Adele’s dramatic weight loss has brought the SIRTfood diet back into the headlines. The diet plan, based on the 2016 book The SIRTfood Diet, proposes weight loss occurs by activating sirtuins.
Popular social media articles explain that the diet ‘turns on your skinny genes’, which may raise a few eyebrows in the science-minded crowd. (Where exactly is that ‘skinny gene’?)
I’m diving into the science of the fascinating SIRT genes, explaining how they work and showing you how to check your SIRT gene variants. The Lifehacks section will explain the scientific research on different sirtuin activators and how you could apply these solutions to ‘hack’ your sirtuins for healthy aging and increased metabolism. I end with my thoughts on whether the SIRTfood diet works based on the exact foods included vs. a general reduction in calories eaten.
Sirtuins: background and overview
Sirtuins are a family of seven proteins that are important in removing acetyl groups from molecules.[ref]
What are acetyl groups and why should I care? Acetyl groups within the nucleus of the cell attach to the DNA at certain points, marking and opening up the DNA for transcription. Think of them as a chemical post-it note, pointing to what needs to be transcribed into a protein or enzyme for the cell.
Sirtuins remove the acetyl group at the right time, allowing the DNA to compact again and protect it from damage. Essentially, sirtuins turn off a protein. This is an essential function to regulate proteins that are important for aging, metabolism, circadian rhythm, and cell growth.
Sirtuins respond to the energy level changes in a cell. They regulate the transcription of other proteins based on how much energy is available.
In addition to removing acetyl groups in the cell nucleus, some sirtuins are active in the mitochondria and the cytoplasm of the cell. These mitochondrial sirtuins are important in energy production, metabolism, and cellular health.
Let’s take a deeper dive into several sirtuin genes:
SIRT1: Energy sensor, metabolism, and adipose tissue
The SIRT1 protein is located in all cells. Its job in the nucleus of the cell is to remove the acetyl groups that mark which genes should be translated into their proteins. Thus, SIRT1 influences when other proteins are made by the cell. It’s a regulator, reacting to the energy available in the cell.[ref]
Essentially, when cellular energy is low, SIRT1 is one way some proteins are turned off to conserve cellular energy.
SIRT1 and metabolism:
SIRT1 acts as a cellular sensor of how much food (energy) is available. At a cellular level, the level of NAD+ is one-way SIRT one is activated. NAD+ is created and used in the mitochondria during energy production. When energy is low, such as during calorie restriction or hard exercise, the ratio of NAD+ to other mitochondrial molecules rises. This increase in NAD+ triggers an increase in SIRT1 expression.
By affecting the expression of different proteins involved in metabolism, circadian rhythm, and autophagy, SIRT1 affects both overall metabolic rate (and weight) as well as longevity.
Insulin resistance causes SIRT1 levels to decrease. Research shows that increasing SIRT1 will improve insulin sensitivity, especially in situations of insulin resistance. SIRT1 does this by repressing the translation of a gene called PTP1B, a protein tyrosine phosphatase that is a regulator of insulin signaling.[ref]
Calorie restriction (40% fewer calories than normal) increases SIRT1. It is thought to be a mechanism by which calorie restriction increases lifespan in some animals.[ref]
SIRT1 in your fat cells:
Adipose tissue (fat cells) can be either white or brown.
- White adipose tissue, what we think of as fat, is found in areas throughout the body (you know – the belly, love handles, thighs, etc).
- Brown adipose tissue, or brown fat, is a good kind of fat that burns through a lot of energy. It keeps babies warm, producing heat without shivering.
SIRT1 acts on PPARγ to induce brown adipose tissue and suppress the formation of white adipose tissue.[ref]
SIRT1 and cancer:
As we age, one thing to keep in mind is the balance between the needed cellular regeneration and prevention of the out of control growth of cancerous cells.
While it may seem like we always want to increase SIRT1, there could be trade-offs when it comes to preventing a cancerous cell from being destroyed.
