On this episode of X10, we talk about the TRIIM trial and question whether or not its participants have become biologically younger.
Script
If you’re lucky, right now you’re aging at a rate of one year per year—that is, your biological age is the same as your chronological age. If you are unlucky, you might be aging faster biologically than you are aging chronologically: you might be forty, for example, but the general condition of your body may be more like that of a typical fifty-year-old.
Really lucky people may be aging slower, biologically speaking: they might be 40, but they’re as fit as a typical 30-year-old. As far as we know, no one is so lucky that they age in reverse and get biologically younger with each passing year, but a 2019 study seems to suggest that something like that can be done, and it has to do with your immune system.
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Your immune system is a complex network of biochemical mechanisms that protect you from all manners of external and internal threats. It’s not only able to tell friends from foes, it can also learn to recognize new threats and react accordingly.
This is all made possible thanks to a tiny, innocent-looking organ sitting behind your breastbone: the thymus. No, not that one. Yeah, this thymus. Thank you. Where was I? Ah, yes. The thymus’s job is to train immune cells to know the difference between your own bodily tissues that need to be left alone and enemies that need to be mercilessly slain.
And guess what? The thymus is the one and only organ in your body that only gets better and better as you age. I bet you didn’t expect that! And you were right, because it’s not true. Actually, the thymus is among the first things that fail in your body: before you’re even out of high school, it starts turning into a disgusting blob of fat. I’m not even kidding.
Thymic involution—that is, the gradual replacement of functional thymic tissue with fat—is nearly universal in mammals, birds, reptiles, fishes, and many other animals. It starts very early on in life, well before any sign of age-related decline appears; in humans, researchers think involution may begin as early as the first year of life, or at least childhood, but there’s no doubt that by the time we’re teens, it’s already happening, and it progresses throughout life.
As the thymus turns into mostly fat and its function declines, the population of fresh T cells—that is, cells capable of learning to recognize and kill new threats—shrinks, leaving us more and more open to diseases. That is one of the reasons why elderly people are more vulnerable to infectious diseases and don’t respond to vaccines as well.
T cells don’t recognize only viruses and bacteria as threats, they also target cancer cells; this ability lies at the core of modern cancer immunotherapy, which seeks to fight cancer by using the immune system against it. Research suggests that as the immune system declines, so does the ability to fight cancer, which may partly explain why cancer rates skyrocket with age. Some researchers go as far as to suggest that while DNA mutations are necessary for cancer to happen, the faltering of the immune system induced by the collapse of the thymus may be a more important factor in age-related cancer than DNA mutations.
Scientists aren’t sure why thymic involution even happens. Given that it begins so early in life, researchers hypothesize that it’s not simply a consequence of the negative effects of aging, though it does contribute to making aging worse.
A number of hypotheses have been put forward to explain involution, and you’ll find links about that in the description below, but whatever the reason may be, researchers think that restoring the thymus back to its youthful glory may be very important for preserving our health later in life.
That’s precisely what a group of researchers set out to do in a small trial between 2015 and 2017. However, what they did seems to have done more than just regenerating the thymus: it appears to have partly rejuvenated nine lucky guys.
The trial was called TRIIM, standing for Thymus Regeneration, Immunorestoration, and Insulin Mitigation. TRIIM enrolled nine fairly healthy men between the ages of 51 and 65, the age range right before immune collapse really begins, and treated them for a year with a mix of human growth hormone and two other compounds known as DHEA and metformin.
Previous studies in both mice and human HIV patients have shown that growth hormone safely induces regrowth of thymic tissue; that’s why TRIIM patients were given it. However, administering growth hormone can induce side effects similar to diabetes, and that’s why researchers added DHEA and metformin to the mix—they’re known for their antidiabetic effects.
The TRIIM trial culminated in a paper published in 2019, and the results went far beyond what the researchers were expecting or even looking for.
Seven out of the nine volunteers displayed significant thymic regeneration, meaning that the excess fat in the thymus was replaced with functional tissue; the other two volunteers happened to have low thymic fat to start with, so their gains weren’t very pronounced.
The treatment also increased the production of different types of fresh T cells, which is pretty much what the researchers wanted; but as boosting the immune system might have the side effect of increasing inflammation, the researchers looked for markers of that. Interestingly, they found that inflammation was either decreased or unchanged.
Administering growth hormone might also cause an increase in prostate cancer risk, but a risk index analysis showed that the patients’ risk for that particular cancer had decreased.
As far as unexpected effects go, TRIIM had many positive ones. One of them was a decline in the number of T cells with a protein called PD-1 on their surfaces. A high number of PD-1-positive cells inhibits the ability of the immune system to seek and destroy cancer, so this decline was a good thing.
TRIIM patients also had an increased lymphocyte-to-monocyte ratio. Lymphocytes and monocytes are two different types of immune cells, and TRIIM patients ended up having more of the former than the latter, which indicates a reduced risk of contracting different types of cancers. It appears that a high lymphocyte-to-monocyte ratio also correlates with better outcomes for other age-related conditions, such as heart disease, and even with all-cause mortality.
During the trial, some of the patients had their hair growing from white to dark again. This wasn’t true for most of the patients and the researchers couldn’t properly document the phenomenon, but it was an intriguing side effect nonetheless.
Still, reversal of epigenetic age takes the cake as the most remarkable, unexpected effect of TRIIM. Tests known as epigenetic clocks measure specific features of your DNA to estimate your biological age as opposed to your chronological age. People with a lower biological age than chronological age are aging more slowly, and vice versa.
The biological age of TRIIM patients was measured using four different epigenetic clocks at different points during the treatment and after its conclusion. All four clocks showed similar reductions in biological age, meaning that the patients were getting biologically younger. The data showed that this reversal accelerated as the treatment progressed, and as with many effects observed in this trial, this benefit persisted for months after the trial was concluded.
One of the epigenetic clocks, very aptly named GrimAge, is able to accurately predict the patient’s remaining lifespan and age of death; according to this clock, the patients’ lifespan was extended by about two years!
This is all great, but, of course, there are caveats. A key limitation of the study was the number and diversity of patients: there were only nine of them, and they were all male. Also, TRIIM did not have a control group, and no one has replicated its results yet.
Even though the biological age reduction measured by the epigenetic clocks is nothing short of amazing, what epigenetic clocks measure isn’t exactly the same as aging itself, and, of course, none of the patients have actually lived longer than expected yet.
Additionally, DHEA and metformin, the two compounds administered together with growth hormone, are known to have anti-aging effects of their own, so it’s possible that some of the effects observed in TRIIM were due to them rather than to the regeneration of the thymus. So, it’s definitely early to draw conclusions.
To address some of these issues, the researchers are planning a new, expanded trial called TRIIM-X. This new trial is going to be very similar to the previous one, except it will study many more men and women of all ethnicities between the ages of 40 and 80. TRIIM-X will be a randomized trial with a control group, will last twelve months, and is expected to be completed in October 2022.
We’re looking forward to the results, and we’ll be sure to make an episode about that. So, if you want to be sure you don’t miss it, you can subscribe to our channel, click the little bell icon, and select “all notifications”. Your friends might be interested in TRIIM too, so sharing this video with them and giving it a like won’t hurt.
Thanks so much for watching this episode; if you want to know more about TRIIM, the thymus, and the immune system, check out the description below; you’ll find links to papers and videos. Speaking of videos, if you would like to help us make more videos like this one, you can do so by becoming a Lifespan Hero—that is, one of the patrons who support us with their kind monthly donations. To find out more about that, visit lifespan.io/hero.