Sirtuins & Aging – Sirt1, Sirt3 & Sirt6 Explained
Sirtuins are a group of NAD+ dependent signaling proteins that regulate cellular health. Sirtuins are found throughout the world in nearly all species of life, from yeast cultures to mice and monkeys.
Sirtuins come in different forms like SIRT6 or SIRT1 and these proteins play a key role in regulating cellular maintenance(homeostasis). Homeostasis is a vital function in ensuring things function as they should. Sirtuins have only been researched since the 1990s which in scientific terms, is a very short time! Massive leaps in our understanding of the body have been made possible as researchers dive into these fascinating proteins.
Sirtuins – the Master of Cells.
Imagine your body to be an aristocratic household. There are people working on different tasks to ensure the house remains in top condition. The cleaners go around dusting and picking up litter. The cooks prepare delicious food for the guests. The maids look after the guests and make sure everyone is comfortable.
At the top of the household is the lord & lady who hire and maintain the staff. They pay the bills and commission their staff to do what’s needed to enhance their houses prestige.
The Lord and Lady here are like the sirtuins. They manage everything that happens in your cells and ensure the body is running as it should.
NAD+ is like money for the masters of the house. Without it, they can’t buy the staff or materials needed to maintain their home. NAD+ is vital to maintaining the efficiency and function of the sirtuins, but it declines with age.
Sirtuin Proteins – What do Sirtuins do?
Proteins are usually referred to as nutritional elements of your diet such as what you’d find in a steak. However, sirtuins, like many other forms of protein in the body are actually just groups of molecules.
Proteins are made from amino acids and are found all over the body. There are at least 10,000 different proteins and they are essential for the structure, function, and regulation of the body's tissues and organs.
Sirtuins are one of these essential protein groups and the sirtuin group comes in 7 varieties.
Here is a rough guideline of the 7 sirtuins.
Table 1. The 7 Sirtuins
So, sirtuins generally manage cells from the mitochondria or nucleus. The nucleolus which is where SIRT7 operates is a region in the nucleus that is involved with assembly and production of our cells ribosomes. At the most basic level, sirtuins main function is to remove acetyl groups from other proteins.
Acetyl groups are parts of a molecule (moiety) that are added to or removed from other molecules. This serves as a form of communication that can alter the way our cells act in the body. Acetyl groups are like tags on our molecules that let our proteins gather the relevant information needed to interact with each other.
Sirtuin deacetylation is simply when a sirtuin removes an acetyl group from a molecule. This then allows that molecule to perform a necessary function. The opposite of this is acetylation which is when a sirtuin adds an acetyl group to a molecule.
One example of deacetylation can be found with histone proteins. Histones make up a condensed form of DNA that is tightly packed and needs to be read. This DNA (blueprint) has to be read so that the body can see what instructions it needs for gene expression. In order to read and unpack this DNA, it needs to be given an acetyl group to open (acetylation).
Reading the DNA is a crucial part of our cellular biology, but having DNA unwound and unpacked can leave it vulnerable to damage.
Like an old map, the DNA needs to be read but must be packed back for safe keeping. To do this our sirtuins deacetylate the histones allowing that part of the DNA to close back up. This silences the expression of that gene but also protects it for when it is needed next time.
Sirtuins play a variety of roles in the cell, but each one has a different task. Let’s examine 3 sirtuin groups that have shown great promise in longevity research.
SIRT1 Benefits – The Master of Metabolism and Aging.
SIRT1 is a nutrient-sensing nicotinamide adenosine dinucleotide (NAD)-dependent protein that removes acetyl groups from proteins throughout the body. It serves the body in multiple ways from the control of gene expression to metabolic regulation (Rahman et al 2011).
SIRT1 Functions – Image adjusted from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123438/
“SIRT1 is a nutrient-responsive protein that facilitates the whole-body response to reduced food availability [in many different ways]” It provides many important functions which we will explore below.
SIRT1 initiates Hepatic glucogenesis which serves a crucial role in maintaining glucose homeostasis to meet our bodies’ energy demands, particularly when calories are in short supply. Glucogenesis means our blood glucose levels remain stable even in the absence of the regular intake of carbohydrates. You may be familiar with this concept if you have ever tried a ketogenic diet as there are many health benefits associated with it.
Fatty acid oxidation
This process provides the main source of energy for many of our bodies’ tissues including the heart and skeletal muscle. It is critical during times of fasting, illness, or physiological stress.