In regards to autophagy, one important gene that SIRT1 acts upon is called p53. This is a tumor suppressor gene that needs to be available in cells in the right amount to cause cell death in a cancerous cell. The p53 protein stops the process of cell division, which allows for either a repair of the damaged DNA or apoptosis (cell death).
There are several animal and cell studies showing that inhibiting SIRT1 may help to combat cancer.[ref]
Don’t get me wrong here. I am not suggesting the SIRTfood diet will promote cancer. Instead, I want to clarify that if you have cancer, be cautious, and thoroughly investigate supplements that increase SIRT1 activity.[ref] Talk with your doctor, of course.
SIRT3: Longevity and Metabolism
SIRT3 is a mitochondrial protein and has also been studied in regards to longevity and metabolic syndrome. It is involved in turning on and off several important mitochondrial genes. Higher levels of SIRT3 are connected to longevity.
SIRT3 and metabolism:
SIRT3 is also involved in metabolism, and a study with mice lacking SIRT3 had greater obesity and insulin resistance on a high-fat diet. The reduction of the SIRT3 function was found to lead to mitochondrial dysfunction and metabolic syndrome.[ref][ref]
SIRT3 regulates the activity of proteins that are important for mitochondrial function, such as those needed for fatty acid oxidation and for reducing oxidative stress.[ref]
Researchers have found that both exposure to cold and reducing calories upregulates SIRT3.[ref]
SIRT3 function is also important in preventing cancer. Mice with the gene deleted are more likely to have tumors, and human breast cancer tissue shows deletion of SIRT3 in 40% of carcinomas.[ref]
A December 2014 study in Cell Metabolism found that noise-induced hearing loss in mice could be prevented with nicotinamide riboside, which is a precursor to NAD+ (nicotinamide adenine dinucleotide) and a derivative of vitamin B3. The researchers found nicotinamide riboside activated SIRT3 in the mitochondria. This increase in SIRT3 prevented the noise-induced hearing loss. Moreover, the addition of nicotinamide riboside (NR) was effective either before or after the hearing loss.[ref]
SIRT1 acts on SIRT3: post-translational modification
Interestingly, SIRT1 acts to deacetylate SIRT3 in a post-translational manner. I mentioned above that acetylation marks a gene to be translated into a protein, but that is only part of the picture. Acetyl groups also act upon proteins after they have been created, and acetylation or deacetylation of a protein can change the way it functions in a cell.[ref]
In the case of SIRT3, the SIRT1 protein can regulate the SIRT3 activity and mitochondrial function.[ref]
Why is this important? We often think of changing one gene to alter one function – like pulling a lever to turn something on or off. But it can often be more complicated than just that single lever; the interactions between the sirtuins may also be important in overall metabolism.
SIRT6: Mitochondrial energy, gluconeogenesis, and cancer prevention
SIRT6 also functions in mitochondrial energy production.
One role of SIRT6 is to help regulate the production of glucose in the liver during fasting. Called gluconeogenesis, the liver produces glucose to regulate blood glucose levels. SIRT6 interacts with several other proteins in turning off and on genes that regulate liver glucose production. Animal models of obesity and diabetes have reduced SIRT6 levels.[ref]
NAD+ and Sirtuins:
I mentioned above that the way SIRT1 detects a change in cellular energy levels is through the change in the ratio of NAD+ to NADH. (Read my full in-depth article on NAD+ here.)
The ratio of NAD+ to NADH changes when there are stresses to the cell. This can include lack of food (calorie restriction for a few days), hard exercise, and also oxidative stress. Through sensing the changes in NAD+, the sirtuins act as stress adaptors.[ref]
SIRT genetic variants
Looking at the research on genetic variants can tell you two things:
- In general, genetic variant research explains the connection between changes in a protein (e.g. more or less SIRT1) and the outcome.
For example, if a genetic variant that increases SIRT1 activity is linked with a longer lifespan, then it follows that increasing SIRT1 activity may have a positive impact on lifespan.
