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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 1  |  Page : 1-5

Cellular senescence due to physical inactivity: A review


Department of Oral Pathology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, Tamil Nadu, India

Date of Submission21-Feb-2022
Date of Acceptance23-Feb-2022
Date of Web Publication22-Apr-2022

Correspondence Address:
Suganya Panneer Selvam
Department of Oral Pathology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhi.IJHI_7_22

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  Abstract 

Fundamental building blocks of our bodies are called as cells. Cellular changes play a major role in the ageing process. Cellular senescence is a process where there is inability of the cells to proliferate due to loss of replicative or growth potential. Physical inactivity is the absence of any movement produced by muscles of body, which requires energy. Various molecular mechanisms are responsible for cellular senescence. One important factor is telomere, which protects chromosome and is chiefly responsible for the replicative process. Physical activity is found to be associated with reduced disease risk and increased longevity through various cellular and molecular mechanisms. However, evidences relating to cellular senescence and physical inactivity are found in sparse. This review aims to discuss the importance of physical activity and role of telomere in senescence and other aging processes.

Keywords: Cellular senescence, chromosome, exercise, replication, telomeres


How to cite this article:
Ramesh S, Ramasubramanian A, Selvam SP. Cellular senescence due to physical inactivity: A review. Int J Histopathol Interpret 2019;8:1-5

How to cite this URL:
Ramesh S, Ramasubramanian A, Selvam SP. Cellular senescence due to physical inactivity: A review. Int J Histopathol Interpret [serial online] 2019 [cited 2022 May 24];8:1-5. Available from: https://www.ijhi.org/text.asp?2019/8/1/1/343728




  Introduction Top


A permanent state of cell cycle arrest that leads to declined regenerative potential and function of tissues due to lack of tissue remodelling during development and injury, thereby leading to inflammation and process of formation of tumours in aged organisms, is known as cellular senescence. Senescent cells differ from normal cells due to the presence of features such as lack of proliferative markers, inhibitors of cell cycle, β-galactosidase enzyme activity associated with cellular senescence, and tumour suppressors and often markers of DNA damage with predominant excretion of signalling molecules.


  Types of Cellular Senescence Top


Cellular senescence is classified into different categories based on the causative factor for its occurrence. Some of them are as follows:

  • Senescence induced by deoxyribonucleic acid (DNA) damage: Damage to DNA is irreparable and may lead to senescence or apoptosis depending upon the duration and magnitude of damage. Certain drugs and radiation can produce multiple damages to DNA.[1]
  • Senescence induced by oncogenes: Senescence can be caused due to either inactivation of tumour suppressor genes likephosphatase and tensin homolog (PTEN) or activation of tumour developing genes or oncogenes such asrat sarcoma viral oncogene homolog (RAS) and B-Raf murine sarcoma viral oncogene homolog B1 (BRAF).[2]
  • Senescence induced by oxidative agents: These agents produce senescence by damaging cellular components and partly affect DNA. They can be either oxidative agents like H2O2 or products produced from cell metabolism that act as an oxidizing agent.[3]
  • Senescence induced by chemotherapeutic agents: Chemotherapeutic agents are certain drugs that are used for the treatment of cancer. These drugs act through various mechanisms that inhibit selective enzymes, whereas certain drugs directly act upon DNA producing damage to it.[4] Drugs that can produce senescence are bleomycin, palbociclib, etc.



  Effects of Physical Activity Top


Physical inactivity is one of the reasons for the prevalence of major non-communicable diseases, such as coronary heart disease (CHD), type 2 diabetes, breast cancer, and colon cancer, which result in decrease in life expectancy. On the other hand, physical activity, which utilizes the energy produced by the body, has been proved to revert some of the abovementioned conditions that are produced due to physical inactivity. Some of the effects of physical activity in healthy adults are listed as follows:[6]

  • Lowers risk of CHD, type 2 diabetes, high blood pressure, breast cancer, and colon cancer.
  • Decreases incidence of stroke, hypertension, metabolic syndrome, depression, etc.
  • Comprises beneficial effects such as cardiovascular and muscular fitness, enhanced healthy bones, and improved cognitive function of the body.

