Excess visceral fat tissue distorts the operation of metabolism, reduces life expectancy, raises risk of age-related disease, and increases lifetime medical costs. Some fraction of these detrimental effects are mediated by cellular senescence: more senescent cells are created than would otherwise be the case, given extra visceral fat. Given that the accumulation of senescent cells is one of the root causes of aging, we might argue that being overweight literally accelerates the aging process. In the open access paper here, researchers explore some of the underlying mechanisms by which senescent cells are generated more readily in obese individuals. It is worth noting, however, that the epidemiological data on weight shows that any increase above a healthy level is harmful. More is worse, but any gain is bad to some degree.
Subcutaneous adipose tissue (SAT) is the largest and best storage site of excess fat in the body provided that new cells can be recruited as needed (hyperplastic obesity). Inappropriate expansion of the adipose cells (hypertrophic obesity) promotes insulin resistance and other obesity-associated metabolic complications and is a consequence of inability to recruit new adipose cells. This has been shown both in vitro and in direct studies of human adipose cell turnover in vivo.
Our previous extensive studies have shown large inter-individual differences in ability of human SAT stromal vascular fraction (SVF) cells to undergo adipogenesis. Furthermore, markers of reduced SAT adipogenesis are associated with genetic predisposition for type 2 diabetes (T2D) and first-degree relatives (FDR), like individuals with manifest T2D, are characterized by hypertrophic obesity. Human SAT contains a pool of adipose progenitor cells but the detailed signals for recruiting new adipose cells and the reasons for the large individual differences are unclear. Bone morphogenetic protein 4 (BMP4) is important for the commitment of mesenchymal progenitor cells into the adipogenic lineage and BMP-signalling is regulated by different secreted inhibitors. We found Gremlin-1 (GREM1) to be an important BMP4 antagonist and increased in hypertrophic obesity. Thus, impaired commitment of progenitor cells could be one reason for the reduced adipogenesis.
Cell senescence is, in part, a consequence of repeated progenitor cell mitogenic expansion and there is a 10% annual cell turnover in human SAT. Cell senescence leads to permanent cell cycle arrest, secretion of different senescence-associated proteins and inhibited cell differentiation. We here characterize mechanisms for the impaired SAT adipogenesis in adult human subjects with hypertrophic obesity including FDR/T2D. A key mechanism for the impaired adipogenesis in hypertrophic obesity / T2D is increased progenitor cell senescence, dysregulated p53 and P16ink4 and secretion of senescence-associated secretory phenotype (SASP) factors antagonizing normal cell adipogenic differentiation.