Epigenetic clock analyses of cellular senescence and ageing.

Donna Lowe,Kenneth Raj,Steve Horvath

doi:10.18632/oncotarget.7383

Donna Lowe, Kenneth Raj + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.7383

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Abstract

A confounding aspect of biological ageing is the nature and role of senescent cells. It is unclear whether the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are descriptions of the same phenomenon instigated by different sources, or if each of these is distinct, and how they are associated with ageing. Recently, we devised an epigenetic clock with unprecedented accuracy and precision based on very specific DNA methylation changes that occur in function of age. Using primary cells, telomerase-expressing cells and oncogene-expressing cells of the same genetic background, we show that induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell. However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway, highlighting the independence of senescence from cellular ageing. Consistent with this, we observed that telomerase-immortalised cells aged in culture without having been treated with any senescence inducers or DNA-damaging agents, re-affirming the independence of the process of ageing from telomeres and senescence. Collectively, our results reveal that cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.

Highlights

While ageing at the level of the organism is obvious and understood, the biological aspect of ageing is far from clear
The following features of this clock demonstrates that its age estimates capture several aspects of biological age: (a) it can accurately measure the age of cells regardless of tissue types including brain, liver, kidney, breast and lung [34] (b) its accuracy (r = 0.96 on subjects aged between 0 to 100 and r = 0.77 in middle age subjects) is substantially higher than that of other molecular markers such as telomere length (r = 0.5) [36] (c) it is able to predict mortality independent of health, life-style or genetic factors [37] (d) its measurements correlate with cognitive and physical fitness amongst the elderly [38] and (e) it is able to detect accelerated ageing induced by various factors including obesity [39], Down syndrome [40] and HIV infection [41]
To determine whether senescent cells alter their DNA methylation state in an age-dependent manner, we used primary endothelial cells (ECs) that were derived from the human coronary artery of a 19 year old male

Summary

Introduction

While ageing at the level of the organism is obvious and understood, the biological aspect of ageing is far from clear. The following features of this clock demonstrates that its age estimates capture several aspects of biological age: (a) it can accurately measure the age of cells regardless of tissue types including brain, liver, kidney, breast and lung [34] (b) its accuracy (r = 0.96 on subjects aged between 0 to 100 and r = 0.77 in middle age subjects) is substantially higher than that of other molecular markers such as telomere length (r = 0.5) [36] (c) it is able to predict mortality independent of health, life-style or genetic factors [37] (d) its measurements correlate with cognitive and physical fitness amongst the elderly [38] and (e) it is able to detect accelerated ageing induced by various factors including obesity [39], Down syndrome [40] and HIV infection [41].

Results

Conclusion