  Hallmark Pathways of Cellular Senescence Top


As mentioned earlier, many etiological factors are responsible for senescence in a cell. Direct damage to DNA produces senescence in a cell. This is accompanied by the process called DNA damage response (DDR). The activators of DDRs are double-stranded DNA breaks (DSBs), which on prolonged activity in unresolved cases can produce cellular senescence. These DSBs promote the binding of an enzyme to the DNA damage site, which leads to cell cycle repair, DNA damage, and apoptosis. This enzyme that specifically targetsbeta-hexosaminidase A (HZAX) genes is called as Ataxia telangiectasia mutated (ATM) kinase.[7] Phosphorylation plays a major role in transduction of signals through activity of two important kinases, namely checkpoint kinase 1 (CHK1) and checkpoint kinase 2 (CHK2).[8]

Cellular senescence is also produced due to arrest in normal cell cycle and production of cyclin-dependent kinase inhibitors (CDKi’s). This leads to secretion of secretory phenotype that is associated with cellular senescence exhibiting mitochondrial dysfunction, namely SASP. Activation of this phenotype results in resistance to a process where the programmed cell death occurs known as apoptosis. This prevents the death of cell, which is further exposed to altered metabolism due to stress in endoplasmic reticulum. All these changes occur in three levels, namely genetic/epigenetic level, messenger ribonucleic acid (mRNA) level, and protein level.[9],[10]


  Mechanisms of Cellular Senescence Top


Many studies have been done in order to review about constant increase in the number of stimulus that produces senescence and the possible mechanisms involved. Various signalling pathways signal these stimulus to activate tumour suppressor gene, namely p53, which converges other genes in the activation of CDKi’s such as p16 and p47. This inhibition of cyclin-dependent kinase (CDK) complexes leads to proliferation arrest and senescence is activated by the presence of hypophosphorylated form of Enterobacteria phage RB9 (RB9) gene, which plays a crucial role in cellular senescence.[11],[12]

As mentioned earlier, triggers and stresses that are multiple activate signalling pathways, which cover the activation of cell cycle inhibitors and Rb gene, which is a tumour suppressor gene. Loss of telomere length and agents that damage DNA trigger DDR, which leads to activation of p53 and a target gene p21. Senescence is associated with CDKs that activate p16, p38, and p53. In SASP pathway, transforming growth factor-β functions as a key role and regulates the cell cycle inhibitors such as p21, p27, and p15.[13],[14]


  Effects of Senescence on Disease Top


Senescence has both beneficial and adverse effects on disease. Many research have been done in order to find out the effects of senescence. Some of them are listed as follows.

Beneficial activity:

    A. Cancer: Senescence controls tumour progression as it is associated with its pathology. Pro-senescent agents (CDK4 inhibitor) produce regression of tumour.[15]

    B. Fibrosis: Senescence has been associated with pathology and restricts fibrosis, except in the case of idiopathic pulmonary fibrosis, where senescence favours fibrosis. The final fate of senescent cells may also have pathophysiological consequences because, given their altered phenotype, effective removal could be more beneficial for the maintenance of endothelial homeostasis.[16]

    C. Vascular diseases: It is found that senescence inhibits atherosclerotic plaque formation. It also interferes with pathology.[17]

    D. Metabolic diseases: Senescence has a deterministic role to play in obesity and diabetic conditions. It produces systemic inflammation and insulin resistance.[18]

    E. Neurological diseases: Pathologies of Alzheimer’s disease and Parkinson’s disease have been related with senescence.[2],[19]



  Biomarkers of Cellular Senescence Top


Various biomarkers are available to mark the presence or progression of senescence. Some of them are discussed as follows:

  • DDR: Direct DNA damage receptor is identified by the presence of phosphorylated p53, which is a key signalling protein. This can be used as a marker for cellular senescence.[4]
  • Arrest of cell cycle: This is measured in two ways. First, proliferations of cells are measured by colony-formation potential by conducting certain assays. Second, CDKs can be used by measuring their expression potential, especially p16 and p21.[20]
  • Secretory phenotype: Enzyme Linked Immuno Sorbent Assay (ELISA) or immunostaining that measures the protein secretion and expression is also used to mark cytokines such as interleukin (IL)-1a, IL-6, IL-8; chemokines like C-C Motif Chemokine Ligand 2 (CCL2); and Matrix Metalloproteinases (MMPs) such as MMP-1 and MMP-3.[21]
  • Resistance to apoptosis: Although not regularly used, the upregulation of B cell Lymphoma (BCL) proteins such as Bcl-2 and Bcl-w were used as a biomarker.[22]
  • Size of cell: It is carried out in in vitro studies. Bright field microscopy is used where the enlarged cell body and the irregular shape of senescent cell are evaluated. Changes in cell shape can also be detected by the use of immunofluorescence targeting vimentin, actin, or other cytoplasmic proteins.[23]
  • Plasma membrane composition: Plasma membrane contains an oxidized form of protein vimentin and other markers like Dishevelled, Egl-10 & Pleckstrin domain (DEP) and Dipeptidyl peptidase 4 (DPP4). These have been proposed as markers and hence not widely used.[24]
  • Lysosomal content: Lysosomal content is seen increased in cases where there is marked senescence. The first test, which assesses senescence, is done by finding out the common maker that marks increased lysosomal activity, namely Senescence-Associated beta-galactosidase (SA-βgal).[25]
  • Mitochondrial content: Electron microscopy can be used to analyse the size and shape of mitochondria, and MitoTrackers are used to measure the membrane potential of mitochondria.[26]
  • Metabolism: It is not used as there is lack of information about the effects of metabolism on cells that induce senescence.
  • Endoplasmic reticulum stress: Not a marker of senescence due to its inconsistency.



