Like many aspects of our lives, epigenetic processes can get out of control during aging. Now, exciting new findings have revealed that the secret to keeping our aging epigenomes “in line” is removing LINE-1 RNA from cells, which stabilizes heterochromatin and reverses signs of aging!
Previous studies have shown how age-associated heterochromatin loss associates with the reactivation of repetitive and transposable elements, such as the LINE retrotransposons, which promote genome instability – a hallmark of senescent/aging cells. Cytoplasmic accumulation of LINE-1 complementary DNA also induces toxicity by activating a pro-inflammatory response, while pharmacologically blocking the reverse transcriptase machinery inhibits aging. However, LINE-1 RNA activity also maintains open chromatin states during early embryogenesis. Given these unflappable findings, eager researchers led by Juan Carlos Izpisua Belmonte (Salk Institute for Biological Studies, California) and Valerio Orlando (KAUST, Saudi Arabia) hurriedly sought to explore links between LINE-1 RNA expression, heterochromatin loss, and aging in cells from human patients with premature aging syndromes characterized by disorganized heterochromatin.
Let’s hear from Della Valle, Reddy, and colleagues on how keeping our aging epigenome “in line” can reverse signs of aging:
- LINE-1 RNA accumulation occurs as an early event in cultured cells isolated from patients with premature aging (progeroid) syndromes
- Increased levels of LINE-1 RNA bind to and inhibit the activity of the histone-lysine N-methyltransferase SUV39H1, resulting in a loss of heterochromatin and an induction of senescence markers
- LINE-1 RNA depletion in patient cell lines via antisense oligonucleotides:
- restores heterochromatin-associated histone H3 K9 and K27 trimethylation modifications, inhibiting the loss of heterochromatic gene silencing
- counteracts the expression of genes associated with the senescence-associated secretory phenotype
- reverses accelerated DNA methylation-based epigenetic aging measured using the “Skin and Blood” and “PhenoAge” epigenetic clocks
- Systemic delivery of antisense oligonucleotides to deplete LINE-1 RNA levels in a premature aging mouse model rescues tissue histophysiology and, importantly, increases life span
- Transcriptional profiling after LINE-1 RNA depletion demonstrates the enrichment of pathways related to nuclear chromatin organization, cell proliferation, and transcription regulation and the downregulation of pathways related to aging, inflammatory response, innate immune response, and DNA damage
These data show that targeting LINE-1 RNAs with antisense oligonucleotides stabilizes heterochromatin and reverses signs of aging in premature aging syndromes. The authors also note the need to explore additional epigenetic mechanisms that act in parallel to SUV39H1 inhibition to compromise chromatin stability and define whether LINE-1 RNA overexpression is a cause or consequence of aging.
Keep your aging epigenome in line over at Science Translational Medicine, August 2022.