As my longtime readers know, I have been touting the benefits of vitamin D for a very long time. In fact, we included it in a rundown of our top five anti-aging vitamins. Regarding vitamin D specifically, new research has shown that this fat soluble vitamin provides a host of positive changes to our bodies, including improved immunity, a lowered risk of type 2 diabetes, lower risk of high blood pressure and it may even help boost your mood. Now, a new study by the The Harvard Gazette surrounding possible vitamin D benefits reveals a link between a person’s Body Mass Index (BMI) and their vitamin D levels. One of the key points is that those with higher BMIs tend to have lower levels of vitamin D. This may be caused by the fact that vitamin D is a fat-soluble vitamin. Higher body fat levels can interfere with the body’s ability to absorb and utilize vitamin D. Senior author of the study, JoAnn E. Manson, chief of the Division of Preventive Medicine at the Brigham and Women’s Hospital and principal investigator of VITAL, the study where the results were derived from, shared a major insight: “This study sheds light on why we’re seeing 30 to 40 percent reductions in cancer deaths, autoimmune diseases, and other outcomes with vitamin D supplementation among those with lower BMIs but minimal benefit in those with higher BMIs, suggesting it may be possible to achieve benefits across the population with more personalized dosing of vitamin D,” said Manson. “These nuances make it clear that there’s more to the vitamin D story.” What stood out to me was that the research showed that people with higher BMI tend to have lower levels of 25-hydroxyvitamin D (25(OH)D), the form of vitamin D measured to determine a person's vitamin D status. This is because vitamin D gets stored in the fat cells. Thus, people with higher BMI have more fat cells and less circulating vitamin D. As is pointed out in the article, this is important information. It means that if we can properly dose vitamin D for people with a high BMI, they may be able to see more of the benefits of vitamin D supplementation along with a healthy diet and exercise routine. If you’re thinking of starting an exercise routine, you should check out this blog as well: 3 Reasons You Should Start an Exercise Routine - Dr. P

At some point, osteoarthritis affects a majority of people as they age. This happens because over time, the protective cartilage that acts as a buffer for the ends of bones wears down, often causing pain and discomfort. Unfortunately, osteoarthritis is the most common form of arthritis and can harm any joint, most often the joints in people’s hips, knees, spine and hands. I have recently uncovered an exciting and timely article that will appeal to anyone involved in orthopedic regenerative medicine. While great strides have been made in treating osteoarthritis, we still have a long way to go to treat, prevent and reverse this disease. As this study in Arthritis, Research & Therapy points out, osteoarthritis (OA) is a mechanically driven disease, but it also depends on co-existing inflammatory processes. One interesting fact pointed out in the study was that ACL reconstruction was performed to prevent the development of osteoarthritis, however 38 different studies demonstrated that OA occurs even after ACL reconstruction. I can attest to this with my orthopedic patients as well. What I most appreciate about this study is that the authors stress the importance of addressing molecular pathways in addition to conventional and existing treatments. They ask wonderful questions: How do we turn on the NRF2 pathway? How do we counteract IL-1, IL-6, and TNF? Yet, just inhibiting the master inflammatory cytokines did not seem to have the results that one would expect. Perhaps the most crucial aspect of this paper is the discussion on mitochondrial-associated pathways. This illustration tells the story. I suspect that fixing mitochondrial problems will give us a quantum leap when dealing with stem cells and regenerative medicine. Furthermore, it will likely help prevent osteoarthritis from developing in the first place. We already know some methods of increasing mitochondrial health, such as NAD, photobiomodulation, and the hormesis effect caused by moderate oxidative stress and the use of extracorporeal shock wave therapy, to name a few. They all can stimulate the mitochondria. As my longtime readers know, mitochondria are the bedrock of our health and specifically relating to OA, the health of our joints. One thing not addressed in the paper was the use of peptides. These could include mitochondrial peptides such as FLG and Humanin for mitochondrial health and, for general healing, BCP157 and Thymosine Beta-4. I hope you enjoyed my insights from this thought-provoking article. I also encourage you to read this post regarding new OA treatments as well: A Possible New Way of Treating Osteoarthritis: Senolytic Agents - Dr. P

I recently wrote a piece exploring the exciting anti-aging modalities of the diabetic medicine, metformin, which you can read here. In this article, I’d like to expand upon that work by examining a scientific clinical trial called the TRIIM. TRIIM stands for Thymus Regeneration, Immunorestoration, and Insulin Mitigation (TRIIM). This trial is one of the first to ever report an increase, based on an epigenetic age estimator, in predicted human lifespan utilizing a currently accessible aging intervention. The initial clinical trial ran from 2015 to 2017 and was run by immunologist Dr. Gregory Fahy, the chief scientific officer and co-founder of Intervene Immune in Los Angeles. The study was approved by the US Food and Drug Administration in May 2015 and dealt with the thymus gland, whose primary function is to help develop T-lymphocytes (“T” is for the thymus). The way this process works is that our bone marrow produces immature T cells that go through the bloodstream to the thymus. They then mature into functional T cells, essential for first-line immunity against foreign cells, including viruses and cancers. The TRIIM trial for thymus regeneration was and is a clinical study aimed at evaluating a novel approach for the renewal of the thymus gland, a critical organ in the immune system. The process where the thymus gland function decreases is called thymic involution, after which, there appears to be very little functional mass left in the thymus gland, even between 25 and 50 years of age. In the study, which involved nine men receiving a novel concoction of hormones and unique compounds, tests showed that T cell count was rejuvenated in each participant. Researchers also used magnetic resonance imaging (MRI) to determine the thymus's composition at the study's start and end. They found that in seven participants (out of nine), accumulated fat had been replaced with regenerated thymus tissue. Regeneration was so clear-cut that it was statistically significant at many time points in seven out of nine participants. Two others showed about a 10% increase in functional thymic mass, but the growth did not reach