Increased cell senescence in human metabolic disorders

Abstract

Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders.

Figure 1. Linking aging to chronic diseases.

The hallmarks of aging, including cell senescence, are functionally intertwined and drive the pathophysiology of many chronic disorders, affecting tissues directly involved in disease development. Indeed, senescent cells promote or exacerbate human age-related conditions by inducing chronic inflammation and tissue dysfunction via their SASP. SASP factors are responsible for a number of negative effects, including stem cell dysfunction, immune cell recruitment, fibrogenic myofibroblast induction, and extracellular matrix secretion. The left side of the figure displays the most common cell types and mechanisms that cause tissue damage, all of which contribute to the age-related chronic diseases depicted to the right. The right side of the figure depicts some of the most common chronic diseases associated with aging. CVD, cardiovascular disease.

Figure 2. Pathological role of senescent cells in tissue dysfunction and chronic metabolic disease.

Cell senescence is a state of cell cycle arrest with senescent cells displaying characteristics such as being enlarged, flattened, and of irregular shape, elevated expression of p53, p21, p16, cyclin D1, and ZMAT3 proteins, increased lysosomal SA-β-gal activity, enhanced γ-H2AX phosphorylation, decreased mitochondrial content, decreased LMNB1 expression, and SASP acquisition. Increased accumulation of senescent cells in key metabolic tissues (liver, adipose tissue, skeletal muscle) promotes local tissue dysfunction and systemic deleterious effects with IR and the development of common age-related diseases such as T2D, NAFLD/NASH, and sarcopenia. FA, fatty acid.

Figure 3. Cell senescence as likely mediator of the bidirectional relationship between IR and hyperinsulinemia.

Senescent cells accumulate in multiple tissues in obesity, T2D, and NAFLD/NASH, including AT and the liver. Increased CS in those tissues may cause IR, which, in turn, leads to hyperinsulinemia. Hyperinsulinemia, on the other hand, may induce senescence in both adipocytes and liver cells, contributing to an increase in CS burden in the AT and liver. Thus, CS may enable and fuel a vicious cycle between IR and hyperinsulinemia, which plays a considerable role in the development of several metabolic diseases and their consequences.