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Mitochondrial dysfunction and cell senescence: deciphering a complex relationship.

mitochondria cellullar senescence ageing senescence senolytics senostatics

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#1 Engadin

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Posted 22 June 2019 - 10:34 PM

F U L L   T E X T ( . P D F ) :   Willey Online Library






Cellular  senescence  and  mitochondrial  dysfunction  have  both  been defined  as  classical hallmarks of the ageing process. Here, we review the intricate relationship between the two. In  the  context  of  ageing,  it  is now  well  regarded that  cellular  senescence  is  a  key  driver in both ageing and the onset of a number of age-related pathologies. Emerging evidence has pinpointed mitochondria as one of the key modulators in the development of the senescence phenotype,  particularly  the  pro-inflammatory  senescence  associated  secretory  phenotype (SASP). This review focuses on the contribution of homeostatic mechanisms, as well as of reactive   oxygen   species (ROS) and   mitochondrial   metabolites   in   the   senescence programme.  Furthermore,  we  discuss  emerging  pathways  and  mitochondrial-mediated mechanisms that may be influencing the SASP and, subsequently, explore how these may be exploited to open up new therapeutic avenues.



1. Introduction


Cellular  senescence  was  first  described  in  cultured  normal  human  fibroblasts  when  it  was observed that they ceased to proliferate following a finite number of cell divisions[1]. It has since been established that this initial observation reflects a specific type of senescence that occurs  in  response  to  telomere  attrition [2].  It  is  now well established that  senescence  is  a biological programme that can occur in response to a number of stresses and is a feature in multiple   physiological   and  pathological   processes.   It   has   been   demonstrated   that senescence  can  occur  as  a  consequence  of  oxidative  stress,  oncogene  activation, or chromatin  modifications, amongst  other  forms  of  stress [3]. Most  notably, it  has  been suggested  that senescence  has  evolved  as a cellular  process  to  avert  cell  replication  on  a damaged  DNA  template,  therefore  acting  as  an  effective  mechanism  to  prevent tumour progression[4]. Furthermore,  recent  evidence  has  emerged  that  senescence  also  plays  a key  role  inthe  healing  of  wounds,  tissue  repair, and  during  embryonic  development [5,  6]. Transient senescence, whereby damaged cells are eliminated, clearly has beneficial effects for an organism. However, persistence ofsenescent cells leads paradoxically to deleterious effects. There is now substantial evidence that an accumulation of senescent cells is a driver of the ageing process[7].


Senescent  cells  can  be  identified  by  several  notable  markers  and  morphological  changes that distinguish them from proliferating cells and other non-dividing cells. However no single marker  that  unequivocally  identifies  senescent  cellshas  been  identified  so  far. The  most prominent feature of senescence is the cell cycle arrest; therefore senescent cells exhibit an upregulation of genes that enforce the cell cycle arrest, such as p16, ARF, p21and p53[8].

