SIRT1

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Sirtuin 1 (SIRT1) is the most extensively studied protein in the family of sirtuin, which stands for the silent mating type information regulation 2 protein. Scientists heavily implicated the protein's capacity in health span and lifespan extension. SIRT1, has a shared gene in other species, including yeast. The shared gene in other animal species allows scientists to study how modulating the levels of SIRT1 impact lifespan. A study of yeast about 20 years ago revealed that genetically increasing SIRT1 levels increases lifespan by 30% in the species. This protein depends on nicotinamide adenine dinucleotide (NAD+) to function. With sufficient NAD+, SIRT1 removes molecular markers from other proteins, such as histones, which are wrapped by DNA. Scientists classify SIRT1 as a class III histone deacetylase.

SIRT1 functions

SIRT1 function

SIRT1 is a NAD+-dependent deacetylase, meaning SIRT1 removes molecular tags, acetyl groups, from proteins. Proteins from which SIRT1 removes these acetyl groups include histones, proteins which DNA wraps around, and non-histone proteins. With deacetylating activithy of SIRT1, it controls gene expression, metabolism, and aging.[1]

Sirt1 has been heavily implicated in controlling the metabolism and health of the cell’s powerhouse, mitochondria. SIRT1 also plays an important role in reducing defective mitochondria. This reduction in defective mitochondria occurs through a process termed mitophagy. Mitophagy entails the cell’s disposal of defective mitochondria through degradation.[2]

Research on SIRT1 in aging

Studies indicate high expression of SIRT1 in the brain, heart, kidney, liver, pancreas, skeletal muscle, spleen, and fat tissue (white adipose tissue).[3][4][5] An initial study of Sir2, a version of SIRT1, in yeast life span extension demonstrated that integrating a second copy of the gene into normal, wild type, yeast increases its lifespan by 30%. In contrast, mice with mutant Sir2 genes have a reduced lifespan of 50%.[6][7]

A recent study in genetically altered mice with excess Sirt1 demonstrated delayed aging and heart protection with threefold to eightfold increases in Sirt1 levels.[8][1]

SIRT1 and exercise

It's well known that regular exercise promotes health. Research suggested that SIRT1 plays a significant role in these effects from exercise.[9][10] It also suggested SIRT1-related adaptations from exercise occur in the liver, kidney, brain, heart, and skeletal muscle.[11]

A major effect of exercise entails protecting brain function. Improvements in brain function from exercise result in increased resistance to cellular stress,[12][13][14]increased production of neurons,[15][16] and increased production of mitochondria in neurons.[17][18] The molecular mechanism mediating exercise’s effects in protecting brain function may stem from it increasing SIRT1 levels.[19][20] Exercise-stimulated SIRT1 function can result in these effects on brain protection.[21][22][23][24][25][26]

SIRT1 depends on sufficient levels of NAD+, which decline as people age. Exercise makes NAD+ molecules more readily available for SIRT1. NAD+ exists in higher concentrations in its non-reduced form, as opposed to having electrons as NADH. This helps SIRT1 function. Regular exercise also rejuvenates aged skeletal muscle, partly due to stimulating SIRT1 function.[27]

Resveratrol stimulates SIRT1

Resveratrol, a plant compound found in grapes, berries, and peanuts, improves brain function through stimulating SIRT1.[28] Resveratrol can stimulates SIRT1 activity up to eight-fold.[29][30][31] Although the effectiveness of resveratrol activating SIRT1 remains debatable, research on various animals, demonstrated resveratrol stimulates SIRT1 function to protect against declining brain function.[32][33]

