Scientists have discovered an RNA-based mechanism that is involved in core hallmarks of a number of accelerated aging conditions and shown that therapies targeting this RNA reverses some of these hallmarks in human cells and extend life spans in mouse models.
The preclinical research points to a new target in various progeria syndromes and has spurred a search for other RNAs involved in aging, Valerio Orlando, professor of bioscience at the King Abdullah University of Science and Technology, Saudi Arabia, told BioWorld Science. Orlando is corresponding author of a paper in Science Translational Medicine, August 10, describing the research. The researchers say their findings point to a new avenue for the possible treatment of premature aging and may also be relevant to other aging-associated pathologies.
Progeroid syndromes, such as Hutchinson-Gilford syndrome are rare genetic conditions, but the accelerating aging they cause has features in common with regular physiological aging. One of the main markers of both is the loss and subsequent disorganization of heterochromatin, the condensed form of DNA that is involved in functions that are crucial for maintaining genomic stability. Loss of heterochromatin leads to alterations in gene expression and the reactivation of repetitive and transposable elements, or 'jumping genes' – DNA sequences that move from one location in the genome to another.
These include long interspersed nuclear element (LINE) retrotransposons, which are involved in maintaining the open chromatin state required for gene expression during early embryogenesis, but subsequently are normally repressed in somatic cells by heterochromatin. While re-expression of LINE is thought to affect genomic stability, a direct connection between accelerated aging and LINE expression has not previously been directly observed in the lab.
Orlando and colleagues investigated whether LINE-1, the most abundant LINE in humans and which is known to be more active during loss of heterochromatin, plays any role in the progression of progeria syndromes. They examined the correlation between LINE-1 re-expression, heterochromatin erosion and the aging of phenotypes in cells derived from patients with progeria syndromes. LINE-1 expression was 4-7 times higher in progeroid syndrome cells compared to healthy donor cells, in both syndromes where the mutation is known and where it is not.
The researchers found LINE-1 RNA and deregulation of the histone lysine methyltransferase SUV39H1 (suppressor of variegation 3-9 homolog 1) frequently occurred in human progeroid syndromes. In mouse models, the aberrant interaction of LINE-1 RNA and SUV39H1 led to heterochromatin erosion and the loss of tissue specific genetic programs.
When LINE-1 RNA was depleted in human progeroid cells using antisense oligonucleotides the senescent phenotypes were ameliorated, while in the premature aging mouse model this therapy restored tissue homeostasis and extended the life span.
Mice were treated with antisense oligonucleotides from eight weeks of age. This reduced expression of LINE-1 in tissues including skin, muscles, kidney and spleen. Histological analyses showed there were improvements in all these tissues. The researchers note that in the mouse model, LINE-1 antisense oligonucleotides did not display any of the side effects typically observed with nucleotide reverse transcriptase inhibitor antiretroviral compounds, such as the HIV therapy lamivudine, which have recently been proposed as anti-aging compounds.
A gene ontology analysis showed that in treated mice, pathways associated with aging, inflammatory response, innate immune response and DNA damage were down regulated. At the same time, nuclear chromatin organization and transcription regulation pathways were enriched.
"The interest [in LINE-1 RNA] stemmed from the fact that retrotransposon RNAs are aberrantly expressed during aging and sparse evidence of an association between LINE-1 RNA and chromatin opening," Orlando said. "We thus postulated a molecular interaction between LINE-1 RNA and SUV39H1, leading to chromatin loss."
While the correlation between the expression of repetitive elements such as LINE-1 and aged phenotypes has been studied in depth, it was not known if this is a consequence of genetic drift caused by senescence, or if LINE-1 RNA has an active role in aging progression. In a series of experiments, the researchers demonstrated LINE-1 deregulation is an early event and proceeds both loss of heterochromatin and onset of a senescence phenotype.
They subsequently demonstrated that LINE-1 RNA causes heterochromatin loss by repressing SUV39H1. The researchers say this previously undescribed function of LINE-1 RNA as a negative regulator of SUV39H1 enzymatic activity might help explain previous studies on LINE-1 expression and its effects on chromatin opening and activation in early embryonic development.
While the research demonstrates LINE-1 RNA activation is causal, the researchers say they cannot exclude other epigenetic mechanisms acting in parallel to SUV39H1 inhibition to compromise chromatin stability.
Taken overall, "These data support LINE-1 specific antisense oligonucleotides as a promising approach to ameliorate premature aging phenotypes," the researchers conclude.
Orlando said the team now plans to develop more precise L1 RNA based pharmacological tools, for example, based on nanoparticles, or which have organ specific effects, and to identify other RNAs involved in chromatin homeostasis and aging.