Dominic Denk

Urolithin A nudges aging immune cells toward a youthful profile in 28 days An international research team focused on aging reports that urolithin A at 1,000 mg per day shifted human immune profiles toward a more naive-like, less exhausted CD8+ state and increased fatty acid oxidation capacity, with additional functional gains.

Urolithin A supplementation for 28 days shifted immune cell profiles in older adults toward a more youthful, less exhausted state and enhanced mitochondrial fatty acid oxidation capacity. doi.org/g99kft

Thanks for the interest in our study and reading it thoroughly.

Important to emphasize the limitations of the trial: proof-of-concept study and its design does not allow concluding efficacy. We are excited to now take this a step further and study this in cancer (in line with our preclinical data).

Describes the study showing Urolithin-A supplementation modulates immune remodeling, boosts T cells and reduces inflammaging. Colors are grey and tan with the word Urolithin-A in red.

In a RCT, Urolithin-A boosted CD8⁺ T cells and improved immune metabolism, hinting at a new way to slow age-related immune system decline and inflammaging. buff.ly/qaGyGF0

Urolithin A works by inducing mitophagy (clearance of damaged mitochondria).

#medsky #aging

Thanks for highlighting our study!

This was a true team effort: @loewe-fci.bsky.social, @goetheuni.bsky.social, @ciml.bsky.social ( @rafajarguello.bsky.social ), @buckinstitute.org
Sponsor: Timeline.
Independent, investigator-initiated study.
Huge thanks to our volunteers.

Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy Anti-tumor immunity is limited by reduced T cell persistence and antigen presentation. Denk et al. show that Urolithin A, a natural metabolite of pomegranate extract, enhances antigen presentation in ...

This was the natural translation of our cancer work, where UA enhanced antitumor immunity in preclinical models.

www.cell.com/immunity/ful...

Our goal was always to bring our findings to humans and improve #immunotherapy. This study is the first critical step.

We found that UA expands naïve CD8+ T cells in the blood - fresh soldiers that can respond to threats, such as infections and cancer. These are the cells that we lose the most during immune aging. We also observed changes across other immune readouts.

In our study, 50 middle-aged adults received either UA or a placebo for 4 weeks. We aimed to assess if the immune system changes after UA intake. Neither our volunteers, nor us knew the assignment (double-blind, placebo-controlled study).

UA triggers #mitophagy - a cellular clean-up that renews mitochondria. Healthier mitochondria are essential for T cell function.

As we age, #mitochondria (“the cells’ powerhouse”) decline, which contributes to immune aging.

We reasoned that targeting immune-cell mitochondria could slow immune aging (and aspects of aging more broadly).

T cells with dysfunctional mitochondria induce multimorbidity and premature senescence Mitochondrial stress in immunological T cells induces the symptoms of systemic aging.

This immune decline is not isolated. It fuels body-wide chronic inflammation ( #inflammaging ) contributing to muscle loss, heart disease & more.

www.science.org/doi/10.1126/...

Bottom line: Immune health is central to whole-body health.

As the immune system ages, we face more infections, poorer vaccine responses, and higher cancer risk.

There are no drugs that directly halt or reverse this process.

In our randomized, double-blind, placebo-controlled trial, we find that Urolithin A expands naive CD8+ #Tcells and improved immune readouts.

georg-speyer-haus.de/en/newsroom/...

This is strikingly fast (1 month) and offers a direct path to targeting immune aging.

More background 🕵️👇

Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial - Nature Aging Immune aging fosters multimorbidity and compromises control of infection and cancer. In a phase 1 randomized controlled trial in middle-aged adults, Denk and colleagues administer the mitophagy induce...

Excited to share our new study in @nataging.nature.com !🎉

www.nature.com/articles/s43...

We show that Urolithin A, a pomegranate-derived gut metabolite, counteracts key signs of immune #aging in a phase I trial!

#immunology #aging @loewe-fci.bsky.social @goetheuni.bsky.social #immunosky

Happy to repost the study in @cp-immunity.bsky.social now with the cover illustrating the Janus-faced role of IL-17RA in #colorectalcancer.

More information below by @domdenkmd.bsky.social or the latest issue of Immunity:
www.cell.com/immunity/cur...

#DarmkrebsmonatMärz

@proloewe.bsky.social

IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis Members of the interleukin-17 family are associated with tumor progression in various settings. Denk et al. find that, in colorectal cancer, IL-17RA switches from tumor promotion during early tumorigenesis to tumor suppression during tumor invasion and…

Online now: Online now: IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis

Fresh from @cp-immunity.bsky.social
"A Surprising Shift from Foe to Friend:
Researchers discover dual role of inflammatory signaling in colorectal cancer"

👏Congratulations @domdenkmd.bsky.social and all coauthors!! 🎉

Read the full article here:
www.cell.com/immunity/ful...

