What baffles me most about health-related conversations in the United States is that human longevity is rarely talked about outside scientific circles. Think about it—from prescription medications and dietary protocols to moms oxygenating their kids in sunscreen—every recommendation under the vast health umbrella is tailored to living healthier, longer lives.  While infectious disease, climate change, body composition, and cancer continue to dominate mainstream health discussions, it’s rare to overhear two New York City strangers gloat about the world’s rising life expectancies—or, more notably, that the global population of those ages 60+ more than doubled in the past three decades…How’s that for newsworthy? Maybe that doesn’t sound so impressive to the general layman; one might recommend ‘eating healthy’ and ‘being active’ because that’s obviously all it takes to become immortal (unfortunately, a simple two-term equation for immortality won’t do). Jokes aside, science has progressed insofar as to reveal the deep underpinnings of life’s complexities. And as a result, people are capitalizing on these progressions and implementing practical ways of tipping the health scale in their favor.

A 2019 article in the journal Nature covered a study by a research team at the University of California, Los Angeles (UCLA), who suggests that not only can we slow down the mammalian aging process, but it might also be possible to reverse some of its associated physiological processes [1]. The study consisted of nine healthy men between 50 and 60 years old who, for one year, consumed a cocktail of three common drugs: human growth hormone (hGH), metformin, and dehydroepiandrosterone (DHEA). On average, they shed about 2.5 years from their biological ages, and their immune systems showed significant signs of rejuvenation—perhaps the first piece of evidence demonstrating a possible reversal in the biological clock. UCLA geneticist Dr. Steve Horvath, whose methods were used to estimate the participants’ epigenetic ages—based on various biomolecular markers, contrary to one’s chronological age—said the study’s results “felt futuristic” and that while he expected a slowing down of aging, a reversal was surprising [2]. 

I’d expect that after having read this paragraph, you’re now asking if this concoction is one you should be adding to your wish list. Although the researchers caution the results are only preliminary, their study is remarkable. How they attacked age-related immune system deterioration is rather clever. Exciting findings? Absolutely. But there are some things to keep aware of before Big Pharma starts replacing your daily newspapers with hGH drinks. 

Led by Dr. Greg Fahy, the team of researchers sought to prevent or reverse signs of the gradual deterioration of the immune system attributed to natural age development (i.e., immunosenescence). The size and function of the immune system are primarily dependent on the thymus, a small organ in the upper chest critical for optimal immune response, converting white blood cells into T-cells that are used in protecting the immune system against infectious cells. Thymal activity typically peaks around ages 1-2, after which point the thymus decreases in size and activity through a process called thymic involution [3]. With size and activity reductions also come functional weaknesses.  To combat this thymic deterioration, Fahy and his colleagues administered human growth hormone in an attempt to restore any lost thymic tissue and function. The trials were dubbed Thymus Regeneration, Immunorestoration, and Insulin Mitigation (TRIIM) for ease of remembrance.

We just learned that a happy thymus = a happy immune system. And all things equal, a happy immune system = a longer life. Though hGH administration might show signs of thymal rejuvenation, there’s a catch to using high amounts of it. Prior animal studies revealed that short and long-term hGH exposure could lead to elevated insulin levels, and higher insulin could tread dangerous waters with high blood pressure and diabetes. No matter how effective hGH might be for longevity, those are not side effects worth playing around with. Fahy and his team incorporated metformin and DHEA, efficacious blood sugar regulators, to mitigate some of the diabetogenic effects accompanying hGH administration. 

During the TRIIM trial’s first week, Fahy and his colleagues only administered hGH (0.015 mg/kg—just to contextualize hGH dosing, professional athletes and bodybuilders typically take about double the amount these men took) to obtain an initial insulin response. They then added DHEA the following week to observe the insulin suppression by DHEA alone, and then threw in metformin during the third week. Doses were adjusted to maximize participants’ insulin growth factor (IGF-1) and minimize insulin levels.

