Cellular and epigenetic drivers of stem cell ageing

Abstract

Adult tissue stem cells have a pivotal role in tissue maintenance and regeneration throughout the lifespan of multicellular organisms. Loss of tissue homeostasis during post-reproductive lifespan is caused, at least in part, by a decline in stem cell function and is associated with an increased incidence of diseases. Hallmarks of ageing include the accumulation of molecular damage, failure of quality control systems, metabolic changes and alterations in epigenome stability. In this Review, we discuss recent evidence in support of a novel concept whereby cell-intrinsic damage that accumulates during ageing and cell-extrinsic changes in ageing stem cell niches and the blood result in modifications of the stem cell epigenome. These cumulative epigenetic alterations in stem cells might be the cause of the deregulation of developmental pathways seen during ageing. In turn, they could confer a selective advantage to mutant and epigenetically drifted stem cells with altered self-renewal and functions, which contribute to the development of ageing-associated organ dysfunction and disease.

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Fig. 1: Molecular damage in ageing stem cells.
Fig. 2: Systemic factors and changes in the local microenvironment affect stem cell function during ageing.
Fig. 3: Epigenetic drift and clonal expansion altering adult stem cells during ageing.
Fig. 4: Shadowed activation of developmental pathways in stem cells during ageing.
Fig. 5: A model of stem cell ageing by epigenetic integration of damage signals and deregulation of developmental pathways.

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Acknowledgements

F.N. is supported by the Alexander von Humboldt Foundation and the German Federal Ministry for Education and Research. K.L.R. is supported by a European Research Council Advanced Grant (StemCellGerontoGenes). The Fritz Lipmann Institute is a member of the Leibniz Association and is financially supported by the federal government of Germany and the State of Thuringia.

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M.E., F.N., A.O. and K.L.R. contributed equally to writing, revising, researching and discussing the article.

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Correspondence to Maria Ermolaeva or Francesco Neri or Alessandro Ori or K. Lenhard Rudolph.

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Glossary

Quiescence

A reversible state that can describe non-dividing stem cells. Cells are in the G0 phase of the cell cycle, characterized by very low metabolic, transcriptional and proliferative activities.

Progenitor cells

Cells that are constantly generated from stem cells with reduced self-renewal and high proliferative activity; needed for production of cell types for tissue regeneration and homeostasis.

HIF1–PKD2/PKD4 pathway

A signalling pathway that adjusts cellular metabolism to reduced levels of oxygen (hypoxia), by suppressing the entry of glycolytic metabolites into mitochondria.

p38

A MAPK that regulates expression of innate immune molecules and stress effectors in response to cell-extrinsic and cell-intrinsic stimuli.

FOXO

A subgroup of the forkhead family of transcription factors regulated by the insulin–PI3K–AKT pathway and involved in induction of stress response and survival genes.

Myeloid bias

Myeloid bias designates preferential differentiation of haematopoietic stem cells into myeloid cells, such as monocytes, macrophages, neutrophils, platelets and dendritic cells.

Co-chaperone

A protein that regulates the activity of chaperones, such as heat shock protein 70 (HSP70) and HSP90, during protein folding.

Polycomb group protein

A chromatin remodeller implicated in the timely silencing of developmental genes.

Nucleotide excision repair

(NER). A DNA repair pathway responsible for removal and repair of DNA helix-distorting lesions, such as cyclobutane pyrimidine dimers and pyrimidine (6–4) pyrimidone photoproducts.

Non-homologous end joining

(NHEJ). A DNA repair pathway that repairs double-strand DNA breaks by directly ligating the broken ends without the use of a homologous template (a rapid but error-prone process).

Heterochronic parabiosis

An experimental procedure in which two animals of different age, for example, one young and one old, are surgically connected so that their blood circulations are shared.

Gut microbiome

The ensemble of commensal bacterial strains that inhabit the digestive tract of an organism.

Exosomes

Vesicles released by cells containing RNAs and proteins, which have several functions, including cell-cell communication.

Fibrosis

The excessive deposition of extracellular matrix proteins caused by aberrant tissue repair and chronic inflammation.

Reserve stem cells

Pools of cells already committed to differentiation, generally quiescent, that upon injury can de-differentiate and revert to a stem-like state.

Epimutations

Alterations of a specific chromatin modification in a specific genomic locus.

Retrotransposon

A class of transposable DNA sequences using RNA as a mobile intermediate.

Spurious transcription

An RNA transcription process starting from an intragenic or intergenic region.

Progeroid mice

Mice carrying mutations in genes that are mutated in human progeroid syndromes that are characterized by segmental premature ageing (affecting specific organs).

Aneuploidy

The irregular deviation of chromosome numbers from the normal situation — not including doubling of chromosome numbers as in tetraploidy.

Dysbiosis

A deviation in the composition of bacterial strains and taxa in the microbiome of an organ or organism characterized by decreases in overall complexity and overgrowth of certain species.

Lateral inhibition

A mechanism by which cells of one type enforce a difference in cell fate and/or cell identity in neighbouring cells.

Thymic involution

A reduction in the thymus mass and in the output of naive T lymphocytes.

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Ermolaeva, M., Neri, F., Ori, A. et al. Cellular and epigenetic drivers of stem cell ageing. Nat Rev Mol Cell Biol 19, 594–610 (2018). https://doi.org/10.1038/s41580-018-0020-3

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