statistical significance because their baseline thymic fat contents were low for some reason. The probability that thymus regeneration did not occur was about one billionth (p<9x10-17), meaning that MRI evidence of thymic regeneration was rock solid. Granted, this was a small trial, but it has great significance. Several of the blood markers of aging showed a reversal. Why is this so important in the anti-aging community? As we age, the thymus naturally shrinks and becomes less functional, leading to a decline in immune system function and an increased risk of infection and disease. This is essentially immunosenescence, where our immune system becomes less competent as we age, leading to various age-related diseases and putting us at risk of all-cause mortality. The TRIIM trial aims to investigate (and stave off) this decline using a novel combination of hormones and other agents to regenerate the thymus and restore its function. In the original TRIIM study, the researchers looked at several parameters, but the epigenetic age was the most important. Epigenetic age is a measure of a person's biological age based on the state of their epigenome. It refers to the chemical modifications to DNA and its associated proteins that regulate gene expression. These modifications, which do not alter the underlying genetic code, can change in response to various environmental and lifestyle factors and accumulate over time. When this happens, specific genes will either be activated or silenced. This may be one of the most significant contributors to age. Epigenetic age better predicts age-related disease and mortality than chronological age. It has been suggested that it may be a valuable tool for monitoring the effects of aging and the efficacy of interventions aimed at slowing or reversing the aging process. Several methods for measuring epigenetic age include the DNA methylation age (DNAmAge) and the epigenetic clock. DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically represses gene transcription. DNAmAge measures the extent to which DNA methylation patterns are consistent with aging, and the epigenetic clock measures the age-associated methylation patterns at specific positions in the genome. Both methods are highly correlated with chronological age and have been used to demonstrate that some interventions, such as calorie restriction and exercise, can slow the pace of aging and reduce the risk of age-related disease. The Magic Drug Combinations Let's break down the medications used in the study. These compounds include metformin, DHEA (Dehydroepiandrosterone), and human growth hormone (HGH). Combining metformin, DHEA, and human growth hormone (HGH) in the TRIIM trial for thymus regeneration is an innovative approach to improving immune function in older adults. Each of these compounds has been shown to have various beneficial effects on health and well-being. By combining them, the trial aims to target multiple pathways involved in aging the thymus and immune system. Study subjects were also provided 3,000 IU of vitamin D3 and 50 mg of elemental zinc daily. Metformin’s Effects Metformin is a widely used antidiabetic medication that has been shown to have various health benefits beyond its primary use in treating type 2 diabetes. In the context of the TRIIM trial, metformin targets specific pathways involved in the aging of the thymus and immune system, potentially leading to enhanced regenerative potential and improved immune function. There are several pathways by which metformin is thought to impact the thymus and immune system. Improved Insulin Sensitivity Metformin has been shown to improve insulin sensitivity, which may benefit the thymus and immune system. Insulin resistance has been linked to age-related decline in the thymus and immune system, and improving insulin sensitivity may help to restore these processes. Energy Metabolism Metformin has been shown to impact energy metabolism, which may affect the regenerative potential of the thymus and immune system. By modulating energy metabolism, metformin may help optimize the balance between energy production and consumption, which is essential for maintaining cellular function and preventing age-related decline. Antioxidant Effects Metformin has been shown to have antioxidant effects, which may help to reduce oxidative stress and prevent damage to cells in the thymus and immune system. Anti-Inflammatory Effects Metformin has been shown to have anti-inflammatory effects, which may help to reduce chronic low-grade inflammation that is associated with age-related decline in the thymus and immune system. DHEA’s Effects DHEA is a naturally occurring hormone that is produced by the adrenal glands. It has been shown to have various beneficial effects on health and well-being, including improved immune function, increased energy and mood, and reduced risk of various age-related diseases. By supplementing with DHEA, the trial aims to restore levels of this hormone that naturally decline with age, potentially leading to improved immune function and other health benefits. DHEA is also thought to stimulate multiple pathways in the body, which may contribute to its beneficial effects. Enhanced Immune Function DHEA has been shown to enhance immune function, potentially by increasing the production and activity of immune cells such as T-cells and natural killer cells. DHEA is a precursor to the production of other hormones, including testosterone and estrogen, and supplementing with DHEA may help restore hormone levels that decline with age. Anti-Inflammatory Effects DHEA has been shown to have anti-inflammatory effects, potentially by reducing the production of pro-inflammatory cytokines and increasing the production of anti-inflammatory cytokines. Antioxidant Effects DHEA has been shown to have antioxidant effects, potentially by scavenging free radicals and reducing oxidative stress. Brain Function DHEA has been shown to improve cognitive function, potentially by reducing the accumulation of beta-amyloid plaque in the brain, a hallmark of Alzheimer's disease. Human Growth Hormone Human growth hormone is a naturally occurring hormone produced by the pituitary gland that regulates growth and development. HGH has been shown to have various beneficial effects on the human body, including improved immune function, increased muscle mass and strength, and improved skin and hair quality. Human growth hormone (HGH) is thought to contribute to thymus regeneration through several potential mechanisms. Cell Growth HGH has been shown to stimulate cell growth and division, which may contribute to the regeneration of the thymus and improve immune function. By promoting the growth and division of cells in the thymus, HGH may help restore the thymus gland's size and position. Immune Function HGH has been shown to regulate immune function, which may contribute to the regenerative potential of the thymus and improved immune function. HGH may help to balance the immune response and prevent age-related decline in immune function. Antioxidant Effects