Chapter 185
Changing Aging — 22
In a trial of diabetic macular edema for nineteen patients who failed conventional therapy, dose escalation of a pro-apoptotic drug (foselutoclax, a BCL inhibitor, Unity Biotechnology) given directly into the eye promoted visual acuity, vascular repair, and favorable remodeling of the retina. In a study of five patients with mild Alzheimer’s disease using oral (pills) dasatinib and quercetin for twelve weeks, eleven plasma-based and six cerebrospinal fluid–based biomarkers of cellular senescence improved. There was also evidence that some pro-inflammatory molecules were released, such as interleukin 6, which may indicate an unwanted inflammatory reaction to disintegrated senescent cells. In postmortem brains of patients with severe COVID, there was evidence of abundant senescent cells compared with age-matched controls. Different senolytics cleared the cells in organoid experiments. In two different animal models of COVID, senolytics cleared senescent cells and markedly reduced inflammation. Incorporating deep-learning AI has accelerated discovery of new potent senolytic small molecules.
The widely prescribed sodium-glucose cotransporter inhibitor (SGLT-2) drugs, like empagliflozin (Jardiance) or canagliflozin (Invokana), have been shown to reduce mortality in people with type 2 diabetes, and major outcomes in people with heart failure with preserved ejection fraction, but the mechanism for this benefit has been elusive. In the mouse model, SGLT-2 inhibitors eliminate senescent cells and improve survival, even when started at middle age. If this is verified in humans, it would be interesting to repurpose this class of drugs for promoting longevity.
A second-generation senolytic using engineered T cells (CAR-T) targeting the urokinase plasminogen receptor was tested in aged mice. Beyond clearing the senescent cells, a single injection provided lasting improvement of exercise capacity and metabolic function, including lower blood sugars. This work with CAR-T has been extended to rejuvenating the gut of aged mice. In a parallel way, gearing up natural killer T cells for removal of senescent cells, which worked in aged mice with lung fibrosis, is moving toward clinical assessment.
One missing link is a precise way to target senescent cells for these various elimination strategies. The problem, as touched on earlier, is that some senescent cells are doing good things in the body, and we currently don’t have a selective approach to eliminate only the bad ones. It’s just not that simple, as you might have been led to believe from the various mouse experiments I’ve reviewed.