Extending life: disease pattern shift

3. Biology of tumours and ageing

Cancerigenesis is a multistep process. A single genomic alteration in the cell is not sufficient to determine cancer development. The first damage gives the cell a competitive advantage in comparison with the other cells and for this reason its replication is faster with a clonal selection. Further hits give further advantages and further clonal selection to the development of an overt clinical cancer.
We know that tumour frequency is strictly connected with ageing at least until the extreme ages period. How ageing and cancer are related can be explained by a small group of rare autosomal recessive inherited cancer syndromes. These syndromes are connected with the alteration of genes related to a correct DNA replication. The alteration of these genes leads to the accumulation of damages in the genomic DNA, such as those that can be found over longer time in the physiological ageing process. This accumulation of rapid DNA damages leads to the development of malignant tumours and also to signs of premature ageing. One of these syndromes in fact is a true progeroid syndrome with a complete ageing process in the early stages of life (Werner syndrome). So genetic damage accumulation is a common process related to ageing and tumour development. This fact raises the question of how in the extreme ages of life tumour frequency decreases, when the level of DNA damage accumulation should be at the maximum level. There can be at least two explanations: the first one is that the organism in the extreme ages of life has lower possibilities of growing a cancer. The second explanation can be related to a specific genetic predisposition to reach the extreme ages of life that is connected also with a low level of cancer development risk.
Understanding individual cancer predisposition can be important in explaining the extreme ageing predisposition. Ponder has hypothesized that apart from familiar predisposition to cancer there is an individual predisposition8. This is related to the fact that any genetic individual code is different, with different single nucleotides in many sequences of the genome. This is called ‘single nucleotide polymorphism’ (SNP) and is connected with most of the individual’s physical characteristics, but also with the predisposition to specific diseases. In such a way several different SNPs can define different levels of risk of developing a disease, such as a tumour. Following this hypothesis, Pharoah reported that a “substantial fraction of sporadic cancers (non familiar cancers) may occur in a predisposed minority of the population”9.
The same can be hypothesized for the capability of successful ageing. We know that in long-living families of centenarians the siblings tend to live longer than siblings of short-living families. They have a 3 to 4 times probability of reaching the 80s and 90s compared to short-living families10. In a similar analysis performed in Trieste using nonagenarians’ families (Fig. 5) a similar pattern was found. The interesting fact is that only about 10% of the siblings of the long-living families has a successful ageing, while the other 90% die at a normal age. So there must be a large number of genetic characteristics (SNPs) inherited in different proportions from relatives that give a final genetic pattern to win a successful ageing in the lottery of life.

fig. 5: Trieste longevity study: siblings of nonagenarians live longer in comparison with siblings of people dying at normal age
In the Trieste longevity study comparing the causes of death of siblings of short- and long-living families, no differences were found for the major diseases in the two groups except for perinatal deaths which were quite common at that time. In long-living families, perinatal deaths of the siblings are almost half of those in short-living families (fig. 6). This leads us to consider that factors connected with the birth period are also related to the ageing process. But in Western countries nowadays there are almost no perinatal deaths anymore, so a mechanism of natural selection related in some way also to ageing is lost. For these reasons a major number of bad ageing characteristics can be transmitted to the next generation. This fact raises the provocative idea that we cannot be so sure that the optimistic longevity projections for the next decades are really true.

fig. 6: Trieste longevity study: causes of death among siblings of long-lived and short-lived individuals

8 BAJ Ponder, “Cancer Genetics”, Nature 411:336-341(2001).
9 P.D. Pharoah, A. Antoniou, M. Bobrow, R.L. Zimmern, D.F. Easton, B.A. Ponder, “Polygenic susceptibility to breast cancer and implications for prevention”, Nat. Genet. 31:33-36 (2002).
10 T.T. Perls, E. Bubrick, C.G. Wager, J. Vijg, L. Kruglyak, “Siblings of centenarians live longer”, Lancet 351:1560 (1998).

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