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Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

Chronic inflammation induces telomere dysfunction and accelerates ageing in mice
Chronic inflammation induces telomere dysfunction and accelerates ageing in mice
Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-?B induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-?B, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.
Jurk, Diana
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Wilson, Caroline
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Passos, João F.
e3ce80c2-52c0-4df4-b07b-457e97103a57
Oakley, Fiona
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Correia-Melo, Clara
a05bb7ac-c159-4ef0-b3c3-94629e88bf60
Greaves, Laura
6739a5f3-d382-411b-976b-f3c14a37eea2
Saretzki, Gabriele
aa5a5a0c-5e50-432f-aae8-4098a1a1f9a5
Fox, Chris
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Lawless, Conor
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Anderson, Rhys
8f506aca-d68e-43dc-bded-a33a7e74447f
Hewitt, Grame
ad7464ae-4980-4ecb-8748-ce0135139a20
Pender, Sylvia L.F.
62528b03-ec42-41bb-80fe-48454c2c5242
Fullard, Nicola
ed6994de-0c47-4bb5-8381-110d1071fd13
Nelson, Glynn
51ae5d50-0ac7-4814-8f47-0ca5e566ed16
Mann, Jelena
23defaa6-4d36-4d53-909c-f1375ee73df8
van de Sluis, Bart
952c8b80-6d18-4f09-a36c-562a3a4201a2
Mann, Derek A.
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von Zglinicki, Thomas
87182e17-0a7f-498f-af8c-45c8f9282d3c
Jurk, Diana
f271403a-16ea-451d-9132-4718ec1a1f23
Wilson, Caroline
32416f0f-c68d-4b70-9acd-cf8b5095cfd7
Passos, João F.
e3ce80c2-52c0-4df4-b07b-457e97103a57
Oakley, Fiona
f5f32319-966d-46b1-b774-bd7548022ff3
Correia-Melo, Clara
a05bb7ac-c159-4ef0-b3c3-94629e88bf60
Greaves, Laura
6739a5f3-d382-411b-976b-f3c14a37eea2
Saretzki, Gabriele
aa5a5a0c-5e50-432f-aae8-4098a1a1f9a5
Fox, Chris
06b59c5d-a369-4443-b5ae-d9a06f622d9f
Lawless, Conor
925e0047-861d-4ac2-9f95-0764caab12ff
Anderson, Rhys
8f506aca-d68e-43dc-bded-a33a7e74447f
Hewitt, Grame
ad7464ae-4980-4ecb-8748-ce0135139a20
Pender, Sylvia L.F.
62528b03-ec42-41bb-80fe-48454c2c5242
Fullard, Nicola
ed6994de-0c47-4bb5-8381-110d1071fd13
Nelson, Glynn
51ae5d50-0ac7-4814-8f47-0ca5e566ed16
Mann, Jelena
23defaa6-4d36-4d53-909c-f1375ee73df8
van de Sluis, Bart
952c8b80-6d18-4f09-a36c-562a3a4201a2
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d
von Zglinicki, Thomas
87182e17-0a7f-498f-af8c-45c8f9282d3c

Jurk, Diana, Wilson, Caroline, Passos, João F., Oakley, Fiona, Correia-Melo, Clara, Greaves, Laura, Saretzki, Gabriele, Fox, Chris, Lawless, Conor, Anderson, Rhys, Hewitt, Grame, Pender, Sylvia L.F., Fullard, Nicola, Nelson, Glynn, Mann, Jelena, van de Sluis, Bart, Mann, Derek A. and von Zglinicki, Thomas (2014) Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nature Communications, 2 (4172). (doi:10.1038/ncomms5172). (PMID:24960204)

Record type: Article

Abstract

Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-?B induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-?B, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.

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e-pub ahead of print date: 24 June 2014
Published date: 24 June 2014
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 367110
URI: https://eprints.soton.ac.uk/id/eprint/367110
PURE UUID: 7c38d747-8a12-46f4-a664-d525e5016107
ORCID for Sylvia L.F. Pender: ORCID iD orcid.org/0000-0001-6332-0333

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Date deposited: 30 Jul 2014 11:50
Last modified: 10 Sep 2019 00:48

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Contributors

Author: Diana Jurk
Author: Caroline Wilson
Author: João F. Passos
Author: Fiona Oakley
Author: Clara Correia-Melo
Author: Laura Greaves
Author: Gabriele Saretzki
Author: Chris Fox
Author: Conor Lawless
Author: Rhys Anderson
Author: Grame Hewitt
Author: Nicola Fullard
Author: Glynn Nelson
Author: Jelena Mann
Author: Bart van de Sluis
Author: Derek A. Mann
Author: Thomas von Zglinicki

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