SR9009/Stenabolic: Potent REV-ERB Agonist
Stenabolic, often referred to by its chemical name SR9009, is a new research chemical being studied because of its influence over the genetic underpinnings of our circadian rhythm.
Research on this fascinating substance suggests that it can improve circadian rhythm and its downstream influence on glucose and lipid metabolism, exercise performance, and mental health. Amazingly, research also indicates that SR9009 may be a therapeutic option for cancer.
But with a lack of long-term and acute human evidence and unknown relative safety for humans, SR9009 is controversial at best, and special care should be taken before using it.
What Is SR9009/Stenabolic?
Often considered a SARM, as so many of these research chemicals are, SR9009, otherwise known as Stenabolic is deemed to be a REV-ERBa receptor agonist.
While that sounds a bit daunting, this means SR9009 can influence our circadian rhythm and the downstream influences of this system such as wakefulness, sleep quality, and even metabolic processes like glucose and lipid metabolism (1, 2).
When ingested, SR9009 travels to tissues of the body such as muscle and the liver where it activates this REV-ERBa receptor within cells. This receptor is a nuclear receptor and thus plays a role in how the cell’s nucleus functions.
But the reason that SR9009 has gained popularity, as of late is the overall influence this chemical has over our circadian rhythm. But we aren't just concerned with being able to fall asleep and wake feeling refreshed.
Amazingly, this regulated cycle of hormone release and gene expression also influences how our bodies store and utilize fuel such as glucose and fat. Furthermore, this system also seems to control how our muscles function concerning energy usage and fatigability and even affects our immune response (3, 4).
Together, being able to target and activate this nuclear receptor is attractive for some different reasons such as circadian re-alignment for shift work populations or those with erratic schedules. Arguably though, the potential body composition effects are likely the primary reason that SR9009 has come into the spotlight.
However, with a lack of evidence, particularly in human populations, long-term and even acute side effects of the drug are unknown. This fact is without mentioning the lack of information regarding safe dosing, making use of this chemical risky at best.
Gene Expression, Feedback Loops & Circadian Rhythm
It's known that our bodies function according to a daily cycle of gene expression and hormonal output under a system known as our circadian rhythm. This rhythm allows the different cells, organs, tissues, hormones, and genes to function on a daily cycle according to when we sleep, wake and even eat (5).
Within the hypothalamus; a region of the midbrain, is a bundle of neurons known as the suprachiasmatic nucleus (SCN). This region of the brain is widely considered to be a master regulator of this daily rhythm of hormonal output and gene expression, and it does so by creating feedback loops of expression and repression (6).
To better understand, the SCN acts like a director where it tells other genes and proteins to either turn on or turn off, based on the time of day and your typical daily cycle. Once these genes are turned on, they send signals to the SCN that they received the message and no longer need stimulation.
This cycle is a feedback loop and helps ensure that these genes and proteins only function when they are supposed to according to your individual schedule. In this context, this is considered a negative feedback loop, because the return signal results in some reduction of gene expression.
Within the SCN, there are two specific genes we are concerned with known as BMAL1 and CLOCK. These genes are considered master regulators of our circadian rhythm. Once expressed, BMAL1 and CLOCK stimulate the expression of downstream genes known as Period (Per) and Cryptochrome (Cry).
Once the Per and Cry genes are expressed, they travel into the nucleus and prevent further expression of the CLOCK and BMAL 1 genes. In essence, once activated the Per and Cry genes provide negative feedback to BMAL1 and CLOCK, telling them they have been expressed and no longer need to be told to do so (7, 8).
Altogether, this seesaw-like interaction between BMAL1 and CLOCK and Per and Cry creates a daily cycle of gene expression and repression, which in turn, regulates how our hormones, genes, and bodies function each day (9).
Summary: Genes located within the suprachiasmatic nucleus, which is a region of the hypothalamus regulate our circadian rhythm. These genes and others they influence, operate according to a negative feedback loop, meaning as one gene is expressed, another is repressed. Ultimately, this cycle of gene expression and repression determines how our bodies function within a daily cycle.
The Role of REV-ERBa Receptors
Research indicates that when the REV-ERBa receptor is activated, such as through the use of SR9009, this represses or inhibits the activation and function of the BMAL1 gene (1).
