One of the most remarkable discoveries in the last decade is the role that sirtuins play in regulating lifespan. Sirtuins are a family of proteins found in organisms from single-cell bacteria to humans. Sirtuins and aging are linked, and it is a common theme for organisms from a simple single-celled bacteria to a complex human body.
We have barely begun to uncover the secrets of these proteins, and yet they are somehow involved in every experiment targeting longevity. All the previously discussed approaches to increase longevity are related to sirtuins. The Calorie Restriction Diet and Intermittent Fasting work to increase longevity through their influence on sirtuin activity.
This article summarizes the scientific literature on sirtuins and aging and explores ways to mimic the effects of the beneficial dietary restrictions discussed on this site by pharmacological intervention.
What are sirtuins?
In humans, there are seven enzymes that belong to the sirtuin family. SIRT1, SIRT6, and SIRT7 are found mainly in the cell nucleus. SIRT 2 is found mainly in the cytoplasm, but it can cross over to the nucleus where it has a role in regulating the cell cycle. SIRT3, SIRT4, and SIRT5 are the mitochondrial sirtuins.
Sirtuins regulate the first step of gene expression, in which DNA is copied into RNA.
Aging is accelerated with oxidative stress, and with oxidative stress comes DNA methylation. DNA methylation involves reactive molecules that bind to DNA segments and can repress the expression of those genes.
When transcription occurs, the RNA copies of the DNA will no longer contain the repressed genes. The sirtuin-type proteins SIRT1, SIRT2, SIRT6 and SIRT7 facilitate the repair of methylated DNA and regulate modifications to the epigenome. With age, this corrective process becomes less efficient and is eventually dominated by epigenetic modifications and DNA damage.
SIRT1 levels decrease with age, and its deficiency promotes the expression of aging genes. Studies in mice encoded with an extra copy of the SIRT1 gene reveal less DNA damage over time.
Long-lived humans are often found with more SIRT3 than peers in their age group. Mice without the SIRT3 gene have decreased oxygen utilization and increased production of reactive oxygen species that damage DNA and the cellular tissue they come into contact with.
SIRT6 functions include DNA repair, telomere protection, and genome stability.
SIRT7 regulates the cell cycle and rRNA transcription.
Metabolic Syndrome as a Programmable Disease
In the article on persistent hunger, we read about how metabolic disorders – like obesity, diabetes, and hypertension – can be seen as programmable diseases. What this means is that some repressed genes may have had vital functions in metabolic processes. The older we are and the more oxidative stress we are exposed to, the more difficult we find it to maintain our youthful skeletal muscle and fat composition.
We know this intuitively as we often say of a young person: she is young and can afford to eat all she desires.
SIRT2 controls adipose tissue development. SIRT3 regulates mitochondrial metabolism and ATP production. SIRT4 regulates insulin secretion, mitochondrial metabolism, and it is involved in DNA repair. However, SIRT4 does inhibit fatty acid oxidation. SIRT5 regulates the urea cycle, but it has the effect of reducing fatty acid oxidation. SIRT6 is involved in cholesterol homeostasis, regulation of glycolysis and gluconeogenesis.
Sirtuin Influence on Programmed Cell Death
Programmed cell death is triggered by two factors: cell stress and signals from the organism’s regulatory systems. Cell stress can be anything that impairs the cell’s functions. Regulatory signaling for programmed cell death, however, can affect even healthy cells because a healthy cell is not necessarily aligned with the health and homeostasis of the organism.
A well-regulated system for programmed cell death is vital to the survival of the organism, and it is one of the principle components of biology. Too little cell death can result in autoimmune diseases and cancer. Too much cell death can lead to degenerative diseases like Alzheimer’s and Parkinson’s.
SIRT1 regulates cell survival and longevity. SIRT2 controls the cell growth cycle.
Methods to Increase Sirtuin Activity
If the deficiency in sirtuins leads to accelerated aging, then the reverse could also be true. The question is: can we increase lifespan by increasing sirtuin levels?
