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 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.
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.
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.
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 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.
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.
DHEA has been shown to have antioxidant effects, potentially by scavenging free radicals and reducing oxidative stress.
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.
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.
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.
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.
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.
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.