HGH has been shown to have antioxidant effects, which may help to reduce oxidative stress and to avoid damage to cells in the thymus and immune system. By reducing oxidative stress, HGH may help promote the health and function of cells in the thymus, which is essential for maintaining overall immune function. Insulin Sensitivity HGH has been shown to regulate insulin sensitivity, which may impact the regenerative potential of the thymus and immune system. By improving insulin sensitivity, HGH may help restore the balance between energy production and consumption, which is essential for maintaining cellular function and preventing age-related decline. One fact to keep in mind, HGH needs to be converted into insulin-like growth factor 1 (IGF-1) in the body to have its full effects. HGH is produced by the pituitary gland and released into the bloodstream, where it can stimulate the liver and other tissues to produce IGF-1. IGF-1 is responsible for many of the effects of HGH in the body, including promoting cell growth and division, regulating metabolism, and regulating immune function. It is important to note that while HGH and IGF-1 are related, they are not interchangeable and have different effects on the body. HGH is a hormone produced by the pituitary gland and regulated by the hypothalamus. In contrast, IGF-1 is produced by various tissues in response to HGH and has a more widespread impact on the body. In the context of thymus regeneration and improved immune function, the effects of IGF-1 are thought to be most important. However, more research is needed to determine the specific mechanisms by which these hormones contribute to these processes. To be clear, there is some controversy surrounding HGH. Some physicians and scientists in the anti-aging field feel that HGH may speed up aging rather than retard it. Remember, HGH does increase cell growth, which may speed up aging. Using this line of thinking, HGH may have some benefits in the short run but not in the long run. In the TRIIM trial, HGH was used for only one year and then stopped. The T cells produced by the process live for at least twelve years, meaning, if you were to use growth hormone for a one-year course once every 12 years or so, that would be relatively safe and avoid any long-term effects. Another concern about using HGH is the increase in blood glucose. Luckily, in the study, metformin and DHEA were included. Both compounds can decrease blood glucose, correcting the rise in blood glucose caused by HGH and nullifying the effect. Conclusion Here are some of the significant takeaways from this study: First and foremost was that the participants were 2.5 years younger by four different DNA methylation tests. In addition: The subjects significantly increased the number of T-cells, lasting many years. There was a higher lymphocyte-to-monocyte ratio. More monocytes result in increased CD38 enzyme. The CD 38 enzyme will diminish the body’s NAD levels. CD-38 is a big consumer of NAD. A reduced expression of PD-1. PD-1 is a receptor that cancer cells hijack to trick immune T-cells into thinking that the cancer is not a threat and they should not be attacked. Improvement in kidney function. There is now a new TRIIM trial called the TRIIM-X trial. The new TRIIM-X trial will enroll many participants, who will be given the hormone and agent combination and closely monitored over time to assess its effects on the size and function of the thymus. The study will also evaluate the safety and tolerability of the treatment and its impact on other aspects of a person’s health. In the original TRIIM, the participants took HGH alone (0.015 mg/kg, or ~3 IU for a person weighing 70 kg) 3-4 times per week for one week and then added DHEA (50 mg) the following week. The week after, the same doses of HGH and DHEA were combined with metformin 500 mg. The PUR-FORM Protocol Our practice decided to enhance the TRIIM trial and design with what we feel will be a better TRIIM trial for thymus gland rescue. In this trial, we will utilize berberine in place of metformin. On many different levels, berberine will be a better choice than metformin. We will stick with DHEA, and DHEA and berberine will be used daily. Instead of HGH, we will utilize either Ipamorelin or Sermorelin. Sermorelin and Ipamorelin are synthetic peptides that stimulate human growth hormone (HGH) release from the pituitary gland. This is a better approach because the body will continue producing HGH. While both compounds effectively increase HGH levels, they work slightly differently and have other benefits and drawbacks. Both peptides are effective at increasing HGH levels and have similar safety profiles. However, some studies have suggested that Ipamorelin may be more effective at increasing HGH levels than Sermorelin. Thus, we will stick with Ipamorelin. Ipamorelin is a growth hormone secretagogue that works by binding to the growth hormone secretagogue receptor, which activates a signaling pathway that leads to the production and release of HGH. Ipamorelin has a longer half-life than some other peptides, meaning it stays active in the body longer. It is also well-tolerated and has few side effects. The Ipamorelin dosage would be a dose of about 300mcg/day three times a week. We will also have the patients take maca root every other week. The maca root stimulates both the hypothalamus and pituitary gland. This stimulation will increase the release of HGH. Another aspect will be the utilization of the Thymosin Beta 4 peptide. We will utilize this daily, taking it for one month rather than skipping a month. (For more on peptides, you’ll enjoy this interesting post: Understanding the Power of Peptides.) We will also add a few more wrinkles. In this case, we would work on increasing the T cells going to the thymus gland. This would be accomplished by using Stem X cell, which increases stem cells including T cell output from the marrow. We will also utilize Beta-Glucan, which has a very beneficial effect on thymus health and function. The last aspect will be the intravenous (IV) administration of specific amino acids, particularly arginine and ornithine, which have increased human growth hormone (HGH) levels. These amino acids work by stimulating the release of HGH from the pituitary gland. Arginine is a semi-essential amino acid, meaning the body can synthesize it, but it may not be produced sufficiently under certain conditions. It has been shown to stimulate HGH release intravenously at doses ranging from 0.5 to 1.5 grams per kilogram of body weight. Ornithine is a non-essential amino acid that can also stimulate HGH release. It works by increasing the production of nitric oxide, which enables the release of HGH. Intravenous administration of ornithine at 0.1 to 0.5 grams per kilogram of body weight has increased HGH levels. The IV therapy would be done monthly and supplemented by Neo-40 to stimulate nitric oxide production. If you’d like to learn more about epigenetics, biological clocks and how NAD is an anti-aging powerhouse, you’ll enjoy this article as well.

