Urolithin A is a compound generated by gut microflora from ellagitannins. The compounds are hydrolyzed in the stomach into ellagic acid, which is subsequently converted by the gut microflora into urolithin A. However, not everyone has the right microflora to be able to make the metabolite.
As reported last year by NutraIngredients-USA, start-up life sciences company Amazentis has developed a method to deliver finely calibrated doses of urolithin A. Preliminary data published in Nature Medicine indicated that urolithin A may improve mitochondrial function by stimulating mitophagy, a process by which damaged mitochondria are recycled to permit a renewal with healthy mitochondria. These potent beneficial effects were observed in C. elegans, mammalian cells and rodents.
Phase 1
Data from a Phase 1 double-blind, randomized, placebo-controlled clinical trial in healthy elderly individuals were presented last week at the International Conference on Frailty and Sarcopenia Research (ICFSR) taking place in Barcelona, Spain.
The single-center, multi-part (single and multiple ascending doses) double-blind, randomized, placebo-controlled study included 60 healthy elderly subjects. Part A involved orally administering single increasing doses of urolithin A (250mg, 500mg, 1000mg, and 2000mg). During Part B, 250mg, 500mg, and 1000mg were selected for four weeks of daily oral dosing and their impact on skeletal muscle mitochondrial biomarkers was investigated along with safety and bioavailability.
The data supported the safety of the ingredient, with no serious and no product-related non-serious adverse events were reported during either trial. The trial also supported that urolithin A was bioavailable to blood and skeletal muscle.
The function of mitochondria declines with age, while aging is a known risk factor for a number of common age-related and neurodegenerative disorders. This led to the proposition that secondary mitochondrial dysfunction may lead to degenerative diseases.
Results from part B of the study indicated that the compound upregulated mitochondrial gene expression in elderly skeletal muscle tissue and decreased plasma acylcarnitine metabolites, which has been linked to skeletal muscle insulin resistance and lipid-induced mitochondrial stress.
“We are pleased to report these first clinical data that demonstrate both the safety of Urolithin A and the translation of its biological effects to elderly human subjects. Urolithin A holds promise for the management of age-related decline in mitochondrial and skeletal muscle function, for which there are currently no pharmaceutical therapies and where nutritional strategies have had limited impact to date,” said Chris Rinsch, PhD, CEO and co-founder of Amazentis.
Mitochondrial stimulation
“It's exciting to see that orally administered Urolithin A is increasing mitochondrial gene expression in human muscle tissue following a 4-week treatment,” said Johan Auwerx, MD, PhD, Professor at the École Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
“Combined with the lowering of plasma acylcarnitines, this is the first evidence that Urolithin A stimulates mitochondria in the muscle of humans and is consistent with our earlier preclinical observations, which demonstrated that such molecular changes were coupled to enhanced muscle function.”
Results of a second, non-interventional study conducted by Amazentis revealed the strong link between low mobility status in elderly and declining mitochondrial function in skeletal muscle.
“These results set the stage for Phase 2 clinical studies featuring a longer intervention period and designed to assess the impact of Urolithin A on muscle and mitochondrial function in the healthy elderly population,” said Patrick Aebischer, MD, Chairman of Amazentis and Professor at the EPFL.
Dietary supplement products
Dr Rinsch told NutraIngredients-USA last year that the company intends to launch its own proprietary dietary supplement products, or to partner with the right players, but he stressed that Amazentis is not an ingredient company.
“We will launch when we’re ready and we can stand behind it,” he said.
To watch a video from the EPFL researchers
Sources: International Conference on Frailty and Sarcopenia Research (ICFSR), Barcelona, Spain.
OC30 - Orally-administered urolithin A is safe and modulates muscle and mitochondrial biomarkers in a randomized, double-blind, placebo-controlled phase 1 clinical trial in elderly
Authors: A. Singh et al.
OC46 - Mitochondrial dysfunction as a driver for age related muscle decline and frailty syndrome: A clinical study comparing active versus pre-frail elderly
Authors: J.P.M. van Diemen et al.