- Individually, learning about your genetic weaknesses and strengths can help you focus efforts on the areas that you need to improve.
For example, if you have typical or reduced SIRT1 activity and want to increase lifespan, then targeting SIRT1 with the solutions in the Lifehacks section may make sense for you.
SIRT1 Genetic Variants:
Check your genetic data for rs3758391 (23andMe v5; AncestryDNA):
- C/C: typical
- C/T: lower cardiovascular disease mortality, somewhat better cognitive function in aging, less likely to have degenerative heart valve disease in old age
- T/T: elevated SIRT1 expression[ref][ref]; lower cardiovascular disease mortality, better cognitive function in aging[ref]; less likely to have degenerative heart valve disease in old age[ref]
Members: Your genotype for rs3758391 is —.
Check your genetic data for rs12778366 (23andMe v4, v5; AncestryDNA):
- C/C: reduced risk of diabetes complications[ref] 30% reduced mortality risk in aging population, better glucose tolerance[ref]
- C/T: reduced risk of diabetes complications, somewhat reduced mortality risk
- T/T: typical
Members: Your genotype for rs12778366 is —.
Check your genetic data for rs932658 (23andMe v4):
- C/C: typical
- A/C: somewhat increased SIRT1 activity, decreased risk of medication-related osteonecrosis of the jaw
- A/A: increased SIRT1 activity, decreased risk of medication-related osteonecrosis of the jaw[ref]
Members: Your genotype for rs932658 is —.
SIRT3 Genetic Variants:
Check your genetic data for rs511744 (23andMe v4; AncestryDNA):
- T/T: increased lifespan (avg. of 1.3 years in this study)[ref]
- C/T: typical lifespan
- C/C: typical lifespan
Members: Your genotype for rs511744 is —.
Check your genetic data for rs11246020 (23andMe v4; Ancestry DNA):
- C/C: typical
- C/T: increased risk of metabolic syndrome
- T/T: 50% increased risk of metabolic syndrome, reduced function[ref][ref]
Members: Your genotype for rs11246020 is —.
Check your genetic data for rs185277566 (23andMe v4 only):
- C/C: decreased SIRT3, increased risk of heart attack[ref]
- C/G: decreased SIRT3
- G/G: typical
Members: Your genotype for rs185277566 is —.
SIRT6 genetic variants:
Important in metabolic regulation, telomere maintenance, and mitochondrial respiration. Deficiency in SIRT6 can lead to increased triglycerides and LDL cholesterol, which increases the severity of coronary artery disease.
Check your genetic data for rs352493 (23andMe v4, v5; AncestryDNA):
- T/T: typical
- C/T: risk of increased severity in CAD
- C/C: increased risk of more severe coronary artery disease[ref]
Members: Your genotype for rs352493 is —.
The SIRTfood diet starts with a low calorie (1000 – 1500 calories) induction week coupled with drinking lots of green smoothies. Then the diet plan moves through several phases, with specific food recommendations.
Let’s take a look at how this stacks up to what research studies show.
Multiple studies show that calorie restriction of about 40% will increase SIRT1 expression.[ref] If you are normally eating 1800-2000 calories a day, dropping your caloric intake per the SIRTfood diet recommendation should increase SIRT1 expression.
Would you have to do the SIRTfood diet plan to have an increase in SIRT expression? Well, studies indicate a calorie restriction of about 40% increases sirtuin activity regardless of which foods are being eaten. Consistently restricting calories also makes people grumpy and irritable. Intermittent fasting programs that reduce calories for a few days, though, also should increase SIRT1.
Foods on the SIRTfood diet:
The SIRTfood diet claims that the specific foods turn on your skinny genes. Let’s take a look at the foods recommended: Arugula, buckwheat, blueberries, capers, celery, chilies, chocolate, coffee, garlic, green tea, kale, lovage, olive oil, onions, parsley, red wine, strawberries, turmeric, and walnuts.
