NO link between calorie restriction and mitochondria.
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Adipose Tissue↗
Biomedical subjects
Leonard Guarente
Publications and source records attributed to Leonard Guarente.
Calorie restriction, SIRT1 and metabolism: understanding longevity.
Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.
Animals↗
Science fact and the SENS agenda. What can we reasonably expect from ageing research?
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Aging↗
Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria.
IDE (insulin-degrading enzyme) is a widely expressed zinc-metallopeptidase that has been shown to regulate both cerebral amyloid beta-peptide and plasma insulin levels in vivo. Genetic linkage and allelic association have been reported between the IDE gene locus and both late-onset Alzheimer's disease and Type II diabetes mellitus, suggesting that altered IDE function may contribute to some cases of these highly prevalent disorders. Despite the potentially great importance of this peptidase to health and disease, many fundamental aspects of IDE biology remain unresolved. Here we identify a previously undescribed mitochondrial isoform of IDE generated by translation at an in-frame initiation codon 123 nucleotides upstream of the canonical translation start site, which results in the addition of a 41-amino-acid N-terminal mitochondrial targeting sequence. Fusion of this sequence to the N-terminus of green fluorescent protein directed this normally cytosolic protein to mitochondria, and full-length IDE constructs containing this sequence were also directed to mitochondria, as revealed by immuno-electron microscopy. Endogenous IDE protein was detected in purified mitochondria, where it was protected from digestion by trypsin and migrated at a size consistent with the predicted removal of the N-terminal targeting sequence upon transport into the mitochondrion. Functionally, we provide evidence that IDE can degrade cleaved mitochondrial targeting sequences. Our results identify new mechanisms regulating the subcellular localization of IDE and suggest previously unrecognized roles for IDE within mitochondria.
Amino Acid Sequence↗
Essential role of limiting telomeres in the pathogenesis of Werner syndrome.
Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening.
Aging, Premature↗
Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.
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.
3T3-L1 Cells↗
Mammalian SIRT1 represses forkhead transcription factors.
The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
Acetylation↗
Calorie restriction extends yeast life span by lowering the level of NADH.
Calorie restriction (CR) extends life span in a wide variety of species. Previously, we showed that calorie restriction increases the replicative life span in yeast by activating Sir2, a highly conserved NAD-dependent deacetylase. Here we test whether CR activates Sir2 by increasing the NAD/NADH ratio or by regulating the level of nicotinamide, a known inhibitor of Sir2. We show that CR decreases NADH levels, and that NADH is a competitive inhibitor of Sir2. A genetic intervention that specifically decreases NADH levels increases life span, validating the model that NADH regulates yeast longevity in response to CR.
Culture Media↗
Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes.
The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.
Animals↗
The Sir2 family of protein deacetylases.
The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
Aging↗
Saccharomyces cerevisiae SSD1-V confers longevity by a Sir2p-independent mechanism.
The SSD1 gene of Saccharomyces cerevisiae is a polymorphic locus that affects diverse cellular processes including cell integrity, cell cycle progression, and growth at high temperature. We show here that the SSD1-V allele is necessary for cells to achieve extremely long life span. Furthermore, addition of SSD1-V to cells can increase longevity independently of SIR2, although SIR2 is necessary for SSD1-V cells to attain maximal life span. Past studies of yeast aging have been performed in short-lived ssd1-d strain backgrounds. We propose that SSD1-V defines a previously undescribed pathway affecting cellular longevity and suggest that future studies on longevity-promoting genes should be carried out in long-lived SSD1-V strains.
Alleles↗
Superoxide dismutase 1 knock-down induces senescence in human fibroblasts.
Reactive oxygen species (ROS) such as superoxide radicals are responsible for the pathogenesis of various human diseases. ROS are generated during normal metabolic process in all of the oxygen-utilizing organisms. The copper-zinc-containing SOD (SOD1) acts as a major defense against ROS by detoxifying the superoxide anion. In model organisms, SOD1 has been shown to play a role in the aging process. However, the exact role of the SOD1 protein in the human aging process remains to be resolved. We show that SOD1 RNA interference (RNAi) induces senescence in normal human fibroblasts. This premature senescence depends on p53 induction. In contrast, in human fibroblastic cells with inactivated p53, the SOD1 RNAi is without effect. Surprisingly, in cancer cells (HeLa), the SOD1 RNAi induces cell death rather then senescence. Together, these findings support the notion that in normal human cells the SOD1 protein may play a role in the regulation of cellular lifespan by p53 and may also regulate the death signals in cancer cells.
Aging↗
Genetics and the specificity of the aging process.
The identification and study of long-lived mutant animals has provided valuable insights into the mechanisms that limit the life-span of organisms. Findings with the gene SIR2 suggest that the rate of aging can be regulated under certain conditions. Indeed, increased expression of SIR2 lengthens life-span by acting on biological processes that promote survival under conditions of scarcity. In addition, studies of mutant strains of Caenorhabditis elegans, in particular daf-2, clk-1, and isp-1 mutants, suggest that the biology of reactive oxygen species in the mitochondria and elsewhere might be the main determinant of life-span in this organism. Thus, the aging process may be more specific than previously anticipated on evolutionary grounds.
Aging↗
How does calorie restriction work?
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Aging↗
Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease.
Nicotinamide adenine dinucleotide (NAD) is a ubiquitous biological molecule that participates in many metabolic reactions. Recent studies show that NAD also plays important roles in transcriptional regulation, longevity, calorie-restriction-mediated life-span extension and age-associated diseases. It has been shown that NAD affects longevity and transcriptional silencing through the regulation of the Sir2p family, which are NAD-dependent deacetylases. Many human diseases are associated with changes in NAD level and/or the NAD : NADH ratio, raising the possibility that the Sir2p family might play a role in these diseases.
Aging↗
Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration.
Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.
Adenosine Triphosphate↗
Separation of mother and daughter cells.
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Cell Separation↗
Model organisms as a guide to mammalian aging.
Recent studies on aging in model systems such as yeast and roundworms have revealed conserved regulation of the process in response to nutrient availability and specific genes that appear to mediate this regulation. Here we review these findings with a focus on the nematode Caenorhabditis elegans and the budding yeast Saccharomyces cerevisiae and highlight general features of the regulation of aging that may have implications for mammals.
Aging↗