If you thought that reversing your biological age was science fiction, think again. The TRIIM (Thymus Regeneration, Immuno-Restoration, and Insulin Mitigation) study, was the first human clinical study intended to show that human aging could be reversed. Initial results obtained from the study, indicate that particular changes which affect DNA as a result of aging, may be reversible.
While you cannot reverse your chronological age, the results of the TRIIM study showed that it is possible to rewind your biological clock and scientists were shocked at the results. In the last few years, scientists have also created tests which can accurately calculate your biological age. Scientists have also learned that a person’s biological age is the superior predictor for longevity when compared with chronological age.
The objective of the TRIIM study was to examine whether recombinant human growth hormone (rhGH) could be used in the prevention and/or reversal of immune-senescence (slow and progressive breakdown of the immune system caused by aging) in middle aged healthy males, representative of the age range subsequent to the breakdown of the T-cell Receptor (TCR). Generally, the TCR begins to collapse after age 60, and is associated with increased incidences of atherosclerosis, autoimmune conditions, cancer, infectious disease and overall mortality.
Your chronological age is the actual number of years that have passed since you were born. Generally, this is the main way people express their actual age.
Biological age, which is also known as functional or physiological age, refers to aging as a result of the breakdown in the body’s cells and tissues. Biological age is determined by developmental factors which include:
A person with a significantly lower biological age than his or her chronological age will live longer than a person whose biological and chronological age is similar.
During the last decade, both medical and clinical methods of studying how to improve aging has primarily been conducted using animal subjects. The results obtained in the animal studies showed reversal in aging using physiological methods in mature mammals. However, there had not been any evidence showing that epigenetic age can be reversed, until now.
Even though epigenetic age is not the only gauge that encompasses all characteristics of aging, today it provides the most precise determination of biological age as well as risk of age‐related disease. This substantiates using epigenetic clocks to determine the success of accepted aging interference on a realistic timescale. The TRIIM study clearly supports this methodology, having confirmed the reversion of epigenetic age with important statistical impact despite only having one‐year pilot study having only 9 volunteers.
An epigenetic clock is a test method of calculating a person’s age based on levels of DNA methylation, a biomarker of aging. Today, epigenetic clocks are a far superior to the chronological age method for determining biological age. The TRIIM study relied on four estimators of aging were used to show that epigenetic aging was reversable in humans. The TRIIM study researchers focused on being able to restore the thymus and saw protective changes in the subject’s immunology, lowered risk for many age-related diseases, and an average decrease of epigenetic age of approximately 2.5 years. The predictor of human morbidity and mortality known as the Grim Age, showed a decrease of 2 years in epigenetic compared to chronological age and continued even 6 months the study ended.
Medical researchers discovered that by taking a specific combination of drugs, the subjects were able to reverse their biological age. The changes in the biological age were calculated by the DNA changes which accrue as people get older.
The study was made up of nine volunteers, who were all white males and ranged between 51 and 65 years of age. The volunteers received a drug cocktail which included a non-prescription hormone supplement (DHEA), a medication used in treating diabetes (Metformin), and growth hormone. The study was conducted in the United States and every volunteer self-administered the drugs multiple times during the week for an entire year. After a year of the regimen, scientists examined the DNA of each volunteer and determined from the results that on the average, each of the subjects took 2.5 years off their biological age.
The TRIIM study was created to see if it was possible to regenerate the thymus and/or reversal of any immunosenescent tendencies in mature healthy males with minimal risk and side effects. The study results not only proved this possibility, but also brought to light confirmation that multiple characteristics of aging biomarkers could be reversed in males.
Earlier animal studies had already established that growth hormone activated regeneration of the thymus, successfully restoring it to its youthful state and also reversing immune deficiencies caused by aging. However, growth hormone alone could not account for reversing epigenetic aging as there were other immunological and non-immunological factors involved.
In the first week of the study, growth hormone was dosed at .015 mg/kg to gent the initial insulin response. In the second week of the study, DHEA 50 mg was added to the growth hormone to assess whether insulin suppression had occurred. During the third week, metformin was added to the protocol at a dose of 500 mg. In the fourth week, researchers made necessary adjustments to each individual volunteer’s dosage based on their response.
A key concern for the study participants was whether elevated mitogen levels, particularly IGF-1, would intensify cancerous and/or precancerous foci in their prostate. These changes could be readily detected via measuring PSA and/or percent free levels of PSA. Yet, the complete prostate cancer risk index (PSA, percent free PSA, as well as the ration of percent free PSA to PSA), became better after the 15th day of the study and sustained the positive benefits until the study was concluded. At the sixth month of the study, a short spike in PSA levels was observed in 2 of the subject volunteers, however this quickly reversed.
