This open access paper is largely focused on type 2 diabetes, a condition that in most patients can be reversed even quite late through low-calorie diets and weight loss, but the principle of targeting senescent cells and chronic inflammation produced by an age-damaged immune system can be applied to many age-related conditions. While removing senescent cells is the most straightforward and practical approach to dealing with their bad behavior, and clinical development, there is a faction within the research community who would prefer to develop drugs that alter the behavior of senescent cells to be less damaging. This is a much more challenging undertaking, nowhere near any clinical application, but fits better with the prevailing scientific goal of mapping all of the biochemistry of such cells.
A chronic proinflammatory status is a pervasive feature of aging. This chronic, low-grade, systemic inflammation occurring in the absence of overt infection (sterile inflammation) has been defined as "inflammaging" and represents a significant risk factor for morbidity and mortality in the elderly. There is growing epidemiological evidence that a state of mild inflammation is associated with and predicts several age-related diseases (ARDs), including type 2 diabetes mellitus (T2DM) and its complications (e.g., cardiac death). The life expectancy of T2DM patients is about 6 years shorter than that of nondiabetic individuals of similar age.
Together with immunological factors, cellular senescence and the senescence-associated secretory phenotype (SASP) are currently held to be the largest contributors to inflammaging; however, a key role of senescence in patients with the most common ARDs (e.g., diabetes) has yet to be conclusively demonstrated. Significantly, at least two major molecular changes responsible for diabetes complications and also associated with physiological aging and T2DM, that is, oxidative stress and endoplasmic reticulum (ER) stress, have recently been related to senescence acquisition and/or SASP modulation. These findings suggest that the SASP can contribute to the endothelial dysfunction characterizing aging as well as T2DM.
Here we review the latest data connecting oxidative and ER stress with the SASP in the context of aging and T2DM, with emphasis on endothelial cells (ECs) and endothelial dysfunction. Moreover, since current lifestyle interventions and medications are unable to reduce the mortality of diabetic patients from cardiovascular disease, we also outline a gerontological, SASP-centered view of the vascular complications of diabetes that could provide a broader range of therapeutic options.