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Review
. 2017 Nov 5:455:93-102.
doi: 10.1016/j.mce.2016.08.047. Epub 2016 Aug 31.

Cellular senescence: Implications for metabolic disease

Marissa J Schafer  1 , Jordan D Miller  2 , Nathan K LeBrasseur  3
Affiliations
Review

Cellular senescence: Implications for metabolic disease

Marissa J Schafer et al. Mol Cell Endocrinol. .

Abstract

The growing burden of obesity- and aging-related diseases has hastened the search for governing biological processes. Cellular senescence is a stress-induced state of stable growth arrest strongly associated with aging that is aberrantly activated by obesity. The transition of a cell to a senescent state is demarcated by an array of phenotypic markers, and leveraging their context-dependent presentation is essential for determining the influence of senescent cells on tissue pathogenesis. Biomarkers of senescent cells have been identified in tissues that contribute to metabolic disease, including fat, liver, skeletal muscle, pancreata, and cardiovascular tissue, suggesting that pharmacological and behavioral interventions that alter their abundance and/or behavior may be a novel therapeutic strategy. However, contradictory findings with regard to a protective versus deleterious role of senescent cells in certain contexts emphasize the need for additional studies to uncover the complex interplay that defines multi-organ disease processes associated with obesity and aging.

Keywords: Aging; Diabetes; Exercise; Inflammation; Obesity; Senolytics.

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Figures

Fig. 1
Fig. 1
Projected rising trends in obesity and aging. Historical (solid blue line) and forecasted (dotted blue line) percentage of the U.S. population that is 65 years or older (West et al., 2014; United States Census Bureau, 2014), compared to historical (solid red line) and predicted (dotted red line) percentage of the population that is obese (Finkelstein et al., 2012; Ogden et al., 2010).
Fig. 2
Fig. 2
Biomarkers of senescence. Senescent cells display features unique to non-senescent counterparts, and identification of multiple markers is important for confirming a senescent identity. Cell cycle is arrested (identifiable by a loss of proliferative markers) through the activity of cyclin dependent kinase inhibitors, including p16INK4a and/or p53/p21. This may be induced by several forms of cellular dysfunction, such as mitochondria-generated ROS, telomere attrition, and DNA damage, which may be unresolvable within telomeres (TAF). Transition to a senescent state may be accompanied by changes in morphology and nuclear dynamics, such as the formation of senescence-associated hetero-chromatin foci (SAHF) and reductions in the nuclear lamina marker lamin B1. Senescent cells develop a unique secretome, the senescence-associated secretory phenotype (SASP), which is compositionally context dependent and imparts potent paracrine effects.
Fig. 3
Fig. 3
Senescent tissues in obesity-related disease. Senescent phenotypes have been identified in metabolically active tissues, including visceral adipose, pancreas, liver, cardiovascular tissue, and skeletal muscle. Obesity-related changes in the microbiota also induce senesecence in the liver.
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