SIRT1 increases Adiponectin production which is very beneficial to our health and longevity. Adiponectin is a hormone that is extremely important in facilitating the essential tasks of regulating insulin sensitivity, metabolizing glucose and lipids, and maintaining cardiovascular homeostasis.
“Adiponectin is a fat-derived hormone that appears to play a crucial role in protecting against insulin resistance/diabetes and atherosclerosis. Decreased adiponectin levels are thought to play a central role in the development of type 2 diabetes, obesity, and cardiovascular disease in humans.” (Achari et al, 2017 ).
We all know how bad inflammation is to our health. Inflammation is when our white blood cells fight off invaders and illness. But sometimes inflammation can be created when there is no apparent need for it, for example with arthritis. Inflammation is highly correlated with Cancer, Heart disease, Diabetes, Asthma, and Alzheimer’s disease. SIRT1 has been shown to aid our cells in fighting inflammation (Gillum et al, 2011).
Autophagy comes from the ancient Greek word for “self-eating” and it refers to the process by which the body recycles or destroys cells that are no longer beneficial, or worse, detrimental, to our health. It is an essential process that ‘cleans’ up the body and keeps it running smoothly. Autophagy benefits multiple parts of the body including the liver, immune system, and lymphatic system. There is strong evidence to show that SIRT1 is a powerful facilitator of autophagy (Ou, Xuan et al 2014).
“SIRT1 may induce autophagy directly…SIRT1 regulates autophagy machinery through multiple mechanisms” (Kitada et al 2016).
Fights Metabolic Deficiencies
Global populations as a whole are encountering more and more dietary & metabolic-related illnesses. From obesity to diabetes. SIRT1 research is showing promising signs that it can help tackle these issues.
”SIRT1 stimulates hepatic fatty acid oxidation, augments insulin secretion, increases circulating adiponectin levels, and reduces inflammation, discovery of SIRT1 activators would allow clinicians to treat multiple features of diabetes simultaneously” (Gillum et al, 2011).
SIRT1 is just one of seven sirtuins that can aid our health across a wide spectrum of longevity fields. Boosting SIRT1s’ efficacy is a hot topic as researchers are starting to explore its heavy reliance on NAD+.
SIRT3 Benefits – The Cell Protector
SIRT3 has been linked to cell longevity and durability by protecting cells from stress-induced damage. It is also associated with sustaining mitochondrial integrity as it plays a big role in the biology of mitochondria. For this reason, it has been associated with treatment potential in “cancer genetics, aging, neurodegenerative disease, and stress resistance” (Ansari et al, 2016).
”SIRT3 is critical for maintaining mitochondrial integrity and function, which can regulate cell survival, death and metabolic pathways, helping to control the balance between health and disease. With its central role in mitochondrial biology, SIRT3 contributes to cell survival by modulating oxidative stress pathways” (Chen et al, 2014).
Image adjusted from: https://www.semanticscholar.org/paper/Sirtuin-3-(SIRT3)-and-the-Hallmarks-of-Cancer.-Alhazzazi-Kamarajan/c56821397de9cb416b9297d03bd57baa1eadeefd
Below we will look at some of the health benefits that SIRT3 provides.
SIRT3 Mitochondrial Activity
SIRT3 plays a pivotal role in mitochondrial function by deacetylating and activating various mitochondrial enzymes.
How important are these mitochondrial enzymes that SIRT3 regulates?
Well, they are involved in critical biological functions such as “fatty acid β-oxidation, amino acid metabolism, the electron transport chain, and antioxidant defences” (Kincaid et al, 2013). This also allows for mitochondrial energy metabolism to increase. This lets our mitochondria generate a large amount of adenosine triphosphate (ATP), which is the primary energy currency of our cells.
SIRT3 Prevents Cell Death
Apoptosis is a process similar to autophagy, in which our bodies select certain cells to be terminated based on their damage or inefficient function. SIRT3 can prevent over-use of apoptosis by protecting our cells from damage. Kincaid et al 2013, states that this protection is afforded by “lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore”.
SIRT3 Fights Free Radicals
Free radicals or reactive oxygen species are oxygen-containing molecules with an uneven number of electrons. For this reason, they are highly reactive which allows them to facilitate large chain chemical reactions. While they do serve a process in the body, they are extremely volatile and are linked to a host of diseases.
They contribute to:
- Cardiovascular disease
- Neurodegenerative disease
- Inflammatory conditions
SIRT3 helps fight free radicals by “limiting oxidative stress, and reducing reactive oxygen species production with a decrease in mitochondrial membrane potential”(Chen et al, 2014). Because of the known risks of high amounts of free radicals in the body, this is one of the biggest benefits of SIRT3 functioning.
