Aging, Acetate, and Aβ: Sirtuins Regulate Metabolism and More

The extension in lifespan achieved by eating fewer calories depends on activation of sirtuins, a family of NAD-dependent protein deacetylases that control the expression of key metabolic pathway genes. But the sirtuins may regulate metabolism in a more direct manner as well, according to a report in the June 21 PNAS online. John Denu and colleagues at the University of Wisconsin Medical School in Madison show that two mammalian sirtuins, SIRT1 and SIRT3, directly deacetylate and activate the metabolic enzyme Acetyl-CoA synthetase. The significance to aging is unclear as yet, but the results show that the regulation of energy pathways by sirtuins occurs at multiple levels.

The finding is of interest to those studying diseases of aging and may be of particular interest to those studying Alzheimer disease (AD) given that calorie restriction (CR) reduces Aβ production and amyloid pathology in mice (Wang et al., 2005; Patel et al., 2005). Coincidentally, another recent report from Giulio Pasinetti’s laboratory at the Mt. Sinai School of Medicine, New York, shows that neuronal SIRT1 has a hand in that process, too, by enhancing the non-amyloidogenic α-secretase cleavage of the amyloid precursor protein. In other aging news, Korean researchers report that a kinase inhibitor, CGK733, may delay cellular senescence.

First, the acetate story. The enzyme AcetylCoA synthetase (AceCS) metabolically activates acetate by conjugating it to CoA, after which the AcetylCoA (AcCoA) can be used as an acetyl donor or building block for fatty acids, or burned for energy in mitochondria. Starting from the observation that sirtuin deacetylates and regulates an AceCS in bacteria, authors William Hallows, Susan Lee and Denu wondered whether mammalian AceCSs might do the same. They showed that mouse cytosolic AcetylCoA synthetase, AceCS1, became acetylated on a catalytic residue in cultured cells, and that expression of SIRT1 in cells dramatically reduced the amount of the acetylated protein. Of all the mammalian sirtuins, 2-7, only SIRT1 (the sirtuin associated with life extension by CR) caused the deacetylation of AceCS1 in cells.

Sirtuin-catalyzed deacetylation activated AceCS1 in the test tube, and also when expressed in cells. Acetylated recombinant AceCS1 was inactive, but incubation with SIRT1 rendered it fully active. In cells, overexpression of AceCS1 led to a 60 percent increase in the incorporation of acetate into fatty acids. Coexpression with SIRT1, but not SIRT2, led to an additional increase, more than doubling the rate of fatty acid synthesis compared to vector alone.

In vitro assays with purified recombinant sirtuins revealed that SIRT3, which did not deacetylate AceCS1 in cells, was as potent at activating the enzyme as SIRT1. In cells, SIRT3 is located in mitochondria, while both AceCS1 and SIRT1 are cytosolic. Mammals do have a mitochondrial AcetylCoA synthetase, AceCS2, and the researchers showed that SIRT3 deacetylates AceCS2 in vitro, raising the possibility that SIRT3/AceCS2 could be the mitochondrial counterpart to the SIRT1/AceCS1 pair.

Both SIRT1 and SIRT3 have been implicated in regulating lifespan—SIRT1 is required for life extension by calorie restriction in animal models, while SIRT3 gene variants have been linked to long life in the elderly (Rose et al., 2003; Bellizzi et al., 2005). Though acetate metabolism is impaired in older people (Skutches et al., 1979), its role in aging and the significance of sirtuin regulation remain to be seen.

It is clear that at the same time a semi-starvation regimen is staving off death, it delays aging and the onset of aging-related diseases. The reduction of Aβ production and accumulation in mice as a result of calorie restriction is mediated by SIRT1 in neurons, according to Pasinetti and colleagues’ new study. In press in the Journal of Biological Chemistry since June 2, their paper shows that SIRT1 decreases Aβ generation and increases non-amyloidogenic amyloid precursor protein processing by α-secretase. SIRT1 acts by inhibiting ROCK1 kinase expression, a condition that has been previously shown to increase α-secretase (see ARF related news story). The results further support the idea that sirtuin activators, like the red wine ingredient resveratrol, might be useful for slowing the accumulation of Aβ (Chen et al., 2005; Marambaud et al., 2005; ARF related news story).

