Sir2-Independent Life Span Extension by Calorie Restriction in Yeast

Kaeberlein, Matt; Kirkland, Kathryn T.; Fields, Stanley; Kennedy, Brian K.

doi:10.1371/journal.pbio.0020296

Cited by 410 publications

(423 citation statements)

References 38 publications

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“…Another CR pathway induced by 0.05% glucose (Kaeberlein et al 2004(Kaeberlein et al , 2005bEaslon et al 2007) has recently been characterized. Interestingly, this severe CR condition does not require respiration or the Sir2 family to extend life span.…”

Section: Requirement Of Respiration and The Sir2 Family In Aat1 Mdh1mentioning

confidence: 99%

“…Variations in CR protocols have also been described in which limitation of amino acids and/or further reduction in carbon source are employed (Jiang et al 2000(Jiang et al , 2002. Many studies have shown that the Sir2 family plays an important role under moderate CR conditions (0.5% glucose) (Lin et al 2000(Lin et al , 2002Wood et al 2004;Lamming et al 2005;Easlon et al 2007); however, Sir2 appeared to be dispensable under more severe CR conditions (Jiang et al 2000(Jiang et al , 2002Kaeberlein et al 2004;Lamming et al 2005;Easlon et al 2007). Although these CR regimens may represent other longevity pathways that function in parallel to moderate CR in rich media, it remains highly possible that moderate CR also induces other proteins in addition to the Sir2 family to extend life span .…”

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confidence: 99%

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The malate–aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast

Easlon¹,

Tsang²,

Skinner³

et al. 2008

Genes Dev.

133

118

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Recent studies suggest that increased mitochondrial metabolism and the concomitant decrease in NADH levels mediate calorie restriction (CR)-induced life span extension. The mitochondrial inner membrane is impermeable to NAD (nicotinamide adenine dinucleotide, oxidized form) and NADH, and it is unclear how CR relays increased mitochondrial metabolism to multiple cellular pathways that reside in spatially distinct compartments. Here we show that the mitochondrial components of the malate-aspartate NADH shuttle (Mdh1 [malate dehydrogenase] and Aat1 [aspartate amino transferase]) and the glycerol-3-phosphate shuttle (Gut2, glycerol-3-phosphate dehydrogenase) are novel longevity factors in the CR pathway in yeast. Overexpressing Mdh1, Aat1, and Gut2 extend life span and do not synergize with CR. Mdh1 and Aat1 overexpressions require both respiration and the Sir2 family to extend life span. The mdh1⌬aat1⌬ double mutation blocks CR-mediated life span extension and also prevents the characteristic decrease in the NADH levels in the cytosolic/nuclear pool, suggesting that the malate-aspartate shuttle plays a major role in the activation of the downstream targets of CR such as Sir2. Overexpression of the NADH shuttles may also extend life span by increasing the metabolic fitness of the cells. Together, these data suggest that CR may extend life span and ameliorate age-associated metabolic diseases by activating components of the NADH shuttles.[Keywords: Calorie restriction (CR); Sir2; aging; NADH shuttles; respiration; metabolism] Supplemental material is available at http://www.genesdev.org.

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Section: Requirement Of Respiration and The Sir2 Family In Aat1 Mdh1mentioning

confidence: 99%

mentioning

confidence: 99%

The malate–aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast

Easlon¹,

Tsang²,

Skinner³

et al. 2008

Genes Dev.

133

118

View full text Add to dashboard Cite

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“…Reports suggest that they might mediate the action of dietary caloric restriction on lifespan extension (Tissenbaum and Guarente, 2001;Libina et al, 2003;Lamming et al, 2005), although conflictions reports exist (Kaeberlein et al, 2004(Kaeberlein et al, , 2005. Research in yeast found that Sir2 and its homolog, Hst2, mediate the lifespan extension effect of caloric restriction in a complementary fashion (Lamming et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the e-amino group of lysine residues, we investigated whether FOXO3 deacetylation by SIRT1 or SIRT2 facilitates FOXO3 ubiquitination and subsequent proteasomal degradation. We found that SIRT1 and SIRT2 promote FOXO3 poly-ubiquitination and degradation. Proteasome-inhibitor treatment prevented sirtuininduced FOXO3 degradation, indicating that this process is proteasome dependent. In addition, we demonstrated that E3 ubiquitin ligase subunit Skp2 binds preferentially to deacetylated FOXO3. Overexpression of Skp2 caused poly-ubiquitination of FOXO3 and degradation, whereas knockdown of Skp2 increased the amount of FOXO3 protein. We also present evidence that SCF-Skp2 ubiquitinates FOXO3 directly in vitro. Furthermore, mutating four known acetylated lysine residues (K242, K259, K290 and K569) of FOXO3 into arginines to mimic deacetylated FOXO3 resulted in enhanced Skp2 binding but with inhibition of FOXO3 ubiquitination; this suggests that some or all of these four lysine residues are likely the sites for ubiquitination. In the livers of mice deficient in SIRT1, we detected increased expression of FOXO3, indicating SIRT1 regulates FOXO3 protein levels in vivo. Furthermore, we found that the elevation of SIRT1 and Skp2 expression in malignant PC3 and DU145 prostate cells is responsible for the downregulation of FOXO3 protein levels in these cells. Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation.

