Shikuwasa Nobiletin Citrus of Longevity
FOOD

Shikuwasa: The Powerful Longevity Promoting Fruit & the Benefits of Nobiletin

Shikuwasa is just one of those fruits you can't get anywhere else in the world. A powerful citrus with a surprising potential to be the answer to serious health conditions like Alzheimer's. It's endemic to the Ryukyus and has a deceptive lime or Calamansi like appearance, but tastes completely different to its other green citrus cousins.

What is Shikuwasa?

When you’re in the Ryukyus, you really get to feel the omnipresence of Shikuwasa; from Shikuwasa flavoured ice-cream to Shikuwasa cakes, you can tell that this small little green ball is a Ryukyuan national treasure. But it isn’t just its tangy, sweet and sour taste which makes it a beloved, timeless favourite. Some say that Shikuwasa’s omnipresence can also be felt through the youth of the Ryukyuan elders, its longevity promoting benefits all part of the diets that make the Ryukyuans renown for their long-lasting, fulfilled and happy lives.

‘Shii’ means ‘sour’ in Uchinaaguchi, the endangered and native language of the main island, and ‘kwasaa’ means ‘food’. This ‘sour food’ has a bitter, sweet and sour taste like a lime but with a unique, tarty, sweet flavour that refreshes and quenches your thirst and keeps you coming back for more.

It also contains out-of-the-ordinary levels of Nobiletin, the main flavonoid found in Citrus fruit that’s been scientifically proven to protect the brain from age-related neurological damage, with anti-cancer, anti-inflammatory and anti-oxidative properties.

What is Nobiletin?

Nobiletin is the new and exciting name in the world of pharmacology. This non-protein compound is found in the peel of citrus fruits, mainly Citrus depressa or shikuwasa, also known as Taiwan tangerine, Okinawa lime.1 This fruit is commonly found in the Ryukyu Islands. Despite its humble origins, Nobiletin has quite an extraordinary effect on the body. Research has found that the benefits of NOB or Noliletin include preventive action against cardiovascular disease, neuroprotective effect, anticancer effect, anti-inflammatory effect, and antioxidative effect.2 


To understand the function of Nobiletin, it is essential to understand its chemical composition. NOB is highly lipophilic, which means it can be absorbed in our body with ease and act directly on various organs without changing its composition. Let's review Nobiletin's effects one by one.


Alzheimer's and neurodegenerative disease: 


First, Nobiletin is famously proved to be effective against Alzheimer's. Groundbreaking research published in "Biochemistry" in 2005 establishes Nobiltein as an effective neurotrophic factor (factors that control growth and healing of nerves). 

These researchers found that Nobiletin promotes neurite outgrowth and acts better than nerve growth factors. When put in simple terms it means that Nobiletin promotes nerve and brain growth and healing. 3  Nerve growth factors are natural chemicals that promote the healing of neurons, unit cells of the brain. 

Using NGF of Nerve growth factors to prevent Alzheimer’s and other similar progressive neurodegenerative disorders (disorders where nerve fibres get degenerated) can be treated with Nobiletin and can be treated faster due to its high absorption. The researchers also found that the effect of Nobiletin on cell proliferation started within 3 minutes of administration of the drug. 

In another study published in 2016, this theory was proved clinically. This study was concluded on ageing rats to see the effect of Nobiletin on cognitive impairment or memory loss. 


Among the 50 rats used in this study, the 20 who were given Nobiletin showed remarkable cognitive improvement in a standard Morris water maze test (standard test scientists do in lab’s to evaluate mice’s memory). 4 5  The study showed that after one year of intervention with nobiletin-rich extract, the advancement of the cognitive impairments of the patients was prevented successfully without any side effects. 

This effect has been confirmed to work in humans too. In one study done on eleven patients with mild-to-moderate Alzheimer's disease, six were administered with Nobiletin.5  The study showed that after one year of intervention with nobiletin-rich extract, the advancement of the cognitive impairments of the patients was prevented successfully without any side effects. 

