The authors of today's open access paper use the provocative question "how young can you die of old age?" as a framing device, a way to consider what is known of the way in which type 2 diabetes and obesity harm people over the course of years and decades. These are, of course, very well studied conditions. A great deal of time has been spent and a great deal of ink spilled on the topic of exactly what excess visceral fat and the pathologies of diabetes do to an individual, at the level of cells, at the level of organs, and, most visibly, to overall health and mortality. What is new, as of recent years, is the understanding that a sizable degree of the pathology of these conditions is mediated by senescent cells.
Factions within the research community have long seen diabetes as a form of accelerated aging, and evidently so given what it does to mice and people. Now, however, one can more literally argue that both obesity and diabetes produce accelerated aging. This is the case because they produce, through raised inflammation, metabolic stresses, and other means, a faster increase in the numbers of senescent cells present in the body. Senescent cells actively cause tissue dysfunction via their pro-inflammatory secretions, and their accumulation is an important contributing cause of degenerative aging. Removing senescent cells produces a narrow form of rejuvenation in mice, and the first senolytic therapies capable of a targeted destruction of senescent cells are undergoing human trials and, in some cases, readily available to self-experimenters.
How young can one die of old age? Our present societies of comfort and calories, with sizable populations of patients who are both obese and diabetic at ever younger ages, seem set on chasing an answer to that question.
Type 2 diabetes (T2D) is an enormous global medical and economic burden and its prevalence is on the rise with an ever ageing, increasingly obese population. It is a debilitating, chronic disease affecting almost half a billion people worldwide. T2D is often presented as a multimorbid disease cluster as it is a major risk factor for the premature onset of multiple age-related conditions such as chronic kidney disease, stroke, impaired wound healing, infection, depression, cognitive decline, and inflammation. T2D is especially a high-risk factor for cardiovascular mortality and cardiac remodelling, with coronary vessel disease and atherosclerosis being primary reasons for the increased incidence of cardiovascular dysfunction.
T2D is more common in an ageing host and "accelerated ageing" has been proposed as a pathogenic mechanism, including cell ageing leading to a complex phenotype termed senescence. Over the past 30 years, cellular senescence has been identified as a possible trigger of general tissue dysfunction and ageing phenotypes. Senescent cell load is low in young individuals but increases with ageing. When senescent cells accumulate they contribute to tissue dysfunction in the context of ageing and related pathologies. Several studies have shown that senescence accumulates in multiple cardiovascular cell populations and is linked with cardiovascular diseases (CVD) including heart failure (HF).
In T2D, comorbidities including obesity, hypertension, and atherosclerosis all have the ability to increase the number of senescent cells. However, the relationship between T2D and myocardial senescence may be both complex and complementary. The microenvironment of systemic metabolic stress in T2D could be permissive to the development and accumulation of senescent cells. On the other hand, senescent cells may contribute to the cardiac parenchyma dysfunction and comorbidities observed in T2D. Overall, it is likely that these complex interactions might lead to a malicious positive feedback in which systemic metabolic dysfunction in the early stages of T2D leads to immune cell senescence that in turn contributes to the worsening of cardiac function and tissue metabolism, which further increases the formation of senescent cells while decreasing their removal.
The aim of this review is to spark discussion and help generate hypotheses that may link senescence to cardiometabolic complications in T2D. We hypothesize that clearing senescent pro-inflammatory immune cells or targeting the SASP (Senescence-Associated Secretory Phenotype) may present opportunities for the development of revolutionary therapies for diabetic cardiomyopathy and its complications, leading to advances in its treatment and prevention. Furthermore, we review our current understanding of the metabolic remodelling of both heart tissue and senescent immune cells in T2D, and we discuss potentially fundamental mechanisms by which these metabolic responses influence and intersect each other to ultimately determine the prognosis of the myocardial inflammation.