Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

Abstract

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-generation sequencing, we found that transcripts of many genes native to heterochromatic regions and TEs increased with age in fly heads and fat bodies. A dietary restriction regimen, known to extend life span, 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 life span. Mutation of Dicer-2 led to an increase in DNA double-strand breaks. Treatment with the reverse transcriptase inhibitor 3TC resulted in decreased TE transposition as well as increased life span 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 life span.aging | heterochromatin | transposable elements | dietary restriction | silencing

Tightening the connection between transposable element mobilization and aging

“…Previously, it had been shown that a modest increase in Sir2 (7) or decrease in Adar (adenosine deaminase acting on RNA) activity (8), genetic interventions that increase heterochromatic repression, also lead to an extension in life span. In the present study, Wood et al (4) now show that these same life span-extending interventions also exhibited an age-dependent reduction in RTE activity. Extending these findings, Wood et al (4) show that two additional interventions predicted to maintain heterochromatic repression, increased expression of Su(var)3-9 or Dicer-2, resulted in both an age-dependent reduction in RTE activity and life span extension.…”

“…In the present study, Wood et al (4) now show that these same life span-extending interventions also exhibited an age-dependent reduction in RTE activity. Extending these findings, Wood et al (4) show that two additional interventions predicted to maintain heterochromatic repression, increased expression of Su(var)3-9 or Dicer-2, resulted in both an age-dependent reduction in RTE activity and life span extension. Taken together, these data suggest a robust relationship between repression of RTE activity and longevity.…”

“…In a tour de force, Wood et al (4) used this method to visualize directly the rate of mobilization of an endogenous retrotransposon in fat body cells by counting the number of GFP-positive cells through the cuticle of the living anesthetized fly in a large cohort of flies constituting three different genetic backgrounds during aging, with and without calorie restriction. These studies demonstrated two important features of RTE mobilization with age.…”

A somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan

“…2b, side panel). We used a reporter of transposition for the endogenous gypsy retrotransposon ( gypsy-TRAP )924, a known target of Piwi in the ovary25, to detect transposition in fat body cells and found that piwi mutant fat bodies displayed significantly higher levels of gypsy transposition relative to controls (Fig. 2c).…”

“…The short interfering RNA pathway suppresses TEs in all tissues of plants and animals, whereas the activity of the Piwi-interacting RNA (piRNA) pathway is thought to be primarily restricted to the gonads of metazoans45. Loss or decline of these pathways results in genomic instability and cellular dysfunction caused by TE reactivation and transposition6789.…”