This conclusion is confirmed by the findings of Guillaumond et al., displaying that when expression of the REV-ERBa receptor is highest, this accompanies a significant reduction of BMAL1 expression, suggesting a repressive link between the two (10).
This is likely because research suggests an integral role between REV-ERB receptors and the functionality of the negative feedback loop.
As mentioned earlier, BMAL1 and CLOCK induce expression of Per and Cry genes. When Per and Cry are turned on, this tells BMAL1 and CLOCK to turn off. But when this process doesn't work correctly, and BMAL1 and CLOCK aren't turned off, this results in erratic gene expression throughout the body, causing dysfunction throughout the entire circadian rhythm system (8).
Research indicates that when mice have the REV-ERBa receptor removed, they display irregular circadian rhythms and non-typical cycles of gene expression. These findings suggest that explicitly targeting the REV-ERBa receptor might help regulate expression of BMAL1 genes and thus, circadian rhythm and its downstream influences as a whole (11).
Summary: SR9009 works by activating the nuclear receptor REV-ERBa. This receptor plays an integral role in regulating our circadian rhythm, which could have downstream influence on many biological and metabolic processes.
Potential Benefits Afforded By SR9009
Research suggests that through activating the REV-ERBa receptor and thus modulating circadian rhythm, SR9009 may have many therapeutic benefits worth considering.
Do understand though that many, if not all of these findings are a result of rat or mouse models. Whether these benefits will translate to humans is not known. If these benefits do translate to humans, it’s also unknown at which dose they will occur. Please consider this fact when learning of these potential benefits.
Circadian Rhythm Alignment
We've discussed the intricacies of how your circadian rhythm influences your body, but we also need to consider what affects your circadian rhythm. In addition to your regular habits like when you eat or when you go to sleep, zeitgebers play an integral role in your daily rhythm.
Zeitgeber is just a term to describe some stimulus that sends signals to your brain to regulate your daily rhythm. The sun, for example, is easily the most apparent zeitgeber since it was likely the our master zeitgeber before our current technological age. Now, zeitgebers come in many forms, such as our alarm clocks and even our phone screens (12).
What research seems to suggest is that SR9009 acts kind of like a zeitgeber, only indirectly.
As you can imagine, your exposure to zeitgebers plays an integral role in how your circadian rhythm functions. For instance, our tablets and smartphones emit light from the blue spectrum in a similar manner as the sun. Thus, when exposed to these devices late at night, our brains are receiving signals that it's daytime, since devices like this emit light similar to that of the sun. This, unfortunately, creates misalignment with our circadian rhythm.
What SR9009 does is act like a zeitgeber. When ingested, this chemical activates the REV-ERBa receptor, which essentially re-initiates an optimal rhythm of the expression of genes like those mentioned earlier: CLOCK and BMAL1.
To better understand, consider a recent study where mice had their circadian rhythms almost completely abolished and then repaired through SR9009 (4).
Mice were exposed to a regular and standard schedule of light and dark for one week. By doing this, scientists can generate a regular circadian rhythm that all of the mice follow.
After the one week trial, these same mice were then exposed to 12 days of complete darkness. Since light exposure is a zeitgeber, having total darkness interrupts the normal cycle, creating misalignment.
Essentially, these mice establish a circadian rhythm based on when the light is present and when it is not; very much like how our daily routines fluctuate based on when the sun is up or down. By removing light entirely, these mice no longer have the signal (zeitgeber) to initiate the physiological and hormonal actions the body usually carries out during light hours.
As you can imagine, this creates a misaligned rhythm of hormonal output and gene expression, resulting in different adverse effects. Note: this often affects the blind in a similar manner.
Interestingly, when the mice received SR9009, the adverse effects of complete dark exposure diminished. In particular, these mice displayed actions associated with light and dark exposure (a standard cycle), despite total darkness (4).
What this tells us is that SR9009 could potentially be a useful tool for aligning our circadian rhythms. This, of course, could be meaningful in a world of constant stimuli and artificial zeitgebers, wreaking havoc on our rhythms.
Additionally, these findings could be relevant for shift work populations, the blind, and even individuals experiencing jet lag. However, human trials should be considered to determine if SR9009 is safe for human consumption.