Cognitive impairment of Alzheimer's includes a lot of symptoms including memory loss, attention problems, language etc. Unfortunately, these researchers did not specify exactly which impairments were stopped. They just mentioned that the MMSE and ADAS-J cog values (tests to assess cognition) were the same 1 year apart. Here is a link to the study.


Heart disease:


Nobiletin has been known to prevent cardiovascular complications as well. Dr Bo-fang Zhang from China published an article describing the benefit of using Nobiletin in preventing myocardial ischemia and reperfusion injury; heart attack.6 This study was also done in rats, showing significantly lower heart cell death after a heart attack on mice on Nobiletin pre-treatment. Nobiletin also restored the impaired heart function and prevented further heart cell damage. Multiple studies are confirming this effect. 

Another study done in 2017 shows that it prevents cardiac hypertrophy induced by pressure-overload. 7 It is a common condition in people with high blood pressure and can often lead to left ventricular hypertrophy or even heart failure or arrhythmia. Just ingesting Nobiletin prevented such diseases in mice. 


Antioxidant: 


Nobiletin is a polymethoxylated flavone (PMF). PMF compounds such as Nobiletin have been proven to act as potent antioxidants by preventing free radical production and prevent cellular damage.8 They also prevent inflammation and cellular ageing.


Anti-ageing: 


Being an antioxidant, Nobiletin naturally acts as an anti-ageing agent as well. The primary effect of the drug is against a hallmark of ageing: Metabolic deterioration.9  One study showed that Nobiletin strengthens metabolic fitness and delays the signs of ageing.9 In this experiment, the mice on Nobiletin showed better energy expenditure, tolerance to temperature change, endurance, strength, and inflammatory reactions, all signs of youth.
Circadian Rhythym
Nobiletin has been found to improve circadian rhythm.

Circadian rhythm: This study also showed a curious effect of Nobiletin. That is its effect on the circadian rhythm. Many researchers have suggested circadian rhythm over the years as the key factor behind health, metabolism, and ageing. There have been countless studies proving that circadian reprogramming basically resets most organ functions and delays ageing on a cellular and physical level. 11 12 


Newer studies tie circadian rhythm and Nobiletin by stating the latter's significant impact on the former. One study dubbed NOB as a "clock amplitude-enhancing molecule." According to the study, when this drug was given to obese mice, it counteracted the progression of metabolic syndrome. 


Not only that, it increased circadian clock protein levels and caused major gene remodelling in the liver, basically creating healthy circadian rhythm genes.13 As the liver is the most crucial producer of enzymes, hormones, and control centre of metabolic activities in our body, resetting the circadian rhythm of liver cells means curing and preventing not only ageing but other metabolic disorders as well. 


A study proves this effect by showing how Nobiletin prevents insulin resistance, thereby diabetes, and fatty liver by reprogramming hepatocytes or liver cells. 14 The researchers mentioned that "NOB may serve as a nutritional preventive strategy" to prevent metabolic disorders.

Cancer: Nobiletin has pronounced effects on almost every major health issue. It has also been used as a prevention of cancer. Researchers have proved that Nobiletin prevents cancer from forming and from spreading in labs.15 Nobiletin has been shown to reduce the speed of proliferation and spread of bone osteosarcoma, breast adenocarcinoma, and breast adenocarcinoma cells in different studies.


Interestingly, the same researchers also showed that cancers that disrupt the circadian rhythm are most affected by Nobiletin, which leads to the belief that it is through circadian rhythm that the drug enacts its effects. This citrus extract also is effective against lung cancer and colon cancer cells, two of the most common cancers after breast cancer. 16 17


 The massive benefits of Nobiletin have made it a favourite of most biohackers. This ingredient is completely natural and safe to consume; there is virtually no risk of using Nobiletin or shikuwasa extract powder to prevent everything from ageing to cancer. The benefits are well recorded, well researched, and proven beyond doubt.

