Human ageing processes may hinder cancer development

A new study, published in Aging Cell, has found that human ageing processes may hinder cancer development.

Ageing is one of the biggest risk factor for cancer.

However, the biological mechanisms behind this link are still unclear.

Each cell in the human body is specialised to carry out certain tasks and will only need to express certain genes.

Gene expression is the process by which specific genes are activated to produce a required protein.

Gene expression analyses have been used to study cancer and ageing, but only a few studies have investigated the relationship between gene expression changes in these two processes.

In an effort to better understand the biological mechanisms researchers from the University of Liverpool’s Integrative Genomics of Ageing Group, led by Dr. Joao Pedro De Magalhaes, compared how genes differentially expressed with age and genes differentially expressed in cancer among nine human tissues.

Normally, a healthy cell can divide in a controlled manner. In contrast, senescent or ‘sleeping’ cells have lost their ability to divide.

As we age, the number of senescent cells in our bodies increase, which then drive many age-related processes and diseases.

Genetic mutations triggered by things such as UV exposure can sometimes cause cells to replicate uncontrollably – and uncontrolled cell growth is cancer. Cells are often able to detect these mutations and in response go to sleep to stop them dividing.

The researchers found that in most of the tissues examined, ageing and cancer gene expression ‘surprisingly’ changed in the opposite direction.

These overlapping gene sets were related to several processes, mainly cell cycle and the immune system. Moreover, cellular senescence changed in the same direction as ageing and in the opposite direction of cancer signatures.

The researchers believe the changes in ageing and cellular senescence might relate to a decrease in cell proliferation, while cancer changes shift towards an increase in cell division.

Dr. De Magalhaes, said: “One of the reasons our bodies have evolved to have senescent cells is to suppress cancers.

But then it seems that senescent cells accumulate in aged human tissues and may contribute to ageing and degeneration.

Importantly, our work challenges the traditional view concerning the relationship between cancer and ageing and suggests that ageing processes may hinder cancer development.

While mutations accumulate with age and are the main driver of cancer, ageing tissues may hinder cell proliferation and consequently cancer.

So you have these two opposite forces, mutations driving cancer and tissue degeneration hindering it.

This may explain why at very advanced ages cancer incidence levels off and may even decline.”

However, an alternative explanation comes from evolutionary biology.

First author Kasit Chatsirisupachai, explains:

“And aged tissue might actually be a better environment for a rogue cancer cell to proliferate because the cancer cell will have an evolutionary advantage.”

Dr. De Magalhaes: “Our results highlight the complex relationship between ageing, cancer and cellular senescence and suggest that in most human tissues ageing processes and senescence act in tandem while being detrimental to cancer.

But more mechanistic studies are now needed.”

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Aging is an inevitable time-dependent decline in physiological organ function and is a major risk factor for one of the most significant causes of human morbidity and mortality, namely cancer. According to the US National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) Database, 43% of men and 38% of women will develop an invasive cancer over a lifetime.

Among these, 23% of men and 19 % of women will die from cancer. More than half of cancers occur in individuals older than 70 [1].

Improvements in healthcare and healthier nutrition have increased the average life expectancy over the past century.

According to the World Health Organization (WHO) life expectancy is now exceeding 80 years in most developed countries. As the population is aging, cancer is becoming an ever more important health burden worldwide.

The underlying mechanism in both cancer and aging is the time dependent accumulation of cellular damage [2].

Cancer and aging may seem like opposite processes – cancer cells have the ‘gain of function and fitness’ whereas aging cells are characterized by a ‘loss of function and fitness’ [2].

However, the two traits do share many common characteristics (Table 1), for which a comparative review will be presented.

Table 1

Hallmarks that are either shared or divergent in aging and cancer.

Feature	Aging	Cancer
Genomic instability	Increased	Increased
Telomere attrition	Shortened telomeres	Shortened telomeres but telomerase activation
Epigenetic alteration:
DNA methylation	Global hypomethylation	Hyper- of tumor suppressors and hypo- of oncogenes
Histone modification Non-coding DNA	Complex miRNA deregulation; for example, miR17-92 downregulation	Complex miRNA deregulation, for example, miR-17-92 upregulation
Proteostasis:
Chaperoning	Impaired	Augmented
Proteasome activity	Impaired	Augmented
Autophagy-lysosome activity	Impaired	Augmented
Deregulated nutrient sensing	Inhibition of insulin and mTOR signaling increase lifespan	Inhibition of insulin and mTOR signaling is antineoplastic
Cellular senescence	Increased	Prevalent in premalignant tumors but evaded in fully malignant tumors
Stem cell	Exhausted	Potential nidus for tumorigenesis

Genomic instability

One of the immediate common hallmarks to both aging and cancer is the occurrence of genomic instability.

The human DNA is vulnerable to mutagens such as exogenous radiation and endogenous free radicals, to which we are exposed constantly over a life-time.

Indeed, cells in the human body undergo cell-division billions of times during which the DNA is replicated, each time with the risk of introducing or suffering mutational events.

