Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?

Abstract

Inflammation is well understood to be a physiological process of ageing however it also underlies many chronic diseases, including conditions without an obvious pathogenic inflammatory element. Recent findings have unequivocally identified type 2 diabetes (T2D) as a chronic inflammatory disease characterized by inflammation and immune senescence. Immunosenescence is a hallmark of the prolonged low-grade systemic inflammation, in particular associated with metabolic syndrome and can be a cause as well as a consequence of T2D. Diabetes is a risk factor for cardiovascular mortality and remodelling and with particular changes to myocardial structure, function, metabolism and energetics collectively resulting in diabetic cardiomyopathy. Both cardiomyocytes and immune cells undergo metabolic remodelling in T2D and as a result become trapped in a vicious cycle of lost metabolic flexibility, thus losing their key adaptive mechanisms to dynamic changes in O2 and nutrient availability. Immunosenescence driven by metabolic stress may be both the cause and key contributing factor to cardiac dysfunction in diabetic cardiomyopathy by inducing metabolic perturbations that can lead to impaired energetics, a strong predictor of cardiac mortality. Here we review our current understanding of the cross-talk between inflammaging and cardiomyocytes in T2D cardiomyopathy. We discuss potential mechanisms of metabolic convergence between cell types which, we hypothesize, might tip the balance between resolution of the inflammation versus adverse cardiac metabolic remodelling in T2D cardiomyopathy. A better understanding of the multiple biological paradigms leading to T2D cardiomyopathy including the immunosenescence associated with inflammaging will provide a powerful target for successful therapeutic interventions.

Diabesity in Elderly Cardiovascular Disease Patients: Mechanisms and Regulators

“…The adipose tissue also releases proinflammatory adipokines (TNF-α, IL-6, MCP-1, leptin and resistin) [ 165 ] and, in consequence, develops HF [ 166 ]. The systemic metabolic dysfunction in the early stages of T2DM leads to immune cell senescence, contributing to the worsening of cardiac function and tissue metabolism [ 167 ].…”

Diagnostic and prognostic biomarkers reflective of cardiac remodelling in diabetes mellitus: A scoping review

“…There are two key pathological processes that cause the development of DM: inadequate insulin production by beta islet cells of pancreas, and insulin resistance (IR), which results from impaired insulin response in peripheral tissues. DM is a heterogenous disease with multiple organs involved in the aetiology: liver, skeletal muscles, pancreas, kidneys, brain, small intestine, and adipose tissue 5 . Hyperglycaemia associated with DM consequently triggers a surfeit of macro‐ and microvascular complications 6 …”

“…5 DM progression leads to specific changes to myocardial structure, function, and metabolism, collectively defined as diabetic cardiomyopathy (dbCM). 5,10 Hyperglycaemia, insulin resistance as well as lipotoxicity drive numerous fibrogenic pathways, triggering generation of reactive oxygen species (ROS), enhancing neurohumoral responses, stimulating growth factor cascades (i.e., TGF-β/Smad3 and PDGFs), inducing pro-inflammatory cytokines and chemokines, generating advanced glycation end-products (AGEs), stimulating the AGE-receptor for AGE (RAGE) axis, and up-regulating fibrogenic matricellular proteins. 11 Despite DM-triggered fibrogenic signalling sharing common characteristics in multiple tissues, diabetic myocardium develops more pronounced and clinically significant fibrosis.…”

“…DM is a heterogenous disease with multiple organs involved in the aetiology: liver, skeletal muscles, pancreas, kidneys, brain, small intestine, and adipose tissue. 5 Hyperglycaemia associated with DM consequently triggers a surfeit of macro-and microvascular complications. 6 The risk of CVD morbidity in DM is approximately two-three times more likely compared to those without DM.…”

“…The Framingham Heart Study concluded that type‐2 diabetes mellitus (T2D) independently increases the HF risk up to two‐fold in men and five‐fold in women compared to matched controls 8,9 . Thus, accelerated HF is a common clinical manifestation of CVD in T2D 5 . DM progression leads to specific changes to myocardial structure, function, and metabolism, collectively defined as diabetic cardiomyopathy (dbCM) 5,10 .…”