Finally, Korean researchers are reporting a new way around the aging that occurs at the cellular level—replicative senescence. In an online publication in Nature Chemical Biology, Tae Kook Kim and colleagues at the Korea Advanced Institute of Science and Technology in Daejeon describe a high-throughput, cell-based screen for compounds that reverse cell senescence. For a model, they induced senescence by expression of a dominant negative form of telomeric repeat factor-2 (TRF2) protein, a protein essential for telomere formation.

The screen turned up a small molecule that could reversibly kick-start replication of normal senescent cells. Using a novel magnetic nanoprobe capture technology, the investigators identified the target of the compound (a kinase inhibitor) as the ataxia telangiectasia mutated (ATM) protein, and to a lesser extent ATM- and Rad3-related protein (ATR), both checkpoint proteins that regulate p53 and cell replication in response to DNA damage. The compound was selective for ATM and ATR kinase activities—it did not inhibit the related PI3K, or downstream pathways like AKT activation.

Loss of ATM function in humans results in ataxia telangiectasia, where cells show accelerated senescence, yet treatment with CGK733 had the opposite effect of delaying senescence. The authors suggest that the compound may “fine-tune” the elevated kinase activity of ATM in senescent cells so that it is below the threshold for inducing senescence but still adequate for the other functions including telomere maintenance, control of ROS and DNA damage, and DNA replication.—Pat McCaffrey

Comments

  1. I enjoyed reading your news article on "Aging, Acetate, and Aβ: Sirtuins Regulate Metabolism and More." I would like to point your attention to our article, "Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2" (published online in PNAS on June 20, 2006), which describes the connection among mitochondria, sirtuins, and acetyl-CoA synthetase 2.

    View all comments by Bjoern Schwer

  2. Calorie restriction (CR) or dietary restriction (about 60 percent of ad libitum or normal calorie consumption) has been known to possess numerous useful benefits for aging (Cohen et al., 2004; Wood et al., 2004) and age-related disorders such as Alzheimer disease (Mattson et al., 2003; Patel et al., 2005). The recent paper by Qin et al. is a valuable addition to the growing literature on the beneficial effects of CR on AD mechanisms. Qin et al. explains how CR relates to the activation of the mammalian sirtuin protein SIRT1 and, in turn, how this activation promotes a non-amyloidogenic, α-secretase pathway for amyloid precursor protein (APP) processing and reduces amyloid-β production in Tg2576 mice. The authors also elegantly utilized viral transfection systems to show that SIRT1 expression in Tg2576 neurons and CHO-APPswe cells significantly attenuates the production of amyloid-β peptides. Most interestingly, they demonstrated that increased SIRT1 expression following a CR regimen reduces expression levels of the Rho kinase ROCK1, and that reduced ROCK1 levels somehow activate the non-amyloidogenic processing of APP (Qin et al., 2006). Perhaps a subsequent challenge in CR-related research is to demonstrate a clear link between a decrease in the expression of ROCK1 and the increase in the activity of α-secretase.

    Can CR serve as a reliable treatment for AD?
    The answer to this question is not simple. On a positive note, CR-associated mechanisms are the most known and reliable pathways that promote anti-aging effects in diverse groups of organisms ranging from yeasts to mammals. These effects seem to be consistently associated with an increased expression of SIRT1 (Bordone and Guarente, 2005).

    Although “eat less, age well, and remember well” appears to be the new mantra in cutting-edge research on human aging, there are some unfavorable aspects to using CR as a therapy to treat AD patients (Anekonda and Reddy, 2006; Anekonda, 2006). First, eating less is not a popular treatment, as it involves giving up favorite tastes. Second, at least for now, there are not many research articles showing the long-term benefits of eating less in humans (Dirks and Leeuwenburg, 2006). Third, inappropriate CR may have severe adverse effects in humans (reviewed in Dirks and Leeuwenburg, 2006).

    What is needed is advice on the amount of calorie restriction that individuals need, as determined by scientific studies.

    Can CR mimetics serve as a reliable treatment for AD?
    People do not need to give up their favorite tastes in order to gain the healthful benefits from CR. Trans-resveratrol (simply resveratrol) found in the skin of purple grapes and in 70 or so other plant species, when ingested in a predetermined regimen, mimics the effects of CR on a diverse group of organisms (Howitz et al., 2003; Laming et al., 2004; Wood et al., 2004). Resveratrol operates by triggering an increased expression of SIRT1. Resveratrol not only possesses numerous therapeutic benefits in both animal models and humans (reviewed in Baur and Sinclair, 2006), but also interferes favorably in multiple pathways associated with AD pathology (reviewed in Anekonda, 2006).

