Life Extension Magazine®
Older People Grow 2.5 Years Younger - Life Extension

Issue: March 2020

Older People Grow 2.5 Years Younger

A study conducted in collaboration with researchers from Stanford University and UCLA showed that a combination of nutrients, hormones, and a drug resulted in significant human age reversal. Patients measured 2.5 years younger than they would have without treatment.

Scientifically reviewed by: Dr. Amanda Martin, DC, on February 2020. Written By Chancellor Faloon.

Worldwide media coverage in September 2019 described publication of the first clinical trial to demonstrate significant reversals of biological aging in a study group of humans!

A major advance in healthy longevity potential was published on September 8, 2019, in the journal Aging Cell.1

A combination of nutrients, hormones, and a drug resulted in significant human age reversal, as measured by DNA methylation, in nine men aged 51 to 65.

The study was conducted by Dr. Greg Fahy and colleagues at the biotechnology company Intervene Immune, Inc., in collaboration with researchers from Stanford University and the University of California, Los Angeles (UCLA).

The study protocol consisted of individualized doses of:

1. Human growth hormone (hGH),

2. DHEA, and

3. Metformin.

Study subjects were also provided with 3,000 IU of vitamin D3 and 50 mg of elemental zinc daily.

After one year, the study participants were 2.5 years younger, as measured by multiple DNA methylation aging tests, than they would have been without treatment.

This innovative protocol resulted in multiple, system-wide, anti-aging benefits:

  1. Regenerated thymic structure,

  2. Improved immune function with signs of increased cancer protection,

  3. Improved prostate cancer markers (PSA and percent free PSA),

  4. Regenerative effects on kidney function and bone marrow, and

  5. On average, 2.5 years of age reversal, as measured by four different DNA methylation tests.

This study, called the TRIIM trial, captured worldwide media attention.

Favorable commentary was published in the prestigious journal Nature.2

It was the first topic of discussion on Joe Rogan’s podcast with Harvard scientist David Sinclair.3 (Joe Rogan reaches more people than many network TV shows.)

In fact, according to Altmetric,4 three months after publication, the paper was number four out of 1,455 in attention score (99th percentile) among similar sources, and in the top 5% of all “research outputs” ever scored.

TRIIM stands for:

  • Thymus Regeneration,
  • Immunorestoration, and
  • Insulin Mitigation = TRIIM

This combined protocol was designed to reach just the first two of the above goals.

The TRIIM trial results, therefore, were far greater than expected.

Regeneration of the Thymus

The thymus is a gland located behind the sternum (breastbone) and in front of your lungs, and it is responsible for the development of T-cells.

Beginning at the age of one, although the thymus continues to grow, it begins to become replaced with fatty tissue.6 The absolute mass of functional thymic tissue continues to increase until the early teenage years, but after that, progressive replacement by fat combined with a slow loss of thymic volume—a process known as thymic involution—results in a net decrease in thymic function. By the time we reach 50 years of age, the functional mass of the thymus is just a fraction of what it was at the onset of adolescence.7

The shrinkage, or involution, of the thymus has been correlated with:

  1. Reductions in functional thymus-educated immune cells (T-cells),8

  2. Reductions in T-cell receptors,9

  3. Increased risk of several diseases,10 and

  4. Increased risk of all-cause mortality.11

Earlier research had shown that growth hormone treatment can regenerate the thymus gland in animals and relatively young immunodeficient HIV patients,12-14 but the thymus of HIV patients is not normal. Until the TRIIM trial, hGH had never been used with the aim of reversing immunological aging in otherwise healthy, aging volunteers.

“Cocktail of Drugs Gives First Hope That ‘Biological Age’ Can Be Reversed

plants growing in a beaker

As seen in Forbes, September 9, 2019

Scientists at Intervene Immune and Stanford Medical Center say they have proven that ‘epigenetic aging can be reversed in humans.’

…they are optimistic that a person’s biological age can be reversed.”5

Age markers reversed by 2.5 years!