References

  1. ↑ 1.0 1.1 Shahedur Rahman, Rezuanul Islam. Mammalian Sirt1: insights on its biological functions. Cell Commun Signal, 2011; DOI: 10.1186/1478-811X-9-11.
  2. ↑ Bor Luen Tang. Sirt1 and the mitochondria. Mol Cells, 2016; DOI: 10.14348/molcells.2016.2318.
  3. ↑ Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.
  4. ↑ GS Kelly. A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 2. Altern Med Rev, 2010; 15(4): 313-328.
  5. ↑ S Voelter-Mahlknecht, U Mahknecht. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylase gene sirtuin 1. Int J Mol Med, 2006; 17(1):59-67.
  6. ↑ Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.
  7. ↑ M Kaeberlein, M McVey, L Guarente. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 1999; 13(19): 2570-2580.
  8. ↑ Hsu CP, Odewale I, Alcendor RR, Sadoshima J. Sirt1 protects the heart from aging and stress. Biol Chem. 2008;389:221–231. doi: 10.1515/BC.2008.032.
  9. ↑ Z Radak, E Koltai, AW Taylor M Higuchi, S Kumagai, H Ohno, S Goto, I Boldogh. Redox regulating sirtuins in aging, carloric restriction, and exercise. Free Radic Biol Med, 2013; 58: 87-97.
  10. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  11. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  12. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  13. ↑ Z Radak, AW Taylor, H Ohno, S Goto. Adaptation to exercise-induced oxidative stress: from muscle to brain. Exerc Immunol, 2001; 7: 90-107.
  14. ↑ S Siamilis, J Jakus, C Nyakas, A Costa, B Mihalik, A Falus, Z Radak. The effect of exercise and oxidant-antioxidant intervention on the levels of neurotrophins and free radicals in spinal cord of rats. Spinal Cord, 2009; 47: 453-457.
  15. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  16. ↑ I Sarga, N Hart, IG Koch, SI Britton, G Hajas, I Boldogh, X Ba, Z Radak. Aerobic endurance capacity affects spatial memory and SIRT1 is a potent modulator of 8-oxoguanine repair. Neuroscience, 2013; 252: 326-336.
  17. ↑ K Marosi, K Felszeghy, RD Mehra, Z Radak, C Nyakas. Are the neuroprotective effects of estradiol and physical exercise comparable during ageing in female rats? Biogerontology, 2012; 13: 413-427.
  18. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  19. ↑ F Gomez-Pinilla, Z Ying. Differential effects of exercise and dietary docosahexaenoic acid on molecular systems associated with control of allostasis in the hypothalamus and hippocampus. Neuroscience, 2010; 168: 130-137.
  20. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  21. ↑ H Jeong, DE Cohen, I. Cui, A Supinski, JN Savas, JR Mazzulli, JR Yates, L Bordone, L Guarente, D Kraine. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med, 2012; 18: 159-165.
  22. ↑ L Liu, Q Zhang, Y Cai, D Sun, X He, L Wang, D Yu, X Li, X Xiong, H Xu, Q Yang, X Fan. Resveratrol counteracts lipopolysaccharide-induced depressivelike behaviors via enhanced hippocampal neurogenesis. Oncotarget, 2016; 7: 56045-56059.
  23. ↑ CY Ma, MJ Yao, QW Zhai, JW Jiao, XB Yuan, MM Poo. SIRT1 suppresses self-renewal of adult hippocampal neural stem cells. Development, 2014; 141: 1697-4709.
  24. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  25. ↑ SA Shah, M Khan, MH Jo, MG Jo, FU Amin, MO Kim. Melatonin stimulates the SIRT1/nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. CNS Neurosci Ther, 2017; 23: 33-44.
  26. ↑ SJ Wang, XH Zhao, W Chen, N Bo, XJ Wang, ZF Chi, W Wu. Sirtuin 1 activation enhances the PGC-1a/mitochondrial antioxidant system pathway in status epilepticus. Mol Med Rep, 2015; 11: 521-526.
  27. ↑ Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.
  28. ↑ Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.
  29. ↑ MT Borra, BC Smith, JM Denu. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem, 2005; 280: 17187-17195.
  30. ↑ Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.
  31. ↑ BP Hubbard, DA Sinclair. Small molecule SIRT1 acitvators for the treatment of aging and age-related diseases. Trends Pharmacol, 2014; 35: 146-154.
  32. ↑ Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.
  33. ↑ LL Du, JZ Xie, XS Cheng, XH Li, FL Kong, X Jiang, ZW Ma, JZ Wang, C Chen, XW Zhou. Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi. Age (Dordr), 2014; 36: 613-623.
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