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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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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 SchwerOregon Health and Science University
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:
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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.
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