  Features of Senescence Top


    a. The senescence growth arrest is essentially permanent and cannot be reversed by known physiological stimuli. However, some senescent cells that do not express the CDKi p16INK4a can resume growth after genetic interventions that inactivate the p53 tumor suppressor.[28] So far, there is no evidence that spontaneous p53 inactivation occurs in senescent cells, although such an event is not impossible.

    b. Senescent cells increase in size, sometimes enlarging more than twofold relative to the size of non-senescent counterparts.[29]

    c. Senescent cells express a senescence-associated β-galactosidase,[24] which partly reflects the increase in lysosomal mass.[30]

    d. Cells that senesce with persistent DDR signalling harbour persistent nuclear foci, termed DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). These foci contain activated DDR proteins, including phospho-ATM and phosphorylated ATM/ataxia telangiectasia and Rad3-related substrates[31] and are distinguishable from transient damage foci.[32] DNA-SCARS include dysfunctional telomeres or telomere dysfunction-induced foci.[33]

    e. Senescent cells with persistent DDR signalling secrete growth factors, proteases, cytokines, and other factors that have potent autocrine and paracrine activities.



  Physical Activity and Telomeres Top


There is a significant association present between the telomere lengths with physical activity. This was reported when excessive telomere shortening in the skeletal muscle of endurance athletes with severe fatigued athlete myopathic syndrome was compared to that of age- and training volume-matched athletes conducted by Collinset al.[34] As a follow-up study by the Collins et al. group, shorter minimum telomere lengths were observed in those endurance athletes with the highest number of years and hours spent training. Hence, these results indicate that long-term endurance training by highly trained athletes may be a significant stressor to skeletal muscle and to satellite cell telomeres, which is indicated by the shorter minimum telomere lengths.

On the other hand, physical inactivity leads to the loss of bone mineral density and skeletal muscle mass with advancing age, which has important consequences for morbidity and mortality in older men and women. Fewer studies of telomere biology have been performed in these tissues, but the results generally indicate a similar association to that observed for cardiovascular disease (CVD) disease and metabolic disease.

Skeletal muscle is unique in that it consists of multinucleated muscle fibres and multiple niche populations of singularly nucleated cell types, the well-characterised being satellite cells.[35] Skeletal muscle is also considered to be post mitotic, with only the satellite cells actively dividing when new nuclei are needed with skeletal muscle fibre. When skeletal muscle satellite cells are activated to divide and incorporate into muscle fibres as new myonuclei, the fibre’s average telomere length is reduced.[34]


  Conclusion Top


Physical activity helps to maintain physical fitness of body, thereby reducing the risk of being exposed to various pathological conditions. This in turn increases the life expectancy by decreasing the rate of disease progression and disease occurrence. Senescence is associated with impaired cell proliferation potential, which may be associated with many reasons in which physical inactivity is one. Hence, a thorough understanding regarding the correlation of physical activity and senescence is required as senescence plays a dual role in disease progression.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Muñoz-Espín D, Serrano M. Cellular senescence: From physiology to pathology. Nat Rev Mol Cell Biol 2014;15:482-96.  Back to cited text no. 1
    
2.
Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer 2015;15:397-408.  Back to cited text no. 2
    
3.
Hernandez-Segura A, de Jong TV, Melov S, Guryev V, Campisi J, Demaria M. Unmasking transcriptional heterogeneity in senescent cells. Curr Biol 2017;27:2652-2660.e4.  Back to cited text no. 3
    
4.
Wiley CD, Flynn JM, Morrissey C, Lebofsky R, Shuga J, Dong X, et al. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 2017;16:1043-50.  Back to cited text no. 4
    
5.
Warburton DE, Charlesworth S, Ivey A, Nettlefold L, Bredin SS. A systematic review of the evidence for Canada’s physical activity guidelines for adults. Int J Behav Nutr Phys Act 2010;7:39.  Back to cited text no. 5
    
6.
Shiloh Y. The ATM-mediated DNA-damage response: Taking shape. Trends Biochem Sci 2006;31:402-10.  Back to cited text no. 6
    
