Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila.
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.
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Jason G
0000-0003-3349-4994
JG
Wood
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Brian C
BC
Jones
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Nan
N
Jiang
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Chengyi
C
Chang
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Suzanne
S
Hosier
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Priyan
P
Wickremesinghe
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Meyrolin
M
Garcia
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Davis A
DA
Hartnett
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Lucas
L
Burhenn
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.
Nicola
N
Neretti
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912 stephen_helfand@brown.edu.
Stephen L
SL
Helfand
D000818:Animals; D031204:Caloric Restriction; D002843:Chromatin / Q000378:metabolism*; D004251:DNA Transposable Elements / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D005838:Genotype; D006570:Heterochromatin / Q000378:metabolism; D019259:Lamivudine / Q000494:pharmacology; D008136:Longevity / Q000235:genetics*; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D002843:Chromatin; D004251:DNA Transposable Elements; D029721:Drosophila Proteins; D006570:Heterochromatin; D018626:Retroelements; D019259:Lamivudine; C478069:DCR-2 protein, Drosophila; D043244:Ribonuclease III; D020365:RNA Helicases
aging; dietary restriction; heterochromatin; silencing; transposable elements