Researchers have demonstrated how a secret weapon made in the gut, produced by consuming foods like pomegranate and walnuts, can rejuvenate the immune system in middle age, shielding us from cell damage, inflammation and chronic diseases including cancer.
Researchers at Germany’s Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, have spent years investigating the metabolite urolithin A (UA), a natural compound that’s produced by gut bacteria in response to ingested ellagitannins from foods such as pomegranates, almonds, walnuts and some berries. The new study follows on from a breakthrough in 2022, when the team found that UA induced a biological pathway that rejuvenates the cellular power plants – mitochondria – in T cells, equipping these immune cells with more cancer-fighting might. But it goes far beyond cancer.
“Three years ago, we discovered that urolithin A could powerfully expand a special population of long-lived, anti-tumor T cells in our laboratory models,” said principal investigator Dr Dominic Denk, a physician-scientist at University Medicine Frankfurt. “Our goal was always to translate our findings from the lab into the clinic.”
As we age, we experience immunosenescence, the gradual deterioration of both the adaptive and innate immune systems, increasing inflammation and incidence of infection and diseases such as cancer. One of the main changes is a loss of the innate immune system’s naive T cells, the first line of defense against pathogens, and an increase in the adaptive immune system’s memory T cells. This essentially makes our bodies less able to fight infections and more prone to “inflammaging” – a red flag for the onset of chronic, age-related disease.
So if we could biologically “reprogram” T cells, fitting out their tired old engines with new sources of power, it could essentially slow this natural deterioration of the immune system and in turn also suppress the negative health impacts that come with it.
In a randomized, double-blind, controlled trial involving 50 healthy adults aged 45-70 years, participants were given either UA supplements or a placebo for 28 days, with immune-related health markers assessed before and following treatment.
What they found was that UA safely rejuvenated the immune systems in several ways. It boosted the number of well-functioning CD8+ T cells (also known as cytotoxic T lymphocytes, or CTLs), which are important for fighting pathogens. These cells were found to have more peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a protein that acts as the master controller of mitochondrial biogenesis – where cells generate new mitochondria. The participants receiving UA supplements also had lower oxidative stress in cells and a change in a number of inflammatory markers.
Essentially, UA triggered mitophagy, the process that recycles and renews the power source in cells, significantly increasing the number of young, naive T cells. It also improved the immune system’s ability to clear harmful bacteria.
The production of UA is largely dependent on the gut’s microbiota, but it’s believed that microbial groups including Proteobacteria, Clostridium, Bifidobacterium, Eubacterium, and Enterococcus faecium play a role in breaking down the bioactive polyphenol (ellagitannins) found in foods like pomegranate. UA has become an increasingly popular metabolite in research, which we first touched on in 2019. Its impact on mitochondria has led to studies on its broad health potential, including using UA to treat depression and improving muscle endurance and strength, while reducing inflammation and oxidative stress in athletes. It’s even being studied as a promising obesity treatment, where it was shown to boost brown fat burn and encourage white fat to turn brown in mice.
“This study is that critical first step and shows that urolithin A can safely enhance immune function in humans,” said Denk. “We are particularly excited about its potential in cancer treatment.”
And while the Georg-Speyer-Haus researchers have focused on UA for cancer treatment, this trial shows that benefits extend far beyond that – and could be particularly useful for slowing middle-age cellular dysfunction.
“This successful clinical translation is a testament to our strategy at the Frankfurt Cancer Institute, to combine our findings with clinical expertise to accelerate the development of novel therapies that can truly make a difference” said Dr Florian Greten, Director of Georg-Speyer-Haus. “A robust immune system has broad implications. By rejuvenating immune cells, we could make life-saving cancer treatments effective for more patients. We have already initiated a follow-up study in patients undergoing immunotherapy and are very eager to see whether our results will also have a positive effect here as well.”
The research was published in the journal Nature Aging.
Source: Georg-Speyer-Haus
