In a small human trial, drugs seemed to rejuvenate the body’s ‘epigenetic clock’, which tracks a person’s biological age, writes Alison Abbott for Nature. Volunteers shed years of biological age and their immune systems were boosted, according to epigenetic analysis from the University of California.
The findings of the study were published in the journal Aging Cell .
For a 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 organisers – but researchers caution that the findings are preliminary because the trial was small and did not include a control arm, Nature reports.
“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.”
“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.”
“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, according to Nature.
“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 more 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,” reports Nature.
“White blood cells are produced in bone marrow and then mature inside the thymus, where they become specialised 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 nine 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, the Nature article continues. 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, Naturereports, “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.
“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 told Nature. 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, writes Nature.
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, Naturereported.
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”.
Journal – Ageing Cell
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans.
Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study).
The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment.
This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
Gregory M Fahy, Robert T Brooke, James P Watson, Zinaida Good, Shreyas S Vasanawala, Holden Maecker, Michael D Leipold, David TS Lin, Michael S Kobor and Steve Horvath.
Previously, Steve Horvath, a human geneticist and biostatistician at the University of California, Los Angeles, gathered and analysed data on more than 13,000 human tissue samples.
The result, Nature reported in 2014, is a cellular biological clock that has impressed researchers with its accuracy, how easy it is to read and the fact that it ticks at the same rate in many parts of the body – with some intriguing exceptions that might provide clues to the nature of ageing and its maladies.
Horvath's clock emerges from epigenetics, the study of chemical and structural modifications made to the genome that do not alter the DNA sequence but that are passed along as cells divide and can influence how genes are expressed. As cells age, the pattern of epigenetic alterations shifts, and some of the changes seem to mark time.
To determine a person's age, Horvath explores data for hundreds of far-flung positions on DNA from a sample of cells and notes how often those positions are methylated – that is, have a methyl group attached, wrote W Wayt Gibbs for Nature.
He has discovered an algorithm, based on the methylation status of a set of these genomic positions, that provides a remarkably accurate age estimate – not of the cells, but of the person the cells inhabit.
White blood cells, for example, which may be just a few days or weeks old, will carry the signature of the 50-year-old donor they came from, plus or minus a few years. The same is true for DNA extracted from a cheek swab, the brain, the colon and numerous other organs.
This sets the method apart from tests that rely on biomarkers of age that work in only one or two tissues, including the gold-standard dating procedure, aspartic acid racemization, which analyses proteins that are locked away for a lifetime in tooth or bone, according to Nature.
Medical researchers might be able to use the epigenetic clock to better diagnose and classify illnesses even without really understanding how the biology works. But Horvath hopes that the science won't stop there.
[link url="https://www.nature.com/articles/d41586-019-02638-w"]First hint that body’s ‘biological age’ can be reversed[/link]
[link url="https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028"]Reversal of epigenetic aging and immunosenescent trends in humans[/link]
[link url="https://www.nature.com/news/biomarkers-and-ageing-the-clock-watcher-1.15014"]Biomarkers and ageing: The clock-watcher[/link]