[ExI] Rejuvenation of aging thymus

[Stuart LaForge]

This is pretty good news. The thymus is the gland in which our T-cells  
(white blood cells that fight infections) get trained to distinguish  
self-proteins which belong in the body from foreign-proteins which  
mark invaders like viruses as well as malfunctioning cells like cancer  
that are to be destroyed by the immune system. The thymus works great  
up until adolescence after which most of the active tissue gets  
replaced by inactive fat so that the aged thymus becomes a shadow of  
its former self. There was a small clinical trial in California for a  
cocktail of human growth hormone and 2 diabetes drugs that apparently  
reverses aging of the thymus and thereby rejuvenates the immune  
system. It does so by reversing the epigenetic changes (methylation)  
to DNA that cause thymic shutdown and aging.
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https://www.nature.com/articles/d41586-019-02638-w

A small clinical study in California 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 results were a surprise even to the trial organizers — but  
researchers caution that the findings are preliminary because the  
trial was small and did not include a control arm.

“I’d expected to see slowing down of the clock, but not a reversal,”  
says geneticist Steve Horvath at the University of California, Los  
Angeles, who conducted the epigenetic analysis. “That felt kind of  
futuristic.” The findings were published on 5 September in Aging Cell.

“It may be that there is an effect,” says cell biologist Wolfgang  
Wagner at the University of Aachen in Germany. “But the results are  
not rock solid because the study is very small and not well controlled.”

Marks of life
The epigenetic clock relies on the body’s epigenome, which comprises  
chemical modifications, such as methyl groups, that tag DNA. The  
pattern of these tags changes during the course of life, and tracks a  
person’s biological age, which can lag behind or exceed chronological  
age.

Scientists construct epigenetic clocks by selecting sets of  
DNA-methylation sites across the genome. In the past few years,  
Horvath — a pioneer in epigenetic-clock research — has developed some  
of the most accurate ones.

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. Butgland 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.

The Thymus Regeneration, Immunorestoration and Insulin Mitigation  
(TRIIM) trial tested 9 white men between 51 and 65 years of age. It  
was led by immunologist Gregory Fahy, the chief scientific officer and  
co-founder of Intervene Immune in Los Angeles, and was approved by the  
US Food and Drug Administration in May 2015. It began a few months  
later at Stanford Medical Center in Palo Alto, California.

Fahy’s fascination with the thymus goes back to 1986, when he read a  
study in which scientists transplanted growth-hormone-secreting cells  
into rats, apparently rejuvenating their immune systems. He was  
surprised that no one seemed to have followed up on the result with a  
clinical trial. A decade later, at age 46, he treated himself for a  
month with growth hormone and DHEA, and found some regeneration of his  
own thymus.

In the TRIIM trial, the scientists took blood samples from  
participants during the treatment period. Tests showed that blood-cell  
count was rejuvenated in each of the participants. The researchers  
also used magnetic resonance imaging (MRI) to determine the  
composition of the thymus at the start and end of the study. They  
found that in seven participants, accumulated fat had been replaced  
with regenerated thymus tissue.

Rewinding the clock
Checking the effect of the drugs on the participants’ epigenetic  
clocks was an afterthought. The clinical study had finished when Fahy  
approached Horvath to conduct an analysis.

Horvath used four different epigenetic clocks 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,” he says. What’s more, the effect  
persisted in the six participants who provided a final blood sample  
six months after stopping the trial, he says.

“Because we could follow the changes within each individual, and  
because the effect was so very strong in each of them, I am  
optimistic,” says Horvath.

Researchers are already testing metformin for its potential to protect  
against common age-related diseases, such as cancer and heart disease.  
Fahy says that the three drugs in the cocktail might contribute  
separately to the effect on biological ageing through unique  
mechanisms. Intervene Immune is planning a larger study that will  
include people of different age groups and ethnicities, and women.

Regenerating the thymus could be useful in people who have underactive  
immune systems, including older people, he says. Pneumonia and other  
infectious diseases are a major cause of death in people older than 70.

Cancer immunologist Sam Palmer at the Herriot-Watt University in  
Edinburgh says that it is exciting to see the expansion of immune  
cells in the blood. This “has huge implications not just for  
infectious disease but also for cancer and ageing in general”.

doi: 10.1038/d41586-019-02638-w
References
1.
Fahy, G. M. et al. Aging Cell https://doi.org/10.1111/acel.13028 (2019).

Stuart LaForge