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Sirtuin Activating Compounds as Candidates for Anti-Aging Drugs


Silent information regulator 2 (Sir2) enzymes [1] or Sirtuins (SIRT1-7) are NAD+-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging[2]. At present, the NAD+/sirtuin pathway is one of the few mechanisms described to mediate calorie restriction (CR) effects in organisms. Calorie restriction has been observed to prolong lifespan as well as maintain proper organismic health, and while mechanisms that explain this phenomena are still being studied, various findings suggest that CR can delay the changes associated with aging such as stem cell diminution, genomic instability, organelle dysfunction, cellular deterioration and certain nutrient imbalances [3]. A study using transgenic mouse models showed that CR stimulated the synthesis of the protein SIRT1, a substance that has been shown to prolong lifespan, and found that giving SIRT1-activating compounds orally simulated the favorable effects of CR. These results call attention to the potential of SIRT1-activating compounds to offer a pharmacological substitute to CR against aging, neurodegeneration and other associated conditions[4].


These studies on sirtuin modulation stimulated interest in the discovery of sirtuin activating compounds, or STACs. Resveratrol is a natural compound shown to activate SIRT1, and has potentials in treatment and prevention of obesity, tumorigenesis and aging-related decline in heart function and neuronal loss. Due to its poor availability, various reformulated version of resveratrol have been developed such as resVida, Longevinex and SRT501[5]. Another study showed that resveratrol mimics the anti-aging effects of CR in lower organisms. Mice fed on a high-fat diet but were given resveratrol have been observed to have lower chances of  insulin resistance, increased mitochondrial content, and prolonged survival rates[6]. A study on the effect of STACs on the life spans of C. elegans and D. melanogaster showed that in the wild type worms C. elegans, lifespan was extended up to 14% by resveratrol. In D. melanogaster, lifespan was extended up to 23% with fisetin and up to 29% with resveratrol [7].


Another study on small molecule activators SRT1720 and structurally related compounds SRT2183 and SRT1460, found that these substances were 1,000 times more potent than resveratrol.
Of these compounds, SRT1720 was the most effective, since it stimulated 750% SIRT1 activity. These compounds were able to prevent insulin resistance and diabetes in already diabetic mice and in mice given a high-fat diet, and have also demonstrated that they can slow down metabolic disturbances in rats. These STACs improved glucose utilization and insulin sensitivity in metabolic tissues such as the  liver, muscle and fat, and have been shown to produce similar effects with calorie restriction on mitochondrial and metabolic function in mammals in vivo. This holds promise for treating diseases associated with the ageing population like type 2 diabetes[8]. Another study observed that treatment with SRT1720 can potentially lower hepatic lipid accumulation to some degree by directly reducing the expressions of lipogenic genes. It has also been shown to decrease the development of non-alcoholic fatty liver disease in MSG mice[9].


Another study, however, provided evidence that neither the Sirtris series nor resveratrol are direct SIRT1 activators due to their highly promiscuous profiles, and may utilize a different molecular mechanism independent of direct SIRT1 activation [10]. A report by Sirtris founder David Sinclaire stated that that certain hydrophobic moieties found in SIRT1 substrates are responsible for SIRT1 activation by STACs, and a single amino acid in SIRT1 named Glu230, was critical for activation by all previously reported STACs and new activators.  In primary cells modified to be activation-defective, the metabolic effects of STACs were absent. This demonstrates that an allosteric mechanism is responsible for direct activation of the SIRT1 enzyme [11].


Compared with natural compounds like resveratrol, the synthetic STACs demonstrate greater potency and target selectivity. Although SIRT1 research has shown much advancement, questions such as whether other sirtuin family members will be amenable to activation  and whether STACs will ultimately prove safe and efficacious in humans still remain[2].


References:

1.       Liang F, Kume S, Koya D.  (2009) SIRT1 and insulin resistance. Nat Rev Endocrinol 5: 367–373.

2.       Sinclair DA, Guarente L. (2013) Small-Molecule Allosteric Activators of Sirtuins. Annu Rev Pharmacol Toxicol. 54: 363-380.

3.       Michan S. (2014) Calorie restriction and NAD⁺/sirtuin counteract the hallmarks of aging. Front Biosci (Landmark Ed) 19:1300-19.

4.       Gräff J, Kahn M, Samiei A, Gao J, Ota KT, Rei D, Tsai LH. (2013) A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J Neurosci 33 (21): 8951-60.

5.       Villalba JM, Alcain FJ. (2012) Sirtuin activators and Inhibitors. Biofactors 38 (5):349-359.

6.       Baur JA, et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-342.

7.       Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Sinclair D, et al. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430.

8.       Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ. (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450.

9.       Yamazaki Y, Usui I, Kanatani Y, Matsuya Y, Tsuneyama K, et al. (2009 Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice.  Am J Physiol Endocrinol Metab. 297(5):E1179-86.

10.   Pacholec M, Bleasedale JE, Chrunyk B, Cunningham D, Flynn D, et al. (2010) SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1. J Biol Chem Journal 285: 8340-8351.

11.   Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Sinclair DA. (2013) Evidence for a common mechanism of sirt1 regulation by allosteric activators” Science 339 (6124): 1216-1219.


 
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