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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


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