Summary: Research suggests that SR9009 may be a powerful tool for realigning a misaligned circadian rhythm. This could be meaningful for those with circadian rhythm disorders, shift work populations or even those experiencing jet lag.
Having a misaligned circadian rhythm has been associated with some different mental health problems such as anxiety, bipolar disorder, and depression. For example, seasonal affective disorder, or seasonal depression is mostly influenced by light exposure and our circadian rhythms as a result. And just as with many of the other adverse effects of misalignment, this isn’t entirely surprising (13).
Our circadian rhythms influence how our hormones and genes are expressed, and this also includes our genes and hormones associated with mental health, like dopamine. But unfortunately, even genetic variations of the genes related to circadian rhythm, such as BMAL 1 and CLOCK can present issues related to mental health, suggesting that targeting these genes through SR9009 could provide some positive influence (14, 15, 16).
What researchers show is that secondary to improving sleep patterns, (which is a good indication of circadian alignment), rats provided with SR9009 also display a reduction of anxiety-like symptoms, suggesting a therapeutic property of the drug.
When mice were supplied with SR9009, the researchers note a prominent anxiolytic or anti-anxiety effect. Using a standard maze model for assessing anxiety, researchers showed that when administered SR9009, mice spent more significant amounts of time in the center of the testing maze and more time exploring open areas. This, according to the authors, is evidence of an anti-anxiety effect.
Also, the same mice were exposed to a subsequent anxiety test that employs marbles. When placed into a cage with marbles on top of traditional bedding, mice typically bury the marbles in an attempt to remove the stimuli that are triggering anxiety. Researchers showed that when mice were treated with SR9009, they buried around 20% fewer marbles than control, suggesting fewer feelings of anxiety.
What is also quite interesting, as the authors note, is that the anxiolytic effects afforded by SR9009 were similar to that of benzodiazepines. Amazingly, this research also suggests a reduced chance of dependence on SR9009, which is a primary concern with benzodiazepines, apart from general safety (17).
Thus, if these findings translate to humans with minimal side effects, SR9009 might present a promising alternative to traditional anxiolytic medication.
While the evidence here is not very strong for humans, the theoretical framework for SR9009 positively influencing mental health does exist. Whether the noted anxiolytic effects of SR9009 displayed in mice will translate to humans and other mental health disorders is unfortunately unknown.
Summary: Secondary to improving sleep patterns, SR9009 seems to pose anti-anxiety influence, at least in mice. It is, however, unknown if these benefits will translate to human subjects.
In the context of endurance exercise, there are two primary factors of concern.
First, exercise endurance relies heavily on the oxidative capacity of your muscles or the ability of your muscles to use oxygen and fat molecules to produce usable energy.
Second is your muscle's mitochondrial content. Mitochondria are organelles within our muscles that metabolize fatty acids to eventually generate ATP, which is the body's primary usable energy source. Essentially, the more functioning mitochondria you have means a greater ability to produce energy when you need it, such as during endurance exercise (18).
What's so exciting is that research in mouse models suggests that SR9009 can help improve the oxidative capacity of your muscles while also stimulating the generation of additional mitochondria. Together, these benefits allude to a potent performance enhancing the effect of SR9009.
Research on this subject is indeed promising. When compared to mice that had REV-ERBa receptors removed, mice with functioning and active REV-ERBa receptors displayed significantly higher V02 max, greater time to exhaustion, and a greater willingness to exercise (19).
Additionally, these same mice displayed a more significant presence of mitochondria and a significantly higher rate of oxygen consumption, suggesting more effective and efficient mitochondria. This was corroborated by findings of increased running time, distance covered, and amount of oxygen consumed (19).
Should these findings translate to humans, SR9009 may prove to be a potent performance-enhancing drug, both during training and athletic events.
Further, it's worth mentioning that the exercise benefits afforded by SR9009 are quite similar to those found with Cardarine, which is a PPAR delta receptor agonist. However, it seems that SR9009 might do so without the serious adverse effects of Cardarine, such as the potential for cancer development.
Again, it’s worth mentioning that the relative safety and side effects of SR9009 in human subjects is currently unknown.
