bims-minfam 2024-09-15 papers

Issue of 2024–09–15
nine papers selected by
Ayesh Seneviratne, Western University

FEBS Lett. 2024 Sep 09.

RNA Modifications Shape Hematopoietic Stem Cell Aging: Beyond the Code.

Inge van der Werf, Jenna Sneifer, Catriona Jamieson.

Hematopoietic system aging is characterized by both hematopoietic stem cell (HSC) and niche degeneration resulting in myeloid lineage-biased differentiation, reduced B cell and T cell lymphopoiesis, increased HSC mobilization, and fat deposition in the bone marrow. Both alterations in RNA splicing and editing during HSC aging contribute to increased myeloid lineage skewing and inflammation-responsive transcription factors, underscoring the importance of epitranscriptomic mechanisms in the acquisition of an age-related phenotype.

Keywords: ADAR1; APOBEC3; Aging; Hematopoiesis; RNA Editing; RNA Splicing; Stem Cells

DOI: https://doi.org/10.1002/1873-3468.15014

Trends Cell Biol. 2024 Sep 12. pii: S0962-8924(24)00162-4. [Epub ahead of print]

Epigenetic regulation of hematopoietic stem cell fate.

Yiran Meng, Claus Nerlov.

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.

Keywords: aging; epigenome; fate decision; hematopoietic stem cell; inflammation

DOI: https://doi.org/10.1016/j.tcb.2024.08.005

Nat Commun. 2024 Sep 09. 15(1): 7858

Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis.

Md Mesbah Uddin, Seyedmohammad Saadatagah, Abhishek Niroula, Bing Yu, Whitney E Hornsby, Shriienidhie Ganesh, Kim Lannery, Art Schuermans, Michael C Honigberg, Alexander G Bick, Peter Libby, Benjamin L Ebert, Christie M Ballantyne, Pradeep Natarajan.

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly influence the incidence of CHIP, while ASCVD and other traditional ASCVD risk factors do not exhibit such associations. Additionally, baseline synonymous passenger mutations are strongly associated with CHIP status and are predictive of new CHIP clone acquisition and clonal growth over extended follow-up, providing valuable insights into clonal dynamics of aging hematopoietic stem and progenitor cells. This study also reveals associations between germline genetic variants and incident CHIP. Our comprehensive longitudinal assessment yields insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.

DOI: https://doi.org/10.1038/s41467-024-52302-9

Immunity. 2024 Sep 10. pii: S1074-7613(24)00409-6. [Epub ahead of print]57(9): 2010-2012

The inflammaging clock strikes IL-11!

Saad Khan, Veronica Chang, Daniel A Winer.

Chronic inflammation is considered a hallmark of aging. In a recent issue of Nature, Widjaja et al. examined genetic and pharmacologic inhibition of interleukin (IL)-11 on aging pathology and found that inhibiting IL-11 signaling increases lifespan and healthspan in mice.

DOI: https://doi.org/10.1016/j.immuni.2024.08.010

Immunity. 2024 Sep 10. pii: S1074-7613(24)00374-1. [Epub ahead of print]57(9): 2005-2007

An anti-aging vaccine: BCG turns back the clock on remyelination failure.

Janssen M Kotah, Bart J L Eggen.

Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.

DOI: https://doi.org/10.1016/j.immuni.2024.08.001

Nat Aging. 2024 Sep 12.

Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

Jing Hou, Kai-Xuan Chen, Chen He, Xiao-Xiao Li, Mei Huang, Yang-Zi Jiang, Yu-Rui Jiao, Qiao-Ni Xiao, Wen-Zhen He, Ling Liu, Nan-Yu Zou, Min Huang, Jie Wei, Ye Xiao, Mi Yang, Xiang-Hang Luo, Chao Zeng, Guang-Hua Lei, Chang-Jun Li.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

DOI: https://doi.org/10.1038/s43587-024-00694-0