Citrus Compound Significantly Increases Lifespan and Healthspan in Aging Models

Key Points: 

• Nomilin—a naturally-occurring compound in citrus fruits such as lemons, grapefruits, and oranges, as well as in tangerine seed and peel—increased roundworm lifespan by 24%.
• Dietary nomilin supplementation improved healthspan and lifespan in a mouse model of premature aging.
• The lifespan- and healthspan-enhancing properties of nomilin in animals are linked to the activation of detoxification functions.

Researchers from several Shanghai universities collaborated in a study showing that a naturally-occurring compound in citrus fruits—such as lemons, grapefruits, oranges, and tangerines—extends lifespan and healthspan in animals. In roundworms, nomilin increased lifespan by 24%, which the researchers report occurs through a mechanism that enhances detoxification pathway activity. In mouse models of premature aging, the compound has protective effects in several organs, including the brain, heart, and liver, where it also works by increasing the activity of genes involved in detoxification. The research was published in Nature Communications, and the participating institutions included Shanghai University of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine, and ShanghaiTech University.

Detoxification Is Linked to Worm Longevity

Increasing evidence has shown that the activity of detoxification enzyme genes and resistance to toxins are increased in long-lived flies, worms, and rodents. Detoxification gene activity is increased in the liver and shows more resistance to liver-targeting toxins in several types of mice, including long-lived species of mice, genetically altered mice, and dietary-restricted mice. Recent research showed that genes involved in drug metabolism and detoxification were more active in the livers of mice that had received 17 known interventions that increase lifespan. This suggests that focusing on detoxification may be a useful intervention therapy for increasing lifespan.

In roundworms, the activity of the detoxification pathway is under the control of two genes called NHR8 and DAF-12. These two genes are called nuclear hormone receptors and are required for the longer lifespan and healthspan in roundworms, indicating that NHR-8 and DAF-12 are required for the longevity of roundworms.

In this research article, Chinese researchers propose that the activation of nuclear hormone receptors mediating detoxification gene activity may be a strategy for lifespan-extending interventions and aging-related diseases.

Next, the researchers tried to identify whether there is a mammalian counterpart to roundworm NHR-8 and DAF-12. Using human cells, they found that, out of all the nuclear hormone receptors involved in detoxification, nomilin only activated the pregnane X receptor. Additionally, the researchers confirmed that nomilin binds the human pregnane X receptor using a very sophisticated technique called crystallography, which can be used to study the arrangement and bonding of atoms. Taken together, these data suggest that, in mammals, nomilin may work through hPXR to enhance lifespan and healthspan.

Nomilin Improves Healthspan of D-galactose Induced Early-Senescence Mice

To test whether nomilin could improve healthspan in mammals, the researchers used a mouse model of premature aging. This model, which uses a compound called D-galactose, reproduces premature aging by triggering cell senescence, which is when cells stop growing and dividing as a result of aging, in several organs. In the liver, D-galactose induced liver inflammation, and the inflammatory cells infiltrated into the liver tissues, but nomilin significantly reversed these changes.

Age-related damage was also observed in the central nervous system. D-galactose increased the number of dead brain cells in the hippocampus, which is critical for learning and memory, while nomilin treatment reduced the number of dead cells. 

The researchers demonstrated that D-galactose decreased mice’s performance abilities in a variety of tasks for various cognitive functions, such as short- and long-term memory. However, nomilin was able to reverse the effect of D-galactone on cognitive abilities, in some cases all the way back to the levels seen in untreated animals. The tests were used to measure cognitive abilities. Additionally, the motor abilities of mice were compromised by D-galactose treatment, which was rescued with nomilin. When they repeated all of these experiments in mice lacking the pregnane X receptor, the ability of nomilin to reverse the aging effects of D-galactose was lost.

The researchers then repeated these experiments in several other mouse models of aging. In one of these models using doxorubicin-induced senescence in mice, those that also received nomilin had far less heart atrophy and scarring, less inflammation of the liver, and improved detoxification function. In another model using genetically altered mice that are characterized by premature senescence, nomilin improved age-related disorders such as motor impairments, anxiety-like behavior, and memory deficits.

Will Drinking Orange Juice Make Me Live Longer?

Interestingly, citrus and grapefruit juices may contain a large amount of nomilin or its precursors, but most of them would be removed in the “debittering” processing in the orange juice industry because of their bitter taste. In this study, the researchers showed that nomilin-treatments did not change the mice’s body weight and food consumption, indicating that nomilin may be a safe component. Therefore, these results suggest that a revisit of the “debittering” process may be needed given the potential beneficial function of nomilin. Whether the consumption of nomilin-containing citrus fruits and juices improves longevity and aging in healthy mice and humans needs to be investigated.