Society for Endocrinology - a world-leading authority on hormones

The Endocrinologist

Issue 130 Winter 2018

Endocrinologist > Winter 2018 > Features

Ageing: the role of oxidative stress and mitochondria

Gabriele Saretzki | Features

The ageing process is complex and its detailed mechanisms are not yet well understood. However, cellular senescence might play an important role.


Cellular senescence in its various forms ‒ replicative, premature or oncogene-induced ‒ is a stress response.1 Senescence is an irreversible growth arrest. However, post-mitotic cells can also become senescent, although without the growth arrest feature.2

Replicative senescence is best characterised in human somatic cells such as fibroblasts by a continuous telomere shortening.3 However, telomere shortening can be accelerated by increased oxidative stress4,5 and thus has immediate significance for the ageing process, where telomeres are thought to be a possible biomarker.6 However, this is often just related to average telomere length while there is large heterogeneity between individual telomeres,7 a dynamic regulation of telomere homeostasis by telomerase and TERRA telomere transcription products8,9 and, most importantly, there can be DNA damage in telomeres without shortening.10,11

The direct association between senescence and the ageing process has been demonstrated by ablating these cells from an organism, either genetically12 or by using senolytics.13 López-Otín et al. have provided a comprehensive characterisation of the ageing phenotype.14


Most oxidative stress within cells is generated by mitochondria. Mitochondrial dysfunction and increased reactive oxygen species (ROS) are features of senescent cells which can be ameliorated with uncouplers and ROS-scavenging agents.15

Paradoxically, mitochondria seem to be essential and required for senescence induction, while ablating them prevents senescence and associated features such as DNA damage and senescence-associated secretory phenotype (SASP).16

During senescence and ageing, there is an accumulation of pathological mitochondrial mutations while the mutation numbers do not increase.17 Importantly, there is a certain threshold of around 70‒80% of mutated mitochondrial DNA molecules before a phenotype appears.

ROS are thought to be an important source of mitochondrial mutations. ROS are generated at different sites in the electron transport chain, in particular at complexes 1 and 3 during normal physiological functioning of mitochondria.18 There is also a reverse electron flow back from complex 2 to complex 1.19 Paradoxically, in some lower organisms, such as worms and flies, it has even been shown that lowering mitochondrial ROS results in a decrease in organismal lifespan.20,21 It is known that ROS also have important signalling functions,22 so that complete scavenging of ROS has a rather detrimental effect for mitochondria, cells and organisms.

Recent discoveries show the presence and function of mitochondrial micro RNAs regulating mitochondrial oxidative phosphorylation,23 and of hormone-like mitopeptides, such as humanin, which are involved in regulation of cellular energetics, insulin sensitivity and glucose homeostasis.24


‘Dysfunctional mitochondria activate inflammation as well as senescence, and can stimulate the innate immune response. Thus, their role and that of cellular oxidative stress remains an important field of research.’

An important research topic is the relationship between oxidative stress, mitochondria and ageing. It has long been known that ageing is associated with a low level, chronic inflammatory process25 and low level inflammation seems to correlate best with longevity in humans.26 Inflammation is also a prominent feature of many age-related diseases.27

To some extent, SASP, which results in a lot of secreted pro-inflammatory molecules,28 might contribute to the process of inflammation and so-called ‘inflammageing’.25 Via dysfunction and ROS production, mitochondria directly contribute to SASP and senescence.15

Baker et al. have demonstrated in a senescence clearance mouse model that not only were life- and health-span increased, but also that expression of inflammatory genes was decreased upon removal of senescent cells in various tissues, including heart, muscle and kidney.12

While the master inflammation regulators NFκB (nuclear factor-κB) and IL-1α (interleukin-1α) were thought to be responsible for SASP,29 a new concept regarding a specific mitochondria-driven SASP has been presented (mitochondrial dysfunction-associated senescence or MiDAS).30 This, however, remains controversial amongst researchers working on ageing.