If you’ve been following the latest headlines in the scientific literature about longevity and anti-aging, then you no doubt have heard about metformin. To some scientists, it is a borderline miracle drug, capable of extending lifespan through a host of biological pathways. To others, metformin has some legitimate uses in the treatment of type 2 diabetes and they remain skeptical about its anti-aging benefits. And still, to a select few, the buzz surrounding metformin in terms of longevity is empty hype. If you’re confused about what to think, don’t be. In this article I am going to share my opinion on metformin and why I am excited about its use in regenerative medicine therapies. What is Metformin? Metformin is a widely used drug for the treatment of type 2 diabetes. It is derived from a plant called the French Lilac, which has been used as an herbal remedy for treating excessive urination caused by diabetes since the Middle Ages. Metformin, the drug, was first described in 1922 and approved by the FDA in 1994.Metformin and Anti-Aging Over the last few years, studies have shown that metformin may have life-extending properties, but the drug's efficacy as an anti-aging remedy is still controversial due to a lack of long-term research. More recently, the controversy is diminishing because some of the bigger names in the field of longevity have been touting it. For instance, Dr. David Sinclair, co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, takes metformin daily for its anti-aging properties. As time goes on, more and more anti-aging specialists will likely be using metformin. Potential Benefits of Metformin One of the largest areas of interest when it comes to metformin and anti-aging is how it affects the way our bodies process sugars. As you already know, there is overwhelming evidence that consuming large amounts of sugar regularly can speed the process of aging and conversely, there is little controversy that diets low in sugars may promote longevity. Some studies have suggested that metformin may work by activating the AMP-activated protein kinase pathway (AMPK), a key master regulator of cellular metabolism. AMPK is a key energy sensor in cells, and it regulates energy balance by sensing changes in the cellular AMP/ATP ratio. When cellular energy levels are low, AMPK kicks in and stimulates energy-producing processes, such as glucose uptake and utilization, and suppresses energy-consuming processes, such as lipid synthesis and protein production. Metformin has been shown to activate the AMPK pathway by increasing the cellular AMP/ATP ratio. Additionally, AMPK activation by metformin has been shown to improve insulin sensitivity and to have various beneficial effects on cellular metabolism, including reducing oxidative stress and inflammation and promoting cellular survival. These are all essential pillars in the longevity field. The mTOR Pathway Another mechanism that promotes longevity is metformin's effect on the mTOR pathway. The mTOR (mammalian target of rapamycin) pathway is a central signaling pathway regulating cell growth, proliferation, and metabolism. It is activated by growth factors, hormones, and nutrients and regulates many cellular processes such as protein synthesis, metabolism, and autophagy. Studies have shown that metformin can inhibit mTOR signaling, leading to a decrease in cell growth and proliferation and an increase in autophagy. Autophagy is extremely important when it comes to anti-aging, as it is a cellular process that involves the degradation and recycling of cellular components, including damaged proteins and organelles. An increase in autophagy is considered beneficial for the cell, as it helps to maintain cellular homeostasis and can have protective effects in various diseases. Studies in animal models have shown that restriction of the mTOR pathway can extend lifespan and delay aging-related diseases. For example, in mice, reduction of mTOR activity has been shown to increase lifespan and improve healthspan, as well as reduce the incidence of age-related diseases such as cancer, cardiovascular disease, and neurodegeneration. The question is, do these animal studies translate to human beings? This is part of the controversy. Metformin appears to affect the AMPK and the mTOR pathways in a manner beneficial to longevity. It will also activate the AMPK pathway while at the same time diminishing the response of the mTOR pathway. Metformin and Gut Bacteria An important mechanism by which metformin reduces aging is its interaction with gut bacteria. Studies have shown that metformin can alter the composition and diversity of gut bacteria, leading to changes in the production of various metabolites, including short-chain fatty acids, bile acids, and other gut-derived molecules. This can impact glucose metabolism, insulin sensitivity, and other metabolic processes. Another way metformin interacts with gut bacteria is through its impact on the gut-liver axis. Metformin has been shown to reduce glucose production in the liver and increase insulin sensitivity, which can benefit glucose metabolism. However, it is believed that these effects are mediated, in part, by changes in the gut microbiome, including changes in the populations of specific bacteria that are involved in glucose metabolism and insulin regulation. In yet a third benefit, metformin has been shown to affect the gut-brain axis, and changes in the gut microbiome may also play a role in these effects. Studies also indicate that metformin can alter gut permeability. Along these lines, metformin appears to affect the production of neurotransmitters and other signaling molecules in the gut, which can influence brain function and behavior. As we’ve shown, metformin interacts with gut bacteria in several ways, and these interactions are believed to play a crucial role in its effects on glucose metabolism, insulin sensitivity, and other metabolic processes. Why Metformin is Intriguing Metformin is commonly used as a model compound in aging studies because of its potential to extend lifespan and improve healthspan in various model organisms, including yeast, nematodes, fruit flies, and mice. However, metformin is not the only compound being used in anti-aging studies. Other compounds used in anti-aging studies include rapamycin, a drug initially developed to prevent the rejection of transplanted organs, and pterostilbene, resveratrol, and berberine. These compounds have been shown to extend lifespan and improve healthspan in various model organisms. They are being studied to understand the underlying mechanisms and to determine their potential as anti-aging drugs. Other compounds being studied in anti-aging research include sirtuin activators, NAD+ precursors, growth hormone receptor antagonists, and drugs targeting specific aging pathways, such as the insulin/IGF-1 signaling pathway. Exercise and Metformin One ongoing controversy in the anti-aging world is whether exercise and metformin complement each other or cancel each other out. To answer this, we know that exercise and metformin improve fitness, blood sugar levels, and insulin sensitivity. They both also boost mitochondrial function and work the same pathways and have similar effects. The question then arises: Will taking metformin with your exercise regimen amplify the results? We don’t know for sure, but a recent study shows that may not be the case. In fact, according to this one study, exercise and metformin may cancel each other out. In the study, the group of participants taking metformin while exercising had about half the gains in fitness of those taking a placebo with their training. They had negligible improvement in insulin sensitivity. Finally, the people on the placebo had about a 25% rise in mitochondria respiration, while those on metformin saw slight, if any, improvement. But you have to keep in mind that this is a small study and it may have flaws that negate the results. It’s simply too early to tell. According to most of the research I have uncovered, it is recommended that people who combine metformin and exercise continue that regimen unless more specific evidence is found. For instance, Dr. David Sinclair feels metformin probably works as a hormetic substance, meaning that it causes minor damage to our cells so that our cells are