It turns out that we can increase lifespans of laboratory animals by doing just that. We can increase some types of sirtuins using various methods like dietary restriction and nutrient composition. We are also able to influence sirtuin levels in humans through the same methods.
We can manipulate the genes that increase sirtuin levels in animals by turning on and off sirtuin-related genes. The prospect of genetic manipulation is not without controversy, but scientists are already working on drugs to delay or even reverse epigenetic changes, thereby increasing longevity.
Calorie Restriction and Intermittent Fasting
As we read in articles on calorie restriction diets and intermittent fasting, dietary interventions can delay aging and increase healthspan. When restricting calories or fasting, the levels of all sirtuins increase, except for SIRT4. The effects of these sirtuin activity changes have a net positive effect on longevity.
SIRT1 increases in a calorie restriction diet and intermittent fasting. This is a positive effect because SIRT1 is needed for the regulation of gluconeogenesis and fatty acid oxidation when on a calorie restricted diet. Its functions include DNA repair, glucose metabolism, neuroprotection, insulin secretion, IGF-1 signaling, and vascular protection. It is involved in regulating cell survival, longevity, and physical activity. It decreases cellular senescence, oxidative stress, inflammation, neurodegeneration, cardiovascular diseases, adiposity, insulin resistance, and liver steatosis.
SIRT2 also increases in a calorie restriction diet and intermittent fasting, and it is linked to longer lifespan. It is known to reduce oxidative stress and neurodegeneration.
SIRT3 plays key roles during calorie restriction like activating enzymes responsible for ketone production. SIRT3 also responsible for the oxidation of long-chain fatty acids. Its role in metabolic health and longevity is not only in relation to fatty acid oxidation; it is also involved in glucose homeostasis. As a result of its role in metabolic processes, SIRT 3 decreases oxidative stress, neurodegeneration, cardiac hypertrophy, adiposity, and liver steatosis.
A decreasing SIRT4 level is good because it inhibits fatty acid oxidation. However, SIRT4 is also involved in regulating insulin secretion, mitochondrial metabolism, and DNA repair.
The resulting increase in SIRT5 reduces oxidative stress, but it also reduces fatty acid oxidation.
The increasing SIRT6 reduces cardiac hypertrophy, adiposity, liver steatosis, inflammation, and insulin resistance. It is positively correlated with lifespan and it plays a key role in glucose homeostasis.
The increase in SIRT7 provides cardioprotection and thereby decreases cardiac hypertrophy.
The line between nutrients and pharmaceuticals is becoming blurred, and thus the term nutriceuticals. For functional food fans, there are activators of sirtuins that you can ingest and incorporate into your diet.
To mimic the beneficial effects of longevity targeting dietary restrictions, we can target functional food that increases sirtuin activity.
Phenols and Polyphenols
Flavones, stilbenes, chalcones, and anthocyanidins are plant-based SIRT1 activating compounds.
Curcumin plays a role in sirtuin regulation. Curcumin works to increase longevity indirectly by increasing levels of SIRT1, SIRT3, SIRT5, SIRT6, and SIRT7. The beneficial effects of curcumin work only in low doses.
Other natural anti-aging compounds are quercetin, butein, fisetin, kaempferol, catechins, and proanthocyanidins.
Dietary supplementation of polyphenols may protect against neurodegenerative, cardiovascular, inflammatory, metabolic diseases and cancer by enhancing SIRT1 deacetylase activity.
The French Paradox and Red Wine
What was referred to as the French Paradox for a long time had to do with the apparent contradiction that the French cuisine presented to the low-fat high-carbohydrate diet recommendation by establishment nutrition guidelines. The French have a very high content of fat in their cuisine. Butter is used generously and dietary cholesterol was never an issue for the French people, as they had lower rates of cardiovascular disease than countries that adopted the low-fat dogma.
Much of the attention of scientists turned to a compound in red wine called resveratrol, which was used to increase the lifespan of laboratory animals. It was theorized that red wine was the reason behind the French people’s longevity, but the quantities of resveratrol in red wine are too small to have such a marked effect.
