Mitochondrial function, age-related immune decline, and urolithin A

New study that shows promise for inflammaging

As we age, mitochondrial dysfunction increases, which limits cellular energy production and leads to increased oxidative stress. Mitochondrial dysfunction can affect all cell types, but the immune system, in particular, is susceptible to decline. This can lead to immune cell “exhaustion”, causing a higher susceptibility to infections and inflammaging. Thus, maintaining mitochondrial health can help to slow or eliminate inflammaging.

A new study in Nature aging shows that urolithin A, as a supplement, may hold the key to slowing inflammaging.¹

Background:
Urolithin A is a natural compound that gut bacteria produce by metabolizing specific polyphenols, called ellagitanins, which are found in pomegranates, berries, almonds, and walnuts.

About 40% of the population hosts the right type of gut microbes for converting ellagitanins to urolithin A. However, supplemental urolithin A at 500 mg/day has been shown to raise plasma levels by about 6-fold more than pomegranate juice (assuming you have the right gut bacteria).²

In regard to mitochondrial health, urolithin A has been shown to increase mitophagy, the process by which damaged or defective mitochondria are broken down and recycled. It also increases mitochondrial energy production - but only when mitochondria are under stress. ³

The intervention:
The new study that has longevity science abuzz involved 50 adults (aged 45–70) who took either 1,000 mg/day of urolithin A (UA) or a placebo for 4 weeks.

What did they find?
Urolithin A increased the number of naive, less-exhausted CD8+ T cells, which are the type of immune cell important for fighting infections and cancer. CD8+ T cells are also called cytotoxic T cells and are a type of white blood cell (lymphocytes). Urolithin A also increased natural killer cells and monocytes, while decreasing cytokines (IL-6, TNF, IL-1β). The urolithin A arm of the study also showed improved fatty acid oxidation capacity, which means the immune cells could better use fats for energy due to improved mitochondrial function.

Essentially, urolithin A causes a broadly beneficial reprogramming of immune cells, shifting gene expression toward a healthier state with more energy available.

Why is this important:
T cell exhaustion and dysregulated immune response could arguably be the number one cause of death (I’m lumping together cancer and infectious diseases).

Quality caution on urolithin A supplements:
There are multiple brands of urolithin A supplements on Amazon — some expensive and some relatively cheap. It turns out that the relatively inexpensive urolithin A supplements from brands that I had never heard of don’t actually contain much urolithin A….

SuppCo testing company also tested urolithin A supplements from brands ordered off Amazon. They found four brands that had their labeled amount: CodeAge liposomal*, Timeline Mitopure, Pure Encapsulation Renual (out of stock right now), and Neurogan Health. The other, less expensive brands had little to no urolithin A in them. You can read the full SuppCo report here.

These supplements are expensive (~$50/month) and are more likely to be helpful for someone who is older or who is dealing with a health problem. Personally, I added a couple to my Amazon wish list and am going to check for Black Friday sales.

Want to know more about urolithin A?
Check out the Genetic Lifehacks article that goes into clinical trials for athletic performance, osteoarthritis, and muscle decline in older adults.

1. Denk, Dominic, et al. “Effect of the Mitophagy Inducer Urolithin A on Age-Related Immune Decline: A Randomized, Placebo-Controlled Trial.” Nature Aging, vol. 5, no. 11, Nov. 2025, pp. 2309–22. www.nature.com, https://doi.org/10.1038/s43587-025-00996-x.

2. Singh, Anurag, et al. “Direct Supplementation with Urolithin A Overcomes Limitations of Dietary Exposure and Gut Microbiome Variability in Healthy Adults to Achieve Consistent Levels across the Population.” European Journal of Clinical Nutrition, vol. 76, no. 2, Feb. 2022, pp. 297–308. www.nature.com, https://doi.org/10.1038/s41430-021-00950-1.

3. Huang, Jian-rong, et al. “Urolithin A Ameliorates Obesity-Induced Metabolic Cardiomyopathy in Mice via Mitophagy Activation.” Acta Pharmacologica Sinica, vol. 44, no. 2, Feb. 2023, pp. 321–31. PubMed Central, https://doi.org/10.1038/s41401-022-00919-1.

* Amazon affiliate link. I get a small percentage from amazon sales, that I then use to support my supplement habit.