FROM CITRUS PEEL TO LONGEVITY: WHY NOBILETIN MIGHT BE THE NEXT BIG THING IN ANTI-AGING
The Kaufmann Protocol Rating for Nobiletin (0. 2. 2. 2. 2. 2. 1)
DR. SANDRA KAUFMANN
FEB 2025
MAHA Inaugural Ball
EXCLUSIVE COVERAGE
Trump wins 2024 election
RFK JR
Pursuit of Pet Longevity
FUREVER FAITHFUL
Kate Middleton
CONFIRMS CANCER REMIISSION
From Misinformation to Integrity
PEER REVIEW REVOLUTION
LATEST STORIES
I evaluate new molecular agents on a very regular basis, and whereas most of them are useful, very few stand out as truly different and essential. Therefore, I am presenting nobiletin, as I believe it is going to turn into one of the true “must haves” in any longevity program.
Nobiletin (NOB) comes from oranges and other citrus fruits, although it resides in the peel, which few of us consume on a regular basis. It is a methoxyflavone, aka 5,6,7,8,3′,4′-hexamethoxyflavone, and is most commonly derived from shikuwasa, a popular greenish/ yellow citrus fruit from Okinawa, Japan despite being very sour.
Of note, dried citrus peel, known as Chenpi in Chinese has traditionally been used to promote the circulation of qi throughout the body.
ADVERTISEMENT
.jpg)
The Kaufmann Rating designation, 0.2.2.2.2.2.1, offers a clue as to why I am so enamored with this agent. It does a lot in a lot of categories, in fact, all but one, and has extremely good supportive evidence. But, as there are few human trials, the scores remain at 2’s instead of 3’s making it underappreciated, but still quite useful. That being said, we have thousands of years of actual human use, supporting its efficacy.
Taking an in-depth look at NOB through the lens of the tenets demonstrates that Tenet I, the DNA category, is the only one whereby there is no evidence that our molecule has any activity.
Nobiletin
Nobiletin comes from the peel of oranges and other citrus fruits.
Tenet II, encompassing mitochondrial challenges, demonstrates that, at least in rodent models, NOB contributes to the Electron Transport Chain. It increases Complex II activation, and supports the Complex I and III Supercomplex formation, improving both function and architecture. Also within the mitochondria, NOB up-regulates NRF-2, precipitating an increase in endogenous Free Radical scavenging capacity. It has also been shown, and this is unusual, that NOB can increase the levels of cardiolipin in the mitochondrial lipid layers in skeletal muscle tissues.
In Tenet III or the pathways category, NOB activates AMP Kinase and SIRTUIN 1, although this is not unusual. The activation of Sirtuin 5, however, is a standout characteristic.
.jpg)
ADVERTISEMENT
Our top picks
Dr. Steve Gundry
Health through gut wellness
MHI
The myths around testosterone
Weber Medical
Multi-wavelength light therapy
Dr. Todd Ovakaitys
Why you should save the umbilical cord
ADVERTISEMENT
Nobiletin activates autophagy and even mitophagy in Tenet IV and serves as an anti-inflammatory in Tenet V. In tenet VI addressing individual cell needs, NOB enhances osteoblast differentiation and bone formation in innumerable rodent models and is thought to improve osteoporosis in humans. Lastly, in Tenet VII or waste management, NOB up-regulates the expression of glucose transporter-4, driving glucose into muscles.
Perhaps the most important role for nobiletin, however, is that of an ROR (retinoid acid receptor-related orphan receptor) agonist in the circadian rhythm system. Directly and potently binding to RORα/RORγ nuclear receptors, it supports the core components of the oscillating clock mechanism, which is important for the stability and robustness of circadian rhythms. Long recognized as a particularly effective clock amplitude-enhancing small molecule, it has also been shown to alter the period and phase of the clock cycle. Therefore, nobiletin has the potential to be a potent sleep-assisting molecule for age-related sleep deprivation.
Dr. Sandra Kaufmann
Longevity Physician, Author, Creator of The Kaufmann Protocol
As a possible side effect, please be aware, however, that nobiletin can also affect platelet function. It can prevent platelet aggregation which is helpful if you are having a stroke, but it can also prolong clotting time or increase potential bleeding.
Lastly, unlike many over-the-counter supplements, nobiletin demonstrates high bioavailability and low toxicity and has been extensively taken over the years by innumerable populations, demonstrating its safety. It is, however, fat-soluble, so please take it with food!
