Molecular links between aging and adipose tissue

Picard, Frédéric; Guarente, Leonard

doi:10.1038/sj.ijo.0802912

Cited by 97 publications

(82 citation statements)

References 46 publications

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“…Both PPAR-γ and SIRT1 have previously been implicated in this process [127] but it is as yet unclear if either is playing a role in DRinduced changes observed in white adipose tissue. Histological examination of white adipose tissue from mice on DR confirmed the presence of multilocular adipocytes which may represent an intermediate phenotype between white and brown adipocytes [10].…”

Section: The Role Of Adipose Tissue In Aging Retardation By Dietary Rmentioning

confidence: 99%

Metabolic Reprogramming in Dietary Restriction

Anderson

Weindruch²

2006

Interdisciplinary Topics in Gerontology

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It is widely accepted that energy intake restriction without essential nutrient deficiency delays the onset of aging and extends life span. The mechanism underlying this phenomenon is still unknown though a number of different, nonmutually exclusive explanations have been proposed. In each of these, different facets of physiology play the more significant role in the mechanism of aging retardation. Some examples include the altered lipid composition model, the immune response model and models describing changes in endocrine function. In this paper we propose the hypothesis that metabolic reprogramming is the key event in the mechanism of dietary restriction, and the physiological effects at the cellular, tissue and organismal level may be understood in terms of this initial event.Dietary restriction (DR) is the most successful intervention tested to date in mammals which greatly extends maximum life span and keeps animals 'younger longer' [1][2][3]. Consequently, any hypothesis about the etiology of aging must reconcile the effects of DR on aging. With increased knowledge of the mechanism of DR, we stand to gain a considerable insight into the process of aging.We propose that a change in the regulation of energy metabolism in response to DR is the primary step in the retardation of aging ( fig. 1). First we describe the evidence in support of metabolic reprogramming, a switch to an altered metabolic state, by DR in mice. Next we consider evidence for metabolic shifts in other model organisms where life span is extended by DR or by genetic manipulation. Then we focus on changes in mitochondrial energy metabolism with age and DR in mammals. Next we will explore the effects of altered mitochondrial function in the context of reactive oxygen species (ROS) generation and oxidative stress. Finally we describe the metabolic and morphological changes in white adipose tissue that we believe are a result of altered mitochondrial function. We propose that the activation of adipose tissue through metabolic reprogramming is critical to the mechanism of DR and that it leads to the changes in the animal physiology that are described in the models indicated above. Metabolic Reprogramming in Tissues from Dietary-Restricted AnimalsThe inverse linear relationship between calorie intake and life span in mice [4] suggests that genes central to energy metabolism may be critical in the underlying mechanism of DR in

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Section: The Role Of Adipose Tissue In Aging Retardation By Dietary Rmentioning

confidence: 99%

Metabolic Reprogramming in Dietary Restriction

Anderson

Weindruch²

2006

Interdisciplinary Topics in Gerontology

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“…Since normal aging results in compromised biological functions of the organism and enhanced susceptibility to disease, age-related health complications gained an increased importance during this period. In addition, the shift in demographic curves towards elderly population bound to the rise in regular intake of energy-rich diets tends to exacerbate the epidemic obesity that currently exists (Picard and Guarente 2005).…”

Section: Introductionmentioning

confidence: 99%

Energy restriction ameliorates metabolic syndrome-induced cavernous tissue structural modifications in aged rats

Tomada

Fernandes

Guimarães

et al. 2012

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High-fat (HF) diet regular intake along life highly contributes to vascular dysfunction and to an increment in prevalence of metabolic syndrome (MetS) and erectile dysfunction (ED), a surrogate symptom of occult vascular disease, in the elderly. However, little is known about the effects of energy restriction (ER) alone/or after an HF-feeding period. We show here that in male Sprague-Dawley rats, 16 months of HF-diet consumption led to an increase in body adiposity, blood pressure, lipidemia, C-reactive protein, and insulin resistance and to hypoadiponectinemia, conditions that cluster in MetS. In addition, this treatment strongly favored collagen deposition in cavernous tissue and myocardium. Conversely, for the same time period, the ingestion of 75 % of ad libitum energy intake by controls (ER) extensively counteracted these outcomes. The impact of 6-month ER after 10-month HF period was also analyzed, and despite the decrease in body weight, adiposity, blood pressure, lipidemia, and Creactive protein and improvement of insulin sensitivity, no differences were observed either in adiponectin blood levels or in retroperitoneal fat pad mass. Moreover, this treatment led to a reduction in cavernous tissue collagen deposition, but not in the myocardium, and evidenced differential mobilization of adipose tissue accretions. The data show the ability of HF diet to cause MetS and produce unwanted effects on myocardium and corpora vascular structure. They also indicate that these consequences are preventable upon ER diet starting early, but not later, in life.

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“…Genetic and diet-induced disturbances in insulin and nutrient signaling have been compellingly linked to diabetes, obesity, and accelerated aging (2)(3)(4). In particular, deregulated activity of the nutrient-sensitive kinase mTOR (mammalian target of rapamycin) and of its downstream effector S6 kinase (S6K) by high-fat diet or leptin deficiency promotes fat accumulation, induces insulin resistance, and shortens mouse lifespan (5,6).…”

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confidence: 99%

Mammalian life-span determinant p66 ^shcA mediates obesity-induced insulin resistance

Ranieri

Fusco

Panieri

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

125

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Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lep Ob/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lep Ob/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.O besity and metabolic syndrome represent ramping public health issues in the Western world, due to overnutrition and reduced physical activity, coupled with genetic susceptibility (1). Although a correct lifestyle remains the mainstream solution to this problem, pharmacological strategies are also being actively seeked; to this end, a better knowledge of the molecular players and biochemical mechanisms linking excess body fat to glucose intolerance and an increased cardiovascular risk is critically needed.Genetic and diet-induced disturbances in insulin and nutrient signaling have been compellingly linked to diabetes, obesity, and accelerated aging (2-4). In particular, deregulated activity of the nutrient-sensitive kinase mTOR (mammalian target of rapamycin) and of its downstream effector S6 kinase (S6K) by high-fat diet or leptin deficiency promotes fat accumulation, induces insulin resistance, and shortens mouse lifespan (5, 6). On the other hand, calorie restriction and hypomorphic mutations or pharmacological blockade within the insulin and mTOR/S6 kinase signaling cascades increase longevity both in lower model organisms and in mammals (7-11), and adipose-specific deletion of the insulin receptor (IR) extends lifespan of FIRKO mice (12).Mice lacking the 66-kDa isoform of the adaptor Shc (Src ...

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Molecular links between aging and adipose tissue

Cited by 97 publications

References 46 publications

Metabolic Reprogramming in Dietary Restriction

Metabolic Reprogramming in Dietary Restriction

Energy restriction ameliorates metabolic syndrome-induced cavernous tissue structural modifications in aged rats

Mammalian life-span determinant p66 ^shcA mediates obesity-induced insulin resistance

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Molecular links between aging and adipose tissue

Cited by 97 publications

References 46 publications

Metabolic Reprogramming in Dietary Restriction

Metabolic Reprogramming in Dietary Restriction

Energy restriction ameliorates metabolic syndrome-induced cavernous tissue structural modifications in aged rats

Mammalian life-span determinant p66 shcA mediates obesity-induced insulin resistance

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Mammalian life-span determinant p66 ^shcA mediates obesity-induced insulin resistance