Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice

Some findings:

  • Hesperetin is a promising Cisd2 activator with no detectable toxicity

  • Hesperetin delays aging and promotes longevity in naturally aged WT mice

  • Hesperetin attenuates whole-body metabolic decline in old mice

  • Hesperetin reduces fat and improves glucose homeostasis in old mice

  • Hesperetin slows down skeletal muscle aging in old mice

  • Hesperetin slows down cardiac aging in old mice

  • The anti-aging effect of hesperetin is mainly dependent on Cisd2

  • Hesperetin treatment results in a younger transcriptome pattern

  • “The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day.”

Full Paper:

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Details from the paper: 8.7% Increase in Median Lifespan, 13.9% increase in Max lifespan.

to investigate if hesperetin is able to slow down aging and extend a healthy lifespan, we treated naturally aged mice started at 21-month old with dietary hesperetin and monitored their survival rate. Intriguingly, hesperetin significantly extends the lifespan of the aging mice (Fig. ​(Fig.1A).1A). The median lifespan of the hesperetin-treated WT mice was increased by 2.25 months (8.7%; from 25.95- to 28.2-month old) relative to Veh-treated WT mice (p = 0.04), with the maximum lifespan increase being 4.1 months (13.9%; from 29.5- to 33.6-month old).

Hesperetin, a flavanone class of citrus flavonoid, is a derivative of hesperidin found in citrus fruits such as oranges, grapes, and lemons. It has been extensively reported that hesperetin exerts neuroprotective effects in experimental models of neurodegenerative diseases.

full paper

http://sci-hub.wf/10.1080/10408398.2021.1875979

The clinical application of Hst is still limited because its low water solubility and poor in vivo bioavailability issues might necessitate high doses of oral administration to overcome therapeutic concentration. Additionally, the Hst penetration to blood–brain barrier is another limitation in brain diseases treatment. However, to solve these limitations, new Hst delivery systems have been developed such as inclusion complexes with nanoparticles and cyclodextrins. These new Hst formulations should be standardized and tested clinically to ensure CV and neuroprotective effects. Also worth of note is that, well- designed clinical trials are pivotal to study the other poten- tial effects of Hst, already stated in preclinical studies. The safety, efficacy, and cheap availability of Hst make this molecule as a good candidate for the development of food supplements for the management of diseases related with oxidative stress and inflammatory status.

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Poor bioavilability of hesperetin and hesperidin. Not water soluble. Per the following paper, “parallel supplementation with probiotics should be carried out to maximize the potential of the formulation.” More bioavailable formulations are in development.

Hesperidin reduces arterial stiffness in old mice to levels comparable to young mice:

Hesperidin is reputed to be an anticancer agent in “numerous cancer types”:

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Looks like it works very similar to Rutin, ruin has a 10% life extension in mice I think I remember.

Well, I have tried almost every variety of supplements in my local health food store.
And, I am working on Amazon as well, happen to have a large bottle of Diosmin - Hesperidin 1000mg tablets on the shelf. It was recommended for leg circulation and blood pressure control.
I stopped taking it because my blood pressure is well under control because seldom registers above 120 systolic.

So, with rapamycin and my life-extending supplements, 30% here 20% there, etc., I will soon pass 100% and become Benjamin Button. :baby:

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would be great to know when this becomes available!

Someone check my math, but dose was 0.5% of food in the 2nd paper.

“The low-fat diet was also enriched with hesperidin (0.5%; Research Diets), which was administered to old mice for four-weeks.”

So if a typical mouse eats 3g/day food, this is 0.015 g/day. Translating to a 70kg human from a 30g mouse, this is a 35g/day dose.

:face_with_open_eyes_and_hand_over_mouth:

Hesperidin is available on Amazon right now:

https://www.amazon.com/s?k=hesperidin+500mg&crid=36BGBCSJN9OND&sprefix=hesp%2Caps%2C150&ref=nb_sb_ss_ts-doa-p_6_4

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Yes - I see GRAS notices on Hesperidin, but not on Hesperetin. I also wonder what percent of Hesperidin is the Hesperetin that was in the initial study referenced above.

https://www.fda.gov/media/139254/download

Hayashibara discusses published and corroborative unpublished rat and human studies to support their conclusion that ingested glucosyl hesperidin is first metabolized to hesperidin and then to hesperetin, which is subsequently absorbed. Hayashibara states that the exposure to hesperetin is 3 to 3.7-fold higher after the ingestion of glucosyl hesperidin relative to the exposure following the ingestion of equivalent amounts of hesperidin. Hayashibara concludes that glucosyl hesperidin is absorbed into and metabolized in the body by the same pathway as hesperidin, which provides a basis to incorporate hesperidin safety assessments into their glucosyl hesperidin safety assessment.

