Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

/pdf/resveratrol-improves-health-and-survival-of-mice-on-a-high-nclsf2ace3.pdf

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

https://www.cell.com/cell/pdf/S0092-8674(05)00109-1.pdf

Mitochondria, Oxidants, and Aging

https://www.medicinalgenomics.com/wp-content/uploads/2013/01/Resveratrol-rescues-mito-function-through-sirtuin-and-PGC-1.pdf

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Therapeutic potential of resveratrol: the in vivo evidence.

Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the agerelated diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.

/pdf/a-mitochondrial-paradigm-of-metabolic-and-degenerative-32cv8y7bvd.pdf

A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

Calorie restriction extends lifespan in organisms ranging from yeast to mammals. In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction. Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by the fat regulator PPAR-gamma (peroxisome proliferator-activated receptor-gamma), including genes mediating fat storage. Sirt1 represses PPAR-gamma by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). Mobilization of fatty acids from white adipocytes upon fasting is compromised in Sirt1+/- mice. Repression of PPAR-gamma by Sirt1 is also evident in 3T3-L1 adipocytes, where overexpression of Sirt1 attenuates adipogenesis, and RNA interference of Sirt1 enhances it. In differentiated fat cells, upregulation of Sirt1 triggers lipolysis and loss of fat. As a reduction in fat is sufficient to extend murine lifespan, our results provide a possible molecular pathway connecting calorie restriction to life extension in mammals.

/pdf/sirt1-promotes-fat-mobilization-in-white-adipocytes-by-2b91la0kqe.pdf

Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.

http://web.mit.edu/biology/guarente/references/14.pdf

Superoxide dismutase 1 knock-down induces senescence in human fibroblasts.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2006.09.036

Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway.

Nature 429, 771–776 (2004). It has been drawn to our attention by Vincent Keng that the image in the bottom-left frame of Fig. 1c of this Letter presents identical data to the one above it on the right. A mistake made by the authors during compilation of Fig.1 caused the wrong bottom-left image to be used instead of the correct image, which is shown below.

/pdf/corrigendum-sirt1-promotes-fat-mobilization-in-white-4rv54u35k4.pdf

Rita Machado de Oliveira

Papers

Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.

Superoxide dismutase 1 knock-down induces senescence in human fibroblasts.

Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway.

corrigendum: Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