Fight Aging!

This article on senolytic therapies to selectively remove senescent cells in old tissues is in part a matter of Unity Biotechnology talking up their position. The company suffered from first mover disadvantage in bringing senolytic drugs into clinical development. The field has made progress very rapidly over the last decade, and startups founded even just a couple of years after Unity's launch benefited from greater knowledge and a selection of better technologies to work with. Still, one can be talking up one's position and also be right. The accumulation of senescent cells is profoundly harmful, a significant contribution to degenerative aging, and senolytics are indeed a promising approach to the treatment of aging. Widespread use will greatly transform the field of medicine.

The interesting thing about small molecule senolytic therapies is that the first of these tested in animals and humans, the dasatinib and quercetin combination, is actually relative good, even though it clears at most half of the senescent cells in a given tissue, and much less than that in many tissue types. Alternative approaches that followed have struggled to improve on its effectiveness, at least going by published data. While the industry moves slowly, and approvals of new drugs are years away yet, there is little to stop an older individual deciding that the clinical trial safety profile for dasatinib and quercetin looks decent, and setting forth to try it for themselves.

Senolytic Therapies Pose Revolutionary Potential to Roll Back Diseases of Aging

Senolytic therapies are, at this point, as revolutionary as checkpoint inhibitors but with broader effectiveness. This approach delays the onset of diseases of aging by removing senescent cells from the body, thus enabling people to remain healthier longer or to regain some degree of function lost to disease. Senolytics is a new field and most of the research is still in academic centers - most notably, the Mayo Clinic. Approval of any therapeutics is years - perhaps even a decade - away. Currently, there are many unknowns. "We're at the stage where we don't know - in humans - which cells senesce and when, so there would be concern if, for example, post-mitotic cells that can't be replaced were suddenly eliminated by senolytics. We also don't know which senescent cells are the most disadvantageous."

"We're all carrying some burden of senescent cells ... usually at a benign level, and it's very likely contributing to the aging process. But, in certain stressed environments, the risk burden increases." A normal aging eye, for example, shows some accumulation of senescent cells but, when a disease - macular degeneration or diabetes, for example - is also involved, senescent cells are even more abundant. Senescent cells express the protein p16. Unity's approach identifies these cells based on their state - specifically their expression of p16 and their secretion of inflammatory factors. The company's lead asset, UBX1325, targets BCL-xl, which senescent cells - but not healthy cells - require for survival. "If you starve them of that, they are eliminated."

UBX1325 is being developed to treat diabetic macular edema (DME) and age-related macular degeneration. Upwards of 100 patients have been treated in early trials. UBX1325 is injected into the eye. As a result, the pathology of the disease is reduced, the anatomy looks good and the patients see better. The average gain was 7.5 letters or two lines on a vision chart. That gain was also seen in patients who had plateaued on anti-VEGF therapy and were treated with senolytics. A single injection appears to confer durable benefit.

"Nephrologists have begun to realize that acute accumulation of senescent cells drives progression of disease and the pathologies associated with it and that this accumulation of inflammatory cells leads to more fibrosis and more inflammation. Senolytics is exciting because it's the first of a class of therapy that has the potential to go after aging more broadly. Senescence seems to affect everyone and all the major organ systems in the body. One of the first things shown in transgenic animals was that if you remove (these cells) there was meaningful improvement in lifespan and healthspan. If we don't recognize aging as a legitimate target for medical intervention, it will be difficult to move the needle."

Oisín's Biotechnologies furthest-advanced senolytics program addresses kidney disease. One application focuses on blocking the progression of acute kidney injury toward chronic kidney disease. The other application is for people with advanced kidney disease who may be approaching renal failure. Eliminating the senescent cells probably won't return those kidneys to full function, but it may retard or halt disease progression. The goal is to eliminate the p16 cells. The company does that by targeting p16+cells with a caspase-9 suicide gene. The senescent cells then die by apoptosis. Although the p16 pathway is critical in identifying senescent cells, it may not be the only possible pathway. Recognizing that, the company's new frailty study targets both the p16 and p53 pathways, creating a synergistic, two-pronged method of killing senescent cells. That approach may be applied to its kidney program in the future.

Senolytics is a completely new type of therapy that, at this admittedly early stage, appears to have great promise. If it delivers on that promise, it will change what it means to age irrevocably.