Somatic Chromosomal Mosaicism as a Mechanism of Aging and Disease
Stochastic mutational damage to nuclear DNA occurs constantly in the body, and near all of it is quickly repaired. Most unrepaired damage occurs in DNA that isn't used, or the change has only has a small effect on cell metabolism, or occurs in a somatic cell that will replicate only a limited number of times. When mutations occur in stem cells or progenitor cells, however, they can spread widely through tissue, producing a pattern of mutations known as somatic mosaicism. It is thought that this can contribute to the progression of aging via a slowly growing disarray of cellular metabolism, particularly through the spread of more severe damage, such as aneuploidy, missing or additional chromosomes. That said, firm evidence for the size of this effect remains to be produced. Researchers here focus particularly on this more severe chromosomal mosaicism, rather than minor damage.
Somatic chromosomal mosaicism is the presence of cell populations differing with respect to the chromosome complements (e.g. normal and abnormal) in an individual. Chromosomal mosaicism is associated with a wide spectrum of disease conditions and aging. This type of intercellular genomic variations is commonly associated with a wide spectrum of genetic diseases ranging from chromosomal syndromes to complex disorders, but dynamic changes of mosaicism rates produced by the accumulation of somatic mutations (i.e. aneuploidy) seem to be an important cytogenetic mechanism for human aging.
Cytogenetic and cytogenomic studies of normal and pathological aging consistently demonstrate an increase in rates of chromosomal mosaicism and instability in relation to age. After age 60, older ages have been associated with higher rates of chromosomal mosaicism and instability. Thus, this data allows us to hypothesize that external inhibition of age-dependent chromosome instability and a decrease of somatic chromosomal mosaicism rates might be an opportunity for anti-aging therapeutic interventions.
Furthermore, somatic cancer-associated mutations commonly occur in aged human tissues of presumably healthy individuals. It is not surprising inasmuch as chromosomal mosaicism and instabilities are risk factors for cancers. In general, aging-related diseases are commonly mediated by chromosomal instability and/or mosaic aneuploidy. The results of molecular genetic studies of aging correlate with observations on mutation load contribution to limiting or shortening the lifespan. Additionally, there is evidence that inhibiting chromosome instability might underlie successful anti-aging strategies. Thus, genetic instability at chromosomal level involved in human aging and/or lifespan shortening is an intriguing target for lifespan-extension and anti-aging interventions.