Activation of transposable elements as a molecular cause of aging

Transposable Elements (TEs) are mobile genetic elements, highly enriched in heterochromatin, that constitute a large percentage of the DNA content of eukaryotic genomes. Aging in Drosophila melanogaster is characterized by loss of repressive heterochromatin structure and loss of silencing of reporter genes in constitutive heterochromatin regions. Using next-gen sequencing, we found that transcripts of many genes native to heterochromatic regions as well as TEs increased with age in fly heads and fat bodies. A dietary restriction regimen, known to extend lifespan, repressed the age-related increased expression of genes located in heterochromatin as well as TEs. We also observed a corresponding age-associated increase in TE transposition in fly fat body cells that was delayed by dietary restriction. Furthermore, we found that manipulating genes known to affect heterochromatin structure, including overexpression of Sir2, Su(var)3–9, and Dicer-2, as well as decreased expression of Adar, mitigated age-related increases in expression of TEs. Increasing expression of either Su(var)3–9 or Dicer-2 also led to an increase in lifespan. Mutation of Dicer-2 led to an increase in DNA double strand breaks. Pharmacological inhibition of TE activity with 3TC resulted in both decreased transposition as well as increased lifespan in TE sensitized Dicer-2 mutants. Together, these data support the retrotransposon theory of aging, which hypothesizes that epigenetically silenced TEs become deleteriously activated as cellular defense and surveillance mechanisms break down with age. Furthermore, interventions that maintain repressive heterochromatin and preserve TE silencing may prove key to preventing damage caused by TE activation and extending healthy lifespan.