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SREBP-1c Mediated Alterations in Fat Metabolism are Essential to Life Extension Achieved via Calorie Restriction

One of the approaches taken in efforts to understand a complex system such as metabolism is to break specific components, one by one, and observe the results: disable a gene, block the interactions of a protein, and so forth. This technique is widely used in investigations of calorie restriction, particularly regarding the way in which calorie restriction extends life span in short-lived species such as mice. It allows researchers to narrow the list of mechanisms and regulators that are most important in the way in which metabolism determines variations in the pace of aging. Calorie restriction is challenging as a topic for research, as near every aspect of cellular metabolism is changed by the adoption of a low calorie diet. While most of the important processes are known at a high level, decades of research have yet to result in a comprehensive understanding of the detailed interaction between metabolism and aging.

Today's open access paper reviews one of the mechanisms known to be vital to the operation of calorie restriction. If it is disabled, then calorie restriction no longer functions to extend life in mice. The mechanism involves alterations in the metabolism of white fat tissue via a master regulator that influences lipid storage and mitochondrial function in that tissue. Fat is metabolically active and via signals can influence the rest of the body in a variety of ways. It is evidently the case that eating fewer calories has a sizable impact on fat tissue, but it is interesting to see just how far researchers have progressed into understanding what that means at the detail level. The other vital mechanisms of calorie restriction are related to autophagy, the cellular processes of maintenance that recycle damaged proteins and cellular structures. Like many of the other ways to modestly slow aging in short-lived species, calorie restriction upregulates autophagy, and indeed requires the correct function of autophagy in order to extend life. When autophagy is disabled, calorie restriction fails to extend life.

SREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction

Caloric restriction (CR), also known as dietary restriction, is a simple and reproducible manipulation that delays the onset of many age-related pathophysiological changes and extends both median and maximum lifespan. The life-extending effect of CR is observed in several species, including yeast, worms and mammals; hence, CR has been widely investigated in aging research. In general, CR animals exhibit low body temperature and plasma insulin, and high plasma dehydroepiandrosterone sulfate (DHEAS). Interestingly, it has been reported that humans with this phenotype live longer than their counterparts. Furthermore, a recent report has revealed the effectiveness of CR in non-human primates, implying that CR can be also beneficial for humans.

Previous studies have suggested that the beneficial effects of CR may involve various mechanisms; for example, the suppression of growth hormone/insulin-like growth factor (GH/IGF-1) signaling, reduction of mechanistic target of rapamycin complex 1 activity, activation of sirtuin, enhancement of mitochondrial biogenesis, attenuation of oxidative and other types of stress, suppression of inflammation, and alteration of the gut microbiome. Thus, the mechanisms underpinning the effects of CR are complex and diverse, and further research is required for them to be fully elucidated.

White adipose tissue (WAT) is a major site of energy storage in the form of triglyceride (TG), but WAT has also become established as an endocrine tissue that secretes adipokines. It is accepted that the characteristics of adipocytes and their secretory profile differ according to their size. Large adipocytes storing a large amount of TG. In contrast, small adipocytes secrete more adiponectin. Moreover, small adipocytes are more sensitive to insulin and play a buffering role for whole-body lipids by absorbing them after a meal and releasing them in the fasting state. Thus, differences in the characteristics of WAT can influence whole-body metabolism.

Recent studies have demonstrated that several models of genetic modification in WAT are associated with differences in lifespan. For example, fat-specific insulin receptor knockout (FIRKO) mice display lower adiposity, enhanced mitochondrial biogenesis, and extended lifespan, compared with a control group. In addition, genetic manipulation of master regulators of adipocyte differentiation in mice is known to alter lifespan. It has also been reported that differences in adipokine secretion profiles affect lifespan. For instance, liver-specific adiponectin transgenic mice are resistant to high-calorie diet-induced obesity and demonstrate an extended lifespan.

CR prevents age-induced adiposity by lowering plasma insulin and leptin concentration and raising adiponectin concentration, while also reducing the size of adipocytes in WAT. Therefore, we hypothesized that the beneficial effects of CR may be partially mediated by functional alterations in WAT. In the process of testing this hypothesis, we identified the sterol regulatory element-binding protein 1c (SREBP-1c), a master transcriptional regulator of lipogenic gene expression, as a mediator of CR. These findings were validated by showing that CR failed to upregulate factors involved in fatty acid biosynthesis and to extend longevity in SREBP-1c knockout mice. Furthermore, we revealed that SREBP-1c is implicated in CR-associated mitochondrial activation through the upregulation of PGC-1α, a master regulator of mitochondrial biogenesis. Notably, these CR-associated phenotypes were observed only in WAT.

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