On the front line of aging research

Two TSRI initiatives tackle age-related disease

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JUPITER, Fla.—Scientists at the Florida campus of The Scripps Research Institute (TSRI) are adding to the growing field of anti-aging medicine, in the global effort to increase the number of years people can enjoy good health. TSRI has obtained a grant to study aging at the genetic level to find keys to longevity that don’t focus on specific diseases. Simultaneously, another team in the Department of Molecular Medicine has developed a molecular model that may provide a new framework for improving the design of osteoporosis treatments. These most recent efforts add to the breadth of TSRI’s work at the micro and macro levels to find ways to help people to live longer, without the serious diseases and disabilities that tend to plague older adults.
At the more comprehensive level, TSRI and Albert Einstein College of Medicine will share in a $9-million grant from the National Institute on Aging, part of the National Institutes of Health, to study how individual genetic differences may form the basis for new therapeutic approaches that target the aging process itself rather than focusing on the treatment of individual diseases. The new five-year study will look to definitively identify genetic differences between those people who have aged well and those who have not—differences that could potentially be used to pinpoint new therapeutic targets that could delay or possibly even reverse many age-related diseases.
“We call them ‘natural longevity mutants’—human centenarians and super-centenarians who have managed to ward off the diseases that normally begin to plague everyone at middle age,” said Paul Robbins, TSRI professor in the Department of Molecular Medicine and Director of the TSRI Center on Aging. “They have changes in their genetic makeup that allow them to live to a ripe old age. If we can validate these variants in animal models and test them to see if they live longer, we can begin to develop drugs that increase healthspan.”
The new studies will make extensive use of a mouse model of accelerated aging created in the laboratory of Laura Niedernhofer, a TSRI associate professor—not only to validate these rare variants, but also to test and validate compounds that target them. “We’ve already used the mouse model of accelerated aging to identify some possible targets and pathways for extending healthy aging,” Niedernhofer commented. “In fact, several different senolytic drugs and young stem cells are already able to extend healthspan in our models.”
Meanwhile, another TSRI team has harnessed advanced mass spectrometry technology to develop a molecular model that may assist in improving the design of osteoporosis treatments. Using a protein analysis method known as hydrogen-deuterium exchange (HDX), the scientists delivered the first dynamic snapshots of a prime target for osteoporosis treatments: a receptor that regulates calcium levels to maintain healthy bones.
While current drug therapies exist to target this receptor—called vitamin D receptor agonists—their therapeutic value is limited because use can result in hypercalcemia, a condition that can weaken bones and even cause kidney stones, due to too much calcium in the bloodstream. Development of a safer therapy was hindered because scientists didn’t fully understand the structures involved.
To address this problem, the TSRI team sought a clearer picture of the structure of the vitamin D receptor. The vitamin D receptor complex regulates bone mineralization by controlling a gene known as BGLAP that is the target of 1α, 25-dihydroxyvitamin D3 (1,25D3), the active hormonal version of vitamin D. Unfortunately, increased levels of 1,25D3 also activate a calcium-regulating gene called TRPV6, which leads to hypercalcemia.
Patrick R. Griffin, co-chair of the TSRI Department of Molecular Medicine, and his colleagues hope to eliminate this threat by developing 1,25D3 that differentially targets BGLAP genes, while avoiding TRPV6.
“Because of our aging population, these kinds of therapeutics are in great demand,” said Griffin. “The idea is that if we could fingerprint how these various ligands interact with the vitamin D receptor, we could provide a kind of roadmap to help develop those that only trigger the non-hypercalcemia gene.”
The scientists used HDX mass spectrometry, a high-precision, high-sensitivity mapping technique that has proven to be a robust method to probe protein conformational or shape changing dynamics within the context of ligand and protein/protein interactions. HDX can show the specific regions of the protein complex that are altered on interaction with specific ligands, information which can be used to infer structural changes that are the result of a specific interaction.
“Our results provide snapshots of distinct conformational ensembles of the receptor, which allows it to adopt different orientations depending on compound structure, DNA and co-activator binding,” explained Jie Zheng, a TSRI research associate and the first author of the study. “This study shows the molecular mechanism of a selective vitamin D receptor modulator versus agonists and how they drive different interactions with co-regulators when associated with sequence-specific DNAs.”
The work of TSRI and researchers across disciplines has a captive audience. It is estimated that in the next 20 years, the number of individuals in the United States over the age of 65 will double, reaching more than 70 million. As such, the need to identify new therapeutic strategies to extend healthspan—healthy aging—is increasingly urgent. As people try everything from infusions of a younger person’s blood to purposeful calorie abstention to lower one’s body temperature, there is a clearly a market for any breakthrough that prevents, delays, slows or mitigates aging and age-related diseases.

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