bims-minfam 2024-11-10 papers

Issue of 2024–11–10
six papers selected by
Ayesh Seneviratne, McMaster University

Oncogene. 2024 Nov 01.

Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential.

Chunxiao Zhang, Taisen Hao, Alessia Bortoluzzi, Min-Hsuan Chen, Xiwei Wu, Jinhui Wang, Richard Ermel, Young Kim, Shiuan Chen, WenYong Chen.

Sex influences many biological outcomes, but how sex affects hematopoietic stem cell (HSC) aging and hematological disorders is poorly understood. The widespread use of young animal models to study age-related diseases further complicates these matters. Using aged and long-lived BALB/c mouse models, we discovered that aging mice exhibit sex-dependent disparities, mirroring aging humans, in developing myeloid skewing, anemia, and leukemia. These disparities are underlined by sex-differentiated HSC aging characteristics across the population, single-cell, and molecular levels. The HSC population expanded significantly with aging and longevity in males, but this occurred to a much lesser degree in aging females that instead expanded committed progenitors. Aging male HSCs are more susceptible to BCR-ABL1 transformation with faster development of chronic myeloid leukemia (CML) than female HSCs. Additionally, the loss of the aging regulator Sirt1 inhibited CML development in aging male but not female mice. Our results showed for the first time that sex-differentiated HSC aging impacts hematopoiesis, leukemogenesis, and certain gene functions. This discovery provides insights into understanding age-dependent hematological diseases and sex-targeted strategies for the treatment and prevention of certain blood disorders and cancer.

DOI: https://doi.org/10.1038/s41388-024-03197-9

Exp Gerontol. 2024 Oct 25. pii: S0531-5565(24)00265-1. [Epub ahead of print] 112619

The biological roots of the sex-frailty paradox.

Beatrice Arosio, Anna Picca.

Aging is a dynamic process that requires a continuous response and adaptation to internal and external stimuli over the life course. This eventually results in people aging differently and women aging differently than men. The "gender paradox" describes how women experience greater longevity than men, although linked with higher rates of disability and poor health status. Recently, the concept of frailty has been incorporated into this paradox giving rise to the "sex-frailty paradox" which describes how women are frailer because they manifest worse health status but, at the same time, appear less susceptible to death than men of the same age. However, very little is known about the biological roots of this sex-related difference in frailty. Inflamm-aging, the chronic low-grade inflammatory state associated with age, plays a key pathophysiological role in several age-related diseases/conditions, including Alzheimer's disease (AD), for which women have a higher lifetime risk than men. Interestingly, inflamm-aging develops at a different rate in women compared to men, with features that could play a critical role in the development of AD in women. According to this view, a continuum between aging and age-related diseases that probably lacks clear boundaries can be envisioned in which several shared biological mechanisms that progress at different pace may lead to different aging trajectories in women than in men. It therefore becomes urgent to consider a holistic approach in the study of aging, declining it from a gender medicine perspective that can also consider the biological roots of the sex-frailty paradox.

Keywords: Alzheimer's disease; Biological aging; Frailty; Gender-paradox; Geroscience; Inflamm-aging; Neurodegeneration

DOI: https://doi.org/10.1016/j.exger.2024.112619

Stem Cell Res Ther. 2024 Nov 06. 15(1): 401

Emerging insights into epigenetics and hematopoietic stem cell trafficking in age-related hematological malignancies.

Yang Xinyi, Reshetov Igor Vladimirovich, Narasimha M Beeraka, Allaka Satyavathi, Dinisha Kamble, Vladimir N Nikolenko, Allaka Naga Lakshmi, Basappa Basappa, Padmanabha Reddy Y, Ruitai Fan, Junqi Liu.

BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
NOVELTY STATEMENT: 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.

Keywords: Aging; BM niche; Clonal hematopoiesis; Diabetes; Epigenetics; Hematological malignancies; Hematopoiesis; Obesity; Signaling pathways

DOI: https://doi.org/10.1186/s13287-024-04008-4

N Engl J Med. 2024 Nov 07. pii: 10.1056/NEJMc2411327#sa5. [Epub ahead of print]391(18): 1759-1760

Frailty in Older Adults. Reply.

Dae Hyun Kim, Kenneth Rockwood.

DOI: https://doi.org/10.1056/NEJMc2411327

Aging Dis. 2024 Oct 03.

Ischemic Stroke and the Biological Hallmarks of Aging.

Fangyuan Cheng, Bo Yan, Pan Liao, Han Gao, Zhenyu Yin, Dai Li, Ping Lei.

With the advent of an aging population, the study of aging and related research has been increasingly prominent, focusing on how to fully understand and delay aging-a key concern for contemporary medical professionals. Stroke is an acute focal neurological deficit. Globally, ischemic stroke accounts for only 60-70% of all strokes, meanwhile, it is the second leading cause of death. With the introduction of the concept of biomarkers of ageing, the research of ischemic stroke or acute brain injury in relation to these biomarkers has remained fragmented. In this review, we aim to consolidate the current evidence, highlighting the intricate relationship between ischemic stroke and aging-related hallmarks during its occurrence. By providing a comprehensive overview, we hope to offer researchers a broader perspective on how acute injury mechanisms intertwine with aging. We hope to present a new viewpoint and a more complete evaluation framework for future research and exploration in the field of aging.

DOI: https://doi.org/10.14336/AD.2024.01059