Retrotransposons as agents of somatic diversity, disease and aging

Transposable elements (TEs) are mobile genetic elements that make up a large portion of the genome of organisms ranging from yeast to humans. Mobilization of TEs may cause deleterious effects in somatic cells, contributing to age-related disorders such as cancer and neurodegeneration, as well as to the cellular and tissue dysfunction occurring in aging. The activity of TEs is suppressed by repressive heterochromatin. We and others have shown an age-related decline in repressive heterochromatin and an increase in TE activity across species from flies to mammals. In flies, we found an age-related decline in the maintenance of repressive heterochromatin is associated with increased TE activity in cells of brain, muscle and fat body. We found that interventions that can extend life span, including dietary restriction (DR) and increased Sirtuin activity, led to the maintenance of a more youthful state of repressive heterochromatin, and prevented the age-related increase in TE activity. Most excitingly, we showed that interventions known to improve repressive heterochromatin, including increasing Suvar39 or the siRNA pathway, prevented the age-related increase in TE activity and remarkably extended life span. As TE surveillance mechanisms weaken through accumulation of macromolecular damage and loss of homeostatic capacity, in part due to genotoxic stresses, there is a failure of TE repression. The consequent increase in TE activity could cause cellular dysfunction, and may be one of the molecular causes of aging. We hypothesize that slowing or reversing the activation of RTEs during aging will have a beneficial effect on tissue function and healthspan.