Urolithin A Can Revitalize Blood Stem Cells in People and Mice, Study Finds

This mitochondrial modulator helps old human blood stem cells grow and copy themselves more efficiently, and it also helps blood stem cells make blood and immune systems for old mice.

Key Points:

Giving urolithin A to old human blood stem cells makes them grow and divide better.
When added to food, urolithin A makes old mice’s immune systems stronger so they can fight off viral infections.
Blood stem cells that are exposed to Urolithin A can make new blood and immune cells better.

Research at the Ludwig Institute for Cancer Research at the University of Lausanne shows that a molecule called urolithin A can make old blood stem cells better at making blood and immune systems. Blood stem cells from old people were given Urolithin A for three days, which made them better able to grow and divide. When urolithin A was added to the food that old mice ate, the blood stem cells were able to rebuild the immune and blood systems, even making the immune response better against viruses. These findings, which were published in Nature Aging, show that urolothin A can prevent the blood and immune systems from getting worse with age.

Metabolism and Blood Stem Cell Aging

All of an organism’s blood and immune cells are made by blood stem cells, which are also called hematopoietic stem cells (HSCs). But as people age, their HSCs’ ability to make new blood drops dramatically, which throws off their immune systems. So, it has been suggested that stopping HSCs from getting older would improve blood and immune systems.

Cellular metabolism is thought to play a big role in controlling the number of HSCs and stem cell function in general. It has been shown that the mitochondrial modulator urolithin A, a natural compound from the ellagitannin family, can improve metabolic fitness in humans and rodents and make worms live longer by keeping mitophagy and mitochondrial function up.

Urolithin A Reverts Blood Stem Cell Aging

Co-lead authors Mukul Girotra and Yi-Hsuan Chiang and colleagues tested the capacity of urolithin A to recover the functions of HSCs. First, they took HSCs from mice older than 18 months (called “old HSCs”) and cultured them for 3 days with 20 μM urolithin A. Then, they put these treated “old HSCs” into mice that did not have HSCs. Urolithin A treatment brought back the regenerative abilities of old HSCs to levels seen in HSCs isolated from 8–12-week-old mice (called “young HSCs”). To find out what urolithin A does to HSCs over the long term, bone from one of the recipient mice was transplanted to another and the mice were watched for 20 weeks. The urolithin A effect was still there after the second transplant. It did the same things that happened after the first transplant: it restored the HSC pool in the bone marrow and made blood just as well as young HSCs.

**(Girotra et al., 2023 | *Nature Aging*)** **Oral supplementation of urolithin A rejuvenates the blood system of old mice.** Old mice (81–84 weeks old) were fed with a control (black) or urolithin A (UA) supplemented (red) diet (50 mg kg/day) for 16 weeks. (left) The old mice on urolithin A -supplemented diets had higher percentages of blood stem cells (HSCs) in their bone marrow. (middle) Transplantation of the bone marrow from old mice on urolithin A -supplemented diets was highly incorporated into the blood systems of recipient mice. (right) Transplantation of 200 purified HSCs from old mice on urolithin A-supplemented diets was highly incorporated into the blood systems of the recipient mice.

In the same way, treating human HSCs from older adults with urolithin A increased their stem cell activities. The researchers used a test called a colony-forming assay to show this. In this test, single HSCs are taken out and tested to see how well they can grow and divide into small groups of cells. Colony-forming tests showed that urolithin A increased the ability of HSCs to form colonies, both when they were first tested on their own and when they were taken from a colony and tested again for their ability to form colonies. It is interesting that urolithin A treatment improves the ability of young human HSCs to repair themselves, though not as much as it does with old human HSCs. All of these results show that exposing old human HSCs to urolithin A for three days in a lab setting improves their ability to make new blood over time.

**(Girotra et al., 2023 | *Nature Aging*)** **Urolithin A improves the viability of old human blood stem cells.** 1000 blood stem cells derived from the bone marrow of anonymous old adults (58–77 years old) were treated for 3 days with 20 μM urolithin A and tested for their ability to grow and divide. Urolithin A increased the ability of single blood stem cells from old humans to grow and divide. CFU, colony-forming unit.

In order to see if increasing hematopoietic capacity improves immune function, lymphocytic choriomeningitis virus (LCMV) was given to old mice that had been fed a diet high in urolithin A for 8 weeks. On the eighth day after infection, the immune response against the virus was tested. The urolithin A diet reversed the loss of immune cells that could recognize the virus that came with getting older. Also, tests were done to make sure that this effect was caused by HSCs and not other cells from old mice that were fed food with urolithin A added to it. All of these results point to the fact that urolithin A may help old mice’s immune systems work better.

Urolithin A vs. NAD+ boosting

As with urolithin A, NAD+ booster supplements can help old HSCs function like they are younger again by making their metabolism work like it did when they were younger. One main difference is that urolithin A does not restore “old” HSC function, while nicotinamide riboside needs to be added to the body all the time.

Altogether, urolithin A supplementation might have a big effect on older people by strengthening their immune and hematopoietic systems. This could lower their risk of hematopoietic failure, make their immune system stronger, and help them respond better to vaccinations. People who are getting chemotherapy could also benefit from taking extra urolithin A because chemotherapy weakens the immune system, making people more likely to get infections and less likely to respond to vaccinations.

When cells get older, they lose the ability to check the quality of their machinery. This causes defective machinery to build up and functions to quickly get worse. The study’s results show that treating old HSCs with urolithin A can fix their metabolic problems and improve the functions of the blood and immune system. This shows that cellular metabolism and cellular dysfunctions related to aging are closely connected.