THE SIRTUIN PATHWAYS: THE GUARDIANS OF THE GENOME, STEM CELLS, AND HEALTH
December 30, 2020
The above diagram shows the locations of the Sirtuin family of proteins as they are found in the cell. Sirtuins are a family of seven proteins that regulate cellular health. The sirtuins are present in the mitochondria (Sirt 3,4,5) and in the cell nucleus (Sirt 1,6,7). The sirtuins represent one of the most important pathways in the body. Remember that the cell and its organelles are analogous to computer hardware while the pathways represent the computer software. As I have said it is much easier to modify the software rather than the computer. When we modify the “software” we potentially modify upstream causes of aging.
The Sirtuins are responsible for a host of functions in the body which can make the difference between health and disease. The following diagram shows just some of the functions. Let us briefly talk about each aspect of this illustration.
SIRTUINS AND CHROMATIN REGULATION
Chromatin is the material that makes up a chromosome that consists of DNA and protein. The major proteins in chromatin are proteins called histones. Their primary function is packaging long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. We see the names facultative and constitutive heterochromatin. All we need to know about these is that constitutive heterochromatin can affect the genes near itself; while facultative heterochromatin results in genes that are silenced but under specific conditions of developmental or environmental signaling cues, it can lose its condensed structure and become transcriptionally active. Thus, we can see that the facultative heterochromatin might be able to be manipulated. This leads to the field of Epigenetics. We will see down the road this can have profound implications in Anti-Aging medicine and disease control.
CELL CYCLE CONTROL
The cell cycle represents the essence of life. It deals with how cells reproduce. Typically, problems in the cell cycle result in many degenerative diseases and cancers.
As cells move through the cell cycle, do they breeze through from one phase to the next? If they’re cancer cells, the answer might be yes. Normal cells, however, move through the cell cycle in a regulated way. They use information about their own internal state and cues from the environment around them to decide whether to proceed with cell division. This regulation makes sure that cells don’t divide under unfavorable conditions (for instance, when their DNA is damaged, or when there isn’t room for more cells in a tissue or organ). Again, we can see the importance of the Sirtuins and the cell cycle. Our health is very dependent upon the proper functioning of the cell cycle.
SIRTUINS AND CELL FATE DECISIONS
The cell fate control is one of the Holy Grails of Regenerative Medicine. Sirtuins have a direct effect on what type of cell a stem cell may become. Sirtuins seem to have importance in the process of creating an IPS (induced pluripotential stem) cell. iPS cells are derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell needed for therapeutic purposes.
Again, the relationship between sirtuins and stem cells is extremely important. It can have profound implications on Regenerative Medicine procedures.
We can see how the sirtuins can control stem cell fate by taking notice of various environmental clues. Sirtuins give clues to the stem cells as to what to do and when to do it. We are leaning more and more about the relationship between the Sirtuin proteins and their effects on stem cells. They maintain stemness which is an essential characteristic of a stem cell that distinguishes it from ordinary cells namely self-renewal.
SIRTUINS AND DNA REPAIR
The sirtuin pathways are very important in the repair of DNA damage. The following diagram give us some insight into this process. The ssDNA is damage to a single strand of DNA while DBS repair represents a double strand break in the DNA. The following illustration shows the difference between single (ssDNA) and double Strand (DSB) DNA breaks.
DNA safekeeping is one of the most important functions of the cell, allowing both the transfer of unchanged genetic material to the next generation and proper cellular functioning. Therefore, cells have evolved a sophisticated array of mechanisms to counteract daily endogenous and environmental assaults on the genome. These mechanisms rely on the recognition of the damaged DNA and its subsequent signaling. If DNA repair is not accomplished, this can lead to a variety of medical problems from cancer to a variety of degenerative diseases. SIRT1, SIRT3 and SIRT6 are involved in the signaling of different DNA repair pathways through key signaling factors. They help accomplish this with a variety of enzymes. Actually, DNA repair is intimately tied into chromatin regulation. Again, we go back to the histones and their importance.
The Sirtuin histone targets are essentially gene targets. A major enzyme the sirtuins work with is PARP. The main role of PARP (found in the cell nucleus) is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signaling the enzymatic machinery involved in the SSB repair. One very significant fact is that the PARP enzyme is a very big consumer of NAD+. This is one of a number of reasons that as we age we need to increase the amount of NAD+ or its precursors that is available to our body. More about NAD+ in a bit.
