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Ageing and the Telomere Connection: An Intimate Relationship with Inflammation. (Ageing Res Rev., Nov 2015)

Zhang J1*, Rane G2*, Dai X1, Shanmugam MK1, Arfuso F3, Samy RP4, Peng Lai MK1, Kappei D5, Kumar AP6#, Sethi G7#.

1Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
3Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, WA, Australia.
4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
5Cancer Science Institute of Singapore, National University of Singapore, Singapore.
6Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, WA, Australia; National University Cancer Institute, Singapore; Department of Biological Sciences, University of North Texas, Denton, TX, USA. Electronic address: csiapk@nus.edu.sg.
7Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, WA, Australia; National University Cancer Institute, Singapore.

*Co-first Authors
#Co-last Authors

Abstract:
Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-κB and overexpression of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF-κB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases.

ARR-D-15-00097R1 Figure 1

Figure: Vicious circle of inflammation and telomere shortening leads to accelerated aging and increases risk of age-related diseases. Inflammatory molecules (colored green) found associated with telomere or telomeric proteins (colored red) in various diseases are depicted. {COPD – Chronic obstructive pulmonary disease; CRP – C reactive protein; CTC1 – CTS telomere maintenance complex component 1; CVD – Cardiovascular disease; DKC –Dyskerin; Hu-GROα – Human growth factor α; ICAM1 – Intercellular adhesion molecule 1; IL – Inter leukin; MCP1 – monocyte chemotactic protein 1; NFκB –Nuclear factor kappa B;PARP1 – Poly(ADP-ribose) polymerase 1; PGC-1α – PPAR gamma coactivator 1 alpha; POT1 – protection of telomeres protein 1; PPAR – peroxisome proliferator-activated receptor; RAP1 – repressor-activator protein 1; RTEL1 – Regulator of telomere elongation helicase 1; TCAB1 – telomere cajal body protein 1; TERC – telomerase RNA component; TERT – telomerase reverse transcriptase; TIN2 – TRF1-interacting protein 2; TNFα – tumor necrosis factor; TRF2 – telomere repeat binding factor 2}.