Sirtuins are a family of proteins involved in epigenetic regulation of a broad range of biological processes. They are enzymes with histone de-acetylation (HDAC) functions, meaning their activity allows histones to wrap around the DNA more tightly and therefore silence gene expression. Sirtuins are NAD-dependent proteins and thus all of their activities require NAD+, a type of coenzyme essential for energy production.
Sirtuins are especially known for their controversy as conserved longevity genes (see section ´Controversies on sirtuins as longevity genes´).
Members of the sirtuins family
Sirtuins (often abbreviated as SIRT or SIR depending on the species) are a type of highly conserved class III histone deacetylases. There are seven sirtuins genes: SIRT1 to SIRT7, all of which share common deactylasing activities whilst also having specific functions.
- SIRT1 is found both in the nucleus and the cytosol. It is largely involved in metabolic regulation and has been associated with insulin resistance, obesity and oocyte maturation. It also modulates the activity of certain transcription factors such as p53 and FOXO.
- SIRT2 is considered to be the founding member of the sirtuin family. It is found in the cytosol and has key roles in regulation of the cell cycle during mitosis and in regulating cell proliferation, motility and apoptosis. It has also been associated with tumour growth in certain cancers.
- SIRT3-5 are located in the mitochondria and have roles in oxidative stress and lipid metabolism.
- SIRT6-7 are nuclear sirtuins involved in regulating gene expression and DNA repair mechanisms.
Sirtuins in lifespan
There is generally a lack of direct evidence for all sirtuin genes, except for potentially SIRT6, in playing a role to extend lifespan in animals.
Specific SIRT genes like SIRT6 have been shown to extend healthy lifespan in one study in mice (increased median lifespan in males and females by 27% and 15%; maximum lifespan by 11% and 15%), as well as in fruit flies.
SIRT6 activity has also been linked to more efficient double-strand break (DSB) repair mechanisms in long-lived rodent species and showed a positive correlation to maximum lifespan. It has also been shown to act as a co-repressor of hypoxia-inducible factor 1-alpha (HIF1α), a transcription factor that responds to oxidative stress and oxygen consumption and which might be a regulator of aging. Additionally, removal of SIRT6 has been linked to a >5-year decrease in lifespan in mice according to several health biomarkers.
Sirtuins in health
Several members of the sirtuin family have demonstrated beneficial effects in maintaining metabolic homeostasis and health.
Sirtuins have a broad range of effects and can affect health in a pleiotropic manner by potentially up-regulating cytoprotective pathways. It has been hypothesised that their activity heightens under conditions of stress, such as in a high-fat diet or during ageing, and might protect against obesity. Sirtuins also appear to both act in response to inflammation and mediate its effects by activating tumour necrosis factor NFκB in conditions of extreme infection such as sepsis. This highlights the importance of sirtuins in restoring homeostasis during states of cellular stress.
Other studies have shown that increasing the activity of sirtuins stabilises telomeres and improves telomere-dependent disease. In wild-type conditions, SIRT1 and SIRT6 might regulate telomere length in a time- and context-specific manner. However, it remains unclear what is the relevance of sirtuins during telomere dysfunction and, viceversa, how telomere shortening impacts the activity of sirtuins.
Controversies on sirtuins as longevity genes
Sirtuin proteins are surrounded by a certain degree of controversy in the field of longevity.
In the late 90s, a number of studies based on work from the Guarente lab and led by Matt Kaeberlein showed that, in yeast, adding an extra copy of the SIRT2 gene increased lifespan, whilst wild-type copies determined longevity of yeast mother cells.
Later on, another study from the Guarente lab in 2001 claimed that the role of SIRT2 in determining lifespan was conserved in C. elegans and potentially in higher organisms. They argued that overexpression of SIR-2.1 (gene homolog to SIRT2 in yeast) could extend lifespan of worms by 50%, occurring via a mechanism upstream of daf-16/FOXO in the insulin-like signalling pathway.
The controversy sparked when a number of independent groups (including scientists such as Linda Partridge, David Gems and Matt Kaeberlein, who was no longer at Guarente's lab) announced that such findings were not reproducible in C. elegans or Drosophila. Despite the non-reproducibility of their findings, the Guarente lab continues defending their results.
David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation. This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%. Of note, lifespan effects of this mild magnitude in C. elegans are generally not considered significant, given the high inherent variability of survival curves generated from different groups.
Conclusions of the controversy
Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes. The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.
However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan. For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨Lifespan¨ that activating SIRT1 with the compound resveratrol might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells. Resveratrol has now been similarly debunked as a molecule with no lifespan extending properties.