References: 

  1. E. Yoshigai, T. Machida, T. Okuyama et al., “Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1β-treated hepatocytes,” Biochemical and Biophysical Research Communications, vol. 439, no. 1, pp. 54–59, 2013.
  2. Huang, H., Li, L., Shi, W., Liu, H., Yang, J., Yuan, X., & Wu, L. (2016). The multifunctional effects of nobiletin and its metabolites in vivo and in vitro. Evidence-Based Complementary and Alternative Medicine, 2016.
  3. Nagase, H., Yamakuni, T., Matsuzaki, K., Maruyama, Y., Kasahara, J., Hinohara, Y., ... & Ohizumi, Y. (2005). Mechanism of neurotrophic action of nobiletin in PC12D cells. Biochemistry, 44(42), 13683-13691.
  4. Bi, J., Zhang, H., Lu, J., & Lei, W. (2016). Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats. Molecular medicine reports, 14(6), 5408-5414.
  5. Seki, T., Kamiya, T., Furukawa, K., Azumi, M., Ishizuka, S., Takayama, S., ... & Yaegashi, N. (2013). Nobiletin‐rich Citrus reticulata peels, a kampo medicine for Alzheimer's disease: A case series. Geriatrics & gerontology international, 13(1), 236-238.
  6. Zhang, B. F., Jiang, H., Chen, J., Guo, X., Li, Y., Hu, Q., & Yang, S. (2019). Nobiletin ameliorates myocardial ischemia and reperfusion injury by attenuating endoplasmic reticulum stress-associated apoptosis through regulation of the PI3K/AKT signal pathway. International immunopharmacology, 73, 98-107.
  7. Zhang, N., Wei, W. Y., Yang, Z., Che, Y., Jin, Y. G., Liao, H. H., ... & Tang, Q. Z. (2017). Nobiletin, a polymethoxy flavonoid, protects against cardiac hypertrophy induced by pressure-overload via inhibition of NAPDH oxidases and endoplasmic reticulum stress. Cellular Physiology and Biochemistry, 42(4), 1313-1325.
  8. Chen, X. M., Tait, A. R., & Kitts, D. D. (2017). Flavonoid composition of orange peel and its association with antioxidant and anti-inflammatory activities. Food chemistry, 218, 15-21.
  9. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
  10. Nohara, K., Mallampalli, V., Nemkov, T., Wirianto, M., Yang, J., Ye, Y., ... & Chen, Z. (2019). Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge. Nature communications, 10(1), 1-15.
  11. Sato, S., Solanas, G., Peixoto, F. O., Bee, L., Symeonidi, A., Schmidt, M. S., ... & Sassone-Corsi, P. (2017). Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell, 170(4), 664-677.
  12. Banks, G., Nolan, P. M., & Peirson, S. N. (2016). Reciprocal interactions between circadian clocks and aging. Mammalian Genome, 27(7), 332-340.
  13. He, B., Nohara, K., Park, N., Park, Y. S., Guillory, B., Zhao, Z., ... & Chen, Z. (2016). The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell metabolism, 23(4), 610-621.
  14. Qi, G., Guo, R., Tian, H., Li, L., Liu, H., Mi, Y., & Liu, X. (2018). Nobiletin protects against insulin resistance and disorders of lipid metabolism by reprogramming of circadian clock in hepatocytes. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1863(6), 549-562.
  15. Lellupitiyage Don, S. S., Robertson, K. L., Lin, H. H., Labriola, C., Harrington, M. E., Taylor, S. R., & Farkas, M. E. (2020). Nobiletin affects circadian rhythms and oncogenic characteristics in a cell-dependent manner. Plos one, 15(7), e0236315.
  16. Sun, Y., Han, Y., Song, M., Charoensinphon, N., Zheng, J., Qiu, P., ... & Xiao, H. (2019). Inhibitory effects of nobiletin and its major metabolites on lung tumorigenesis. Food & function, 10(11), 7444-7452.
  17. Wu, X., Song, M., Wang, M., Zheng, J., Gao, Z., Xu, F., ... & Xiao, H. (2015). Chemopreventive effects of nobiletin and its colonic metabolites on colon carcinogenesis. Molecular nutrition & food research, 59(12), 2383-2394.

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