Mitochondria are the power plants of the cell. Each cell has a herd of them that reproduce like bacteria and have their own DNA, separate from that of the nucleus. One of the causes of aging is progressive mitochondrial dysfunction caused by forms of DNA damage that (a) deprive mitochondria of necessary proteins for correct function, but also (b) allow the damaged mitochondria a survival advantage during replication. Thus a fraction of cells become overtaken by damaged mitochondria, and this causes them to export damaging reactive molecules into surrounding tissues. That contributes to, for example, the formation of damaged lipids involved in the progression of atherosclerosis.
This paper looks at the process of clonal expansion whereby damaged mitochondria overtake a cell. The authors focus on point mutations, however. While point mutations will be carried along in damaged DNA that provides a survival advantage, I think that the existence of mitochondrial mutator mice that have a very high load of point mutations but no premature aging as a result shows that point mutations are not all that important in this process. It is probably deletions and other more serious forms of damage that are significant.
Mitochondrial DNA (mtDNA) mutations have been shown to accumulate with age in a number of human stem cell populations and cause mitochondrial dysfunction within individual cells resulting in a cellular energy deficit. The dynamics by which mtDNA mutations occur and accumulate within individual cells (known as clonal expansion) is poorly understood. In particular we do not know when in the life-course these mtDNA mutations occur.
Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (earlier than 20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age.
We show that, by 17 years of age, there is a substantial mtDNA point mutation burden. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.