Nonetheless, resveratrol does increase SIRT1 activity, and it provides the same benefits for improving mitochondrial activity and metabolic control. Resveratrol not only increases SIRT1 activity, but it also inhibits mTOR signaling, which also promotes longevity.
Niacin and Nicotinamide Riboside (Vitamin B3)
Niacin, Nicotinamide Riboside, and Nicotinamide Mononucleotide are variants of vitamin B3 that can be found in tiny amounts in broccoli, cabbage, avocados, edamame, tomatoes, raw beef and shrimp. These compounds increase levels of NAD+, which are consumed by sirtuins. Activating enzymes involved in the biosynthesis of NAD+ increases SIRT1 levels.
While some people react negatively to niacin with flushes on the face, it is a harmless side effect and goes away within 30 minutes. To avoid the inconvenience, Nicotinamide Riboside and Nicotinamide Mononucleotide provide the same benefit without the side effects of niacin.
The Science Behind Traditional Chinese Medicine
Some natural compounds from Traditional Chinese Medicines (TCMs) are potent SIRT1 activators. Several compounds from TCMs were found to regulate SIRT1 activity. In one study, a total of 19 SIRT1 activators were found in TCMs:
- 20(S)-ginsenoside Rg3 (60%),
- ginsenoside Rb2 (152%),
- ginsenoside Rb3 (28%),
- ginsenoside Rc (88%),
- ginsenoside F1 (22%),
- ginsenoside F2 (45%),
- gypenoside XVII (43%),
- notoginsenoside Ft1 (40%),
- polyphyllin I (24%),
- polyphyllin III (32%),
- polyphyllin VI (31%),
- polyphyllin VII (32%),
- liriopesides B (65%),
- baily saponins C (57%),
- ophiopogonin D (54%),
- saikosaponin A (25%),
- schisandrin B (30%),
- anisodine hydrobromide (60%), and
- schisandrin A (28%).
Note the SIRT1 activation rate of 152% for ginsenoside Rb2 (50 μM) and the activation rate of 88% for ginsenoside Rc (50 μM) as an example of what can be achieved with one herb: Panax ginseng.
Melatonin, a naturally occurring hormone, decreases with age. It is the hormone controlling our sleep function, and it also happens to activate sirtuins. This hormone is now available as an over-the-counter drug in many countries.
Metformin, a compound prescribed as a hypoglycaemic drug to treat type 2 diabetes, acts by SIRT1 activation. Longevity researchers have long advocated using the drug to increase lifespan, but regulatory restrictions in most countries prevent it from being prescribed without some pathological condition.
Gräff J, Kahn M, Samiei A, Gao J, Ota KT, Rei D, et al. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J. Neurosci. 2013;33:8951–60.
Kulkarni, Supriya R. et al. “Fasting Induces Nuclear Factor E2-Related Factor 2 and ATP-Binding Cassette Transporters via Protein Kinase A and Sirtuin-1 in Mouse and Human.” Antioxidants & Redox Signaling 20.1 (2014): 15–30. PMC. Web. 22 Dec. 2017.
McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL, Bohr VA, Chua KF. SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair. Aging (Albany NY). 2009; 1:109-121.
Satoh, Akiko, Liana Stein, and Shin Imai. “The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity.” Handbook of experimental pharmacology 206 (2011): 125–162. PMC. Web. 22 Dec. 2017.
Wang, Yi et al. “Screening SIRT1 Activators from Medicinal Plants as Bioactive Compounds against Oxidative Damage in Mitochondrial Function.” Oxidative Medicine and Cellular Longevity 2016 (2016): 4206392. PMC. Web. 22 Dec. 2017.
Zhiyong Mao, Xiao Tian, Michael Van Meter, Zhonghe Ke, Vera Gorbunova, and Andrei Seluanov. Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence. PNAS 2012 109: 11800-11805.