Researchers at Scripps create new genetic model of premature aging diseases

Innovative development by Scripps Research Institute using zebrafish offers new platform for large-scale drug screening

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JUPITER, Fla.—It's not as if progeria is a common ailment, but the fact that a disease exists that is so odd—accelerating certain aspects of the aging process—makes it important to study and understand, even if only for the ability to better understand how aging and age-related disease truly manifest and develop. So, it's welcome news to hear that progress is continuing on that front as scientists from the Florida campus of the Scripps Research Institute, working with a group of national and international researchers, develop a new genetic model of premature aging disorders.

Announcing their work in late April, the researchers say that it could shed light on these rare conditions in humans "and provide a novel platform for large-scale screening of compounds to combat these and other age-related diseases." Their study was published earlier in April
in the open-access publication PLoS ONE as "Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model" and illustrates how the scientists found a way to use zebrafish to model two rare human genetic disorders: Hutchinson-Gilford Progeria Syndrome and laminopathies.

"This is a robust model system of human aging that corresponds directly to the human genes involved in these diseases," says Shuji Kishi, a Scripps Florida assistant professor who led the study. "This model is ready now and can be used to screen and develop chemical compounds to treat these and other age-related diseases."

According to Kishi, zebrafish display many signs of aging that resemble those in humans, and so the tiny creatures have emerged over the past decade as what a powerful system to study diseases associated with aging and development.

"The zebrafish is a valuable vertebrate model system for the elucidation of novel molecular pathways of aging as well as early development," the authors write in the paper. "In particular, this model organism develops an array of senescence symptoms resembling those in humans, and is amenable to large-scale genetic screens that can be targeted to conserved aging pathways in vertebrates. However, the establishment of human disease-associated premature senescence-bearing fish had not been pursued previously."

The gene associated with both progeria and laminopathies is the lamin A gene (LMNA), which presumably is also involved in the normal process of human aging, although the underlying mechanisms of the process are still rather unclear. In the new research, scientists set out to block the protein production of the LMNA gene in zebrafish.

This resulted in apoptosis, or programmed cell death, as well as interruption of the normal cell cycle. Deletion of some specific amino acid residues in the lamin A protein also produced aging in embryonic zebrafish.

The researchers were intrigued to find in their work that farnestyl transferase inhibitor (FTI), a new class of anticancer drugs, reduced abnormalities in the nuclear membrane and prevented significant aging in the embryonic zebrafish models, which survived to adulthood but with a shortened lifespan.

"Utilizing our 'embryonic senescence' zebrafish model, our next goal will be to find modifier genes as well as chemical compounds to reverse accelerated aging and restore the normal aging process," Kishi says. "These findings could contribute to healthy aging in normal individuals, because the moderate defects of lamin A are also associated with the normal aging process."

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