SIRTUINS AND MITOCHONDRIA
Mitochondria play a critical role in energy production, cell signaling and cell survival. Defects in mitochondrial function contribute to the aging process and aging-related disorders such as metabolic disease, cancer, and neurodegeneration. As time goes on we are realizing the mitochondrial malfunctions leave their footprints on most diseases. Alterations in the expression/activity of SIRT3, SIRT4, SIRT5 are linked with many different diseases. Overall, mitochondrial sirtuins regulate mitochondrial protein networks, orchestrate mitochondrial function, and allow cells to adapt to metabolic stresses. In addition, emerging evidence indicates that sirtuins regulate yet another important cellular process, autophagy.
Autophagy is extremely important in the body’s recycling process. It allows the orderly degradation and recycling of cellular components. The sirtuins and mitochondria are intimately involved in this process. If you encourage autophagy you encourage anti-aging. SIRT3, SIRT4 and SIRT5 (mitochondrial sirtuins) belong to the sirtuin family proteins and are located in the mitochondria. They catalyze NAD+ into a variety of different compounds. They modulate the function of various targets to regulate the metabolic status in cells. Emerging evidence has revealed that mitochondrial sirtuins coordinate the regulation of gene expression and activities of a wide spectrum of enzymes to orchestrate oxidative metabolism and stress responses. Mitochondrial sirtuins act in synergistic or antagonistic manners to promote respiratory function, antioxidant defense, insulin response and adipogenesis to protect individuals from aging and aging-related metabolic abnormalities. The next diagram shows how mitochondria produce energy, namely ATP, the body’s energy currency. ATP keeps the cells alive and it is instrumental in many of the body’s repairs. This is the Krebs cycle and other energy producing cycles.
HOW DO THE SIRTUINS ACCOMPLISH THEIR VARIOUS TASKS?
The basic role of sirtuins is that they remove acetyl groups from other proteins. An acetyl group is a small molecule made of two carbon, three hydrogen, and one oxygen atoms. When Acetyl groups are added to or removed from other molecules that may affect how the molecules act in the body.
In the above diagram the Acetyl group is represented by Ac in the green hexagons. Acetyl groups control specific reactions. Sirtuins work with acetyl groups by doing what’s called deacetylation. This means they recognize there’s an acetyl group on a molecule then remove the acetyl group, which tees up the molecule for its job. One way that sirtuins work is by removing acetyl groups (deacetylating) biological proteins such as histones. For example, sirtuins deacetylate histones, proteins that are part of a condensed form of DNA called chromatin. Here we see the DNA strands wound about the histones.
The histone is a large bulky protein that the DNA wraps itself around. Think of it as a Christmas tree, and the DNA strand is the strand of lights. When the histones have an acetyl group, the chromatin is open, or unwound. This unwound chromatin means the DNA is being transcribed, an essential process. But it doesn’t need to remain unwound, as it’s vulnerable to damage in this position, almost like the Christmas lights could get tangled or the bulbs can get damaged when they’re unwieldy or up for too long. When the histones are deacetylated by sirtuins, the chromatin is closed, or tightly and neatly wound, meaning gene expression is stopped, or silenced. Sirtuins deacetylate a multitude of targets including histones, transcription factors, and metabolic enzymes. Taken together, sirtuins have been implicated in numerous cellular processes including stress response, DNA repair, energy metabolism. Sirtuins are a family of proteins that act as metabolic sensors. They deacetylase a coenzyme NAD+ into free nicotinamide. Basically, they break down acetyl from proteins to maintain their functioning for longer. The ratios of NAD+ and NADH determine the nutritional status of the cell and sirtuins are there to respond to it. NAD+ is an essential currency for energy metabolism and DNA repair. Sirtuins are proteins that evolved to respond to the availability of NAD in the body.
The preceding diagram spells out the relationship between the Sirtuins and NAD+. We see that the sirtuins in response to NAD+ levels influence a number of other pathways which are responsible to a variety of different diseases. The bottom line is the Sirtuins are a family of proteins that act as metabolic sensors. They deacetylase a coenzyme NAD+ into free nicotinamide. The ratios of NAD+ and NADH determine the nutritional status of the cell and sirtuins are there to respond to it. NAD+ is an essential currency for energy metabolism and DNA repair. Sirtuins are proteins that evolved to respond to the availability of NAD+ in the body.
