At the “DKFZ-ZMBH Alliance Forum 2011” recently held in Heidelberg, internationally leading molecular and cell biologists, cancer researchers and epidemiologists presented their latest results on the ageing of cells and organisms and the development of cancer. The three-day meeting, which attracted more than 300 participants, was held to discuss the relationships between the molecular causes of ageing and the altered cellular processes that lead to tumour development and metastasis.
The range of scientific views on the relationship between cancer and age can hardly be better described than with the above-mentioned quotations from two famous cancer researchers in 1986. While the epidemiologist Sir Richard Peto’s claim, formulated with the self assurance and all the pleasure a genteel Oxford professor achieves from making pointed comments, refuted the molecular relationship between ageing and cancer as well as the existence of specific ageing processes altogether, the cell biologist David M. Prescott believed that there was an epidemiological correlation between the increase of cancer incidence and ageing, something that is now virtually undisputed. Scientists from around the world gathered at the DKFZ-ZMBH Alliance Forum (see BIOPRO article “The DKFZ-ZMBH Alliance”) held at the German Cancer Research Center in Heidelberg from 19th to 21st May 2011 to discuss their research results and theories related to the molecular causes of ageing and cancer development. Most participants shared the view of Prescott, who died in February 2011.
Professor Tom Kirkwood from the Institute for Ageing and Health at Newcastle University, UK gave a keynote lecture on the numerous levels at which cancer and ageing are connected with each other. Kirkwood emphasized that animals mostly only age in environments where natural selection barely intervenes. The first molecular theory on the phenomenon of ageing was put forward by Nobel Laureate Peter Medawar in 1952. Medawar’s mutation accumulation theory assumes that the evolutionary impact of adverse events (i.e. damaging mutations) declines with age, i.e. that the evolutionary effect of ageing is negligible. A convincing example of Medawar’s theory is Huntington’s disease, a fatal, neurodegenerative genetic disorder that manifests in older people. The American evolutionary biologist George C. Williams, who expanded Medawar’s mutation accumulation theory, suggested that genes not only react passively to selection pressure, but also have different antagonistic functions and can be actively selected. His “antagonistic pleiotropy” hypothesis is based on the idea that if a gene caused increased reproduction in early life and ageing in later life, then senescence would be adaptive.
An example of “antagonistic pleiotropy” is the tumour suppressor gene p53. In young people, the gene signals defective cells to stop dividing and activate the apoptosis programme, thereby counteracting the development of tumours. In older people, however, the inhibitory effect of p53 on the regeneration of damaged tissue prevails, thus stimulating the ageing process. Dr. Thomas Hofmann of the DKFZ-ZMBH Alliance showed how complicated the situation is in his lecture on the regulation of p53 in promyelocytic leukaemia (PML).In cells that are not exposed to stress, a protein kinase (HIPK2) that is necessary for the induction of apoptosis is ubiquinated by the ubiquitin ligase Siah-1 (a p53-inducible mediator of cell cycle arrest, apoptosis and tumour suppression) and degraded by proteasomes. In cancer cells with DNA damage, so-called checkpoint kinases (ATM/ATR – primary mediators of DNA double-strand breakages) lead to the phosphorylation of Siah-1, which leads to the dissociation of the HIPK2-Siah-1 complex and the stabilization and activation of HIPK2. Lethal damage leads to the phosphorylation of p53 by way of HIPK2, which in turn leads to the induction of apoptosis. The protein zyxin is a regulator of HIPK2 stability.
In the case of sublethal damage, p53 leads to the degradation of HIPK2; the DNA repair machinery is ignited and the cell can recover. Hofmann’s group of researchers at the DKFZ has also been able to show that HIPK2 is an authophosphorylating kinase. The activation of the enzyme upon DNA damage is increased severalfold upon the autophosphorylation of HIPK2.