put in a repair and protection state. This damage inhibits mitochondrial function so that the mitochondria will repair and protect themselves better. However, exercise also “damages” the mitochondria somewhat. This damage will result in the repair of the mitochondria, which is one of the health benefits of exercise. Thus, some stress on the cells is beneficial, but too much may result in damage that is not easily repaired. Dr. Sinclair does not take metformin when he exercises. Might there be a better alternative? Alternatives to Metformin One drug that I am particularly fond of is berberine, which I switched to from metformin many years ago. Berberine is a chemical compound that is similar to metformin in some ways, but different in other critical areas. Metformin works primarily by reducing glucose production in the liver and increasing insulin sensitivity in peripheral tissues. It is believed to activate AMP-activated protein kinase (AMPK), a key regulator of metabolism, which increases insulin sensitivity and improved glucose control. Both metformin and berberine are known to stimulate the AMP-activated protein kinase (AMPK) pathway. However, berberine is thought to be a more potent activator of the AMPK pathway than metformin. Berberine works by several mechanisms, including activation of AMPK, inhibiting glucose absorption in the gut, and improving insulin sensitivity in peripheral tissues. Berberine has also been shown to have antibacterial and anti-inflammatory properties, which may contribute to its glucose-lowering effects. Berberine also influences the gut microbiome, the community of microorganisms that reside in the digestive tract. Some studies even suggest that it can increase the abundance of certain beneficial bacteria and decrease the number of harmful bacteria. As an added benefit, there aren’t any studies showing that berberine has the same potential exercise-canceling benefits as metformin. Thus, I hedge my bets and, at least for now, take berberine over metformin for anti-aging. The evidence is strong in the field of anti-aging that metformin and berberine have solid anti-aging attributes as well as potential anti-cancer properties based on laboratory and epidemiological studies. Lastly, realize that there are several modalities used in our clinic that can offer similar stimulation of anti-aging pathways. These include EBO2, Red Light Therapy, Infrared Sauna, Hyperbaric Oxygen Therapy, and a few others. And this related piece will provide valuable information on another modality: 7 Anti-Aging, Disease Fighting Benefits of Therapeutic Intermittent Hypoxic Training. The real benefits occur when one combines metformin or berberine with these exciting modalities! In addition, if you’ve been exercising and you’d like to level-up your focus, you will enjoy Carissa Raver’s article here: 3 Breathing Exercises to Calm Your Nerves and Improve Performance - Dr. P

Unfortunately, hot flashes are a common symptom experienced by many women during and after menopause. Some women even begin dealing with them in their early 40s. The symptoms are characterized by a sudden warmth or heat that spreads throughout the body, accompanied by sweating and rapid heartbeat. Many people aren’t aware of this, but men may experience hot flashes as well. In males over forty or fifty, symptoms may be increased irritability, mood swings, loss of sex drive and even depression. For both men and women, there are several treatment options for hot flashes, including hormone therapy, antidepressants, and alternative therapies such as herbal supplements and acupuncture. The exact causes of hot flashes still need to be better understood. One thought is that they may be related to changes in hormone levels, particularly estrogen. But many times, hormonal replacement does not solve the problem. Furthermore, hormone replacement may not be an acceptable option for some women. Over the years I’ve continued to research this topic and as I’ve dug deeper, I’ve discovered that there appear to be other causes of hot flashes. Most recently, I came across an article that stated that hot flashes were probably related to the levels of certain neurotransmitters in the brain that are involved in regulating body temperature. One of these neurotransmitters is serotonin, AKA, the “feel-good hormone.” Studies have found that women who experience hot flashes have lower levels of serotonin compared to women who do not experience hot flashes. This is interesting. Additionally, some research suggests that medications that increase serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs), may be effective in reducing the frequency and severity of hot flashes. These medicines are more commonly known as antidepressants, and antidepressant medications are now recommended as a first-line treatment for hot flashes in people who cannot take hormones. I know what you’re thinking. Don’t antidepressants have a host of unwanted side effects? Yes, they do. This is why it’s important to continue to look for ways that we can treat hot flashes and, at the same time, improve a patient's overall health. Now, the real question becomes: How can regenerative medicine help with hot flashes? At PUR-FORM, we utilize intravenous methylene blue as a treatment before a patient receives an IV NAD treatment. Intravenous methylene blue has been shown to increase the effectiveness of IV NAD in several different ways, which I’ll get into below. (For more information on methylene blue, check out my blog post: What Can Methylene Blue Do For You?) First, methylene blue (MB) acts as an electron donor, providing electrons that can restore NAD+ levels in the body. NAD+ is a cofactor in various cellular processes, including energy metabolism, DNA repair, and antioxidant defense. When NAD+ levels become depleted, these processes can be impacted, leading to symptoms such as fatigue, muscle weakness, decreased cognitive function, and general aging. Second, methylene blue has been shown to stimulate the production of NAD+ by activating certain enzymes involved in NAD+ biosynthesis. This helps to ensure that there is an adequate supply of NAD+ available for use in the body. Finally, methylene blue has been shown to have direct protective effects on cells, helping to prevent damage from oxidative stress and other types of cellular injury. This can help reduce inflammation and prevent further damage to cells, ultimately improving symptoms associated with NAD depletion. As one can see, there are several important reasons why we utilize methylene blue when giving intravenous NAD. Increasing NAD levels are related to improved health and slowing down inflammaging. How Methylene Blue Influences Serotonin Levels One aspect of methylene blue worth further study is to ascertain how MB influences serotonin levels. When I devised the protocol for IV methylene blue and IV NAD, I was mindful of a contraindication to methylene blue in patients taking an antidepressant medication. Taking an antidepressant and methylene blue together is generally considered a contraindication because both drugs can affect the neurotransmitter serotonin levels in the brain. Methylene blue is a medication that acts as a selective serotonin reuptake inhibitor (SSRI) and a monoamine oxidase inhibitor (MAOI), both of which increase the levels of serotonin in the brain. Antidepressants, particularly SSRIs, also work by increasing the levels of serotonin in the brain. When taken together, these drugs can cause an excessive increase in serotonin levels, leading to a condition called serotonin syndrome. This was my “Ah ha!” moment! Could IV methylene blue help in the treatment of hot flashes? I investigated the subject in the scientific literature and the pieces started to fall into place. I discovered that some studies use methylene blue to treat hot flashes in postmenopausal women. These studies suggested that MB can reduce the frequency and severity of hot flashes because it works by affecting the levels of the neurotransmitters serotonin and noradrenaline in the brain. Diminished amounts of serotonin and noradrenaline are found in women suffering from hot flashes. Other research has suggested that MB may act on the hypothalamus, a brain region that plays a crucial role in regulating the body's temperature. Precisely, it is