    Can resveratrol or any other herbal equivalents be used as reliable therapeutics for healthy aging or age-related disorders? Herbal compounds may have some side effects that need to be clarified before they are used as therapies. A given herb can possess dozens of pharmacologically useful compounds, but the effects of these compounds need to be substantiated through scientific testing. The composition of active compounds in plants varies, depending on the growth environment, resulting in inconsistent pharmacological performance. It is tedious, time-consuming work, defining the bioavailability of each phytochemical useful in treating AD (reviewed in Anekonda and Reddy, 2005). In addition, the ability of the herbal compounds to cross the blood-brain barrier, any toxic side effects, or any useful synergistic effects must be carefully defined before they are used in treatment of AD.

    For now, it appears that both CR and CR-mimetics require long-term testing on humans to define their safety. Even before considering CR therapies, it is perhaps essential to understand the critical mechanisms associated with CR in AD. To this end, the Qin et al. paper is a step forward.

    References:

    Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul 16;305(5682):390-2. PubMed.

    Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5;430(7000):686-9. PubMed.

    Mattson MP, Duan W, Guo Z. Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. J Neurochem. 2003 Feb;84(3):417-31. PubMed.

    Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE. Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging. 2005 Jul;26(7):995-1000. PubMed.

    Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. PubMed.

    Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005 Apr;6(4):298-305. PubMed.

    Anekonda TS, Reddy PH. Neuronal protection by sirtuins in Alzheimer's disease. J Neurochem. 2006 Jan;96(2):305-13. PubMed.

    Anekonda TS. Resveratrol--a boon for treating Alzheimer's disease?. Brain Res Rev. 2006 Sep;52(2):316-26. PubMed.

    Dirks AJ, Leeuwenburgh C. Caloric restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev. 2006 Jan;127(1):1-7. PubMed.

    Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. PubMed.

    Lamming DW, Wood JG, Sinclair DA. Small molecules that regulate lifespan: evidence for xenohormesis. Mol Microbiol. 2004 Aug;53(4):1003-9. PubMed.

    Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006 Jun;5(6):493-506. PubMed.

    Anekonda TS, Reddy PH. Can herbs provide a new generation of drugs for treating Alzheimer's disease?. Brain Res Brain Res Rev. 2005 Dec 15;50(2):361-76. PubMed.

    View all comments by Thimmappa Anekonda

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References

News Citations

  1. Statins Boost α-Secretase, but Not Through Cholesterol
  2. We Are What We Consume? Foods, Drugs Affect Amyloid, AD

Paper Citations

  1. Wang J, Ho L, Qin W, Rocher AB, Seror I, Humala N, Maniar K, Dolios G, Wang R, Hof PR, Pasinetti GM. Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J. 2005 Apr;19(6):659-61. PubMed.
  2. Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE. Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging. 2005 Jul;26(7):995-1000. PubMed.
  3. Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V, Passarino G, Feraco E, Mari V, Barbi C, BonaFe M, Franceschi C, Tan Q, Boiko S, Yashin AI, De Benedictis G. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp Gerontol. 2003 Oct;38(10):1065-70. PubMed.
  4. Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, Greco V, Maggiolini M, Feraco E, Mari V, Franceschi C, Passarino G, De Benedictis G. A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics. 2005 Feb;85(2):258-63. PubMed.
  5. Skutches CL, Holroyde CP, Myers RN, Paul P, Reichard GA. Plasma acetate turnover and oxidation. J Clin Invest. 1979 Sep;64(3):708-13. PubMed.
  6. Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem. 2005 Dec 2;280(48):40364-74. PubMed.
  7. Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem. 2005 Nov 11;280(45):37377-82. PubMed.

Further Reading

Papers

  1. Anekonda TS. Resveratrol--a boon for treating Alzheimer's disease?. Brain Res Rev. 2006 Sep;52(2):316-26. PubMed.

Primary Papers

  1. Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10230-5. PubMed.
  2. Won J, Kim M, Kim N, Ahn JH, Lee WG, Kim SS, Chang KY, Yi YW, Kim TK. Small molecule-based reversible reprogramming of cellular lifespan. Nat Chem Biol. 2006 Jul;2(7):369-74. PubMed. RETRACTED
  3. Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. PubMed.

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