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Aging and disease    2017, Vol. 8 Issue (5) : 628-642     DOI: 10.14336/AD.2017.0103
Review |
The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks
Aunan Jan R.1,2,*, Cho William C3, Søreide Kjetil1,2,4,*
1Gastrointestinal Translational Research Unit, Molecular Lab, Stavanger University Hospital, Stavanger, Norway
2Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
3Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
4Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Abstract  

Aging is the inevitable time-dependent decline in physiological organ function and is a major risk factor for cancer development. Due to advances in health care, hygiene control and food availability, life expectancy is increasing and the population in most developed countries is shifting to an increasing proportion of people at a cancer susceptible age. Mechanisms of aging are also found to occur in carcinogenesis, albeit with shared or divergent end-results. It is now clear that aging and cancer development either share or diverge in several disease mechanisms. Such mechanisms include the role of genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, decreased nutrient sensing and altered metabolism, but also cellular senescence and stem cell function. Cancer cells and aged cells are also fundamentally opposite, as cancer cells can be thought of as hyperactive cells with advantageous mutations, rapid cell division and increased energy consumption, while aged cells are hypoactive with accumulated disadvantageous mutations, cell division inability and a decreased ability for energy production and consumption. Nonetheless, aging and cancer are tightly interconnected and many of the same strategies and drugs may be used to target both, while in other cases antagonistic pleiotrophy come into effect and inhibition of one can be the activation of the other. Cancer can be considered an aging disease, though the shared mechanisms underpinning the two processes remain unclear. Better understanding of the shared and divergent pathways of aging and cancer is needed.

Keywords aging      cancer      genomic instability      epigenetic      telomere      stem cells      genomic instability      metabolism     
Corresponding Authors: Aunan Jan R.,Søreide Kjetil   
About author:

These authors contribute equally to the manuscript

Issue Date: 01 October 2017
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Aunan Jan R.
Cho William C
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Cite this article:   
Aunan Jan R.,Cho William C,Søreide Kjetil. The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks[J]. Aging and disease, 2017, 8(5): 628-642.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2017.0103     OR     http://www.aginganddisease.org/EN/Y2017/V8/I5/628
FeatureAgingCancer
Genomic instabilityIncreasedIncreased
Telomere attritionShortened telomeresShortened telomeres but telomerase activation
Epigenetic alteration:
DNA methylationGlobal hypomethylationHyper- of tumor suppressors and hypo- of oncogenes
Histone modification Non-coding DNAComplex
miRNA deregulation; for example, miR17-92 downregulation
Complex miRNA deregulation, for example, miR-17-92 upregulation
Proteostasis:
ChaperoningImpairedAugmented
Proteasome activityImpairedAugmented
Autophagy-lysosome activityImpairedAugmented
Deregulated nutrient sensingInhibition of insulin and mTOR signaling increase lifespanInhibition of insulin and mTOR signaling is antineoplastic
Cellular senescenceIncreasedPrevalent in premalignant tumors but evaded in fully malignant tumors
Stem cellExhaustedPotential nidus for tumorigenesis
Table 1  Hallmarks that are either shared or divergent in aging and cancer.
Figure 1.  Lifelong interplay between stem cells in aging and cancer

A simplified model that views aging and cancer from the perspective of alterations within the stem and progenitor cell pool. Over the lifespan of an organism, long-lived cells (such as stem cells) accumulate DNA damage from a number of stresses including intracellular oxidants generated from normal metabolism. The default pathway for such damaged stem cells is to undergo growth arrest, apoptosis or senescence. As more and more stem cells withdraw from the proliferative pool, there is a decrease in the overall number and/or functionality of both stem and progenitor cells. This decrease predisposes the organism to impaired tissue homeostasis and regenerative capacity and could contribute to aging and age-related pathologies. Presumably, some rare cells can escape from this normal default pathway by acquiring additional mutations that allow them to continue to proliferate even in the setting of damaged DNA. These proliferating but damaged cells might provide the seeds for future malignancies. In this scenario, both cancer and aging result primarily from accumulating damage to the stem and progenitor cell compartment. Mutations that allow stem cells to continue to proliferate in the setting of normal growth arrest signals such as DNA damage (for example, loss of p16INK4a or reactivation of telomerase) would temporarily expand the stem cell pool and hence delay age-related pathologies. Over the long term, these mutations would also increase the likelihood of cancer.

During normal aging, stem cells accumulate damage and subsequent stress-dependent changes, for example, de-repression of the CDKN2a (p16INK4a/ARF) locus or telomere shortening. This leads to the increasing abundance of senescent cells (large hexagonal cells) within differentiated tissues. Preneoplastic leasions, arising directly from stem cells or from more committed cells, undergo rapid proliferation (small cells marked with asterisks). These pre-malignant tumor cells rapidly accumulate damage, in part owing to the presence of oncogenes, leading to a higher proportion of tumor cells becoming senescent (cells marked as hexagons filled with white color). Tumor progression to full malignancy is favoured when tumor cells acquire mutations that impair the senescence program (for example, mutations in Trp53 or CDKN2a).

Illustration is modified and based upon Finkel T, Serrano M, Blasco MA. The common biology of cancer and aging. Nature. 2007 Aug 16;448(7155):767-74. Copyright © 2007.

Figure 2.  The dual role of autophagy in cancer

Examples of mechanisms that are related to either tumor suppression or tumor growth where autophagy plays a role. Cx denotes chemotherapy, Rx denotes radioationtherapy.

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