SIRT3 Cancer Treatment?
Some early evidence suggests SIRT3 could play a role in cancer treatment. It has been described as a “tumor suppressor in breast cancer” (Desouki et al, 2014).
Alhazzazi et al, 2013, recognises the role SIRT3 plays in cancer and explores its potential therapeutic benefits. While their findings are inconclusive they do suggest that with “unique biomarkers for each cancer type” sirtuins could provide “effective personalized cancer therapy”. However, because SIRT3 can increase the longevity of our cells it can also protect unwanted cells. Modulation of SIRT3 activity could provide future cancer treatments but more research is required to determine how best to do this.
SIRT3 plays a big role in protecting our cells from stress and boosting mitochondrial function. Because of this, it is being closely studied for its antiaging potential.
SIRT6 Benefits – The DNA Caretaker
To simplify SIRT6 as a DNA caretaker is a little unfair. SIRT6 appears to function in many molecular pathways. However, research has shown that DNA repair and genomic stability are heavily dependent on levels of SIRT6 (Klein et al, 2020).
SIRT6 is now considered to have potential therapeutic benefits in multiple degenerative diseases.
Unlike all other sirtuins, SIRT6 is the only one that can bind NAD+ without acetylated substrate which allows it to work as an NAD+ sensor.
“SIRT6 is …has emerged as an exciting target of several diseases such as cancer, neurodegenerative diseases, aging, diabetes, metabolic disorder, and heart disease” (Akter et al, 2021).
Image adjusted from: https://www.mdpi.com/1422-0067/22/8/4180/htm
Let’s look at some of the benefits of SIRT6 in more detail:
DNA Repair & Genomic Maintenance
SIRT6 appears to play a crucial role in DNA repair & maintenance; “SIRT6 is recruited to double-strand breaks (DSBs) within seconds and further recruits DNA repair factors to initiate DNA damage response” (Klein et al, 2020). To put into perspective how important DSB repair is; “DSBs, [are] the most deadly type of DNA damage” (Gao et al, 2018).
Mao et al, 2011, found that SIRT6 is associated with PARP1 activation and that it “strongly stimulates both pathways of DSB repair, nonhomologous end joining and homologous recombination”. This means that SIRT6 is a vital component of DNA repair and chromosomal activity.
SIRT6 not only plays a role in DSB repair but also there is evidence that it plays a role in “base excision repair (BER). Overexpression of SIRT6 exhibited improved BER efficiency in mouse fibroblasts, whereas deletion increased sensitivity to BER-associated DNA-damaging agents” (Klein et al, 2020). BER could be described loosely as fixing the genome by removing unwanted lesions before they cause unwanted mutations whereas DSB is more akin to fixing DNA after it’s damaged. Both processes are vital to longevity.
Telomeres are the protective caps on the ends of the strands of DNA called chromosomes. Some branches of anti-aging research focus exclusively on these caps as the correlation between telomere length and life span is very strong.
SIRT6 seems to contribute to healthy telomeric activity. Klein et al 2020, found that “depletion of SIRT6 resulted in telomeric defects that resemble those observed in Werner syndrome, an aging disorder”. Li et al, 2017, observed a positive link between “SIRT6 and telomere integrity in the heart”. Furthermore, they found that SIRT6 is involved in the “regulation of telomere integrity and inflammatory responses”. Gao et al 2018 also found evidence for SIRT6 protecting telomere integrity; “SIRT6 plays a role in the regulation of telomere movement upon oxidative damage”.
SIRT6 – Increases Lifespan
Roichman et al, 2021, show that SIRT6 overexpression “leads to a reduction in frailty and lifespan extension in both male and female B6 mice”. This exciting new study boldly claims that “SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging”. Metabolic regulation seems to make up a large component of this lifespan extension leading them to conclude that SIRT6 is a “master regulator of healthy aging”.
Sirtuins Activators for Anti-Aging
The research on sirtuins is quite conclusive, sirtuins do promote longevity and healthy cellular activity. SIRT1 in particular shows promise as an anti-aging super protein.
The question is how do we increase their effectiveness and availability? Let’s look at some organic and supplement-based sirtuin activators.