- Houtkooper, R., Cantó, C., Wanders, R., & Auwerx, J. (2010). The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways. Endocrine Reviews, 31(2), 194-223. doi: 10.1210/er.2009-0026
- Imai, S., & Guarente, L. (2016). It takes two to tango: NAD+ and sirtuins in aging/longevity control. Npj Aging And Mechanisms Of Disease, 2(1). doi: 10.1038/npjamd.2016.17
- Nevoral, J., Landsmann, L., Stiavnicka, M., Hosek, P., Moravec, J., & Prokesova, S. et al. (2019). Epigenetic and non-epigenetic mode of SIRT1 action during oocyte meiosis progression. Journal Of Animal Science And Biotechnology, 10(1). doi: 10.1186/s40104-019-0372-3
- Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X., Shi, X., & Zhai, Q. (2007). SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B. Cell Metabolism, 6(4), 307-319. doi: 10.1016/j.cmet.2007.08.014
- Mouchiroud, L., Houtkooper, R., Moullan, N., Katsyuba, E., Ryu, D., & Cantó, C. et al. (2013). The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell, 154(2), 430-441. doi: 10.1016/j.cell.2013.06.016
- Vaziri, H., Dessain, S., Eaton, E., Imai, S., Frye, R., & Pandita, T. et al. (2001). hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase. Cell, 107(2), 149-159. doi: 10.1016/s0092-8674(01)00527-x
- Pandithage, R., Lilischkis, R., Harting, K., Wolf, A., Jedamzik, B., & Lüscher-Firzlaff, J. et al. (2008). The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. Journal Of Cell Biology, 180(5), 915-929. doi: 10.1083/jcb.200707126
- Zhang, L., Kim, S., & Ren, X. (2020). The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?. Frontiers In Oncology, 10. doi: 10.3389/fonc.2020.01721
- Hirschey, M., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., & Lombard, D. et al. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature, 464(7285), 121-125. doi: 10.1038/nature08778
- Li, L., Shi, L., Yang, S., Yan, R., Zhang, D., & Yang, J. et al. (2016). SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nature Communications, 7(1). doi: 10.1038/ncomms12235
- McCord, R., Michishita, E., Hong, T., Berber, E., Boxer, L., & Kusumoto, R. et al. (2009). SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair. Aging, 1(1), 109-121. doi: 10.18632/aging.100011
- Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., ... & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nature communications, 12(1), 1-18.
- Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S., Liu, J., Finn, M., ... & Helfand, S. L. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. Proceedings of the National Academy of Sciences, 119(5), e2111176119.
- Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., ... & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell, 177(3), 622-638.
- Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R., & Vadysirisack, D. et al. (2010). The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. Cell, 140(2), 280-293. doi: 10.1016/j.cell.2009.12.041
- Alique, M., Sánchez-López, E., Bodega, G., Giannarelli, C., Carracedo, J., & Ramírez, R. (2020). Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging. Cells, 9(1), 195. doi: 10.3390/cells9010195
- TenNapel, M., Lynch, C., Burns, T., Wallace, R., Smith, B., Button, A., & Domann, F. (2014). SIRT6 Minor Allele Genotype Is Associated with >5-Year Decrease in Lifespan in an Aged Cohort. Plos ONE, 9(12), e115616. doi: 10.1371/journal.pone.0115616
- Houtkooper, R., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology, 13(4), 225-238. doi: 10.1038/nrm3293
- Lee, J., Padhye, A., Sharma, A., Song, G., Miao, J., & Mo, Y. et al. (2010). A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition. Journal Of Biological Chemistry, 285(17), 12604-12611. doi: 10.1074/jbc.m109.094524
- Bai, P., Canto, C., Brunyánszki, A., Huber, A., Szántó, M., & Cen, Y. et al. (2011). PARP-2 Regulates SIRT1 Expression and Whole-Body Energy Expenditure. Cell Metabolism, 13(4), 450-460. doi: 10.1016/j.cmet.2011.03.013
- Bai, P., Cantó, C., Oudart, H., Brunyánszki, A., Cen, Y., & Thomas, C. et al. (2011). PARP-1 Inhibition Increases Mitochondrial Metabolism through SIRT1 Activation. Cell Metabolism, 13(4), 461-468. doi: 10.1016/j.cmet.2011.03.004
- Vachharajani, V., Liu, T., Wang, X., Hoth, J., Yoza, B., & McCall, C. (2016). Sirtuins Link Inflammation and Metabolism. Journal Of Immunology Research, 2016, 1-10. doi: 10.1155/2016/8167273
- Amano, H., & Sahin, E. (2019). Telomeres and sirtuins: at the end we meet again. Molecular &Amp; Cellular Oncology, 6(5), e1632613. doi: 10.1080/23723556.2019.1632613
- Palacios, J., Herranz, D., De Bonis, M., Velasco, S., Serrano, M., & Blasco, M. (2010). SIRT1 contributes to telomere maintenance and augments global homologous recombination. Journal Of Cell Biology, 191(7), 1299-1313. doi: 10.1083/jcb.201005160
- Tennen, R., & Chua, K. (2011). Chromatin regulation and genome maintenance by mammalian SIRT6. Trends In Biochemical Sciences, 36(1), 39-46. doi: 10.1016/j.tibs.2010.07.009
- Kaeberlein, M., McVey, M., & Guarente, L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes &Amp; Development, 13(19), 2570-2580. doi: 10.1101/gad.13.19.2570
- Tissenbaum, H., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410(6825), 227-230. doi: 10.1038/35065638
- Burnett, C., Valentini, S., Cabreiro, F., Goss, M., Somogyvári, M., & Piper, M. et al. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature, 477(7365), 482-485. doi: 10.1038/nature10296
- Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature, 477(7365), E1-E2. doi: 10.1038/nature10440
- Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.
- Pearson, K., Baur, J., Lewis, K., Peshkin, L., Price, N., & Labinskyy, N. et al. (2008). Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metabolism, 8(2), 157-168. doi: 10.1016/j.cmet.2008.06.011