Intervene Immune Publishes Thymus Regrowth Trial Results

Intervene Immune is the company formed to commercialize the methology for regrowth of thymic tissue used in the small TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation) trial, a combination of growth hormone, DHEA, and metformin. As I've noted in the past, that the approach involves the use of human growth hormone over an extended period of time makes it less desirable as an intervention, but if one can gain an expectation of some thymic regeneration, leading to an extended improvement in immune function that lasts for years beyond the treatment period, then it might be worth the trade-off. In general, higher growth hormone levels are associated with a worse outcome in the study of aging, while lower levels are associated with a slowing of aging. Using growth hormone for anything other than treating rare clinical conditions of deficiency is something like burning the candle at both ends.

The thymus is an inaccessible organ in the chest responsible for transforming thymocytes created in the bone marrow into T cells of the adaptive immune system. This complicated process takes place in thymic tissue that, unfortunately, atrophies with age, becoming replaced with fat. The less tissue, the fewer T cells are generated, and the worse the function of the immune system over time. The thymus loses much of its mass quite early in life, following childhood, but the later, slower decline over the course of adult life is a different process mediated by chronic inflammation and other factors that arise with old age. The adaptive immune system is vital to health, and thus a great deal of research has taken place over the past few decades into means of thymic regeneration: upregulation of FOXN1 or related genes such as BMP4; engineering of new thymic tissue; delivery of recombinant KGF, delivery of growth hormone; sex steroid ablation; and so forth. Some are more reliable than others, and some, such as KGF, have succeeded in mice and failed in human trials.

The Intervene Immune team has presented a fair amount of data on the results from their trial at recent conferences, including epigenetic age changes, and you'll find it all in the open access paper noted here. The results unfortunately don't include all of the assays of immune cell characteristics one might want in order to be able to compare directly with the effects of sex steroid ablation in human patients, but are intriguing. (In turn the sex steroid ablation trials didn't look at thymic mass in CT scans, an unfortunate omission). Further, it isn't possible to clearly associate all of the outcomes with regrowth of thymic tissue, particularly the epigenetic age effects, given everything else the treatment might be doing. Nonetheless, taken as a whole this is good supporting evidence for those groups working on more direct approaches to the problem of the atrophied thymus, such as Lygenesis and the company Bill Cherman and I founded last year, Repair Biotechnologies.

First hint that body's 'biological age' can be reversed

A small clinical study has suggested for the first time that it might be possible to reverse the body's epigenetic clock, which measures a person's biological age. For one year, nine healthy volunteers took a cocktail of three common drugs - growth hormone and two diabetes medications - and on average shed 2.5 years of their biological ages, measured by analysing marks on a person's genomes. The participants' immune systems also showed signs of rejuvenation.

The latest trial was designed mainly to test whether growth hormone could be used safely in humans to restore tissue in the thymus gland. The gland, which is in the chest between the lungs and the breastbone, is crucial for efficient immune function. White blood cells are produced in bone marrow and then mature inside the thymus, where they become specialized T cells that help the body to fight infections and cancers. But the gland starts to shrink after puberty and increasingly becomes clogged with fat. Evidence from animal and some human studies shows that growth hormone stimulates regeneration of the thymus. But this hormone can also promote diabetes, so the trial included two widely used anti-diabetic drugs, dehydroepiandrosterone (DHEA) and metformin, in the treatment cocktail.

Checking the effect of the drugs on the participants' epigenetic clocks was an afterthought. The clinical study had finished when researchers conducted an analysis. Four different epigenetic clocks were used to assess each patient's biological age, and he found significant reversal for each trial participant in all of the tests. "This told me that the biological effect of the treatment was robust. The effect persisted in the six participants who provided a final blood sample six months after stopping the trial. Because we could follow the changes within each individual, and because the effect was so very strong in each of them, I am optimistic,"

Reversal of epigenetic aging and immunosenescent trends in humans

Thymus regeneration and reactivation by growth hormone administration have been established in aging rats and dogs by restoration of youthful thymic histology and by reversal of age-related immune deficits. The present study now establishes highly significant evidence of thymic regeneration in normal aging men accompanied by improvements in a variety of disease risk factors and age-related immunological parameters as well as significant correlations between thymic fat-free fraction (TFFF) and favorable changes in monocyte percentages and the lymphocyte-to-monocyte ratio (LMR), independent of age up to the age of 65 at the onset of treatment. These observations are consistent with the known ability of growth hormone to stimulate hematopoiesis and thymic epithelial cell proliferation. Our finding of an increase in FGF-21 levels after 12 months of treatment suggests that thymic regeneration by the present treatment may be mediated in part by this cytokine, which we believe is a novel finding.