Kirkwood’s theory (disposable soma theory), which he published in 1977, assumes that the maintenance of reproductive and non-reproductive aspects requires a lot of energy and that at some stage it no longer makes sense for an organism to invest energy (food energy resources) in keeping itself young, i.e. living much beyond the initial breeding years. Organisms only need to pass on their genome to guarantee the survival of the species; energy resources are only used for the maintenance of the body until such time as the selection pressure becomes so minimal that it is no longer worth counteracting the body’s degeneration. Kirkwood’s theory therefore assumes that there is a calculated division of energy between survival and reproduction. August Weismann’s (German evolutionary biologist born in 1834) germ plasm theory around 100 years ago is also based on the division of energy between survival and reproduction. It differentiates between the potentially immortal germ cells through which inheritance takes place in a multicellular organism and the somatic cells that are not agents of heredity. However, it is worth noting that this division is not irrevocable as the examples of the freshwater polyp Hydra (BIOPRO article “The Hydra genome”) and the unlimited growth of tumour cell lines (e.g., HeLa cells) show. Nevertheless, it seems that there are only a few “cancer stem cells” that suspend the ageing process and cause a tumour to become immortal.Leonard Hayflick has shown that normal cells can only undergo a limited number of cell divisions: this “Hayflick limit” (BIOPRO article entitled “Towards transdisciplinary research into ageing”) relates to the fact that each mitosis shortens the telomeres of the chromosomes either until they reach a critical length, or until the enzyme telomerase is inactivated. Telomere shortening eventually makes cell division impossible. In addition, it is correlated with ageing. In immortalised cancer cells and other cells that do not age, the enzyme telomerase restores the length of the telomeres after each round of cell division. Additional ageing processes that happen on the DNA level include copying errors and mutations caused by exogenous factors, in particular reactive oxygen species (ROS). Errors can also occur on the level of transcription, translation and proteins, all of which contribute to the ageing of cells. The mitochondria are the major source of reactive oxygen species and play a major source in cellular ageing. Dr. Aleksandra Trifunovic from the Cologne Excellence Cluster on Cellular Stress Responses in Age-Associated Diseases (CECAD) at the University of Cologne talked about mitochondrial dysfunctions that affect the ageing process.
Dr. Jiři Bartek, head of the Department of Cell Cycle and Cancer at the Danish Cancer Society in Copenhagen, who previously worked at the Heidelberg-based DKFZ, attached the greatest importance to DNA damage. He pointed out that at any point in time, around five billion cells in an adult person actively divide and the integrity of their genome is constantly exposed to the attack of endogenous and exogenous factors. In addition to previously known effects that damage DNA, Bartek described a new source of DNA double-strand breakages and cell ageing, which is caused by a cytolethal distending toxin secreted by many pathogenic bacteria. The cellular DNA repair machinery, in particular the ubiquitin signalling cascade induced by DNA breakages, is hugely important as an anti-cancer barrier.The enzyme poly-ADP-ribosylpolymerase, investigated by Professor Alexander Bürkle from the University of Konstanz is a key enzyme of the aforementioned DNA repair system. Bürkle has shown that the activity of this enzyme decreases with age. On the other hand, Professor Petra Boukamp from the DKFZ-ZMBH Alliance presented results that show that the inactivation of the poly-ADP-ribosylpolymerase-1 gene in human skin cells leads to the destabilization and accelerated shortening of telomeres.
The “Aging and Cancer – from molecules to organisms” conference provided a comprehensive overview of the most important molecular mechanisms currently being investigated and discussed in the field of ageing and cancer development. This article only gives a short overview of current findings. The researchers gathered in Heidelberg expressed many, diverse and sometimes controversial approaches and conclusions, but they nevertheless widely agree that ageing is not the result of a programme stored in the cellular genome, but of defects occurring in the cellular and metabolic processes that accumulate over time. The death of cells (or organisms) takes place when the number of damaged molecules (or cells) has reached a critical number, as was shown mathematically by the theoretical physicist and biologist Professor Geoffrey West from the Santa Fe Institute in New Mexico, USA. Richard Peto’s provocative statement “there is no such thing as ageing” was formulated to highlight that there is no such thing as a genetic ageing programme. The second half of his statement is no longer accepted, as it is known that the processes of cellular ageing and cancer development are connected with each other in many different ways.