The  genes  which  are  upregulated  during  senescence generally  reflect the senescence-inducing  stimuli,  for  example,  the  upregulation  of p16  and  ARF  occurs  predominantly  in response to mitogenic stress [9]. By contrast, p21 and p53 are usually upregulated following the  activation  of  a  DNA  damage  response  (DDR). The  DDR  is  a  key  feature  of  senescent cells  and  is  observed  following a  number  of  stimuli  such  as genotoxic  stress,  replicative exhaustion  and  telomere  attrition. Senescent  cells have  been  shown  to display  a  variety  of markers  of a  DDRsuch  as the  presence  of γH2AX (phosphorylated  Histone  2AX) and 53BP1 foci (p53-binding  protein-1)[10]. In  addition,  senescent  cells  display  an  absence  of proliferative  markers  such  as  Ki67  and  incorporation  of  BrdU  (5-bromodeoxyuridine) [10]. Furthermore, the  presence  of  increased  lysosomal  content  in  senescent  cells  allows  the detection  of β-galactosidase  activity  at  pH  6.0,  referred  to  as  senescence-associated β-galactosidase [11].   Morphologically,   senescent   cells   in   culture   have   an   enhanced intracellular  volume  which  is  associated  with  a  flattening  of  the  cytoplasm,  as  well  as  a vacuolized  appearance [12].  Senescent  cells  also  display  a  unique and  complex secretory phenotype  referred  to  as  the  Senescence-associated  Secretory  Phenotype  (SASP).  This SASP consists of an array of pro-inflammatory cytokinesand chemokines, as well as growth factors   and various proteins   responsible   for   degrading   the   extracellular   matrix [13]. Alongside  the  SASP,  senescent  cells  produce  exacerbated  levels  of  mitochondrial  derived reactive  oxygen  species  (ROS)[14].  Collectively,  the  SASP  in  conjunction  with  enhanced ROS production functions to reinforce the cell cycle arrest in an autocrine manner [15, 16], but can also contribute to senescence in a paracrine manner [17, 18]
2. Cellular senescence is a driver of ageing and age-related disease
Several groups have observedthat senescent cells accumulatewith age in different tissuesand species[19-22]. Furthermore, senescent cells have been observed in a variety of age-related diseases[11, 19, 23, 24].
To address the fundamental question regarding whether senescence plays a causal role in ageing,  mouse  models  were recently developed  which  allow  the  specific  elimination  of senescent  cells. Studies  have demonstrated  that  clearance  of  p16positive  senescent  cells alleviates the onset of a number of age-related pathologies in progeroid and wild type mice [7, 25-27]. Following this initial evidence of causality, the role of senescence in the context of various age-related diseases was investigated by various groups. To date there is evidence using mouse models that senescence plays a causal role in multiple age-related conditions. These include: neurodegeneration [28-30], osteoarthritis [31, 32], osteroporosis [33], atherosclerosis [34, 35], fatty liver disease [36], myocardial infarction [37], diabetes [38, 39], pulmonary fibrosis [40-42], neuropsychiatric disorders [43] amongst others [44-49] (Table 1).
A  key  question  for  the  field  is  to  understand  specifically  how  senescent  cells  exert their detrimental  effects and  thus  contribute  to the  ageing  process. A  popular hypothesis  is  that senescent cells are major contributors to the chronic inflammation which is observed during ageing, via the SASP.
The  SASP is  thought to  signal  the  immune  system to  mediate  the  clearance  of senescent cells, however, it is believed that with advancing age the capacity for the immune system to effectively  remove  senescent  cells  becomes  diminished,  therefore contributing to  their accumulation [50-52].  As  senescent  cells  accumulate partly due  to  reduced  immune clearance,  the  associated  SASP acts in  a  paracrine  fashion to  induce  senescence  in surrounding  cells [18].  This  process  can  therefore  further  exacerbate  the  accumulation  of senescent cells  and  thus  the  associated  chronic  inflammation (Figure  1). In  addition,  it  has been  demonstrated  that  the  SASP  can  be tumourigenic  by  promoting  proliferation  of malignant  cells,  as  well  as  promoting  epithelial-mesenchymal  transition  whereby  epithelial cells  acquire  mesenchymal  like  properties  allowing  them  to  become  invasive  and  promote malignant transformation [13, 53, 54]. At this stage, there is not sufficient evidence to directly conclude  that  the  SASP is  the  maindriver  of  ageing.  However,  a  number  of  studies  have demonstrated  that inhibition  of  pathways  which  suppress  the  SASP have  beneficial  effects on both health span and lifespan [55-60]. Therefore, from a clinical perspective there is great interest in understanding the biological pathways which regulate senescence and the SASP in order to develop drugs which either eliminate senescent cells (senolytics) or alleviate the SASP but do not remove the tumour suppressive ability of senescent cells (senostatic) [61]. So  far, several  drugs  with  senolytic  and  senostatic  properties  have  been  identified  and shown to attenuate age-related disorders in mice. The clinical potential of potential senolytic drugs has been recently reviewed in detail by Kirkland and colleagues [62].Several clinical trials are under way and the first pilot study where senolytic cocktail dasatinib and quercetin were administered to  Idiopathic  pulmonary  fibrosis  (IPF)  patients  was  recently  published [63].
3. Mitochondrial dysfunction is a feature of cellular senescence
From a cellular perspective, the importance of mitochondria as the primary source of energy has been well defined for some time, however, mitochondria are also important in a myriad of  other  cellular  processes  such  as  cell cycle  control,  apoptosis  and  regulating  cellular metabolism [64]. Interestingly  both  mitochondrial  dysfunction  and  cellular  senescence  are consideredkey  hallmarks  of  ageing,  however,  it  is  only  work  in  the  past  decade  that  has begun to uncover the relationship between the two [65].
Cumulative evidence  indicates that senescent cells exhibit a variety of changes in terms of the structure, dynamics and function of mitochondria.
Senescent   fibroblasts   show   an   increase   in   mitochondrial   mass   and   abundance   of tricarboxylic  acid  (TCA)  cycle  metabolites [15,  66,  67]. However,  while  mitochondria  are more  abundant in  senescent  cells they  are  less  functional.  Mitochondria  from  senescent cells  show  a decreased  mitochondrial  membrane  potential, increased  proton  leak and increased generation of ROS [14, 15]. Recently, it was also reported that mitochondria from senescent cells have decreased fatty acid oxidation, which results in increased accumulation of lipids [36].
Senescent  cells also show dramatic changes  in mitochondrial  morphology. Mitochondria from  senescent  cells  exist in  a  state  of  hyper-fusion as  opposed  to  a healthy  mitochondrial network which continuously undergoes fission and fusion events to meet metabolic demands and  allow  the  removal  of  dysfunctional  entities.  This  fused  state  occurs  in  response  to reduced  expression  of  mediators  of  the  fission  process; Drp1(dynamin  related  protein 1) and Fis1 (mitochondrial fission protein 1), as well as an overall reduction in the frequency of fusion and fission events [68, 69].
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Also tagged with one or more of these keywords: mitochondria, cellullar senescence, ageing, senescence, senolytics, senostatics

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