Senolytics can boost a key protective protein, Mayo research shows

Mayo Clinic researchers say senolytics can boost a key protein that could protect us against aging and age-related diseases.

Senolytic drugs developed at the Mayo Clinic were able to clear the bloodstream of senescent cells in both mice and human studies after just one dose. Publishing in eBioMedicine, the study shows that the removal of senescent cells by senolytics significantly boosts the production of a protective protein called α-klotho; senescent cells – which are often termed “zombie cells” – contribute to multiple diseases and negative aspects of aging.

Longevity.Technology: Cellular senescence – the zombie state in which cells forget to die – is one of the nine hallmarks of aging. Disrupting the formation of senescent cells in tissues can lengthen healthspan and reduce the risk of age-related disease. Therapies that try to ensure cells follow the usual pathway of moving from senescence into apoptosis (cell death), or clear them away while they are going about their nefarious business of pumping out toxic chemicals (senescence-associated secretory phenotype, or SASP) while simultaneously encouraging other, healthy, cells to join the dark side of senescence, are called senolytics, and research is focusing on ways to bring these therapies to clinic with more than 20 clinical trials ongoing. Senolytics such as fisetin and quercetin are available as dietary supplements.

“We show that there is an avenue for an orally active, small-molecule approach to increase this beneficial protein and also to amplify the action of senolytic drugs,” says James Kirkland, MD, PhD, a Mayo Clinic internist and senior author of the study [1].

The researchers first showed that senescent cells decrease levels of α-klotho in three types of human cells: umbilical vein endothelial cells, kidney cells and brain cells. They also demonstrated that using the senolytic combination of dasatinib plus quercetin in three types of mice resulted in an increase in α-klotho. Also, an increase in α-klotho was observed after administering dasatinib plus quercetin to clinical trial participants with idiopathic pulmonary fibrosis [2].

“We also are first to link the potential impact of fat-resident senescent cells on brain α-klotho,” says Yi Zhu, PhD, a Mayo Clinic physiologist and biomedical engineer, and first author of the study. “This may open another avenue to investigate the impact of peripheral senescent cells on brain aging [1].”

The protein α-klotho is important to maintaining good health, as it tends to decrease with age; a particular decrease is observed in certain diseases, including Alzheimer’s, diabetes and kidney disease. Animal studies have shown that decreasing α-klotho in mice shortens lifespan and increasing α-klotho in mice by inserting a gene that causes its production can increase lifespan by as much as up to 30% [3].

Discovering ways to increase α-klotho in humans has been a major research goal, but that has been difficult because of its size and instability. Α-klotho is a transmembrane protein, integral to the membrane of the cell and spanning its entirety. The part of the protein that exists outside the cell can become detached or severed from the rest and released into the blood plasma, urine or cerebrospinal fluid as hormonal, soluble, circulating forms. Each of these has a different function, so taking α-klotho orally is not likely to have the desired effect. Add the body’s strictest bouncer – the blood-brain-barrier – into the mix and the size of α-klotho means it won’t be able to get to the brain, being too large to cross (it’s name’s not on the list, it’s not getting in).

So, rather than look at α-klotho as a supplement, administering senolytics, which can be taken orally and which, this study shows, can increase α-klotho in humans, is perhaps the way to go. This research certainly brings hope to sufferers of idiopathic pulmonary fibrosis, a senescence-associated disease that leads to frailty, serious breathing difficulties and death, and may well result in a scalable therapy.

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