What’s important to recognize in the study is that the participants were all considered nine ‘healthy’ men between ages 50-65. Fahy’s experimental design aptly took the participants’ physiological framework differently since they aren’t the exact same person. He and his team looked at the different biomarkers and adjusted their dosage accordingly. This, I thought, worked perfectly in the study’s aim: to administer hGH to participants without any additional risk of developing diabetes, or worse. The design was multifaceted and looked at sufficient health profiles to conclude that the men shed off an average of 1.5 years from their biological age. In other words, say I was one of the nine participants in the study: I came into the study at 20 years old and after having my dosages adjusted during the first three weeks, I remained on those dosages for a year. My epigenetic age would be 1.5 years younger (I would have biomarkers similar to a 19.5 year-old) despite my chronological age rising by a year (I’d be 21 years old by the end of the year). My cumulative life expectancy would have also risen by 2.5 years. And that’s only after one year of clinical trials. 

Though remarkable, the researchers caution that the results are only preliminary, and nobody should just willy-nilly inject themselves with exuberant amounts of all three drugs. I agree with them. More data needs to be conducted to draw safe, definitive conclusions. A few things to consider:

1. The trial is incredibly small—nine is just not enough participants to take anything significant from. Also, one general rule of thumb: the sample population should be representative of the population itself. The trial consisted of only white men, decreasing the clinical significance of the study even more. In order to increase the trial’s efficacy, there should be more variation in the sample since drugs sometimes reveal different effects on women and POC. 
2. What contributed most to the decline in biological age? Was it the cocktail? If so, then some digging is required. Could it have been solely the hGH, with no help from the metformin or DHEA? Or solely the metformin, or solely the DHEA? To figure this out, the study could have included control groups just to make sure these results were not plausible. A lack of control makes it more challenging to show cause-and-effect—it’s almost a necessity. There could have been a synergistic effect between the three drugs, in which case they produce the desired thymic rejuvenation altogether. Maybe the participants unknowingly modified their behaviors during the experiment. Many variables could be at play.
3. Is the epigenetic clock estimation accurate? The clock’s primary barometer for predicting epigenetic age is what Horvath dubbed DNA methylation (DNAm), the biological mechanism responsible for transferring methyl (CH3) groups to DNA for effectively regulating gene expression. Horvath notes that because methyl groups migrate in predictable patterns throughout life, DNA methylation has been a reliable mortality risk estimator for decades [5]. However, Dr. Peter Attia—a physician whose work specializes in human longevity—warns in his blog Deep Dive that life expectancy encompasses more than just DNA methylation: “If the treatment in the study did, in fact, modulate this component of aging and increase longevity, it’s profound. But we should not lose sight of the fact that aging is considered to be a process with more mechanisms than DNAm.” [6]

I think you get the idea… Is it possible that it could make you physically younger? Not sure. Small, uniform sample; one index for longevity estimation; uncertainty using DNA methylation—the trials have quite a few limitations. Indeed, it would be nice to jump right onto the hGH, metformin, and DHEA cocktail. Sounds appealing; we just need more time. No pun intended. 

References

1. Abbott, Alison. “First Hint That Body’s ‘BIOLOGICAL Age’ Can Be Reversed.” Nature News, Nature Publishing Group, 5 Sept. 2019, www.nature.com/articles/d41586-019-02638-w. 
2. Fahy, Gregory M., et al. “Reversal of Epigenetic Aging and Immunosenescent Trends in Humans.” Wiley Online Library, John Wiley & Sons, Ltd, 8 Sept. 2019, onlinelibrary.wiley.com/doi/full/10.1111/acel.13028. 
3. “How to Boost Your Immune System.” Harvard Health, 15 Feb. 2021, www.health.harvard.edu/staying-healthy/how-to-boost-your-immune-system. 
4. [1] Murasko, D. M., and J. Jiang. 2005. Response of aged mice to primary virus infections. Immunol. Rev. 205: 285–296.
5. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. doi: 10.1186/gb-2013-14-10-r115. Erratum in: Genome Biol. 2015;16:96. PMID: 24138928; PMCID: PMC4015143.
6. Attia, Peter. “Can You Reverse Your Biological Age?” Peter Attia, 14 Jan. 2020, peterattiamd.com/can-you-reverse-your-biological-age/.