Investigators from the Center for Advanced Gerotherapeutics at Cedars-Sinai found that aged blood vessel cells play a key role in the development of metabolic disorders, including diabetes. The preclinical findings, published in Cell Metabolism , could lead to new treatments for these complex disorders.
Obesity increases the accumulation of senescent cells, aged cells that have stopped dividing but have not died, in several organs and tissues.
"Senescent cells differ depending on the originating cell types, diseases and other factors. Some senescent cells help with wound healing, but others cause harm and are known contributors to age-related diseases," said Masayoshi Suda, MD, PhD , assistant professor of Medicine at Cedars-Sinai and lead author of the study. "Our goal is to identify and target these harmful types of senescent cells while sparing helpful cells."
Previous research by the investigators showed that eliminating senescent cells with drugs called senolytics improved metabolic function, the body's method for turning food and drink into energy.
In the current study, investigators focused on senescent blood vessel cells. They selectively removed these cells from obese laboratory mice and found that the animals' inflammation and fat mass were reduced—and blood sugar levels improved.
When the investigators transplanted senescent blood vessel cells into lean laboratory mice, those mice developed inflammation in fat tissue and metabolic dysfunction.
Suda said this occurred because senescent blood vessel cells release high levels of inflammatory molecules.
The investigators next treated both groups of mice with fisetin, a naturally occurring senolytic compound, and found that the mice had fewer senescent blood vessel cells and improved diabetic symptoms. Investigators saw a similar decline in senescent blood vessel cells when they treated tissue samples from obese human patients with fisetin.
"Preliminary findings like these are crucial to translating aging research into clinical care," said James Kirkland, MD, PhD , director of the Center for Advanced Gerotherapeutics and senior author of the study. "While more research is needed, we aim to eventually treat multiple age-related diseases simultaneously by using fisetin and related senolytics for aging and metabolic health."
Suda said his team will next work to test this approach in clinical trials.
"If we can target senescent cells safely in humans, it could help address not just diabetes but a range of age-related conditions," he said.
Additional Cedars-Sinai authors include Selim Chaib, Larissa Langhi Prata, Tamar Pirtskhalava, Nino Giorgadze, Sara Espinoza, Nicolas Musi, and Tamar Tchkonia.
Additional authors include Yi Zhu, Utkarsh Tripathi, Karl Paul, Allyson Palmer, Vagisha Kulshreshtha, Christina Inman, Kurt Johnson, Runqing Huang, Carolyn Roos, Luisa Leon-Sanchez, Jordan Miller, Thomas White, Linshan Laux, Laura Niedernhofer, Paul Robbins, Sundeep Khosla and Stefan G. Tullius.
Disclosures: Tamar Tchkonia, Allyson Palmer, Yi Zhu and James L. Kirkland have a financial interest related to this research, including patents and pending patents covering senolytic drugs and their uses held by Mayo Clinic.
Funding: This work was supported by the US National Institutes of Health (NIH) grants R37AG013925, R33AG061456, P01AG062413 (J.L.K., S.K., L.J.N., P.D.R.), U54 AG079754 (P.D.R., S.K., L.J.N), P01AG43376 (P.D.R., L.J.N.), R01AG086085 (S.K.),
R01AG087387 (Y.Z.), and R01 AG063543 (L.J.N.).
