bims-minfam 2022-09-04 papers

Physiol Rev. 2022 Sep 01.

Clonal Hematopoiesis, Somatic Mosaicism, and Age-Associated Disease.

Somatic mosaicism - the occurrence of multiple genetically distinct cell clones within the same tissue - is an evitable consequence of human aging. The hematopoietic system is no exception to this, where studies have revealed the presence of expanded blood cell clones carrying mutations in preleukemic driver genes and/or genetic alterations in chromosomes. This phenomenon is referred to as clonal hematopoiesis and is remarkably prevalent in elderly individuals. Whilst clonal hematopoiesis represents an early step towards a hematological malignancy, most individuals will never develop a blood cancer. Somewhat unexpectedly, epidemiological studies have found that clonal hematopoiesis is associated with an increase in risk of all-cause mortality and age-related disease, particularly of the cardiovascular system. Studies using murine models of clonal hematopoiesis have begun to shed light on this relationship, suggesting that driver mutations in mature blood cells can causally contribute to aging and disease by augmenting inflammatory processes. Here we provide an up-to-date review of clonal hematopoiesis within the context somatic mosaicism and aging and describe recent epidemiological studies which have reported associations with age-related disease. We will also discuss the experimental studies which have provided important mechanistic insight into how driver mutations promote age-related disease and how this knowledge could be leveraged to treat individuals with clonal hematopoiesis.

Keywords: CHIP; age-related clonal hematopoiesis; inflammaging; mosaic chromosomal alterations; therapy-related clonal hematopoiesis

DOI: https://doi.org/10.1152/physrev.00004.2022

Nature. 2022 Aug 31.

Quick course of anti-ageing drug shows success.

Keywords: Ageing

DOI: https://doi.org/10.1038/d41586-022-02295-6

Lancet Healthy Longev. 2022 Jun;3(6): e376-e377

Redefining Age-Based Screening and Diagnostic Guidelines: An Opportunity for Biological Aging Clocks in Clinical Medicine?

Jamaji C Nwanaji-Enwerem, William B Mair.

Keywords: USPSTF; biomarkers; epigenetic aging; oncology; public health

DOI: https://doi.org/10.1016/s2666-7568(22)00114-3

J Exp Med. 2022 Nov 07. pii: e20212437. [Epub ahead of print]219(11):

EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors.

Aurelie Lenaerts, Iwo Kucinski, Ward Deboutte, Marta Derecka, Pierre Cauchy, Thomas Manke, Berthold Göttgens, Rudolf Grosschedl.

Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low-level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit an augmented myeloid differentiation potential and a transcriptome with an enriched C/EBPα signature. Correspondingly, EBF1 binds the Cebpa enhancer, and the deficiency and overexpression of Ebf1 in MPP3 and MPP4 cells lead to an up- and downregulation of Cebpa expression, respectively. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate.

DOI: https://doi.org/10.1084/jem.20212437

Aging (Albany NY). 2022 Aug 29. 14(undefined):

New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.

Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.

Keywords: autophagy; hallmarks of ageing; healthspan; longevity; neurodegeneration

DOI: https://doi.org/10.18632/aging.204248