Researchers here investigate copy number variations in the context of a long-lived human study population, finding similar results to those obtained from other studies. Copy number variations in the genome are one of the forms of inherited difference between individuals. Stretches of DNA have duplications or deletions, leading to more or fewer copies of specific DNA sequences. In recent years, with the growing availability of genetic data, an increased frequency of copy number variations has been shown to correlate with higher mortality rates in human studies, and some specific variations seem to be sufficiently uncommon in older people to suggest that they cause harm over the long term in some way.
It is worth considering that the purpose of progress in science is to gain more knowledge of this sort of intricate relationship between DNA differences and natural variations in life span - to understand how the system works if left to its own devices. The purpose of progress in medicine, however, is to make these differences irrelevant by intervening in our biology to prevent disease and dysfunction. Methods of repairing the causes of aging will in due course lead to rejuvenation treatments and people who never enter the late stage of life, heavily damaged, in which genetic variations become important determinants of how far a failing body can limp along. There isn't all that much of an overlap between the genetics of aging and the effective treatment of aging: the former is the study of what happens when you cannot treat aging, and all of our attention should be focused on efforts to dig ourselves out of that position.
In this study, we explored the impact of copy number variation on mortality at the extreme end of life by performing a genome-wide investigation of the association between CNVs and prospective mortality in nonagenarians and centenarians. As our main result, we found that an increase in the average CNV length significantly associated with a higher mortality, as did an increase in the total part of the genome occupied by deletions. These findings are consistent with the results of a previous study in which the burden of large deletions was found to be associated with higher mortality, suggesting that longer CNVs, especially deletions, are more disadvantageous. The identified association between a higher CNV burden and increased mortality is generally in line with the proposed role of genome instability, that is, a decrease in genome maintenance and hence an accumulation of genomic changes, in lifespan and suggests that even among the very old, the load of genomic alterations is linked to differences in mortality.
Among the specific deletions and duplications, four deletions were consistently associated with higher mortality across the study populations, as were a single deletion in women and two deletions in men. These seven nominally significant CNVs are surrounded by numerous genes, of which two, TRPM3 and STARD13, have previously been implicated in the regulation of human lifespan. The STARD13 gene has moreover been associated with plasma levels of amyloid beta peptides that, among other things, play a role in Alzheimer's disease and hypertension. In addition, also the CCDC3 and IRAK1BP1 genes could be speculated to play a role in human lifespan, as they have been reported to inhibit inflammation, and the majority of the other genes are involved in cell adhesion, which has previously been linked to longevity and age-related diseases. In addition to their more direct effect on genes, for example, alteration of gene dosage and gene disruption, CNVs may also affect regulatory regions or other functional regions that influence gene expression. Only a few of the seven CNVs found to potentially associate with mortality in long-lived individuals in this study contain known regulatory elements, however.
In conclusion, we found that the genomewide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long-lived individuals. Our results indicate that CNVs might be important contributors to the genetic component of human longevity and prompt further investigation.