SIRT1 Activator – Resveratrol
Resveratrol & SIRT1 share an interesting relationship. Resveratrol is a SIRT1 activator and can increase SIRT1s’ efficacy in the body. “Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss” (Vilalba et al, 2012). It should be noted that resveratrol needs NMN to work effectively. As an alternative to resveratrol, extra virgin olive oil and oleic acid work in a similar way and can also help activate SIRT1. Activating & supporting SIRT1 is very important so its worth considering if you want to add certain olis or resveratrol into your own health regime.
Hormesis Sirtuin Activation
Hormesis is the adaptive response of cells and organisms to small stressors. Examples of small stressors include fasting, exercise, and calorie restriction. Note that these stressors are often promoted as elements of a healthy lifestyle. It’s no surprise as SIRT1, SIRT3, and SIRT6 are both upregulated in the presence of small stressors. The exact pathways vary depending on the stressor. Fasting for example triggers sirtuin activity by engaging the bodies’ fat metabolism systems, of which sirtuins play an important role.
NMN Sirtuin Activator
Sirtuins by their nature rely on NAD+ to perform their tasks. They are by definition NAD+ dependent. We know that, as we age levels of NAD+ decline, and so, the ‘fuel’ of our sirtuins
“decline in NAD+ biosynthesis decreases sirtuin activity, likely contributing to the development of age-associated pathophysiologies.” (Imai et al, 2016).
This study goes on to suggest that NAD+ precursors like NMN are being viewed as an “efficient therapeutic intervention against diseases of aging, such as type 2 diabetes, Alzheimer’s disease, heart failure, and hearing loss” (Imai et al, 2016).
In short NMN boosts sirtuin activation.
Sirtuins & Longevity
Sirtuins are massively important to your long-term health and longevity. In particular, SIRT1 research is uncovering exciting antiaging discoveries. Whether you activate your SIRT1 with resveratrol, run 5k once a day, practice intermittent fasting or boost your Sirtuins with NMN, what we do know is that we should all aim to support our sirtuins so that they can support us!
Munehiro Kitada, Yoshio Ogura, Daisuke Koya, Chapter 3 - Role of Sirt1 as a Regulator of Autophagy, Academic Press, 2016, Pages 89-100, ISBN 9780128029374,https://doi.org/10.1016/B978-0-12-802937-4.00003-X.
Alhazzazi TY, Kamarajan P, Verdin E, Kapila YL. Sirtuin-3 (SIRT3) and the Hallmarks of Cancer. Genes Cancer. 2013;4(3-4):164-171. doi:10.1177/1947601913486351
Ou, Xuan et al. “SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress.” Stem cells (Dayton, Ohio) vol. 32,5 (2014): 1183-94. doi:10.1002/stem.1641
Chen, Y., Fu, L., Wen, X. et al. Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis 5, e1047 (2014). https://doi.org/10.1038/cddis.2014.14.
Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell. 2017;16(1):4-16. doi:10.1111/acel.12538
Kincaid B, Bossy-Wetzel E. Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci. 2013;5:48. Published 2013 Sep 6. doi:10.3389/fnagi.2013.00048
Desouki M.M., Doubinskaia I., Gius D., Abdulkadir S.A. Decreased mitochondrial SIRT3 expression is a potential molecular biomarker associated with poor outcome in breast cancer. Hum. Pathol. 2014;45 doi: 10.1016/j.humpath.2014.01.004
Akter R, Afrose A, Rahman MR, Chowdhury R, Nirzhor SSR, Khan RI, Kabir MT. A Comprehensive Analysis into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer’s Disease, Aging, Cancer, Inflammation, and Diabetes. International Journal of Molecular Sciences. 2021; 22(8):4180.
Li Y., Meng X., Wang W., Liu F., Hao Z., Yang Y., Zhao J., Yin W., Xu L., Zhao R., and Hu J. (2017) Cardioprotective effects of SIRT6 in a mouse model of transverse aortic constriction-induced heart failure. Front. Physiol. 8, 394 10.3389/fphys.2017.00394
Qi J, Cui C, Deng Q, et al. Downregulated SIRT6 and upregulated NMNAT2 are associated with the presence, depth and stage of colorectal cancer. Oncol Lett. 2018;16(5):5829-5837. doi:10.3892/ol.2018.9400
Villalba JM, Alcaín FJ. Sirtuin activators and inhibitors. Biofactors. 2012;38(5):349-359. doi:10.1002/biof.1032
Imai, Si., Guarente, L. It takes two to tango: NAD+ and sirtuins in aging/longevity control. npj Aging Mech Dis 2, 16017 (2016)