Interestingly, there are patents around this compound:

Prospective Grant of Exclusive License: Use of the Citrus Flavanones Hesperetin, Hesperidin, and Naringenin in Nutrition for Endothelial Function, Vascular Health, Diabetes, and Insulin Resistance

Thus, hesperidin and its active aglycone form, hesperetin, may be effective agents for the treatment of diabetes, obesity, metabolic syndrome, dyslipidemias, and their cardiovascular complications including hypertension, atherosclerosis, coronary heart disease, and stroke. This technology discloses methods for using a hesperetin or hesperidin composition to treat metabolic syndrome and insulin resistance. Also described is the use of the related citrus polyphenol, naringenin.

https://www.federalregister.gov/documents/2012/07/06/2012-16499/prospective-grant-of-exclusive-license-use-of-the-citrus-flavanones-hesperetin-hesperidin-and

Probably just a matter of time, but even then there is the bioavailability issue that needs to be overcome, but it seems lots of work in that area is going on:

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Should we wait or does it seem there might be some benefit in getting the one from Amazon.

I’m waiting for the bioavailability issue to be addressed. As @Mac says, to duplicate the mouse doses with lifespan benefit (study) you’d have to take something on the order of 30g per day, so it seems unreasonable right now.

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This glaring dosing translation gap was also seen in AKG mice studies. Everyone got terribly excited until you realized the massive human doses.

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Yikes!! That’s a lot.

In the first post I included comments from the researchers regarding human dosing for the “hesperitin” form:

  • “The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day.”

I can’t see anyone selling “hesperitin” by itself. Have you seen any source?

Looks like they are a neutraceuticals based company pushing a niche angle.

This review paper sponsored by Bioactor bv mentions both compounds:

I found no USPTO patent application to the 2011 reference, only a recent application about some type of analog molecule, perhaps bioavailability.

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In their products they only talk about Hesperidin, in this product 65% (never mentioning Hesperetin levels or percentages):

“I’m waiting for the bioavailability issue to be addressed. As @Mac says, to duplicate the mouse doses with lifespan benefit (study) you’d have to take something on the order of 30g per day, so it seems unreasonable right now.”

I think @Mac was referring to the study on reversing arterial stiffness. However, even if the average weight of the mouse strain and grams of daily food intake that he gave are reasonable estimates (3 grams of food/day and 30 gram mouse), his calculation is way off because you have to apply an interspecies dosage scaling factor. So he arrived at a daily human dose of 35 grams for a 70 kg human. And in actuality, you’d want to take 35 and divide by 12.3. So 35÷12.3 = 2.85 grams. (There are different formulas, but 12.3 is a typical factor for mouse to human scaling). Also, in the arterial stiffness study it doesn’t look like they tried a lower dosage, so it’s unclear how much lower the dosage can go while still getting this benefit.

In the lifespan study, they adminstered hesperetin at 100 mg/kg. So if you take this, divide by 12.3, and multiply by 70 for a 70 kg person, you get about 569 milligrams per day for a 70 kg person. Now, as far as what the equivalent is with “hesperidin”, I don’t know yet. In other words, if one group of people took 500 mg of hesperitin with a meal, and a second group ate the same meal with 500 mg of hesperidin, how serum levels of hesperetin compare after digestion? Maybe the answer is in the literature.

In the study below, 8 weeks of hesperidin at 500 mg/day improved muscle mass and reduced fat in cyclists when compared to placebo. Some supplement labels suggest 500 mg one or twice daily. I may try 500 mg with food every 12 hours (plus a good probiotic to improve bioavailability as suggested by researchers). But I’m still reading and researching.

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There are also a few studies with cyclists taking 500mg/day, the results seem quite impressive but I cannot find 500mg pills only 150mg combined with other substances