SIRTUINS AND OXIDATIVE STRESS
The sirtuins help regulate oxidative stress and inflammation. The above diagram shows this very well. In this diagram we see that the sirtuins have a direct effect on a pathway called the NRf2 pathway. This is the major pathway in the body that helps reduce inflammation. Consider it a thermostat of inflammation. When this pathway is stimulated it produces very powerful antioxidant enzymes which will significantly lower inflammation. The antioxidant properties also tie into the NAD/NADH ratio which ideally, we like to be 700/1.
HOW TO INCREASE SIRTUINS
There’s a lot of evidence pointing to the longevity benefits of increased sirtuin activity. If not in over-expression, then increasing sirtuins can still be good for your health in most cases. Glucose restriction extends the lifespan of human fibroblasts because of increased NAD+ and sirtuin activity. Inhibiting insulin shuttles SIRT1 out of the cell’s nucleus into the cytoplasm. Cancers use primarily glucose and glutamine for fuel with the exception of some ketones in rare cases.
Caloric restriction and fasting increase SIRT3 and deacetylate many mitochondrial proteins. Reduction of calorie intake without causing malnutrition is the only known intervention that increases the lifespan of many species including primates. It’s thought that these effects in longevity require SIRT1.
The following illustration demonstrates a variety of methods to help increase sirtuin activity. The chart is broken down into a few different categories. The input and effector categories are the most important to us. We see the sirtuins are very important sensors.
Activating AMPK elevates NAD+ levels, leading to increased
Ketosis. Ketone bodies like beta-hydroxybutyrate promote sirtuin activity. This is essentially a ketogenic diet. Thus, one simple way of increasing the sirtuins is by following a somewhat ketogenic diet. Natural ways of caloric restriction and fasting are still the best ways of signaling energy deprivation which promotes longevity. In an everyday context, a low carb diet is also pro-sirtuin to a certain extent because of the low levels of insulin and glucose. Exercise has anti-inflammatory effects and it increases SIRT1. The long-term benefits of exercise are even thought to be regulated by SIRT1.
Cyclic-AMP (CAMP) pathway activates SIRT1 very rapidly to promote fatty acid oxidation independent of NAD+. CAMP is linked with AMPK (another very important pathway in the body) which gets activated under high energy demands while being energy deprived. This can be accomplished with cold exposure and high-intensity exercise training. Heat exposure and saunas increase NAD+ levels which promote SIRT1 as well. Sweating, cardio, yoga, or infrared saunas will probably have a similar effect on activating heat shock proteins which can increase sirtuins.
Chronic oxidative stress and DNA damage depletes NAD+ levels and decreases sirtuin activity. This will then disrupt DNA repair and impair mitochondrial functioning. That’s why you want to keep stressors acute and followed by recovery.
Melatonin can activate sirtuins and has anti-aging effects. It’s also the main sleep hormone and a powerful antioxidant that helps the brain get more recovery from deeper stages of sleep. Sirtuins also affect the circadian clocks so keeping a consistent circadian rhythm is incredibly important for longevity. NAD+ is under circadian control and when you
you are misaligned you’ll have less energy and lower SIRT1 and SIRT3 activity. The enzyme SIRT1 increases FOXO DNA binding by deacetylating FOXO in response to oxidative stress. FOXO is another very important pathway. FOXO proteins get increased in response to cellular stress and increased energy depletion.
PERHAPS NAD IS THE BEST WAY TO INCREASE SIRTUIN FUNCTION
Maybe the best way to consider NAD+ is to consider it as the energy currency to purchase increased Sirtuin activity. Of all the methods to increase Sirtuin activity NAD+, especially when given intravenously, may be one of the most effective sirtuin stimulators. In the above diagram, STACs are sirtuin activating compounds. In addition to Resveratrol, there is also Pterostilbene which is a better effector than Resveratrol.
THE BOTTOM LINE IS EAT THE ABOVE FOODS, EXERCISE, ESPECIALLY INTERMITTENT HIGH INTENSITY EXECISE, INTERMITENT FASTING, AND CALORIE RESTRICTION WILL INCREASE YOUR SIRTUINS. TAKE PLENTY OF NAD OR ITS SUBSTRATES. WHEN YOUR SIRTUINS ARE INCREASED IT WILL HAVE A WATERSHED EFFECT ON THE OTHER PATHWAYS IN THE BODY. THE DIAGRAM BELOW SAYS IT ALL.
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