@proloewe.bsky.social

Big thanks to my co-authors, our PI Prof. Florian Greten, and other amazing scientists whose work we were able to build on.

This was a great team effort!

Interrogating tumor cell biology, immunity and the mycobiome requires a team of experts that I was blessed to work with.

In addition, we were able to use our own patient-derived organoid biobank and publicly-available datasets.

We show that pro-inflammatory signaling is NOT🚫 generally pro-tumorigenic in CRC.

By showing the effect of IL-17RA on epithelial cells AND immune cells our data proposes several lines of future research, including the potential development of therapies mimicking fungi-induced antitumor immunity.

Co-treatment of IL-17 (activation of IL-17RA) with heat-killed Candida albicans (HKCA, activating the dectin-syk axis in macrophages) sensitizes tumors to immunotherapy. Co-treatment is represented by the green line, showing the strongest tumor repression. Immunotherapy alone (black) does not limit tumor growth in this model (as we have also observed in PMID: 36351375). It is important to note that we do not suggest that it works the same way in humans! Many further studies are required to assess whether activating Dectin signaling (in any way!) is a feasible approach

This means fungi can be protective to instigate an anti-tumor immunity⚡!

When we now use heat-killed Candida (a fungal species) and IL-17A (the signal that binds to IL-17RA) in combination in vivo, we can blunt tumor growth!

The effect of IL-17RA on macrophages. Fungal populations such as yeast are sensed by dectin-1, activating Syk. This induces cytokine production such as IL-1b and IL-18. Our data suggests that IL17RA on macrophages is required to robustly activate the dectin-Syk axis. IL-18 elicits T cell-mediated antitumor immunity.

2)

On myeloid cells, IL-17RA expression is critical to augment Dectin-1 mediated sensing of #fungal populations. This results in inflammasome activation and IL-18 maturation.

So: Fungal populations🍄 induce CD8-mediated antitumor immunity, but this requires IL-17RA!

The effect of IL17RA on intestinal epithelial cells. Our data suggests that IL17RA is critical to limit recycling of EGFR to the cell surface, thereby putting a lid on pro-invasive signaling. Without IL17RA, EGFR availability and subsequent signaling are unleashed - resulting in activation of Src and epithelial-to-mesenchymal transition (EMT).

1) On tumor cells, loss of IL-17RA protects from epithelial-mesenchymal transition, limiting invasion.

IL-17RA appears to be critical to limiting EGFR shuttling back to the cell's surface, thereby blunting Src signaling.

We were able to demonstrate an unexpected dual tumor suppressor function of IL-17RA in late-stage CRC, affecting both tumor cells and the immune system!

Experimental model of invasive CRC: G-H Deletion of IL17RA in intestinal epithelial cells results in less invasion in early tumor stages, here in a experimental model of CRC at 12 weeks. I-J At late stages (in this model at 18 weeks) when tumors have become fully invasive, deletion of IL17RA results in MORE tumor invasion. In other words: IL17RA is surprisingly protective in late stages!

Using a model of invasive colorectal cancer, we could see a time-dependent effect of IL-17RA.

(1) IL17-RA expression fosters tumor growth early on,

(2) but when tumors become invasive, IL17-RA appears protective.

Why is that?

IL-17RA has opposing effects in colorectal cancer, depending on the disease stage: Previous experimental evidence and population data suggest that it promotes early tumorigenesis, thereby associating with a worse outcome in EARLY cancer stages. Yet, in an ADVANCED and metastatic setting, IL-17RA expression is associated with better survival.

We were presented with a paradox:

➡️We know that inflammatory IL-17 promotes tumorigenesis in enterocytes, and in early stages of CRC, a Th17 signature is considered unfavorable.

⚡Yet, in late-stage disease, expression of its receptor IL-17RA is associated with better prognosis in patients.

IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis Members of the interleukin-17 family are associated with tumor progression in various settings. Denk et al. find that, in colorectal cancer, IL-17RA switches from tumor promotion during early tumorige...

Finally announcing our new study in @cp-immunity.bsky.social!

We show that IL-17RA fulfills dual tumor suppressor function in late-stage colorectal cancer (CRC)!

#immunosky #cancer #immunology @loewe-fci.bsky.social
@cellpress.bsky.social
@goetheuni.bsky.social

Read here🧵👇:
tinylink.net/OS41F

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Good morning, all. A rich and diverse list of curated papers in #cancermetabolism and #mitochondrialbiology is ready for you! Don't miss it! Find it here: biomed.news/bims-camemi/... @biomednews.bsky.social

"In the midst of winter, I found there was, within me, an invincible summer."-Albert Camus

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Good Sunday, all! A short but rich summary of papers in #cancermetabolism and #mitochondrialbiology is waiting for you here: biomed.news/bims-camemi/... @biomednews.bsky.social #dontstopreading

“The Eyes See Only What The Mind Is Prepared To Comprehend.”
― Henri Bergson