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Review
. 2022 Feb;24(2):135-147.
doi: 10.1038/s41556-022-00842-x. Epub 2022 Feb 14.

Telomere dysfunction in ageing and age-related diseases

Francesca Rossiello  1 , Diana Jurk  2   3 , João F Passos  4   5 , Fabrizio d'Adda di Fagagna  6   7
Affiliations
Review

Telomere dysfunction in ageing and age-related diseases

Francesca Rossiello et al. Nat Cell Biol. 2022 Feb.

Abstract

Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.

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Conflict of interest statement

Competing interests

F.R. and F.d’A.d.F. are inventors on the patent applications PCT/EP2013/059753 and PCT/EP2016/068162. J.F.P. and D.J. declare no competing interests. I.F.O.M. has applied for European and US patent applications (EP 13721970.5, US 14/400,131 and 15/476,800), covering the use of antisense oligonucleotides targeting RNA species generated at the site of DNA damage, and for AU, BR, CA, CN, EA, EP, JP, KR, MX and US patent applications (AU2016300141, BR1120180017825, CA 2993128, CN 2016800566045, EA 201890379, EP 16750690.6, JP 2018504223, KR 20187005777, MX/A/2018001126, US 15/748,133 and US 17/065,409), covering the use of antisense oligonucleotides for the treatment of cancer characterized by alternative lengthening of telomeres and non-cancer conditions associated with telomere dysfunction, that list F.d’A.d.F. and F.R.

Figures

Fig. 1 |
Fig. 1 |. Telomere shortening and damage and their consequences.
a, Genomic DNA damage (DD) triggers a transient DNA damage response (DDR) that may not be sufficient for senescence establishment. Alternatively, an irreparable, therefore persistent, DNA damage at telomeres causes a protracted DDR and cellular senescence that are associated with SASP-mediated inflammation and consequent fibrosis. These events in a stem-cell context impair stem-cell properties and alter differentiation. Overall this contributes to organismal ageing. b, In proliferating tissues, telomeres are shortened with cell cycle divisions and, when critically short, they trigger a DDR. In non-proliferating, post-mitotic tissues, telomere dysfunction can be driven by irreparable DNA damage within telomeres. In both cases, the persistent DDR activation sustains a senescent phenotype that is characterized by arrested proliferation and SASP activation.
Fig. 2 |
Fig. 2 |. Evidence for a role of cellular senescence and telomere dysfunction in age-related diseases.
Schematic representation of the age-related diseases described in this Review grouped by organs or systems. AA, aplastic anaemia; AD, Alzheimer’s disease; ALD, alcholic liver disease; AMD, age-related macular degeneration; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; IRI, ischaemia–reperfusion injury; MDS, myelodysplastic syndrome; NAFLD, non-alcoholic fatty liver disease; PBC, primary biliary cirrhosis; PD, Parkinson’s disease; T2D, type 2 diabetes.
See this image and copyright information in PMC

References

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