Molecular basis of ageing in chronic metabolic diseases

Abstract

Aim: Over the last decades, the shift in age distribution towards older ages and the progressive ageing which has occurred in most populations have been paralleled by a global epidemic of obesity and its related metabolic disorders, primarily, type 2 diabetes (T2D). Dysfunction of the adipose tissue (AT) is widely recognized as a significant hallmark of the ageing process that, in turn, results in systemic metabolic alterations. These include insulin resistance, accumulation of ectopic lipids and chronic inflammation, which are responsible for an elevated risk of obesity and T2D onset associated to ageing. On the other hand, obesity and T2D, the paradigms of AT dysfunction, share many physiological characteristics with the ageing process, such as an increased burden of senescent cells and epigenetic alterations. Thus, these chronic metabolic disorders may represent a state of accelerated ageing.

Materials and methods: A more precise explanation of the fundamental ageing mechanisms that occur in AT and a deeper understanding of their role in the interplay between accelerated ageing and AT dysfunction can be a fundamental leap towards novel therapies that address the causes, not just the symptoms, of obesity and T2D, utilizing strategies that target either senescent cells or DNA methylation.

Results: In this review, we summarize the current knowledge of the pathways that lead to AT dysfunction in the chronological ageing process as well as the pathophysiology of obesity and T2D, emphasizing the critical role of cellular senescence and DNA methylation.

Conclusion: Finally, we highlight the need for further research focused on targeting these mechanisms.

Keywords: Adipose tissue; Ageing; Cellular senescence; DNA methylation; Obesity; Type 2 diabetes.

Fig. 1

Molecular and cellular hallmarks of ageing. These hallmarks recapitulate the most remarkable features of ageing and depict the mechanisms underlying the pathogenesis of age-related diseases, including obesity and type 2 diabetes. NL, nuclear lamina

Fig. 2

A vicious cycle explains the synergistic association between cellular senescence and type 2 diabetes. The increased senescent cell burden in adipose tissue during ageing and obesity contributes to inflammation, adipocyte progenitor cell dysfunction, impaired insulin responsiveness, and metabolic abnormalities. These effects promote to insulin resistance and type 2 diabetes. Metabolic, inflammatory, and immune perturbations in the diabetic state, in turn, fuel senescent cell accumulation, which contributes to tissue damage and diabetes-related complications. Senolytics and SASP inhibitors seem to be more effective (dark green blunt head arrow) in breaking this malignant positive feedback loop than current glucose-lowering treatments (light green blunt head arrow). SASP senescence-associated phenotype, AT adipose tissue, T2D type 2 diabetes, APC adipocyte progenitor cell, ROS reactive oxygen species, AGEs advanced glycation end products, GH growth hormone, IGF-1 insulin-like growth factor-1

Fig. 3

Schematic chart of a DNA methylation clock throughout the human lifetime. The difference between DNA methylation age and chronological age (i.e., the time elapsed since birth) reflects biological age and may be an indicator of ageing rate and health outcomes. ARDs, age-related diseases; T2D, type 2 diabetes