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.

Build-UPS and break-downs: metabolism impacts on proteostasis and aging

“…4 , Table 1 ). In contrast, deficits in proteostasis contribute to the development of metabolic diseases including diabetes and cancer [ 1 , 2 , 22 ]. Therefore, it is of outstanding interest to understand how metabolic perturbation and proteotoxicity are interconnected to design promising strategies for therapeutic interventions.…”

Neuroinflammation in Alzheimer’s Disease

“…Aging is characterized by dysregulated immune [ 1 ] and metabolic homeostasis [ 2 , 3 ] where there is chronic sterile low-grade inflammation or inflammaging [ 4 ] that involves cellular senescence [ 5 , 6 ], immunosenescence [ 7 , 8 , 9 , 10 ], mitochondrial dysfunction [ 11 , 12 ], defective autophagy [ 13 , 14 ] and mitophagy [ 15 , 16 ], dysregulation of the ubiquitin–proteasome system [ 17 , 18 ], activation of the DNA damage response [ 19 , 20 ], meta-inflammation or metaflammation from chronic overnutrition or obesity [ 21 , 22 ], and gut microbiota dysbiosis [ 5 , 23 , 24 , 25 ]. These are reflected by changes in circulating immune markers including C-reactive protein (CRP) [ 26 ], interleukin-6 (IL-6) [ 27 ], tumor necrosis factor alpha (TNF-α) [ 28 ] and its soluble receptors (tumor necrosis factor receptor I (TNFR-I) and tumor necrosis factor receptor II (TNFR-II)) [ 28 ], vascular cell adhesion molecule I (VCAM-I) [ 29 ], d-dimer [ 30 ], and sirtuin signaling [ 31 , 32 ].…”

Aging mitigates the severity of obesity-associated metabolic sequelae in a gender independent manner

“…Aging is associated with an increase in abdominal obesity and the development of metabolic derangements 28 – 30 . To examine the impact of aging on induction of metabolic derangements, young (7 months at time of analysis) and aged (19 months at time of analysis) male mice were housed a standard temperature (T S ; 22 °C) (Fig.…”