First hint that body’s ‘biological age’ can be reversed
First hint that body’s ‘biological age’ can be reversed
In a small trial, drugs seemed to rejuvenate the body’s
‘epigenetic clock’, which tracks a person’s biological age.
Alison Abbott
05 SEPTEMBER 2019
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. 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.
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).
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