Source: https://www.forbes.com/sites/robinseatonjefferson/2019/09/09/cocktail-of-drugs-gives-first-hope-that-biological-age-can-be-reversed

Growth Hormone Safety

Traditionally, there has been concern that growth hormone treatment can cause insulin resistance, leading to a damaging and pro-aging increase in insulin levels, and might stimulate proliferation of malignant cells,15,16 although actual long-term population studies on hGH safety have not found an increased cancer risk.17

In the TRIIM trial, both problems were apparently successfully contained by the combination protocol employed in this study: insulin levels remained lower than average, and cancer risk seemed to decrease based on three independent indices of cancer risk.

Remarkably, all study subjects showed regeneration of their thymus, which was validated by MRI scanning using a special imaging technique at Stanford after 0, 9, 12, and sometimes also after five months of treatment. Regeneration of the thymus was reflected by the replacement of age-related non-functional fat tissue with functional, fat-free 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 increase did not reach statistical significance because their baseline thymic fat contents were low for some reason. Overall, the probability that thymus regeneration did not occur was about one billionth of one billionth (p<9x10-17), meaning that MRI evidence of thymic regeneration was incontrovertible.1 (MRI scanning was funded in part by Life Extension®.)

plants growing in a beaker

“Turning back time!

As seen in Daily Mail, October 22, 2019

Aging is REVERSED in men using a cocktail of growth hormones and diabetes drugs in study that saw test group shed 2.5 biological years.”

Source: https://www.dailymail.co.uk/health/article-7435427/Aging-REVERSED-small-group-men-study-reveals.html

Immune System Benefits

Several blood tests revealed that there was significant improvement in many biomarkers of immune function from the treatment protocol. Notably, there was an increase in the production of new T-cells, indicating that the basic T-cell manufacturing function of the thymus had been reactivated.

Three classes of new or “naïve” T-cells were shown to increase. Since new T-cells normally seem to survive and function for many years, the hope is that these new immune defenders will continue to protect the TRIIM participants from immunological aging for many years to come.

The trial also uncovered the fact that, according to sophisticated test results, the treated study subjects had an increased lymphocyte to monocyte ratio. A higher lymphocyte to monocyte ratio (LMR) has been linked to better outcomes for many types of cancer, atherosclerosis, cardiovascular disease, stroke,18-21 and all-cause mortality. Furthermore, the increase in LMR did not change even six months after treatment ended.1

Dr. Fahy and his fellow researchers speculated that the benefits of having more lymphocytes in relation to monocytes might be due in large part to the fact that most monocytes express CD38, an enzyme that destroys NAD+ and may drive age-related NAD+ depletion in tissues.22 The LMR increase was driven mostly by a decrease in monocytes.

Although monocytes play an important role in “innate” immunity,23 higher monocyte levels are associated with age-related frailty,24 and CD38 expression increases as we age.

We need NAD+ for a myriad of biochemical processes including DNA repair and cell energy production.25 Therefore, it may be that the TRIIM protocol achieves systemic age-reversing effects at least in part by limiting the levels of NAD+-depleting CD38 monocytes while also restoring youthful thymic immunity.

Reduced Cancer Risk Indicators

Immune function was also improved, as shown by a reduction in PD-1 expression on cytotoxic T-cells.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.26

Drugs that block the PD-1 receptor such as Opdivo® and Keytruda® have become multi-billion-dollar blockbuster drugs in recent years due to the survival improvement they demonstrate against several different cancers.27

Prostate cancer risk decreased in these study participants as shown through decreased PSA and improved percentage of free PSA.1

Additionally, C-reactive protein (a marker for systemic inflammation) decreased significantly.1

Elevated C-reactive protein is a biomarker for risk of both acute and chronic inflammatory conditions, including cardiovascular disease, surgical outcomes, and cancer mortality28-32 and is an important marker for the generalized inflammation that normally accompanies aging (“inflammaging”).

Overall, these results support the hypothesis that improving thymic function can help to prevent cancer and augment defenses against the disease.

Kidney Function

One unexpected discovery was that there was a significant improvement in kidney function, as demonstrated by an increased glomerular filtration rate, or GFR.1

Normally, kidney function never improves as aging proceeds, and end-stage renal failure now costs taxpayers more than $30 billion a year.

During the TRIIM treatment, GFR steadily improved, and the trend even seemed to continue for six months after discontinuing treatment. These results were one sign that perhaps the TRIIM treatment could influence systemic aging and might not be confined only to rejuvenation of the immune system.