Nutrients and glucose stimulate signalling processes in senescent cells, such as the mTor and the NFκB pathways.31,32 NFκB has been shown to modulate oxidative phosphorylation via p53.33 Consequently, a lack of mitochondria reduced the inflammatory signalling in a cell model.16

Another type of inflammation can be induced during cellular injury and leakage of mitochondrial DNA and other components, such as cardiolipin, out of mitochondria. This process can activate damage-associated molecular patterns via pattern recognition receptors.34 Activation of toll-like receptors (TLR9)35 and cytosolic DNA sensors such as cyclic GMP‒AMP synthase (cGAS)36 by mitochondrial DNA may be a result of the evolutionary origin of mitochondria and their resulting similarity to bacteria. In addition, ROS resulting from mitochondrial dysfunction can activate the inflammasome37 while inflammation, in turn, is able to induce senescence in neighbouring cells due to the so-called ‘bystander effect’.38,39


In summary, it is fair to state that mitochondria play an important role in the induction of senescence as well as in ageing. New mechanisms are constantly added regarding the detrimental role of excess ROS generated during ageing and senescence. Dysfunctional mitochondria activate inflammation as well as senescence, and can stimulate the innate immune response. Thus, their role and that of cellular oxidative stress remains an important field of research, while the prevention of senescence using senolytics and senostatics has already reached a translational state.40

Gabriele Saretzki, Lecturer in Ageing Research, Ageing Biology Centre, Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University


  1. Ben-Porath I & Weinberg RA 2005 International Journal of Biochemistry & Cell Biology 37 961‒976.
  2. Jurk D et al. 2012 Aging Cell 11 996‒1004.
  3. Harley CB et al. 1990 Nature 345 458‒460.
  4. von Zglinicki T et al. 1995 Experimental Cell Research 220 186‒193.
  5. von Zglinicki T 2000 Annals of the New York Academy of Sciences 908 99–110.
  6. Sanders JL & Newman AB 2013 Epidemiological Reviews 35 112‒131.
  7. Londoño-Vallejo JA 2004 Cancer Letters 212 135‒144.
  8. Blackburn EH 2005 FEBS Letters 579 859‒862.
  9. Wang C et al. 2015 International Journal of Biological Sciences 11 316‒323.
  10. Hewitt G et al. 2012 Nature Communications 3 708.
  11. Fumagalli M et al. 2012 Nature Cell Biology 14 355–365.
  12. Baker DJ et al. 2016 Nature 530 184‒189.
  13. Kirkland JL & Tchkonia T 2017 EBioMedicine 21 21‒28.
  14. López-Otín C et al. 2013 Cell 153 1194‒1217.
  15. Passos JF et al. 2010 Molecular Systems Biology 6 347.
  16. Correia-Melo C et al. 2016 EMBO Journal 35 724–742.
  17. Greaves LC et al. 2014 PLoS Genetics 10 e1004620.
  18. Quinlan CL et al. 2013 Methods in Enzymology 526 189‒217.
  19. Turrens JF 2003 Journal of Physiology 552 335‒344.
  20. Ristow M & Zarse K 2010 Experimental Gerontology 45 410‒418.
  21. Scialò F et al. 2016 Cell Metabolism 23 725‒734.
  22. Finkel T 2012 Journal of Biological Chemistry 287 4434‒4440.
  23. Gao S et al. 2018 Mitochondrion 38 41‒47.
  24. Kim S-J et al. 2017 Journal of Physiology 595 6613‒6621.
  25. Franceschi C & Campisi J 2014 Journals of Gerontology: Series A 69 Suppl 1 S4–S9.
  26. Arai Y et al. 2015 EBioMedicine 2 1549‒1558.
  27. Rea IM et al. 2018 Frontiers in Immunology 9 586.
  28. Davalos AR et al. 2010 Cancer and Metastasis Reviews 29 273‒283.
  29. Orjalo AV et al. 2009 Proceedings of the National Academy of Sciences of the USA 106 17031–17036.
  30. Wiley CD et al. 2016 Cell Metabolism 23 303–314.
  31. Laberge RM et al. 2015 Nature Cell Biology 17 1049–1061.
  32. Mauro C et al. 2011 Nature Cell Biology 13 1272–1279.
  33. Tornatore L et al. 2012 Trends in Cell Biology 22 557–566.
  34. Fang C et al. 2016 Protein & Cell 7 11–16.
  35. Zhang JZ et al. 2014 International Journal of Molecular Medicine 33 817–824.
  36. Glück S et al. 2017 Nature Cell Biology 19 1061‒1070.
  37. Lane T et al. 2013 Frontiers in Physiology 4 50.
  38. Acosta JC et al. 2013 Nature Cell Biology 15 978–990.
  39. Nelson G et al. 2018 Mechanisms of Ageing & Development 170 30‒36.
  40. 40. Kirkland JL et al. 2017 Journal of the American Geriatrics Society 65 2297‒2301.

This Issue:

Winter 2018

Winter 2018