Additionally, an added concern was the fear there would be an increase in age-related inflammation due to the increase in immune activity. Nevertheless, c-Reactive Protein levels went down as the study progressed hitting its lowest levels the last 3 months of the study. Researchers also observed no change in levels of IL-6, the cytokine associated with increased inflammation.
Moreover, there was no significant changes in levels of electrolytes, hematocrit, hemoglobin, hepatic enzymes, lipids or serum albumin levels. As a result of combining DHEA and metformin in the drug protocol, levels of insulin were effectively controlled and glucose levels remained consistent. The side effects which are associated with rhGH, were also minimal and dosage did not have to be modified. Lastly, eGFR (estimated glomerular filtration rates), the marker that is observed to determine if metformin is working and/or could cause lactic acidosis, showed a remarkable improvement in the last 3 months of the study, with continued improvement 6 months after the study was concluded.
Thymic involution, is the age-related decrease of the thymus, which advances the reduction of vital immune cells in the body which leads to the breakdown of the TCR. Ultimately thymic involution brings about many age-related conditions and/or diseases, and has a substantial effect on longevity. Thymic function also relies on the availability of T-cell progenitors found in bone marrow.
Conversely, when medical researchers studied centenarians (people who have reached the age of 100), noticed that their immune function was well preserved.
The scientists were astonished by the results of the study, because at the end of the study the subjects became 2.5 years younger despite that an entire year had passed. Moreover, this was a breakthrough in the fact that it was the first study of its kind and that further research will likely have a tremendous impact on aging, heath and the treatment of disease. The study was published in Aging Cell Journal, on September 8, 2019.
One of the most important discoveries from the study was the use of epigenetic clocks in order to calculate biological age. The epigenetic clocks, inspect and search DNA for specific characteristic signs related to aging. Throughout our lifetime, new chemical codes are collected alongside the helical structure of our DNA. These codes contain methyl groups of carbon and hydrogen, which adhere to our DNA and can adjust how certain segments of genetic information are read by our cells. The chemical adjustments are referred to as epigenetic changes.
The chemical codes position themselves in separate patterns beside a DNA strand, similar to a barcode. The codes enable scientists to compute the biological age of a person within a span of two to three years. Although the study clearly shows that the changes can be reversed, the initial results have not revealed how this reversal is caused. Originally, the main questions on the minds of the researchers was whether the function of the epigenetic clock was to simply identify the biological progression in the body or whether it was the chemical codes responsible for the change.
Initially, the focus of the study was not to reverse the biological clock, instead, researchers intended on examining changes in the thymus gland tissue caused by growth hormone. The thymus gland turns undeveloped immune cells into dedicated cells whose purpose is to search for and destroy invading pathogens. Thymus gland performance begins to break down shortly after puberty and its function continues to diminish as the gland accrues fat and loses tissue. Studies conducted using growth hormone showed that the tissue lost by the thymus could be recovered in animals and humans. During the study, volunteers, showed signs in an increase in mass of functional thymic tissue and overall signs of recovery, evidenced by the production of new specialized immune cells.
Several months into the study the participants showed more than just an improvement in their immune system health, but also exhibited greater kidney function in filtering toxins from the blood due to the presence of a new metabolite. These findings paralleled a study done on mice in the late 80’s, where growth hormone secreting cells from young mice were transplanted into mature mice and showed a significant improvement in both kidney and thymus function.
The study was conducted under the supervision of Dr. Gregory M. Fahy a cryobiologist and biogerontoligist. In reviewing the results of the study, Fahy contacted biostatistician and geneticist Steve Horvath, a renowned expert in highly accurate epigenetic clocks, who is also a professor at the University of California in Los Angeles.
Horvath was consulted in order to determine if the drug trial had changed the biological ages of the study subjects. Horvath obtained DNA from the subjects preserved blood samples that were taken throughout the study trial. The results were checked using four recognized epigenetic clocks as points of reference. Horvath determined that all of the study subject’s biological ages had lessened during the trial, whereas their estimated total life expectancy was greater than before. The results also showed that the epigenetic signs of age-reversal became highly prominent at nine months into the study and remained undisturbed six months subsequent to completion of the study.
According to Fahy, it is still uncertain what the anti-aging effects were of each drug individually. Due to the fact that the study sample was relatively small, Fahy has said that a much large study is being planned to further test the results of the study.
Critics of the TRIIM study have expressed their concerns over the absence of a control group (subjects given placebo rather than the drug cocktail). Critics argue that it is unknown whether study subjects could have made lifestyle changes or a placebo effect may have had an effect on the overall results of the study (subject’s belief the protocol works rather than the physiological effect).
Despite the precise information over “how,” the drug cocktail reversed the epigenetic clock, the facts clearly show that reversing your biological age is possible in humans and has ignited serious interest in pursuing further larger scale studies.