Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Beerman, Isabel

doi:10.1053/j.seminhematol.2016.11.001

Cited by 41 publications

(33 citation statements)

References 120 publications

(125 reference statements)

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“…1C, D, P=2.86 x 10 -3 , Levene's test). These observations are in keeping with the idea that stem cells preserve their genome integrity by remaining quiescent (minimizing replication-based errors) or through an enhanced capability to prevent or repair DNA damage (14,15).…”

supporting

confidence: 80%

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Brazhnik

Sun

Alani

et al. 2019

Preprint

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Accumulating somatic mutations have been implicated in age-related cellular degeneration and death. Because of their random nature and low abundance, somatic mutations are difficult to detect except in single cells or clonal lineages. Here we show that in single hepatocytes from human liver, an organ normally exposed to high levels of genotoxic stress, somatic mutation frequencies are high and increase substantially with age. Significantly lower mutation frequencies were observed in liver stem cells and organoids derived from them. These results could explain the increased age-related incidence of liver disease in humans and stress the importance of stem cells in maintaining genome integrity.Genome integrity is critically important for cellular function. Evidence has accumulated that loss of genome integrity and the increasingly frequent appearance of various forms of genome instability, from chromosomal aneuploidy to base substitution mutations, is a hallmark of aging (1, 2). However, somatic mutations occur de novo across cells and tissues and are of low abundance. Hence, thus far, of all mutation types only chromosomal alterations could readily be studied directly during in vivo aging using cytogenetic methods (3). More recently it has become possible to also study low-abundant somatic mutations by whole genome sequencing (WGS) of single cells or clones derived from single cells (4-7). Such studies confirmed that like chromosomal alterations also base substitution mutations accumulate with age in human brain (8,9), intestine and liver (4).Due to its high metabolic and detoxification activity liver is more likely to be adversely affected by various damaging agents than most other organs. In humans this may cause agerelated loss of function, most notably a severe reduction in metabolic capacity and multiple pathologies, including fatty liver disease, cirrhosis, hepatitis, infections and cancer (10,11). To test if somatic mutations occur with a high frequency and accumulate rapidly with age we performed WGS on single primary hepatocytes from human donors varying in age between 5 months and 77 years of age. These cells were isolated from healthy human individuals shortly after death through perfusion of whole donor livers (Lonza Walkersville Inc.). Cell viability was higher than 80% and, after staining with Hoechst, hepatocytes were isolated via FACS into individual PCR tubes as diploid single cells (Fig. S1). In total we sequenced 4 single hepatocytes and bulk genomic liver DNA for each of eight human donors (Table S1). Each cell was subjected to our recently developed procedure for whole genome amplification (WGA) and sequencing (5,6). Somatic single nucleotide variants (SNVs) in single cells were identified relative to bulk genomic DNAs at a depth of ≥ 20X using a combination of VarScan2, MuTect2 and Haplotypecaller software with certain modifications (Methods , Table S2). Overlapping mutations, revealed by all three analytical tools, were exclusively considered for further analysis.After adjusting for genomic ...

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supporting

confidence: 80%

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Brazhnik

Sun

Alani

et al. 2019

Preprint

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“…Stem cell exhaustion has been postulated to play a primary role in aging as it interferes with self-renewal of differentiated cells in tissues and organs, slowly curtailing function (Ren, Ocampo, Liu, & Izpisua Belmonte, 2017). Small cross-sectional studies have provided some evidence that hematopoietic stem cells in humans accumulate DNA damage, possibly leading to reduced proliferative potential (Beerman, 2017;de Haan & Lazare, 2017). Studying the effect of aging on stem cells in humans is difficult.…”

Section: Stem Cell Exhaustion Deregulated Nutrient Sensing and Almentioning

confidence: 99%

Measuring biological aging in humans: A quest

et al. 2019

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The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

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“…Aging HSC face the potential of exhaustion. Several parameters differentiate old versus young HSC (reviewed in [44]), such as cumulating random DNA damage [45], reduced telomere length [46,47], increased polarity [48], reduced autophagy [49], and epigenetic reprogramming [50]. Some of these changes are presumably signs of imminent demise whilst others are possibly adaptation mechanisms for sustainability.…”

Section: Etiologies Of Arch: Survival Of the Fittest Agingmentioning

confidence: 99%

Concise Review: Age-Related Clonal Hematopoiesis: Stem Cells Tempting the Devil

et al. 2018

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The recent characterization of clonal hematopoiesis in a large segment of the aging population has raised tremendous interest and concern alike. Mutations have been documented in genes associated with hematological cancers and in non-driver candidates. These mutations are present at low frequency in the majority of individuals after middle-age, and principally affect the epigenetic modifiers DNMT3A and TET2. In 10%-40% of cases, the clone will progress to meet the diagnostic criteria for Clonal Hematopoiesis of Indeterminate Potential, which is associated with an increased risk of hematological cancer and cardiovascular mortality. Blood cell parameters appear unmodified in these individuals, but a minority of them will develop a hematologic malignancy. At this time, the factors put forward as potentially influencing the risk of cancer development are clone size, specific gene, specific mutation, and the number of mutations. Specific stress on hematopoiesis also gives rise to clonal expansion. Genotoxic exposure (such as chemotherapy), or immune attack (as in aplastic anemia) selects/provides a fitness advantage to clones with a context-specific signature. Clonal hematopoiesis offers a new opportunity to understand the biology and adaptation mechanisms of aging hematopoiesis and provides insight into the mechanisms underlying malignant transformation. Furthermore, it might shed light on common denominators of age-associated medical conditions and help devise global strategies that will impact the prevention of hematologic cancers and promote healthy aging. Stem Cells 2018;36:1287-1294.

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Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Cited by 41 publications

References 120 publications

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Measuring biological aging in humans: A quest

Concise Review: Age-Related Clonal Hematopoiesis: Stem Cells Tempting the Devil

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