Resveratrol improves health and survival of mice on a high-calorie diet

Baur, Joseph A.; Pearson, Kevin J.; Price, Nathaniel O; Jamieson, Hamish A.; Lerín, Carles; Kalra, Avash; Prabhu, Vinayakumar; Allard, Joanne; López‐Lluch, Guillermo; Lewis, Kaitlyn N.; Pistell, Paul J.; Poosala, Suresh; Becker, Kevin G.; Boss, Olivier; Gwinn, Dana M.; Wang, Mingyi; Ramaswamy, Sharan; Fishbein, Kenneth W.; Spencer, Richard G.; Lakatta, Edward G.; Couteur, David G. Le; Shaw, Reuben J.; Navas, Plácido; Puigserver, Pere; Ingram, Donald K.; Cabo, Rafael de; Sinclair, David A.

doi:10.1038/nature05354

Cited by 3,822 publications

(3,513 citation statements)

References 45 publications

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“…C57BL/6J male mice were randomly paired to resident males of either the CD1 or the Sv129Ev strain to attain exposure to a gradient of territorial aggression, reportedly higher in CD1 (Bartolomucci et al., 2010; Dadomo et al., 2011; Zou, Storm & Xia, 2013). High‐fat diet (HFD) was previously reported to exacerbate stress‐induced metabolic syndrome‐like (Sanghez et al., 2013) and to shorten lifespan (Baur et al., 2006), prompting us to test the hypothesis that there could be an interaction between stress and hypercaloric diet on survival. Thus, half the mice were randomized to HFD feeding during the last 3 weeks of the CPS phase according to our established protocol (Razzoli et al., 2016; Sanghez et al., 2013, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, half the mice were randomized to HFD feeding during the last 3 weeks of the CPS phase according to our established protocol (Razzoli et al., 2016; Sanghez et al., 2013, 2016). HFD was limited to 3 weeks as chronic HFD per se has a marked effect on lifespan (Baur et al., 2006). The aging phase started subsequently by maintaining the two pair members cohoused in sensory contact until spontaneous death, thus mimicking a lifelong stress threat.…”

Section: Resultsmentioning

confidence: 99%

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Social stress shortens lifespan in mice

et al. 2018

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SummaryStress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Social stress shortens lifespan in mice

et al. 2018

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“…Similarly, resveratrol, a SIRT1 agonist, extends the lifespan of worms and flies. Treating adult mice on a high fat diet with resveratrol induces endocrine changes associated with longevity, such as suppression of IGF-1 and insulin sensitivity, and extends lifespan (Baur et al, 2006). Resveratrol also dramatically inhibits mTOR activation in response to stress through a TSC2-dependent pathway, at least in part through SIRT1 activation (P.D.R, submitted).…”

Section: Sirtuinmentioning

confidence: 99%

Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan

Niedernhofer

Robbins

2008

The International Journal of Biochemistry & Cell Biology

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Ageing is defined by the loss of functional reserve over time, leading to a decreased capacity to maintain homeostasis under stress and increased risk of morbidity and mortality. Ageing is extremely heterogeneous between individuals and even between tissues within an organism, making it challenging to identify the molecular basis of ageing. Much of our current understanding of ageing comes from genetic studies in model organisms seeking genes that either accelerate or decelerate the ageing process. These studies revealed not only causes of ageing, but also signaling mechanisms that both promote and protect against ageing. In all cases, the signaling pathways that influence lifespan are familiar mechanisms that regulate cellular metabolism, growth, proliferation, differentiation and survival. This review highlights the significant overlap in signaling mechanisms implicated in both the cellular response to genotoxic stress and regulation of organism lifespan.

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“…7 It is hypothesized that caloric restriction as well as treatment with resveratrol increases Sirt1 activity, which subsequently diminishes fat cell size and fat content, which leads to improved metabolic control and in the end leads to increased longevity; thus, Sirt1 has been implicated in the intracellular nutrient-sensing pathway. 8 Little is known about this system in human adipose tissue, so this study was undertaken to investigate whether calorie restriction in humans can also influence the Sirt1 expression.…”

Section: Introductionmentioning

confidence: 99%

Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women

et al. 2008

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Objective: Calorie restriction increases the life span in a number of different organisms. This effect is dependent upon activation of the Sirt1 enzyme, and many of the beneficial effects of calorie restriction can be mimicked using resveratrol, which activates the Sirt1 enzyme. Nothing is known about this system in human adipose tissue; therefore, we investigated this system in human adipose tissue. Design: Sirt1 mRNA was measured in adipose tissue biopsies from human volunteers before and after 6 days of total fasting. In addition, adipose tissue from lean and obese individuals was compared and in vitro investigations were performed. Results: Long-term total fasting (6 days) of nine human volunteers increased Sirt1 mRNA expression in subcutaneous adipose tissue more than twofold (0.197-0.454 arbitrary units, Po0.05). Likewise, lean women (n ¼ 12) had more than twofold higher Sirt1 expression in subcutaneous adipose tissue compared to obese women (n ¼ 12; 0.33-0.73 arbitrary units, Po0.05). Sirt1 was equally expressed in the stroma-vascular fraction and the isolated adipocyte fraction. Finally, in vitro, we demonstrated that resveratrol (a Sirt1 activator) significantly enhanced the lipolytic effect of epinephrine in human adipose tissue (Po0.05). Conclusion: Human adipose tissue contains Sirt1 and the expression of Sirt1 can be regulated by calorie restriction as in other species. Furthermore, we demonstrated that resveratrol affects human fat-cell metabolism similar to the effects in rodents (that is, increased epinephrine induced lipolysis). These findings indicated that the beneficial effects of calorie restriction in humans might involve the activation of Sirt1. Thus, based on these findings, we propose that Sirt1 might play important roles for the beneficial effects of calorie restriction in humans.

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Resveratrol improves health and survival of mice on a high-calorie diet

Cited by 3,822 publications

References 45 publications

Social stress shortens lifespan in mice

Social stress shortens lifespan in mice

Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan

Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women

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