thought to inhibit the activity of an enzyme called monoamine oxidase, which is responsible for breaking down serotonin in the brain. This inhibition of monoamine oxidase can lead to an increase in the levels of serotonin in the brain, which can have a positive effect on mood and behavior. Additionally, methylene blue may act as a serotonin reuptake inhibitor (SRI), which can increase the amount of serotonin available in the brain by preventing its reuptake into neurons. The effects of methylene blue can further be enhanced with red-light therapy. The impact of intravenous methylene blue can be increased with light treatment through a process known as photodynamic therapy. Photodynamic therapy involves using light to activate certain drugs, such as methylene blue, to produce a therapeutic effect. In the case of methylene blue, light therapy can help to increase its effectiveness by enhancing its ability to act as an electron donor and restore NAD+ levels in the body. At PUR-FORM, we perform photodynamic therapy using the LightStim bed. A sublingual route (under the tongue) can also be utilized with methylene blue, but one needs to be prepared to brush your teeth several times afterward since methylene blue will color one’s teeth blue. We even have the Theralumen watch, worn over the radial and ulna arteries in the wrist, and it will allow for photodynamic therapy by supplying red light. Light therapy can also increase the production of NAD+ by stimulating the activity of certain enzymes involved in NAD+ biosynthesis. As previously mentioned, NAD+ is a cofactor involved in various cellular processes, including energy metabolism, DNA repair, and antioxidant defense. This can help ensure an adequate supply of NAD+ for use in the body, further enhancing the effects of methylene blue. Evidence also suggests that NAD itself may regulate the body's response to stress, which may be involved in developing hot flashes. NAD may help modulate the activity of certain neurotransmitters and hormones involved in regulating the body's response to stress. In addition to methylene blue and NAD, a few other intravenous compounds may benefit hot flash treatment. Some studies have suggested that magnesium deficiency may contribute to hot flashes, and IV magnesium therapy is a treatment option for women with low magnesium levels. Intravenous vitamin C is also helpful, and vitamin C is an antioxidant that may help alleviate hot flashes by reducing inflammation. OTHER POTENTIAL TREATMENT REGIMENS Some studies have suggested that Intermittent Hypoxia Therapy (IHT) may have therapeutic benefits for treating hot flashes. IHT treats various health conditions, including respiratory and cardiovascular diseases. According to research, IHT may help alleviate hot flashes by reducing inflammation and modulating the activity of certain neurotransmitters and hormones involved in regulating the body's response to stress. IHT also seems to affect the hypothalamus of the brain. Additionally, IHT may help to improve the function of mitochondria. We are aware of how IHT can affect weight loss in the body by its effect on the hypothalamus, and it is believed that similar mechanisms exist regarding the influence of IHT on hot flashes. DIETARY SUPPLEMENTS Several dietary supplements may help alleviate symptoms of menopausal hot flashes, although the evidence supporting their effectiveness varies. Some of the most common supplements include: BLACK COHOSH: This herb has been traditionally used to treat menopausal symptoms, including hot flashes. Studies have shown that black cohosh may effectively reduce the frequency and severity of hot flashes. SOY: Soy contains phytoestrogens, which are plant-based compounds that mimic the effects of estrogen in the body. Some studies have found that soy supplements may help reduce hot flashes in menopausal women. VITAMIN E: Vitamin E is an antioxidant that may help alleviate hot flashes by reducing inflammation in the body. Some studies have found that vitamin E supplements may effectively reduce the frequency and severity of hot flashes. RED CLOVER: This herb is a rich source of phytoestrogens and has been traditionally used to treat menopausal symptoms. Some studies have found that red clover supplements may help reduce hot flashes in menopausal women. GRAPE SEED EXTRACT: Grape seed extract is an antioxidant that may help alleviate hot flashes by reducing inflammation in the body. Some studies have found that grape seed extract supplements may effectively reduce the frequency and severity of hot flashes. NITRIC OXIDE is a naturally occurring compound that dilates blood vessels and improves blood flow. Some studies have suggested that nitric oxide supplements help alleviate hot flashes in menopausal women. One study found that supplementing with L-arginine, an amino acid precursor to nitric oxide, may help reduce the frequency and severity of hot flashes. The study found that women who took L-arginine supplements experienced a significant reduction in the number of hot flashes compared to those who did not take the supplement. Related to Nitric Oxide is BEETROOT EXTRACT, a dietary supplement derived from the beetroot (beta vulgaris) plant. Beetroot extract is rich in nitrates, which the body converts into nitric oxide. Some evidence suggests that beetroot extract supplements may be beneficial in reducing symptoms of menopausal hot flashes. However, the evidence needs to be more extensive, and more research is required to confirm these findings. A study published in the Journal of Women's Health found that supplementing with beetroot extract may help reduce the frequency and severity of hot flashes in menopausal women. The study found that women who took beetroot extract supplements experienced a significant reduction in the number of hot flashes compared to those who did not take the supplement. Another study published in the Journal of Obstetrics and Gynecology found that beetroot extract supplements may help reduce the severity of hot flashes in postmenopausal women. The study found that women who took beetroot extract supplements experienced a significant reduction in the severity of hot flashes compared to those who did not take the supplement. A variety of Beetroot products can be obtained from the company HumanN, which we recommend. One of their most touted products is “SuperBeets.” As time goes on, we will keep expanding our horizons in treating hot flashes and methylene blue will remain a pillar in treating this vexing problem. It's also important to note that methylene blue is not FDA-approved for treating hot flashes and should be used only under the supervision of a healthcare professional. The same holds for some of the other compounds and protocols mentioned. - Dr. P!

Autophagy is a topic that is widely misunderstood. Even well trained physicians will find themselves giving sketchy definitions of what autophagy is to patients or colleagues. That’s because according to Everyday Health's Ultimate Guide to Autophagy, a lot of research still needs to be done so we can fully understand this process. What we do know is that autophagy promotes cell survival by the elimination of damaged organelles and protein aggregates, as well as by facilitating bioenergetic homeostasis. In plain English, this means that autophagy allows for the repurposing of organelles, etc., within the body. But the tentacles of autophagy reach into many aspects of regenerative, anti-aging, and stem cell medicine because the root cause of many diseases are associated with a dysfunction of autophagy. This is why we continue to study the interplay between autophagy and the risk of age-related pathologies. We believe this will eventually facilitate the development of clinical applications that promote long-term health. In the meantime, it seems smart to encourage autophagy with a few common eating strategies, namely caloric restriction or intermittent fasting. - Dr. P If you’re thinking of trying an intermittent fasting routine, you’ll want to read this feature first, where Dr. Purita lays out everything you need to know about IF here: Dr. Purita’s 4-Step Breakdown of Intermittent Fasting You may also be interested in this piece, if you’re currently on a keto diet: Stem Cells, the Ketogenic Diet and Anti-Aging: What’s the Connection?

