Senolytics for Cardiac Regeneration in Diabetics

The latest research published in Diabetes has implicated senescent cardiac stem cells as the link between diabetes and cardiovascular disease [1].

Why does diabetes increase the risk of cardiovascular disease?

Type 2 diabetes mellitus is closely related to aging. Aging is a major risk factor for diabetes, and individuals with diabetes exhibit several characteristics of accelerated aging. For example, diabetic patients show higher levels of systemic inflammation and oxidative stress than non-diabetic patients of the same age [2]. They are also more prone to cardiovascular disease and exhibit impaired tissue regeneration [3].

Why we Age: Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
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Senescent cells also accumulate in greater numbers in diabetic patients. Senescence can be induced by a number of mechanisms, including diabetes-related pathways. However, even in the absence of diabetes, senescent cells have been shown to contribute to systemic inflammation, oxidative stress, cardiovascular disease, and impaired tissue regeneration [4].

Because of this, researchers have hypothesized that diabetes-induced cellular senescence may be responsible for the cardiac degeneration affects seen in diabetic patients [5]. A multi-center collaboration based out of Magna Graecia University in Italy has recently found evidence to support this theory, specifically in the stem cells of the heart.

Heart

The heart is a four-chambered organ located between our lungs. Blood is pumped by the heart through two loops, one to the lungs, oxygenating the blood, and the other out to the rest of the body, delivering that oxygen to our tissues. This constant flow of blood is imperative, and it transports waste through the filters in our kidneys, carries the nutrients we eat from the gut to the rest of the body, and distributes various secreted hormones to other tissues, among many other functions.
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Heart tissue samples from diabetes patients show increased cellular senescence

The researchers used heart tissue samples from 50- to 64-year-old patients with and without type 2 diabetes. Tissue was collected during heart surgery from patients who had recently experienced heart attacks. Tissue from diabetic patients showed higher rates of oxidative stress, reduced telomerase activity and telomere length, and an increase in senescent (p16-positive) cells.

Cardiac stem cells that were isolated and cultured from diabetic patients also had reduced proliferation and capacity to differentiate in vitro. Notably, these cells had higher rates of many senescence and SASP markers compared to the non-diabetic control cells.

Senescence was induced in the non-diabetic control cells by exposing them to conditioned media from the diabetic cells, likely because of the SASP. Senescence was also induced in these cells when cultured in a high-glucose condition, which roughly simulates diabetes.

Lastly, treating the cardiac stem cells from diabetic patients with the senolytics dasatinib and quercetin (D+Q) successfully cleared the senescent cardiac stem cells and improved their ability to proliferate and differentiate in vitro.

Senolytics improve cardiac function in a diabetic mouse model

A model of diabetes was utilized in young mice fed a high-fat diet and given streptozotocin injections. These mice had classic symptoms of diabetes, cardiac dysfunction, and an increased senescent (as measured by p16) cell burden.

Treating these mice with D+Q for four weeks greatly reduced the p16 positive cells and dramatically improved cardiac function by several measures in vivo. Additionally, isolated cardiac stem cells from D+Q treated mice had improved proliferation and differentiation along with a reduced SASP compared to the placebo control.

The main findings emanating from this study are that: i) myocardial tissue of non-aged T2DM patients with ischemic cardiomyopathy is characterized by an exaggerated oxidative stress targeting both cardiomyocytes and cardiac stem/progenitor cells (CSCs); ii) Increased oxidative stress in the myocardium of non-aged T2DM patients associates with an increased number of senescent and dysfunctional T2DM-hCSCs as shown by increased p16INK4a, p53 and p21 expression, reduced telomerase activity and telomere length, reduced proliferation, clonogenesis/spherogenesis and myogenic differentiation; iii) T2DM-hCSCs from non-aged subjects show a senescence-associated secretory phenotype (SASP), as demonstrated by the increased secretion of several SASP factors, including MMP-3, PAI1, IL-6, IL-8, IL-1ß and GM-CSF; iv) a combination of two senolytics, Dasatinib and Quercetin, clear senescent T2DM-hCSCs restoring expansion and myogenic differentiation capacities of the remaining diabetic hCSC pool; v) Diabetic cardiomyopathy in young mice, independently of age and ischemia, causes myocardial cell senescence, affecting CSC regenerative potential, cardiac tissue composition and function; vi) D+Q treatment in vivo removes senescent CSCs and improves cardiac repair, regeneration and function in diabetic mice.

Conclusion 

This study provides a mountain of evidence to suggest that the senescence of cardiac stem cells contributes to heart pathology in diabetic patients. Not only was senescence higher in these cells in diabetic tissue, eliminating senescent cardiac stem cells improved function both in vitro for human cells and in an in vivo mouse model.

By conducting their study on younger patients (those who had heart attacks between the ages of 50 and 64) and using a young mouse model of diabetes, the authors show it is not aging alone that contributes to their findings. Still, there are many cofounding factors that may be at play. It is unlikely to be as simple as diabetes causing senescence, which, in turn, causes cardiac degeneration. This study does not contradict findings from other studies, which suggest that other hallmarks of aging are also involved.

Of course, in vitro studies and mouse models do not always translate to humans, but they are, at this stage, the best research tools available. As senolytic treatments race towards the clinic, it will be exciting to see their potential for treating diabetes-related cardiovascular disease.

Literature

[1] Marino, F. et al. Diabetes-induced cellular senescence and senescence-associated secretory phenotype impair cardiac regeneration and function independently of age. Diabetes (2022). https://doi.org/10.2337/db21-0536

[2] Halim, M. and Halim, A. The effects of inflammation, aging and oxidative stress on the pathogenesis of diabetes mellitus (type 2 diabetes). Diabetes Metab Syndr (2019). https://doi.org/10.1016/j.dsx.2019.01.040

[3] Dunlay, S.M. et al. Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America. American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing and the Heart Failure Society of America. Circulation (2019). https://doi.org/10.1161/cir.0000000000000691

[4] Lewis-McDougall, F.C. et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell (2019). https://doi.org/10.1111/acel.12931

[5] Shakeri, H. et al. Cellular senescence links aging and diabetes in cardiovascular disease. Am J Physiol Heart Circ Physiol (2018). https://doi.org/10.1152/ajpheart.00287.2018