Summary: Research suggests that specifically targeting the REV-ERBa receptor via chemicals like SR9009 might improve exercise performance by enhancing the oxidative capacity of muscles while also inducing mitochondrial biogenesis.
Arguably one of the most exciting effects of SR9009 is its potential influence over metabolic health. This is because of how vital the REV-ERBa receptor is to processes such as glucose and lipid metabolism and also the accumulation of fat tissue via a process known as adipogenesis (3, 4).
As a regulator, the REV-ERBa receptor has significant influence over how our bodies use, tolerate, and process glucose and fat. This is relevant because glucose and lipid management and tolerance plays a significant role in weight gain and the development of metabolic disease.
Mouse research shows us that SR9009 positively influences this system, undoubtedly due to activating the REV-ERBa receptor. Scientists show that administration of this chemical induces significant weight loss. Compared to control, mice treated with SR9009 displayed 60% greater weight loss. Amazingly, this was achieved with no change in food eating behavior (4).
It’s worth mentioning that weight loss was not the only metabolic benefit afforded during this trial. Mice treated with SR9009 showed:
- 12% decrease in plasma triglycerides
- 47% reduction of total cholesterol
- 80% decrease in plasma leptin*
- 72% decrease in the cytokine IL-6 (anti-inflammation)
- 35% reduction of insulin
- 19% reduction of plasma glucose (4).
*Having higher levels of leptin is usually a good thing, as it helps us regulate appetite. But in the case of obese mice (or humans), consistently elevated leptin leads to resistance, much like with insulin. Thus, a reduction is suggestive of improved leptin sensitivity (20).
Based on these findings, SR9009 may be the answer we've been looking for concerning the improvement of metabolic health, reducing weight gain and potentially even treating or preventing the development of metabolic disease and disorders like Type 2 Diabetes.
Again, the lack of human evidence here casts doubt on the safety and reliability of SR9009 in human populations.
Summary: SR9009 positively influences body composition and metabolic health via modulation of the REV-ERBa receptor. In addition to weight loss, SR9009 might promote healthier cholesterol profiles, reduced metabolic-related inflammation and reduced incidence of insulin and leptin resistance.
Amazingly, research suggests that targeting REV-ERB receptors may induce an anti-cancer effect.
As mentioned earlier, activating the REV-ERBa receptor acts as a repressor within the context of regulating genes associated with circadian rhythm. But emerging research suggests that activating this receptor also represses other processes related to cancer development such as the development of tumors, cancer cell proliferation, and cancer cell-related inflammation (21).
This research also suggests two important attributes of SR9009, making it an attractive option.
Additionally, many treatments like chemotherapy have difficulty targeting specific tissues or only apply to one particular type of cancer. Research suggests that SR9009 not only influences many different types of cancer pathways, but it also seems to do so without the traditional toxic effects of chemotherapy drugs on healthy, non-cancerous cells (21).
Considering the potential to target many different cancers and to do so without damaging healthy tissue, SR9009 is a promising agent for treatment if research finds it to be safe for human consumption.
Summary: Targeting the REV-ERBa receptor through SR9009 indicates a potential treatment opportunity for different types of cancers that is non-damaging to healthy tissue.
Similar Influence As Cardarine Without The Cancer Potential
While there are no human trials, SR9009 seems to be valuable for treating cancer, yet displays many of the same benefits as Cardarine; a research chemical implicated in cancer development. Current evidence suggests that SR9009 might instead be of use for treating cancer rather than causing it.
Lack Of Human Evidence
A red flag here is that there are no human trials concerning SR9009. Considering its attractive benefits, this should be alarming or at least indicative that current evidence is not conclusive.
Relative safety for mice is established but not for humans. Further, safe human-equivalent dosages have not been determined. Thus, special care should be taken when considering the use of SR9009.
SR9009 or Stenabolic does indeed show promise for many different treatments. Research suggests that this chemical at least in mice, provides many benefits extending across metabolism, mental health and potentially even as a chemotherapy alternative.
However, the lack of human evidence entirely makes the use of SR9009 somewhat dangerous. At least with other chemicals like Cardarine, you know the risks. Currently, the adverse risks of SR9009 usage are unknown and should be considered before use.
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