Here’s a fact: The more information I uncover in my regenerative medicine research about intermittent hypoxia therapy (IHT) the more I am astounded as to how many benefits it provides.For those not familiar, IHT is a therapeutic approach that involves subjecting a person to repeated episodes of low oxygen levels (hypoxia) interspersed with normal or hyperoxic oxygen levels. This therapy aims to stimulate the body's natural adaptive responses to hypoxia, which can benefit various physiological and biochemical processes.At PUR-FORM, we use an intermittent hypoxia machine that utilizes a face mask, and the device will vary oxygen concentrations from 9%-40%. The duration, frequency, and intensity of the hypoxic episodes can differ depending on the specific treatment protocol and the individual's needs and condition.Excellent Uses for Intermittent Hypoxia Intermittent hypoxia therapy has been studied for various potential therapeutic applications, including improving athletic performance, treating sleep apnea, improving cognitive function, and reducing inflammation and oxidative stress. Some studies have also suggested intermittent hypoxia therapy may have therapeutic effects in conditions such as chronic fatigue syndrome and fibromyalgia. Here is a breakdown of how IHT benefits certain common conditions: INCREASES CARDIOVASCULAR HEALTH: This can result in improved blood flow, reduced blood pressure, and an overall reduction in the risk of cardiovascular disease. This can be considered a non-pharmacologic therapy for many cardiovascular diseases, but it might not be an appropriate treatment for everyone. The same holds for pulmonary problems. IMPROVES IMMUNE FUNCTION: Studies have shown that low oxygen exposure can stimulate the production of specific cytokines and growth factors essential for maintaining a healthy immune system. These factors can improve the ability to fight off infections and disease and reduce the risk of developing autoimmune disorders. Remember, our health is dependent upon our immune system. The stronger our immune system, the stronger we are! IMPROVES OVERALL PHYSICAL FITNESS: Another benefit of intermittent hypoxia training is its ability to improve overall physical fitness. By exposing the body to low oxygen levels, this type of training can increase the production of mitochondria, which are the energy-producing structures within cells. Healthier mitochondria can result in improved energy production and an increased ability to perform physical activities and recover from workouts. This is why many elite Olympic athletes train in Colorado Springs. The high altitude creates IHT conditions. IMPROVES SLEEP QUALITY: Another essential benefit of intermittent hypoxia training is its ability to improve sleep quality. Low oxygen levels can stimulate the production of certain hormones and neurotransmitters that regulate sleep, such as melatonin and adenosine. Improved sleep quality can lead to improved physical and mental performance, reduced stress levels, and reduced risk of several chronic health conditions. For more tips on how to improve your sleep, please read this blog: 3 Secrets to Energy Producing Sleep NEURODEGENERATIVE CONDITIONS: Low oxygen exposure can stimulate the production of certain growth factors, such as brain-derived neurotrophic factor (BDNF), that are important for maintaining the health and survival of nerve cells in the brain. In neurodegenerative conditions, the loss of these growth factors can lead to degeneration and death of nerve cells. Still, exposure to low oxygen levels may help to stimulate their production and improve outcomes. Low oxygen exposure has antioxidant effects, which can help reduce the damage caused by oxidative stress, a critical factor in the development of many neurodegenerative conditions. Intermittent hypoxia training can stimulate neuroplasticity, which refers to the brain's ability to reorganize and form new connections in response to new experiences and stimuli. The increased neuroplasticity can help compensate for the loss of brain function in neurodegenerative conditions and improve cognitive and motor function. Also, did you know that daily exercise may lead to larger brains? Check out my post on this exciting news! GENERAL BODY DETOXIFICATION: Intermittent hypoxia therapy stimulates the body's natural mechanisms for removing waste products, including the lymphatic system, the liver, and the kidneys. The results are improved overall health and reduced risk of disease.The lymphatic system expedites removing waste and toxins from the body, and intermittent hypoxia therapy increases lymphatic circulation and enhances this system's function. This can help to remove waste and toxins more effectively, reducing the load on other organs, such as the liver and kidneys, and helping to maintain overall health. The liver is responsible for detoxification and removing waste products. Intermittent hypoxia therapy improves liver function and increases bile production, which helps to excrete waste products from the body. The kidneys are crucial in filtering waste from the blood and eliminating it from the body as well. Intermittent hypoxia therapy may also stimulate the production of enzymes and hormones that help to break down waste products and improve their elimination from the body. Additionally, intermittent hypoxia therapy stimulates the immune system, which can help to remove waste and toxins more effectively. ATHLETIC PERFORMANCE: Another significant benefit of this type of training is its ability to enhance athletic performance. By exposing the body to low oxygen levels, intermittent hypoxia training can stimulate the growth of new blood vessels, increase the oxygen-carrying capacity of the blood, and improve endurance. This can improve athletic performance, especially in endurance-based sports such as running, cycling, and swimming. INCREASED BLOOD SUPPLY: Intermittent hypoxia will improve the patient’s blood count, and at the same time, it will increase the formation of new blood vessels. IMPROVEMENT IN METABOLIC PARAMETERS: Intermittent hypoxia therapy has been studied for its potential to improve various metabolic parameters, including improved glucose tolerance and improved insulin and leptin sensitivity. This is especially true in those patients coming off a structured weight reduction program. The Bottom Line on IHT Whether you seek to improve athletic performance, enhance mental well-being, or reduce the risk of chronic health conditions, this training can effectively achieve your goals. With its numerous benefits and relative ease of implementation, it is no wonder this type of training is growing in popularity and is likely to become an increasingly popular regenerative medicine modality. - Dr. P If you’re an athlete and you’re interested in learning more about recovery, you’ll want to read this piece on other treatments we offer at PUR-FORM: Athlete Recovery: Quicker, Better, Faster NOTE: Patients with a significant cardiovascular or pulmonary history may not be appropriate candidates.