Most of these inevitable mutations are harmless and the majority is corrected by the DNA repair system. However, a certain degree of accumulated DNA damage occurs with time [3].

The normal mutation rate after repair in the human genome is about one mutation per billion bases per division, witch means that a 1,000 bp gene has a one in a million chance of a single mutation per cell division[4].

Genomic instability in key regulator functions is the most prominent “enabling hallmark” that leads cancer cells to acquire many of the driving cancer traits, such as self sufficiency in growth signals and increased metastatic potential [5].

Genomic instability is a characteristic of almost all human cancers and the rate of mutation is higher than in normal cells in order to acquire all the mutations needed for tumorigenesis [6].

Indeed, with increasing knowledge and lessons learned from whole genome sequencing of numerous cancers, the mutation rate is known to be overall high yet with different rates according to tumor types and site, with some tumors being labeled hypermutated [7].

Lessons from hereditary syndromes

Different mutations in the DNA repair machinery lead to hereditary cancers syndromes such as hereditary non-polyposis colorectal cancer (HNPCC)[8], breast and ovarian cancer with hereditary mutations in BRCA1 and BRCA2 [9] and familial adenomatous polyposis with an almost 100% lifetime risk of colorectal cancer[10].

These are just a few examples of a large group of such cancer syndromes resulting from mutations in the DNA repair machinery, giving rise an increased mutational rate and genomic instability.

Mutations in the DNA repair machinery can also cause progeroid premature aging syndromes of which there are many [11].

Werner syndrome and Bloom syndrome are progeroid syndromes, both of which are caused by mutations in RecQ helicases involved in repair of double stranded breaks and telomere maintenance [12, 13].

They manifest with cancers at a very young age, premature aging signs (greying of hair, loss of organ function and reserve) and a significantly reduced lifespan [14].

Cockayne syndrome (CS) and Xeroderma Pigmentosum (XP) are two other examples of progeroid syndromes, both a result of mutations in the nucleotide excision repair system (NER). The NER mutation in CS affects only actively transcribed genes (TCR-transcription coupled repair) whereas the damage in XP affects the whole genome (GGR-global genomic repair) [15].

They both manifest with features of premature aging, but interestingly only XP manifest with increased susceptibility to skin cancer [15]. The mechanism behind is still unknown, but it has been speculated that it may involve apoptosis of mutated cells in CS [16].

Genomic instability in aging cells

Maintenance of genomic stability appears to be a core function to prevent cancer development as well as aging processes.

Genomic instability and mutations may contribute to aging in several ways, ranging from small point mutations to large translocations and deletions.

In somatic cells, it can give rise to disruption of the phenotype through alterations in the protein coding sequence but probably more common is the alteration of regulatory sequences leading eventually to progressive decline of organ function due to alterations of the proteome and homeostasis [17, 18].

Indeed there is a large variation in gene expression among cells in the same tissue with age, and in an experiment on mice cardiomyocytes in young and old individuals the variation was significant in all genes tested nuclear genes which included 7 housekeeping genes, 3 heart specific genes and 2 protease genes [18].

The increased gene heterogeneity with age seems to be tissue specific, where for instance small intestinal cells accumulated mainly point mutations and cardiomyocytes also carried large rearrangements [19]

This gene heterogeneity is proposed to lead to stochastic deregulation of gene expression among neighboring cells and lead to aging[18]. Genetic instability can also cause aging if the damage is large enough to cause apoptosis or senescence of stem cells leading to the depletion of division competent cells [17].

Rivaling processes

Cancer and aging are in a way rivaling processes [18]. On the one hand, cancer is the result of advantageous mutations that confers an advantage to the neoplastic cell when it comes to growth and metastasis (Fig. 1).

On the other hand, aging is the result of harmful mutations detrimental to the cells physiology or damage leading to senescence, apoptosis and eventually depletion of stem cells [17, 20, 21].

The idea of antagonistic pleiotrophy comes to play where high levels of cell cycle gatekeeper proteins – such as p53 – results in senescence and apoptosis protecting against harmful mutations and tumorigenesis, while low levels allows cells with tumorigenic mutations to propagate and promote cancer [17, 21].

Genomic instability thus reflects the wear and tear on cells over time, leading to controlled cell death and loss of tissue in aging. Yet, it also represents the stochastic risk of accumulating changes that fosters uncontrolled cell division and expansion in cancer, evidenced by the higher lifetime cancer risk of tissues requiring many cell divisions for homeostasis, indicating that the number one cause of tissue cancer variation is just “bad luck” [22].

A deeper understanding of genomic instability may thus help understand its relation to both aging as a process and the role in carcinogenesis with potential for therapeutic interventions in both areas.

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More information: Kasit Chatsirisupachai et al, A human tissue‐specific transcriptomic analysis reveals a complex relationship between aging, cancer, and cellular senescence, Aging Cell (2019). DOI: 10.1111/acel.13041

Journal information: Aging Cell
Provided by University of Liverpool