7.
Bekker-Jensen S, Lukas C, Kitagawa R, Melander F, Kastan MB, Bartek J, et al. Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. J Cell Biol 2006;173:195-206.  Back to cited text no. 7
    
8.
Burd CE, Sorrentino JA, Clark KS, Darr DB, Krishnamurthy J, Deal AM, et al. Monitoring tumorigenesis and senescence in vivo with a p16(INK4A)-luciferase model. Cell 2013;152: 340-51.  Back to cited text no. 8
    
9.
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol 2018;28:436-53.  Back to cited text no. 9
    
10.
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev 2010;24:2463-79.  Back to cited text no. 10
    
11.
Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev 2014;28:99-114.  Back to cited text no. 11
    
12.
Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J, Murillo-Cuesta S, et al. Programmed cell senescence during mammalian embryonic development. Cell 2013;155:1104-18.  Back to cited text no. 12
    
13.
Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 2013;155:1119-30.  Back to cited text no. 13
    
14.
Michaud K, Solomon DA, Oermann E, Kim JS, Zhong WZ, Prados MD, et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 2010;70:3228-38.  Back to cited text no. 14
    
15.
Ramakrishna G, Anwar T, Angara RK, Chatterjee N, Kiran S, Singh S. Role of cellular senescence in hepatic wound healing and carcinogenesis. Eur J Cell Biol 2012;91:739-47.  Back to cited text no. 15
    
16.
Erusalimsky JD. Vascular endothelial senescence: From mechanisms to pathophysiology. J Appl Physiol (1985) 2009;106:326-32.  Back to cited text no. 16
    
17.
Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, et al. Fat tissue, aging, and cellular senescence. Aging Cell 2010;9:667-84.  Back to cited text no. 17
    
18.
Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 2012;7:e45069.  Back to cited text no. 18
    
19.
Chinta SJ, Lieu CA, Demaria M, Laberge RM, Campisi J, Andersen JK. Environmental stress, ageing and glial cell senescence: A novel mechanistic link to Parkinson’s disease? J Intern Med 2013;273:429-36.  Back to cited text no. 19
    
20.
Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008;6:2853-68.  Back to cited text no. 20
    
21.
Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM. Senescence and apoptosis: Dueling or complementary cell fates? EMBO Rep 2014;15:1139-53.  Back to cited text no. 21
    
22.
Cormenier J, Martin N, Deslé J, Salazar-Cardozo C, Pourtier A, Abbadie C, et al. The ATF6α arm of the unfolded protein response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E2 intracrine pathway. Mech Ageing Dev 2018;170:82-91.  Back to cited text no. 22
    
23.
Althubiti M, Lezina L, Carrera S, Jukes-Jones R, Giblett SM, Antonov A, et al. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis 2014;5:e1528.  Back to cited text no. 23
    
24.
Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 2006;5:187-95.  Back to cited text no. 24
    
25.
Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 2007;5:e110.  Back to cited text no. 25
    
26.
Freund A, Laberge RM, Demaria M, Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 2012;23:2066-75.  Back to cited text no. 26
    
27.
Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J 2003;22:4212-22.  Back to cited text no. 27
    
28.
Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965;37:614-36.  Back to cited text no. 28
    
29.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995;92:9363-7.  Back to cited text no. 29
    
30.
Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4A) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A 1996;93:13742-7.  Back to cited text no. 30
    
31.
Narita M, Nuñez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003;113:703-16.  Back to cited text no. 31
    
32.
Brenner AJ, Stampfer MR, Aldaz CM. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene 1998;17:199-205.  Back to cited text no. 32
    
33.
Rae DE, Vignaud A, Butler-Browne GS, Thornell LE, Sinclair-Smith C, Derman EW, et al. Skeletal muscle telomere length in healthy, experienced, endurance runners. Eur J Appl Physiol 2010;109:323-30.  Back to cited text no. 33
    
34.
Collins M, Renault V, Grobler LA, St Clair Gibson A, Lambert MI, Wayne Derman E, et al. Athletes with exercise-associated fatigue have abnormally short muscle DNA telomeres. Med Sci Sports Exerc 2003;35:1524-8.  Back to cited text no. 34
    
35.
Decary S, Hamida CB, Mouly V, Barbet JP, Hentati F, Butler-Browne GS. Shorter telomeres in dystrophic muscle consistent with extensive regeneration in young children. Neuromuscul Disord 2000;10:113-20.  Back to cited text no. 35
    




 

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  In this article
Abstract
Introduction
Types of Cellula...
Effects of Physi...
Hallmark Pathway...
Mechanisms of Ce...
Effects of Senes...
Biomarkers of Ce...
Features of Sene...
Physical Activit...
Conclusion
References

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