitro systems using cell lines have been extensively employed but face important translatability limitations. Induced pluripotent stem cell (iPSC) technology, where a theoretically unlimited range of cell types can be reprogrammed from peripheral cells sampled from patients or healthy individuals, has gained prominence over the last decade. It is a promising avenue to study physiological and pathological biomarker function and response to experimental therapeutics. Such systems are amenable to high-throughput drug screening or multiomics readouts such as transcriptomics, lipidomics, and proteomics for biomarker discovery, investigation, and validation. The present review describes the current state of biomarkers in the clinical context of neurodegenerative diseases, with a focus on Alzheimer's disease and frontotemporal dementia. We include a discussion of how iPSC models have been used to investigate and test biomarkers such as amyloid-β, phosphorylated tau, neurofilament light chain or complement proteins, and even nominate novel biomarkers. We discuss the limitations of current iPSC methods, mentioning alternatives such as coculture systems and three-dimensional organoids which address some of these concerns. Finally, we propose exciting prospects for stem cell transplantation paradigms using animal models as a preclinical tool to study biomarkers in the in vivo context.

AML is a hematologic cancer that is clinically heterogeneous, with a wide range of clinical outcomes. DNA methylation changes are a hallmark of AML but are not routinely used as a criterion for risk stratification. The aim of this study was to explore DNA methylation markers that could risk stratify patients with cytogenetically normal AML (CN-AML), currently classified as intermediate-risk.

DNA methylation profiles in whole blood samples from 77 patients with CN-AML in The Cancer Genome Atlas (LAML cohort) were analyzed. Individual 5'-cytosine-phosphate-guanine-3' (CpG) sites were assessed for their ability to predict overall survival. The output was validated using DNA methylation profiles from bone marrow samples of 79 patients with CN-AML in a separate data set from the Gene Expression Omnibus.

In the training set, using DNA methylation data derived from the 450K array, we identified 2,549 CpG sites that could potentially distinguish patients with CN-AML with an adverse prognosis (intermediate-poor) from those with a more favorable prognosis (intermediate-favorable) independent of age. Of these, 25 CpGs showed consistent prognostic potential across both the 450K and 27K array platforms. In a separate validation data set, nine of these 25 CpGs exhibited statistically significant differences in 2-year survival. These nine validated CpGs formed the basis for a combined prognostic biomarker panel, which includes an 8-CpG Somatic Panel and the methylation status of cg23947872. This panel displayed strong predictive ability for 2-year survival, 2-year progression-free survival, and complete remission in the validation cohort.

This study highlights DNA methylation profiling as a promising approach to enhance risk stratification in patients with CN-AML, potentially offering a pathway to more personalized treatment strategies.

The development of new antiaging medicines is of great interest to the current elderly and aging population. Aging of the hematopoietic system is attributed to the aging of hematopoietic stem cells (HSCs), and epigenetic alterations are the key effectors driving HSC aging. Understanding the epigenetics of HSC aging holds promise of providing new insights for combating HSC aging and age-related hematological malignancies.

Aging is characterized by the progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. During aging, the HSCs undergo both quantitative and qualitative changes. These functional changes in HSCs cause dysregulated hematopoiesis, resulting in anemia, immune dysfunction, and an increased risk of hematological malignancies. Various cell-intrinsic and cell-extrinsic effectors influencing HSC aging have also been identified. Epigenetic alterations are one such mechanism.

Cumulative epigenetic alterations in aged HSCs affect their fate, leading to aberrant self-renewal, differentiation, and function of aged HSCs. In turn, these factors provide an opportunity for aged HSCs to expand by modulating their self-renewal and differentiation balance, thereby contributing to the development of hematological malignancies.

Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena3. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory4. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer5. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.

Definitive haematopoiesis is the process by which haematopoietic stem cells, located in the bone marrow, generate all haematopoietic cell lineages in healthy adults. Although highly regulated to maintain a stable output of blood cells in health, the haematopoietic system is capable of extensive remodelling in response to external challenges, prioritizing the production of certain cell types at the expense of others. In this Review, we consider how acute insults, such as infections and cytotoxic drug-induced myeloablation, cause molecular, cellular and metabolic changes in haematopoietic stem and progenitor cells at multiple levels of the haematopoietic hierarchy to drive accelerated production of the mature myeloid cells needed to resolve the initiating insult. Moreover, we discuss how dysregulation or subversion of these emergency myelopoiesis mechanisms contributes to the progression of chronic inflammatory diseases and cancer.

Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.

Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that messenger RNA (mRNA) decay factors regnase-1 (Reg1; Zc3h12a) and regnase-3 (Reg3; Zc3h12c) are essential for determining lymphoid fate and restricting myeloid differentiation in HSPCs. Loss of Reg1 and Reg3 resulted in severe impairment of lymphopoiesis and a mild increase in myelopoiesis in the bone marrow. Single-cell RNA sequencing analysis revealed that Reg1 and Reg3 regulate lineage directions in HSPCs via the control of a set of myeloid-related genes. Reg1- and Reg3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single-cell assay for transposase-accessible chromatin sequencing analysis revealed that Reg1 and Reg3 control the epigenetic landscape on myeloid-related gene loci in early stage HSPCs via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Reg1- and Reg3-mediated Nfkbiz mRNA degradation primed hematopoietic stem cells toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between posttranscriptional control and chromatin remodeling by the Reg1/Reg3-Nfkbiz axis governs HSPC lineage biases, ultimately dictating the fate of lymphoid vs myeloid differentiation.