Central to a lot of scientific research into aging are tiny caps on the ends of our chromosomes called telomeres. These protective sequences of DNA grow a little shorter each time a cell divides, but by intervening in this process, researchers hope to one day regulate the process of aging and the ill health effects it can bring. A Harvard team is now offering an exciting pathway forward, discovering a set of small molecules capable of restoring telomere length in mice.
Telomeres can be thought of like the plastic tips on the end of our shoelaces, preventing the fraying of the DNA code of the genome and playing an important part in a healthy aging process. But each time a cell divides, they grow a little shorter. This sequence repeats over and over until the cell can no longer divide and dies.
This process is linked to aging and disease, including a rare genetic disease called dyskeratosis congenita (DC). This is caused by the premature aging of cells and is where the team focused its attention, hoping to offer alternatives to the current treatment that involves high-risk bone marrow transplants and which offers limited benefits.
One of the ways dyskeratosis congenita comes about is through genetic mutations that disrupt an enzyme called telomerase, which is key to maintaining the structural integrity of the telomere caps. For this reason, researchers have been working to target telomerase for decades, in hopes of finding ways to slow or even reverse the effects of aging and diseases like dyskeratosis congenita.
“Once human telomerase was identified, there were lots of biotech startups, lots of investment,” says Boston Children’s Hospital’s Suneet Agarwal, senior investigator on the new study. “But it didn’t pan out. There are no drugs on the market, and companies have come and gone.”
Agarwal has been studying the biology of telomerase for the past decade, and back in 2015 he and his team discovered a gene called PARN that plays a role in the action of the telomerase enzyme. This gene normally processes and stabilizes an important component of telomerase called TERC, but when it mutates, it results in less of the enzyme being produced and, in turn, the telomeres becoming shortened prematurely. For the new study, researchers screened more than 100,000 known chemicals in search of compounds that could preserve healthy function of PARN. This led them to a small handful that seemed capable of doing so by inhibiting an enzyme called PAPD5, which serves to unravel PARN and destabilize TERC.
“We thought if we targeted PAPD5, we could protect TERC and restore the proper balance of telomerase,” says Harvard Medical School’s Neha Nagpal, first author on the new paper. These chemicals were tested on stem cells in the lab, made from the cells of patients with dyskeratosis congenita.
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