New target of anti-progeria: scientists successfully reversed the "progeria"

A promising new target for the treatment of premature aging
.

Warner syndrome and Hutchinson-Gilford Progeria are two rare genetic disorders known as Progeria-like that cause signs of
premature aging in children and young adults.
The pathologies and symptoms of people with Progeria-like syndrome are often associated with aging, including osteoporosis, cataracts, heart disease, and type 2 diabetes
.

This aging is characterized by a gradual loss of nuclear structure and underlying tissue-specific genetic programs, but the reason for this is unknown
.
Scientists have identified a potential new target to treat these syndromes
by preventing the loss of nuclear structures.

An international team of researchers led by KAUST has identified new targets for treating syndromes that contribute to premature aging in children
.
Illustrated is a target called long interspersed nuclear element-1 (L1) RNA
.

The target is known as long-spacer nuclear element-1 (L1) RNA, a family of repeats that make up about 17-20% of the mammalian genome, and its function is largely unknown
.
A tightly packed DNA structure called heterochromatin inactivates
these sequences.
There is evidence that heterochromatin depletion during normal aging is associated
with their activation.

"Based on theoretical considerations, we hypothesize that molecular interactions between L1 RNA and a specific enzyme that controls heterochromatin stability may be responsible for premature aging of Progeria syndrome," said
Francesco Della Valle, a research scientist at King Abdullah University of Science and Technology (KAUST).

Sequencing studies conducted by KAUST and the US team showed that L1 RNA expression was higher
in cells collected from individuals with Progeria-like syndrome.
Further studies have shown that increased L1 RNA expression is responsible for the inactivation of the SUV39H1 enzyme, which leads to heterochromatin loss and altered gene expression, thereby promoting cellular aging
.

The researchers were able to block the expression of L1 RNA, reversing the aging process in cells taken from patients with Progeria syndrome and mice
genetically modified to mimic premature aging.
They achieved this using synthetic short nucleotide strands called antisense oligonucleotides (ASOs), which specifically target L1 RNA and cause its degradation
.
Their L1 ASO was modified to improve its ability to
enter and stabilize within cells.
Blocking L1 RNA inside cells restores heterochromatin and counteracts senesgenization-related genes
.
L1 ASOs also extended the lifespan
of Progeria-like mice.

Further research will be needed to determine whether other mechanisms, in parallel with SUV39H1 inhibition, may impair Progeria syndrome heterochromatin stability
.

"Among other observations, our work establishes an important rule," says
biological scientist Valerio Orlando.
"Contrary to previous thinking, abnormal expression of L1 RNA is not the result of the onset of aging, but the cause of aging, at least in Progeria
.
Now, for the first time, we report a specific, rather than global, target that is an important factor in
aging.
”

"Given the similarities between Progeria-like syndrome and aging-related diseases, targeting LINE-1 RNAs may be an effective treatment for Progeria-like syndrome and other age-related diseases characterized by abnormal expression of LINE-1, such as neurodegeneration, metabolism, cardiovascular disease, and cancer
," Orlando said.
This research opens the way
for new strategies that we believe may help extend human life expectancy.
”

Reference:

“LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes” by Francesco Della Valle, Pradeep Reddy, Mako Yamamoto, Peng Liu, Alfonso Saera-Vila, Dalila Bensaddek, Huoming Zhang, Javier Prieto Martinez, Leila Abassi, Mirko Celii, Alejandro Ocampo, Estrella Nu?ez Delicado, Arianna Mangiavacchi, Riccardo Aiese Cigliano, Concepcion Rodriguez Esteban, Steve Horvath, Juan Carlos Izpisua Belmonte and Valerio Orlando, 10 August 2022, Science Translational Medicine.