Don’t worry, this isn’t another gloom-and-doom article telling you that the thing you enjoy, in this case, coffee, is “bad for you”. Like most foods you consume, coffee, and more specifically the caffeine in coffee, affects everyone differently. Some people metabolize coffee quickly. Others don’t. Some people feel anxious and jittery the moment they swallow their first gulp. Others only feel a jolt of energy. And some people get an upset stomach after one cup while others can drink a gallon of coffee and never feel a thing. Since everyone is different, my main goal for this piece isn’t to get you to quit coffee if you love it, but rather, to encourage you to do a quick “caffeine check-in” on how much you’re consuming. The reason for this is because first and foremost, caffeine is a stimulant. When used sparingly and in moderation, the benefits can include alertness, increased performance, elevated memory and brain power and a healthy dose of antioxidants. Some studies have linked regular coffee consumption to increased longevity, lower risk of Type 2 diabetes, and reduced risk of Alzheimer’s and Parkinson’s. Now for the potential negative side effects. Excess caffeine consumption (or minimal for some people) can lead to cardiovascular problems, nervousness, dizziness, irritability, increased blood pressure, arrhythmias, GI issues and sleep problems. Again, depending on how your body digests caffeine, and your intake, you may experience these symptoms with one cup, not at all, or only after your fifth cup (yikes!). When talking to patients, these are the questions I ask when it comes to whether they should cut back on coffee: Are you using coffee (or other forms of caffeine) as a crutch to wake up or get through your day? Do you often feel nervous, jittery or anxious? Do you find yourself feeling irritated for no reason in the afternoon? Do you have an energy crash or dip in the afternoon? Are you having trouble falling asleep? If the answer is ‘yes’ to several of these questions and you’re drinking more than one cup of coffee in the morning, then you likely should consider cutting back on caffeine or quitting altogether. If you consider quitting, you need to know that like any other stimulant, your body will rebel at first. I don’t advise going cold turkey at all. What I do recommend is that you wean yourself off in increments or you will likely be in for several days of tough headaches and a lack of focus. If you normally have two cups a day, I’d cut down to 1 ½ cup for 3-4 days, then 1 cup for 3-4 days, then a half cup for a week and then stop. Or once you get down to a half-cup per week, you can replace your normal cup of coffee with a drink that has less caffeine in it, like green or black tea. If you find that you tolerate one cup just fine, then one tip is to wait to have it until you’ve been awake for at least two hours. This way you aren’t affecting your natural hormones that help you wake up on your own, and you’re no longer training your body to rely on coffee to keep you alert. If you’re looking for alternatives to coffee that provide an energy boost and increased memory or focus, with little-to-no caffeine, we’ve put this post together for you: READ IT NOW: 5 Popular Nootropic Brain Boosters Besides Coffee To read the latest articles from Carissa Raver, CLICK HERE.

I am excited to share with you a very interesting article concerning how motivation is affected by oxidative stress in the brain. This particular article in Neuroscience News begins with researchers asking a simple but important question: “Do differences in metabolites in the brain affect our capacity for motivation?” They posed this question as part of a study looking to ascertain whether certain metabolite levels may be related to (or even improve) motivation, and thus, performance. In order to gather this information, researchers studied oxidative stress in a portion of the brain called the nucleus accumbens, which controls aspects of motivation (among other things). As we know, brain tissue has a very high level of mitochondria. In turn, the mitochondria produce reactive oxygen species, which increase oxidative stress. The oxidative stress is a byproduct of mitochondrial oxidative respiration. For the purposes of this study, the researchers chose glutathione as their go-to antioxidant. In order to measure glutathione’s effect on oxidative stress, researchers performed proton magnetic spectroscopy (PMRS). Proton MRS appeals to clinicians and scientists because its application in the clinical setting can increase the specificity of MR imaging. In this study, PMRS revealed that humans with higher levels of glutathione performed better on tests measuring motivation. This led researchers to believe that an increased antioxidant environment in the brain may promote motivation. Taking this idea one step further, they noted how N-acetyl-cysteine seems to increase glutathione. On a high level, one has to wonder how this could be utilized to motivate individuals or society as a whole. It’s fascinating! At PUR-FORM, we pride ourselves on offering a variety of methods for increasing glutathione and decreasing oxidative stress throughout the body, including the brain. We offer a glutathione IV, Detox Push, NAD+, the EBO2 protocol, whole body cryotherapy, and a number of other modalities to keep you energized and motivated. In fact, you may want to read this right now: 8 Excellent Reasons to Try Cryotherapy After a Long Work Week – Dr. P

Collectively, we call the NRF1 and NRF2 pathways the NRF pathways. These pathways improve the health and number of our mitochondria and at the same time reduce inflammation in the body. As you can imagine, they are vital when it comes to longevity.Fortunately, we have a number of regenerative medicine modalities at our new office that are powerful tools in our anti-aging arsenal. The following treatments are available at our facility and can stimulate the NRF pathways:Red Light Therapy BedEBO2 (Extracorporeal Blood Oxygenation and Ozonation)IVs (NAD, Methylene Blue, and more)HBOT (Hyperbaric Oxygen Therapy)IHT (Intermittent Hypoxia Treatments)As I’ve written, NRF1 and NRF2 are transcription factors that have a multitude of functions. As this article in Health News points out, there are distinct functions of each pathway.NRF1 seems to be involved in metabolism, cellular development, energy production, and mitochondrial DNA transcription and replication. While on the other hand, NRF2 activates the expression of antioxidant genes to attenuate the oxidative damages during inflammation, injury, or disease.I call NRF2 the thermostat of anti-inflammation.NRF1 and NRF2 pathway stimulation can be achieved through exercise, calorie restriction (including fasting) and ingestion of natural nutrients that are NRF activators, and lastly by the effects of ozone on the circulatory system.These two pathways work together to keep us healthy, vibrant and full of energy.Remember, the health of our mitochondria are paramount to our overall health!For further reading on why improving our mitochondrial health is so important, check out this related feature:Mitochondria May Hold the Key to Solving Long Covid, Parkinson’s and Other Ailments***If you’re interested in learning more about any of the NRF-boosting, mitochondria promoting, anti-aging treatments mentioned in this piece, schedule an appointment with a provider here.