As we age, the immune system gradually becomes less adaptable and more prone to fatigue and chronic inflammation—a process known as immune aging. Rather than a simple loss of immune cells, this decline reflects deeper changes in how immune cells produce energy and respond to stress.

At the center of this process are the mitochondria. In immune cells, mitochondria regulate activation, proliferation, and long-term immune memory. When mitochondrial function declines with age, immune cells lose metabolic flexibility, rely on inefficient energy pathways, and become more easily exhausted. Damaged mitochondria also contribute to persistent low-grade inflammation, often referred to as inflammaging.

This has led researchers to focus on mitochondrial quality as a key driver of immune resilience.


Mitophagy: Maintaining Mitochondrial Quality

Cells maintain mitochondrial health through mitophagy, a selective process that identifies and removes damaged mitochondria. Mitophagy supports efficient energy production and reduces cellular stress. However, this quality-control system becomes less effective with age, allowing dysfunctional mitochondria to accumulate.

Supporting mitophagy has therefore emerged as a promising strategy in longevity and immune health research.


Urolithin A and Mitochondrial Renewal

Urolithin A is a natural metabolite produced from dietary ellagitannins found in foods such as pomegranates and certain nuts. What makes it scientifically distinctive is its ability to activate mitophagy, helping cells renew their mitochondrial pool.

Preclinical research first demonstrated that Urolithin A–induced mitophagy could improve mitochondrial efficiency and cellular resilience. More recently, human clinical research has begun to explore its relevance for immune function.


Evidence from a Human Clinical Trial

A randomized, double-blind, placebo-controlled study published in Nature Aging examined Urolithin A supplementation in healthy adults aged 45–70.

After 28 days of daily supplementation (1000 mg), participants showed meaningful changes in immune markers, including:

•      Increased naive-like CD8⁺ T cells, which are essential for responding to new immune challenges

•      Reduced expression of TOX, a marker associated with T-cell exhaustion

•      Increased Ki-67 expression, indicating enhanced immune cell activation and renewal


A Metabolic Shift Toward Efficient Energy Use

Advanced single-cell metabolic analysis revealed that immune cells shifted away from heavy reliance on glycolysis and toward mitochondrial oxidative pathways, including fatty acid and amino acid oxidation. This metabolic profile is characteristic of long-lived, high-functioning immune cells.

The study also found increased expression of PGC-1α, a key regulator of mitochondrial biogenesis, suggesting a coordinated process of removing damaged mitochondria while supporting the formation of healthier ones.


Functional Immune Outcomes

These cellular and metabolic changes translated into improved immune function:

•      Enhanced TNF secretion in response to immune challenge

•      Improved bacterial clearance by monocytes

•      Increased proportions of CD56^dim natural killer cells involved in immune surveillance

Gene expression analysis further supported a shift toward immune resilience and away from pathways linked to exhaustion and chronic inflammation.


A Science-Led View of Immune Aging

Together, these findings suggest that immune aging is closely tied to mitochondrial quality and cellular energy metabolism. Rather than stimulating the immune system directly, supporting mitochondrial renewal offers a more foundational approach to maintaining immune resilience over time.

While larger and longer-term studies are still needed, current evidence positions Urolithin A as one of the most extensively studied compounds for supporting mitochondrial health and age-related immune function.