These foods include polyphenols that have shown to increase SIRTs when consumed in high amounts. The specific polyphenols that are important here are quercetin, curcumin, EGCG, and resveratrol.
While the recommended foods can definitely be part of a healthy diet, I am unable to find evidence that you can eat enough of them to activate the sirtuins. Instead, most of the studies on polyphenols seem to be using amounts of the nutrients for which you would need to use supplements.
Supplements to boost sirtuins:
While the foods in the diet may -or- may not boost sirtuin expression at the dietary level, the following plant compounds have shown in research studies to affect sirtuins at levels obtained by taking supplements.
The average glass of red wine contains around 2 mg of resveratrol. Dietary intake from food sources such as red grapes, apples, or peanuts is less than 1 mg/day.[ref]
Supplement doses of resveratrol range from 150mg to 1,000 mg. This would be equivalent to a whole lot of wine (75 glasses and up per day).
What is the right dosage for resveratrol supplements? Let’s see what clinical trials show us:
- A small clinical trial of older adults found that 1,000 mg of resveratrol daily for four weeks decreased their post-prandial glucose response.[ref]
- Ethnicity matters? A clinical trial using 2,000 mg/day of resveratrol found little effect on insulin resistance, but Caucasians in the studies did have improved insulin sensitivity.
- Another clinical trial found that 150 mg of resveratrol had little effect on insulin sensitivity.[ref]
Berberine is a plant compound that has been used in Chinese medicine for centuries. Studies show it increases SIRT1 expression.[ref]
Vitamin D, Resveratrol, and SIRT1:
Interestingly, SIRT1 interacts with vitamin D in positive ways.
We get vitamin D either from supplements or via sun exposure. Either way, that molecule needs to be converted into an active form of vitamin D (1, 25 D) and then act upon a vitamin D receptor. The active form of vitamin D joining with a vitamin D receptor is important for bone health, oxidative stress reduction in cells, regulation of the immune system, heart health, and more. The active form of vitamin D does a lot, but only in conjunction with the vitamin D receptor.[ref]
Research shows that increasing SIRT1 activity via resveratrol supplementation causes an increase in the vitamin D receptors. This increase, coupled with the active form of vitamin D, increases the positive effects of vitamin D on many systems of the body.[ref]
Drugs that interact with the sirtuins:
The other side of the picture here is that you want to make sure you aren’t sabotaging your goals of increasing sirtuins through a medication that you’re taking.
- Statins, which are prescribed to lower cholesterol, have shown to directly repress SIRT6.[ref]
- Alcohol, the most common drug used, decreased SIRT1 expression in the liver.[ref]
- NSAIDs have shown in some studies to inhibit SIRT1.[ref]
- Metformin, on the other hand, increases SIRT1 activity.[ref]
Upregulating the sirtuins should have positive benefits on metabolism and healthy aging, but I don’t think the research shows that eating specific foods will activate the sirtuins.
The initial phase of the SIRTfood diet should upregulate SIRT1 via calorie reduction alone for anyone who normally eats a diet of around 2,000 calories a day.
For some people, having a diet plan from a book is the motivation needed to make healthy eating changes. While I’m not a nutritionist, the recipes and smoothies look great, as long as you don’t have a digestive issues with a specific ingredient or have problems with oxalates.
All in all, you are likely not to get enough polyphenols, such as resveratrol, via diet to activate the sirtuins in a meaningful manner. Supplements would likely be needed. That said, the calorie restriction and whole foods found in the diet may be enough on their own to promote weight loss for you.
Related Articles and Genes:
A decades-old diabetes drug now holds promise for increasing healthspan. Research shows that metformin may reduce the risk of some of the diseases of aging, thus increasing the number of years someone is healthy.
Vitamin D, Genes, and Your Immune System
Vitamin D is more than just a ‘vitamin’. It is actually a hormone that is essential to so many processes in your body – including your immune system. This article explains how vitamin D interacts with the immune system and which genetic variants are linked with low vitamin D levels. We will wrap up with ways to increase your vitamin D level.