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“…Since NADH has been described as a Sir2p inhibitor, calorie restriction results in higher Sir2p activity Lin & Guarente, 2003), contributing to life-span extension. Nevertheless, the importance of this ratio to the activation of Sir2p has been questioned (Anderson et al, 2003;Kaeberlein et al, 2004;Grubisha et al, 2005).Chronological ageing in yeast has been used as a valuable model to study oxidative damage and ageing of the postmitotic tissues of higher organisms MacLean et al, 2001). In post-diauxic cultures, respiration is the main source of energy for the yeast cell.…”

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confidence: 99%

Chronological and replicative life-span extension in Saccharomyces cerevisiae by increased dosage of alcohol dehydrogenase 1

et al. 2007

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Alcohol dehydrogenase 1 (Adh1)p catalyses the conversion of acetaldehyde to ethanol, regenerating NAD + . In Saccharomyces cerevisiae, Adh1p is oxidatively modified during ageing and, consequently, its activity becomes reduced. To analyse whether maintaining this activity is advantageous for the cell, a yeast strain with an extra copy of the ADH1 gene (2¾ADH1) was constructed, and the effects on chronological and replicative ageing were analysed. The strain showed increased survival in stationary phase (chronological ageing) due to induction of antioxidant enzymes such as catalase and superoxide dismutases. In addition, 2¾ADH1 cells displayed an increased activity of silent information regulator 2 (Sir2)p, an NAD + -dependent histone deacetylase, due to a higher NAD + /NADH ratio. As a consequence, a 30 % extension in replicative life span was observed. Taken together, these results suggest that the maintenance of enzymes that participate in NAD + /NADH balancing is important to chronological and replicative life-span parameters. INTRODUCTIONOne of the features of ageing in Saccharomyces cerevisiae, as well as in other organisms, is the oxidative modification of specific protein targets, whose functions are impaired by such modification. A mild oxidation contributes to marking the protein for degradation (Stadtman & Oliver, 1991), while strong oxidation can promote protein aggregation, making proteins unavailable for proteasome degradation (Grune et al., 2004). The accumulation of these modified proteins in a cell contributes to the ageing phenotype (Harman, 1981;Stadtman, 1992;Stadtman & Levine, 2000;Levine, 2002; Nyström, 2005). In yeasts, replicative ageing refers to the number of cell divisions occurring in a mother yeast cell . Chronological ageing refers to the ability of cells to maintain viability in stationary phase (Herman, 2002).During the last decade investigations of ageing have uncovered physiological and molecular mechanisms involved in this process, as well as providing some clues towards understanding life-span lengthening (Bordone & Guarente, 2005). Calorie restriction is one of the mechanisms that has been consistently proven to extend life span in organisms ranging from yeasts to mammals (Sohal & Weindruch, 1996). In yeast, the replicative life span can be increased by shifting the cells from 2 to 0.5 % glucose (calorie restriction) (Lin et al., , 2004. One of the key molecules is the silent information regulator 2 (Sir2)p, a class III NAD + -dependent histone deacetylase, which is involved in several physiologically important functions such as silencing telomeres and rDNA, maintaining genome integrity, and ageing (Bitterman et al., 2003). Strains that have an extra copy of the SIR2 gene have a life span extended by 40 %, while deletion of SIR2 shortens life span by 50 % (Kaeberlein et al., 1999). Under calorie restriction, the oxygen consumption increases, thus raising the NAD + /NADH ratio by lowering the concentration of NADH. Since NADH has been described as a Sir2p inhibitor, calorie res...

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Sir2-Independent Life Span Extension by Calorie Restriction in Yeast

Cited by 410 publications

References 38 publications

The malate–aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast

The malate–aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

Chronological and replicative life-span extension in Saccharomyces cerevisiae by increased dosage of alcohol dehydrogenase 1

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