Reversal of Epigenetic Age

Within the last six years or so, measurement of DNA methylation patterns has enabled the most accurate measurement of biological age presently available. These DNA methylation “clocks” are an exciting new development and are also allowing scientists to accurately predict future healthspan and lifespan.

Several different “clocks” of this kind have been developed, each with a somewhat different purpose in mind. In combination with other carefully selected clinical markers, they will become increasingly valuable predictors of future healthspan and mortality.1,33,34

Steve Horvath, Ph.D.
Steve Horvath, Ph.D.
Professor of Human
Genetics & Biostatistics,
UCLA Fielding School
of Public Health

What is “Epigenetic Age”?

  • “Biological” age calculated from DNA methylation
  • DNA methylation regulates genes
  • Genes regulate aging
  • Better estimator than chronological age
  • DNA methylation patterns predict risk of disease and death
Slide courtesy of Dr. Greg Fahy.  Photo courtesy of Dr. Steve Horvath.
Slide courtesy of Dr. Greg Fahy. Photo courtesy of Dr. Steve Horvath.

DNA Methylation Tests

Woman holding kale

DNA methylation influences how genes are expressed.

Healthy methylation allows healthy gene expression to support youthful cell function.

Unhealthy methylation patterns result in deleterious gene expression that facilitates the onset of degenerative illness and shortened lifespan.35-37

As we age, our pattern of gene expression changes. By following changes in DNA methylation, we can indirectly follow changes in gene expression and, therefore, changes in biological age.

The first epigenetic aging “clock” was developed by UCLA researcher Dr. Steve Horvath, who assessed the methylation status of a broad array of tissue and cell types, finally settling on 353 specific DNA sites whose methylation is correlated with chronological age.

The TRIIM trial used Dr. Horvath’s original epigenetic clock, as well as three other methylation clocks, to allow a robust analysis of the results of the treatment, and to confirm that different epigenetic analyses agreed, on average, on the impact of the intervention.1

Results of TRIIM Trial

By combining metformin and DHEA with growth hormone for just one year, the thymic benefits of growth hormone occurred with no significant side effects and the unexpected benefit of a 2.5-year biological age-reversal in all patients, according to an average of the four epigenetic clocks.1

Remarkably, although these four clocks depend differently on blood composition and other factors, and although there were some quantitative differences in results between the different clocks, each clock produced results that were essentially the same as all the others with respect to epigenetic aging reversal.

Each clock, by itself, showed highly statistically significant results. In combination, the evidence for aging reversal across all clocks was overwhelming.

Interestingly, the average age reversal of 2.5 years was mirrored almost exactly by the original Horvath DNAm clock result. The DNAm clock for blood is known to correlate with aging of the brain, muscle, and other tissues, supporting a global aging reversal effect of the TRIIM protocol.

Summary

Regenerating thymic function, improving immunity, reversing epigenetic aging, and the other favorable effects seen in the TRIIM trial are required if we are to advance toward a more youthful state.

Dr. Greg Fahy’s company, Intervene Immune, Inc., is seeking to replicate and extend these results in a larger clinical trial that is expected to launch in the first quarter of 2020. The second phase of the clinical trial will not only have many more study subjects, but will also implement more tests, such as clinically significant and hopefully FDA-approvable health endpoints and will include women, minorities, older and younger participants, and those with imperfect health, as well as a control comparator group.

Life Extension® has long advocated for use of several of the various interventions used in the TRIIM trial. These include DHEA and metformin. For those who don’t take metformin, we have discovered other AMPK-activating compounds. Most readers of this publication utilize these and other methods to support healthy, youthful immunity and DNA.

However, we have not previously recommended hGH, or the combination of hGH, metformin, and DHEA, which breaks new ground, and we welcome this advance.

Dr. Fahy’s group is seeking to identify an affordable source of growth hormone as well as other ways to make this longevity protocol available to almost everyone. For more information, see www.interveneimmune.com.

We applaud Dr. Greg Fahy, his team, and all the researchers involved for their arduous and excellent work in this historical clinical trial!

Look forward to future updates!

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

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