One of the many unpleasant complications produced by type 1 and type 2 diabetes is a much reduced ability to heal wounds, leading to ulcers and non-healing injuries. Following the discovery of the importance of senescent cells to degenerative aging, it was found that senescent cell accumulation is important in the pathology of both type 1 and type 2 diabetes. Senescent cells secrete a mix of molecules that provoke chronic inflammation, destructively remodel nearby tissue, and encourage other cells to become senescent, among other outcomes. This signaling, when present for the long term, is harmful to tissue function. Therapies that selectively destroy senescent cells may thus be beneficial for diabetic patients, even while not addressing the root causes of the condition.

Although more than 300 theories have emerged over the years to explain the intrinsic molecular and evolutionary drivers behind organismal aging, the onset of cellular senescence seems to act as a foundational pillar for organ and organismal aging. Diabetes mellitus (DM) is a heterogeneous metabolic disease characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. An intense debate has existed so far addressing whether senescence precedes or follows the onset of chronic inflammation and insulin resistance (IR). Irrespective to “who-precedes-who,” diabetic patients experience an obvious accelerated aging process that increases their susceptibility to morbidity and earlier mortality. Hence, diabetes-affected patients have a significantly shorter life expectancy than non-diabetic individuals, while this life expectancy reduction is largely dependent on diabetes duration.

The major clinical challenge of diabetes is the progressive and expansive morbidity and mortality resulting from the long-term secondary complications. Within the constellation of diabetic complications, the delayed and poorness in triggering and progressing along a physiological repair response following wounding is of major clinical significance. Diabetes undermines skin cells physiology and progressively intoxicates the dermal layer by the accumulation of advanced glycation end products (AGEs) and free radicals derivatives. Accordingly, most if not all of the events encompassed within the cutaneous healing process including hemostasis, inflammation, matrix deposition, angiogenesis, contraction, remodeling, and re-epithelialization are somewhat buffeted by diabetes.

Chronic low-grade inflammation and an increased burden of senescent cells are hallmarks of aging in diabetic subjects. Hyperglycemia per se is known to act as a senescence-promoting factor for cultured cells, and steadily precipitates organs complications and functional demise by different mechanistic pathways. The notion that cellular senescence is an imperceptible underlying force in the pathogenesis of wound chronicity and ulcer recurrence has accrued for years. Consequently, we suggest that diabetes-associated wound healing failure and reduced tissue resilience are clinical translations of an “entrenched” wound senescent cell population, with self-perpetuating and propagating abilities.

This population may be fostered by a diabetic archetypal secretome that induces replicative senescence in dermal fibroblasts, endothelial cells, and keratinocytes. Mesenchymal stem cells are also susceptible to major diabetic senescence drivers, which accounts for the inability of these cells to appropriately assist in diabetic wound healing. The senescent cell population and its adjunctive secretome could be an ideal local target to manipulate diabetic ulcers and resolve non-healing wounds.