Treatment-induced increases in naïve CD4 and naïve CD8 T cells were relatively small compared to changes reported in recombinant growth hormone treated HIV patients, but our volunteer population was pre-immunosenescent and not depleted of naïve CD4 and naïve CD8 T cells at baseline. Positive responses also occurred despite potential complications caused by lymph node aging. Therefore, the small increases observed in these cells and in CD4 T-cell recent thymic emigrants are consistent with the ultimate goal of preventing or reversing the normal age-related collapse of the TCR repertoire at ages just above those of our study population.

There may be both immunological and non-immunological mechanisms of epigenetic aging reversal. Growth hormone, DHEA, and metformin have unique effects that are in opposition to aging, and it is possible that the specific combination of these agents activates a broad enough range of therapeutic pathways to account for the previously unpredictable reversal of epigenetic aging, even independently of the immunological markers we have measured.

Comments

The report seems willfully silent as to the amount of growth hormone administered. It only provides that the initial dose to test for insulin response was approximately 3IU. It seems to me likely the growth hormone is the predominant factor. Maybe I am stating the obvious. Maybe do an MRI on Sly Stalone's Thymus to test the hypothesis.

Posted by: JohnD at September 9th, 2019 12:28 PM

I wonder why not try localized HGH release instead of treating the whole body. Wound't that allow for a higher and more targeted dosage ?

Btw, i am skeptical about epigenetic clock reversal. There might a be good correlation between the said clocks and the bilogical/calendar age before the intervention. But after an intervention we don't even know what the clocks is measuring. It is like resetting the car odometer while replacing the dashboard. It looks newer (it has new parts, so it is newer) but does the changed odometer correctly predict the rest of the car performance ? Same thing here. The growth hormone induced the creation of newer cells, which have less metylation but are the effects superficial or profound ?

Posted by: cuberat at September 9th, 2019 12:30 PM

@JohnD
>The report seems willfully silent as to the amount of growth hormone administered.

>"Side effects were mild, typical of rhGH administration, and did not require dosing modification except in two cases."

Not clear whether it was after the initial dose adjustment.
Again if the initial adjustment had a place, what was the protocol?
Was it the particular target blood hgh level or some percent of the initial base level?

Posted by: Dim at September 9th, 2019 2:03 PM

These researchers will be presenting their data at Raadfest in October. Theses will be good questions to ask them.

Posted by: August at September 9th, 2019 9:27 PM

Don't forget RAAD fest is effectively quackfest.

Posted by: Quackalert at September 9th, 2019 9:31 PM

I vote for Oktoberfest.

Posted by: m. at September 9th, 2019 10:47 PM

So we don't know the full results yet as to whether it actually did regenerate some of the thymus or not?

Posted by: bmack500 at September 10th, 2019 7:57 AM

Unrelated but looks like Insilico Medicine, although being successful in fund raising, is no longer going to be working on aging

"As we grow we will need to focus on what we do best and shelve the projects where there is no clear business model. Many of our longevity projects will need to be divested. For example, we already shut down Young.AI and other initiatives that were too far ahead of their time. "

https://medium.com/@longevity/insilico-secures-37-million-from-top-tier-experts-now-what-cc9dc339ffe1

Sad - but it is the nature of the drug discovery business

Posted by: David Permisov at September 10th, 2019 8:48 AM

@David Permov: In the operational sense at least, working on biomarkers of ageing vs biomarkers of age related disease risk isn't really meaningfully distinct; that's the geroscience hypothesis at least; that the mechanisms leading to age related disease are/are directly coupled to the underlying biochemical mechanisms of ageing. I don't see how that couldn't be true, there's no more parsimonious explanation for the "age related" part of age related disease beyond some evolutionary kill switch that there is no biochemical evidence of in humans. Meanwhile the drug discovery methodologies that In Silico is pioneering are generically applicable, and could massively improve drug discovery workflows.

Posted by: Dylan Mah at September 10th, 2019 2:24 PM

I don't think HGH reduces longevity in humans. A group of 12 Italian centenarians had normal HGH levels and those levels were ~5 times greater than a healthy control group aged 67-98.
(~ .8 vs ~4 ng/ml)

A person could do ONE SINGLE 30 second all-out sprint and increase HGH by 2-10 times.

"Growth hormone responses to treadmill sprinting in sprint- and endurance-trained athletes"
https://www.ncbi.nlm.nih.gov/pubmed/?term=Growth+hormone+responses+to+treadmill+sprinting+in+sprint-+and+endurance-trained+athletes

"Hormone levels in centenarians"
https://vdocuments.mx/hormone-levels-in-centenarians.html

Posted by: Lee at September 10th, 2019 6:12 PM

So basically just taking Metformin & DHEA without the HGH would be useless ? HGH that's not something the average people can take on a daily supplementation.

Posted by: Jonathan Weaver at September 11th, 2019 6:47 AM

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