Arianna Ferrini, PhD

Sirtuins are very ancient in animal evolution and have a highly conserved structure between all kingdoms of life. Sirtuins were originally discovered as regulators of transcription in yeast. The name of the first sirtuin discovered, Sir2, comes from the yeast gene “Silent mating-type Information Regulation 2”. However, nowadays, sirtuins are known to occur in both bacteria and eukaryotes organisms, including mammals. The genome of bacteria and archaea encodes for one or two sirtuins genes. On the other hand, in humans and other mammals, the sirtuin family consists of seven members (from SIRT 1 to SIRT 7). These different members occupy different subcellular compartments: SIRT1, 6, and 7 are mainly present in the nucleus, SIRT2 in the cytoplasm, while SIRT3, 4, and 5 are found in the mitochondria.

Sirtuins function as mono-ADP-ribosyltransferases or deacylases. ADP-ribosylation is the addition of an ADP molecule to a protein and is a common post-translational modification involved in many cellular processes, including cell signaling, DNA repair, apoptosis, and gene regulation. A deacylase, on the other hand, is a hydrolase that removes an acyl group; sirtuins with deacylase function include deacetylase, desuccinylase, demalonylase, and depalmitoylase. Initially, yeast Sir2 was discovered as a histone deacetylase, but mammalian sirtuins also have various non-histone protein substrates. Overall, sirtuins are crucial for cell metabolism and play a key role in cells' response to various stresses, such as oxidative and genotoxic stress.

Sirtuins in aging

Amongst the different cellular mechanisms where sirtuins are involved, a crucial one is genome stability and DNA repair. During the physiological process of aging, there is a gradual loss of genome integrity, characterized by chromatin reorganization, transcriptional dysregulation, and the accumulation of DNA damage. Different sirtuins are involved in DNA repair. SIRT6, for example, is required to repair a specific type of DNA damage by base excision repair 1. In addition, SIRT6 promotes the repair of DNA double-strand breaks 2.

In the early 2000s, there was a significant rise in the interest for sirtuins. It was reported that Sir2 overexpression could extend yeast lifespan by as much as 70% 3. This effect can be attributed to the increase in genomic stability. Of course, when increasing the complexity of the organism (from yeast to mammals), also the complexity of the mechanisms regulating genome stability increases. This means that, in humans, it is still not clear whether activation of sirtuins leads to increased lifespan by improving genome stability. As of 2021, there is not enough evidence showing that sirtuins can significantly improve longevity in humans.

Sirtuins in diseases

SIRT1 is the most studied sirtuin. Several studies have shown that SIRT1 mediates different stress responses, including inflammation. Specifically, SIRT1 can suppress inflammation by regulating the transcription factor NF-kB 4. Inflammation is a particularly important cause of aging and aging-related diseases. Therefore, loss of sirtuin activity during aging is implicated in the pathogenesis of a wide variety of cardiovascular and metabolic diseases where inflammation plays a part, including atherosclerosis, metabolic syndrome, acute cardiac syndromes, cardiomyopathy, heart failure, arrhythmias, hypertension, obesity, fatty liver, and diabetes. The majority of the studies highlighting the role of sirtuins in diseases have been carried out in animal models. However, at the moment, human studies are increasing.

Nevertheless, we already know a lot about sirtuins' role in aging and diseases, mainly from animal studies. For example, we know that SIRT1 is up-regulated by caloric restriction, which is known to slow down the aging process. Up-regulating SIRT1 is also beneficial for the brain 5. Cellular models also suggested that SIRT1 might have a protective role against cancer. Genetic activation of SIRT1 protects against tumors in the gut 6 and the pancreas 7, likely by suppressing β-catenin activity. SIRT2 seems to be related to a healthy weight, with decreased levels in the fat tissue of obese individuals and increased levels following caloric restriction 8. SIRT3 has a strong antioxidant activity. SIRT1, 2, and 3 all provide benefits for metabolic syndrome, for example slowing down glucose production in the liver, supporting the production of healthy cholesterol and improving insulin sensitivity 9. Preliminary research on SIRT4 shows that it might have a protective effect on telomere length 10. Telomers are the end caps on the chromosomes that prevent the chromosomes from deteriorating during aging and disease statuses. SIRT5 plays a role in liver detoxification by regulating the excretion of the urea from the body 11. SIRT6 might be the most important sirtuin for longevity, although research is still preliminary. Mice where the SIRT6, and also SIRT7, genes have been silenced display features of premature aging 1,12. This might be related to the genome integrity and DNA repair mechanisms where SIRT6 is involved.

Sirtuin-activating compounds

Sirtuin-activating compounds (STACs) are molecules that can increase sirtuins levels. After the health benefits of sirtuins overexpression were discovered in yeast and mice, great efforts have been put into the development of compounds that can activate sirtuins with the aim of improving health and longevity.

The compound that was first shown as able to activate SIRT1 is resveratrol (3, 5, 4′-trihydroxystilbene), a natural product existing in grapes and red wines 13. Another natural compound that is structurally similar to resveratrol and has SIRT1-stimulating activity and antioxidant capacity is pterostilbene, found in high amounts in blueberries 13. Curcumin, the active component of turmeric, is known to have potent anti-inflammatory actions and other health benefits. These could be due to the activation of sirtuins expression 13. Melatonin also exerts some of its beneficial effects via sirtuin activation. For example, melatonin has been shown to protect the brain from the effects of aging by up-regulating SIRT1 14.

However, these natural compounds usually have issues with bioavailability and specificity. Therefore, many pharmaceutical companies worldwide are currently working on synthetic analogs of these compounds. At the moment, there are several clinical trials in humans testing different SIRT1 activators. If the effects of sirtuins activation seen in cellular and animal models will be confirmed in humans, STACs could certainly revolutionize medicine and improve our healthspan, if not our lifespan.

About Arianna Ferrini

Arianna is a postdoctoral research fellow at University College London (UK). She holds a PhD in Tissue Engineering and Regenerative Medicine from Imperial College London (UK) and an MSc in Medical and Pharmaceutical Biotechnology from the University of Florence (Italy). She's an enthusiastic science communicator and works as a freelance writer and editor.

References

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