Written by Alexa Heathorn, MS, CNS. Four weeks of daily urolithin A supplementation (1,000 mg) improved immune cell composition, increased naïve CD8⁺ T cells, enhanced mitochondrial function, and reduced markers of immune exhaustion in healthy middle-aged adults, supporting its potential role in promoting immune resilience and healthy aging.

Healthy aging remains a major focus in modern healthcare, with the immune and metabolic systems playing central roles in this process. As the body ages, the immune system shifts toward reduced production of key immune cells and increased chronic low-grade inflammation, known as inflammaging, which is linked to conditions such as cardiovascular disease and cancer.¹ At the same time, mitochondrial function declines. The body becomes less efficient at removing damaged mitochondria, leading to impaired energy production and increased inflammatory signaling, both recognized hallmarks of aging.¹ Because mitochondrial health directly influences immune function, this decline further contributes to immune aging. Despite this knowledge, current strategies to support immune health remain limited to general lifestyle recommendations. This has led to growing interest in targeted interventions, such as urolithin A (UA), a compound known to support mitochondrial health, which was investigated in a recent randomized, placebo-controlled trial.¹

Urolithin A (UA) is a compound produced by gut bacteria through the metabolism of polyphenols found in foods such as pomegranates, berries, and nuts.² Previous research has shown that UA can enhance the removal of damaged mitochondria (mitophagy), improve physical performance, and positively influence immune-related markers.¹ However, despite these promising findings, limited research has examined the effects of urolithin A on immune aging in humans. To address this gap, a recent randomized, double-blind, placebo-controlled trial investigated the impact of UA supplementation on immune function and inflammation in healthy middle-aged adults.¹

This randomized, double-blind, placebo-controlled proof-of-concept trial examined the effects of 4 weeks of urolithin A supplementation on immune health in 50 healthy middle-aged adults.¹ Participants received either 1,000 mg of UA per day or a placebo. Primary outcomes included changes in T cell subpopulations and mitochondrial activity in CD8⁺ T cells.¹ Secondary outcomes included changes in inflammatory markers, immune cell composition, mitochondrial content, and immune cell function.¹

The results were as follows after 4 weeks:

Immune Cell Changes:

• UA did not significantly change total CD3⁺ T cell counts, but it shifted T cell composition toward a more favorable profile.
• UA increased naive CD8⁺ T cells (P = 0.0408), indicating a more “youthful” immune phenotype.
• Markers of T cell exhaustion (TOX) were reduced (P = 0.0161), while cell proliferation (Ki-67) increased (P = 0.0062).

Mitochondrial & Metabolic Function:

• UA improved the ability of immune cells to generate energy from fats and amino acids (P = 0.0061).
• CD8⁺ T cells showed increased mitochondrial biogenesis (PGC-1α) (P = 0.0299).

Inflammation & Immune Response:

• No increase in baseline inflammation was observed.
• Upon stimulation, T cells produced more TNF-α (P = 0.0039), suggesting an improved ability to mount an appropriate immune response when challenged.
• IL-2 levels decreased (P = 0.0145), indicating shifts in immune signaling and regulation.

Other Immune Cells:

• Increases in natural killer (NK) cells (P = 0.0206) and nonclassical monocytes (P = 0.0433) were observed.
• Monocytes showed improved ability to clear bacteria (P = 0.0087).

Safety:

• UA was well tolerated, with no significant differences in adverse events compared to placebo.

Several limitations should be considered when interpreting these findings. The sample size was relatively small (50 participants), which may limit how broadly the results apply to larger or more diverse populations. Additionally, the study included only healthy middle-aged adults, so the findings may not extend to older individuals, those with chronic conditions, or populations with existing immune dysfunction. The intervention period was short (4 weeks), making it unclear whether the observed improvements in immune and mitochondrial function would be sustained over time. Additionally, the study focused on cellular and biochemical markers rather than clinical outcomes, so it remains unknown whether these changes translate to meaningful health benefits such as reduced illness or improved immune resilience. Lastly, some secondary measurements, including certain cytokine analyses, were conducted in smaller subsets of participants, which may limit the strength of those specific findings.

This study suggests that urolithin A supplementation may support key aspects of immune health during aging by improving immune cell composition, enhancing mitochondrial function, and promoting a more responsive immune state. The increase in naïve CD8⁺ T cells and reduction in markers of immune exhaustion point toward a shift in the immune system that resembles a more youthful profile. Improvements in cellular energy metabolism and bacterial clearance further support the role of mitochondrial health in regulating immune function. While longer-term research is needed to determine whether these changes translate into measurable health outcomes, these findings highlight the potential of targeting mitochondrial function as a strategy to support immune resilience and healthy aging.

Source: Denk, Dominic, Anurag Singh, Herbert G. Kasler, Davide D’Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M. Gorol et al. “Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.” Nature aging (2025): 1-14.

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Posted April 1, 2026.

Alexa Heathorn, MS, CNS-c, is a clinical nutritionist specializing in metabolic health, hormonal balance, and gastrointestinal restoration through root-cause functional nutrition. She earned her master’s degree in Nutrition from Bastyr University and is currently a Certified Nutrition Specialist (CNS) candidate. Alexa also works as a research writer and functional health consultant, translating complex science into actionable strategies for practitioners and wellness companies. Learn more at www.bloomedwellness.com.

References:

1. Denk D, Singh A, Kasler HG, et al. Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial. Nat Aging. Nov 2025;5(11):2309–2322. doi:10.1038/s43587-025-00996-x
2. Zhao H, Song G, Zhu H, et al. Pharmacological Effects of Urolithin A and Its Role in Muscle Health and Performance: Current Knowledge and Prospects. Nutrients. Oct 19 2023;15(20)doi:10.3390/nu15204441