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Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

Nature Reviews Molecular Cell Biology volume 18, pages 595–609 (2017)Cite this article

Subjects

Key Points

  • The world's most common diseases are chronic ageing-associated illnesses.

  • Premature ageing diseases and ageing-associated diseases (AADs) share the common hallmarks of increased genomic instability, altered metabolic signalling and reduced regenerative potency.

  • Premature ageing diseases are powerful models to study the cellular and molecular causes and mechanisms of physiological ageing and AADs.

  • Decreased efficiency of DNA repair, shortening of telomeres and loss of heterochromatin underlie the loss of genomic integrity in (premature) ageing and AADs.

  • Increased metabolic signalling contributes to increased levels of oxidative stress, which compromise the integrity of the cellular genome and proteome in ageing.

  • Chronic stress permanently alters cellular fate by inducing senescence and reducing the regenerative capacity of stem cells, which ultimately drives physiological decline in ageing.

  • Segmental progeroid syndromes provide exciting new opportunities to understand and therapeutically correct the loss of cellular homeostasis in ageing and disease.

Abstract

Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson–Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.

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Figure 1: Cellular ageing defects.
Figure 2: Defects in DNA damage repair associated with ageing.
Figure 3: Epigenetic defects associated with ageing.
Figure 4: Mitochondrial ROS-driven ageing defects.
Figure 5: Cellular senescence pathways.

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  1. National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Nard Kubben & Tom Misteli

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  1. Nard Kubben
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N. K. and T. M. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

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PowerPoint slides

Glossary

Nucleotide excision repair

(NER). A DNA repair pathway specialized in the removal of bulky DNA adducts, including ultraviolet damage-induced thymidine dimers.

Non-homologous end joining

(NHEJ). A DNA repair pathway that repairs double-strand breaks through direct ligation of the broken ends without the need of a homologous template.

Oxidative phosphorylation

(OXPHOS). A process by which electrons are transferred from electron donors to electron acceptors, thereby releasing energy in the form of ATP. In prokaryotes, this process takes place in the inner mitochondrial membrane at the site of the electron transport chain.

Ubiquitin–proteasome system

(UPS). A system that degrades proteins marked by degradation-specific ubiquitin marks in an ATP-dependent manner.

Epithelial-to-mesenchymal transition

(EMT). A process by which epithelial cells undergo various molecular changes related to cell–cell adhesion, polarity and invasive properties, in order to become mesenchymal cells. EMT has beneficial roles in wound healing but exerts detrimental effects in organ fibrosis and the initiation of tumour metastasis.

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Kubben, N., Misteli, T. Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol 18, 595–609 (2017). https://doi.org/10.1038/nrm.2017.68

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