A groundbreaking study published in Science Advances has revealed that citrulline—a naturally occurring amino acid found abundantly in melons—may serve as a potent weapon against aging. By analyzing aging-associated metabolic changes in mice, researchers identified citrulline as a significantly downregulated metabolite. Supplementing citrulline helped reduce cellular senescence, DNA damage, and inflammation while regulating macrophage metabolism. Long-term supplementation in elderly mice improved age-related phenotypes and extended their healthy lifespan. This research suggests that "eating melons" might be more than a summer treat—it could be a science-backed longevity strategy.
New Research Confirms: Melons May Offer Real Anti-Aging Power!
A recent study published in the prestigious journal Science Advances has brought exciting news to the wellness world: melon-derived compounds might hold the key to longevity. By conducting an untargeted metabolomic analysis of aging mice, scientists discovered that citrulline—a non-protein amino acid—consistently declines with age. Supplementing citrulline helped delay cellular aging, prevented DNA damage and cell cycle arrest, modulated macrophage metabolism, and reduced inflammation. Even more impressively, long-term supplementation in elderly mice not only rejuvenated their systems but also significantly reversed multiple aging-related phenotypes.
What Exactly Is Citrulline?
Citrulline is a naturally occurring amino acid that doesn’t participate in protein synthesis, but plays a vital role in human metabolism. As its name suggests, citrulline is primarily found in melons. Among natural food sources, watermelon contains the highest concentration—over 200 mg of citrulline per 100 grams. Citrulline is also found in other types of gourds such as winter melon, cucumber, bitter melon, pumpkin, and loofah, as well as in various high-protein foods.
Can Eating Melons Really Fight Aging?
Metabolic dysfunction is widely considered one of the hallmarks of aging. To explore the metabolic contributions to aging, the researchers conducted a comprehensive analysis of the brain, liver, and serum samples from male mice at various ages. Their aim was to identify age-associated metabolic alterations across these tissues.
Interestingly, citrulline and another compound—1,5-anhydroglucitol—were consistently found to be downregulated in all three tissues. In particular, the level of citrulline in the liver tissue of 24-week-old mice (equivalent to older mice) dropped by 50% compared to 6-week-old mice. Likewise, the levels of citrulline in the brain and serum were reduced by about 20%. These observations suggest that citrulline is a metabolite consistently depleted during the aging process.
Citrulline is significantly downregulated during aging
To assess the effect of citrulline on cellular senescence and inflammatory responses, the team used a model of mouse embryonic fibroblasts (MEFs) undergoing oxidative stress-induced senescence. Remarkably, citrulline supplementation led to a significant reduction in γH2AX (a biomarker of DNA damage), inhibited senescence-associated β-galactosidase (SA-β-Gal) activity, and lowered levels of aging markers such as p21 and various inflammatory cytokines.
Further experiments using primary bone marrow-derived macrophages confirmed these findings, showing a consistent anti-aging and anti-inflammatory effect of citrulline in vitro.
The researchers then proceeded to conduct in vivo tests by administering citrulline to both young and aged mice over an extended period. The results were striking: inflammatory cytokine levels in aged mice dropped noticeably, microglial activation in aging brain tissues was inhibited, and DNA damage associated with aging was significantly reduced. These findings strongly support citrulline’s potential as an anti-aging agent.
In vitro and in vivo experiments show that citrulline supplementation can fight aging
How Does Citrulline Combat Aging and Inflammation?
Additional in vitro studies demonstrated that citrulline could drastically reduce the expression of inflammatory cytokines in activated macrophages. In vivo experiments also showed that citrulline supplementation significantly improved survival in mice suffering from LPS-induced acute liver injury and sepsis—two deadly inflammation-driven conditions.
These results suggest that citrulline is effective in reducing inflammatory responses, both in living organisms and isolated cells, potentially extending lifespan and improving overall health.
Delving deeper, the researchers uncovered that citrulline exerts its anti-inflammatory effects by modulating the mTOR signaling pathway in macrophages. Overactivation of the mTOR pathway is known to enhance glycolytic metabolism, thereby aggravating inflammatory responses. Citrulline suppressed mTOR activation in aged macrophages, which in turn led to a downregulation of HIF1α—a key regulator of glycolysis and inflammation. By inhibiting HIF1α, the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β was significantly reduced. This cascade ultimately alleviated chronic inflammation and helped delay the aging process.
Citrulline fights aging and inflammation by regulating macrophage metabolism
These comprehensive results indicate that long-term citrulline supplementation offers considerable health benefits in aging mice, improving aging-related characteristics and extending their healthy lifespan.
Final Thoughts
This exciting scientific discovery elevates the humble melon to a new status as a natural longevity ally. Citrulline, the newly crowned star of anti-aging science, is a naturally occurring treasure found in your favorite summer fruit. With mounting evidence supporting its metabolic, cellular, and systemic benefits, it’s safe to say that the phrase "eating melons" just got a high-tech upgrade.
So next time you bite into a juicy slice of watermelon, remember—you might be doing more than enjoying a treat. You could be feeding your body a powerful anti-aging molecule straight from nature’s pharmacy.
References:
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Xie Z, Lin M, Xing B, et al. Citrulline regulates macrophage metabolism and inflammation to counter aging in mice. Sci Adv. 2025;11(10):eads4957. doi:10.1126/sciadv.ads4957