Type 2 diabetes is largely a self-inflicted problem, a consequence of becoming overweight. Aging makes it easier to reach the threshold needed for a diagnosis of diabetes, but the condition remains in principle avoidable for the majority of people, were they making better choices about diet and exercise. In recent years, researchers have linked an increased burden of cellular senescence to the pathology of type 2 diabetes; the aberrant diabetic metabolism encourages more cellular senescence, and the presence of lingering senescent cells is in turn inflammatory and disruptive to tissue function.
In today’s open access paper, researchers focus on cellular senescence in diabetic kidney disease. In this context the increased burden of senescent cells actively sabotages the function of the kidney. Thus senolytic therapies capable of selectively destroying some fraction of senescent cells can produce measurable improvements in kidney function following a single course of treatment. Given time, and no correction of the lifestyle and physiology that drives diabetes, senescent cells and kidney dysfunction will reemerge, of course. But senolytic drugs nonetheless offer the prospect of meaningfully reducing some of the harms done by aging and obesity.
Maladaptive inflammation and cellular senescence contribute to diabetic kidney disease (DKD) pathogenesis and represent important therapeutic targets. Senolytic agents selectively remove senescent cells and reduce inflammation-associated tissue damage. In our pilot clinical trial in patients with DKD, the senolytic combination dasatinib plus quercetin (D + Q) reduced systemic inflammation, senescent cell abundance, and macrophage infiltration in fat. However, D + Q senotherapeutic effects on diabetic kidney injury, senescence, inflammation, and geroprotective factors have not been established.
Diabetes mellitus was induced with intraperitoneal streptozotocin in male C57BL/6J mice, followed by a 5-day oral gavage regimen of either D + Q (5 and 50 mg/kg, respectively) or vehicle. Kidney function and markers of injury, fibrosis, inflammation, cellular senescence, and geroprotective factors were measured. In vitro studies examined reparative effects of D + Q in high glucose-treated human renal tubular epithelial cells (HK2), endothelial cells (HUVECs), and U937-derived macrophages.
D + Q improved kidney function and reduced markers of kidney injury (glomerular and tubular), fibrosis, senescence (p16Ink4a), macrophage- and senescence-associated inflammation (versus diabetic controls) without altering glucose levels. Additionally, geroprotective factors (α-Klotho, Sirtuin-1) increased. D + Q treatment in vitro reduced high glucose-induced senescence and inflammation (NF-κB) in HK2, HUVECs, and macrophages.
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