Science sub-journal: Scientists have discovered a novel RNA target and tool to help ward off premature human aging

Scientists from institutions such as King Abdullah University of Science and Technology have discovered a new type of RNA target and tool to ward off premature aging
.

Constitutive heterochromatin is primarily responsible for genomic inhibition
of DNA rich in repeats, telomeres, and centrioles 。 Recently, a research paper published in the international journal Science Translational Medicine entitled "LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes", Scientists from institutions such as King Abdullah University of Science and Technology have discovered a new type of RNA target and tool to ward off premature aging
.

Progeroid syndromes are a rare group of genetic disorders that trigger signs of premature aging in children and young adults, such as Werner syndrome and Hutchinson-Gilford Progeria syndrome.
Patients affected by Progeria syndrome often present with symptoms and pathologies associated with aging, such as heart disease, cataracts, type 2 diabetes and osteoporosis
.
This aging is characterized by a progressive loss of core structures and potential tissue-specific genetic procedures, but the reasons behind this are currently unclear to researchers; In this report, the researchers identified a novel target that could hopefully treat these syndromes
by preventing the loss of core structures.

This target is called L1 (Long interspersed nuclear element-1) RNA, a family of repeats that covers 17 to 20 percent of the mammalian genome, but its function is largely unknown, and these sequences can remain inactive
in a tightly wrapped DNA architecture called heterochromatin 。 Based on theoretical considerations, the molecular association between L1 RNA and specific enzymes that control heterochromatin stability may be responsible for
premature aging in patients with Progeria syndrome.

The researchers said that the expression of L1 RNA from the cells of patients with Progeria syndrome has increased, and further tests suggest that the increase in L1 RNA expression may be mainly responsible for the inactivation of an enzyme called SUV39H1, which causes the loss of heterochromatin and changes
in the expression of genes that cause cell aging 。 The researchers then did this by studying patients with Progeria syndrome and genetically engineered modifications to stimulate premature aging in mice to block L1 RNA expression in body cells and reverse the aging process, while the researchers did this using short synthetic nucleotide chains called antisense oligonucleotides (ASOs), which specifically target and cause the degradation
of L1 RNA.

Image source:

This L1 ASO can be modified to improve its ability to enter and remain stable in cells, blocking L1 RNA in cells may help restore heterochromatin function and counteract genes associated with aging, and this L1 ASOs can also extend the lifespan
of Progeria-like mice.
Later researchers also need to delve deeper to determine whether there are other mechanisms that play a parallel role with SUV39H1 inhibition that impair the stability
of heterochromatin in patients with Progeria.
In other observational studies, researchers have established an important rule that, contrary to previous thinking, abnormal expression of L1 RNA may not be the result of the onset of aging, but the cause of aging, at least in Progeria syndrome; Now, for the first time, researchers have reported a specific, not global, target that may play an essential role
in aging.

Professor Orlando said that given the similarities between Progeria syndrome and time-related diseases, targeting LINE-1 RNA may be an effective treatment for human Progeria syndrome and other age-related diseases, which are mainly characterized by abnormal expression of LINE-1, such as neurodegenerative diseases, metabolic and cardiovascular diseases, and cancer.
The results of this paper may provide certain ideas and hope
for the later development of new strategies to extend human life expectancy.

In summary, this study highlights the critical role of L1 RNA in heterochromatin balance in human Progeria syndrome and identifies a possible therapeutic strategy to help treat premature aging and its associated syndromes
in humans.
(Bio Valley Bioon.
com)

Original source:

Francesco Della Valle, Pradeep Reddy, Mako Yamamoto, et al.
LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes, Science Translational Medicine (2022).
DOI: 10.
1126/scitranslmed.
abl6057