Hesperetin restores youth in old rats - enhances lifespan ~8% up to ~14% when given late, restores mitochondria & metabolism, reverses heart damage

[cs3000]

Posting this part from a thread i wrote on Hesperidins beneficial effects on toxic metal protection, diabetes, wound healing etc

Great study on the life promoting effects of hesperitin (the derivative of hesperidin found in orange juice):

*Reverses effects of aging / restores youth
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00838-7
(hesperidin breaks down to some hesperitin in the body)

Hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice.
Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence.

Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age.​

^ that makes it sound like a superpower compound lol.
changes their genetic expression to match that seen in youth more closely. it wasnt profound enough to move them back completely to youth of course. but shifted them more towards that across many measures
its actually a great effect. some measures were profound enough to match or exceed youthful measures.
glycogen synthesis restored completely, reversal of otherwise increased glycolysis.
it improved muscle function, lymphocyte count,

their metabolism completely restored and even EXCEEDED youthful levels in oxygen consumption, CO2 production and basal energy expenditure during light period, & all measures went up significantly higher than non treated aged rats. their mitochondria is thriving again

To study the anti-aging and beneficial effects of hesperetin on age-related metabolic decline, we examined the whole-body energy metabolism and body composition of the old mice treated with hesperetin. Our results reveal that the VO2, CO2 and EE of Veh-treated old (28-month old) WT mice were significantly decreased compared to young (3-month old) WT mice. Importantly and intriguingly, hesperetin treatment for 6 months attenuates these age-related reductions that affect the whole-body metabolism of the old mice during their dark period

their lean body mass % went way up.
and their muscle performance went up a lot. their heart function improved.

Interestingly, after 3 months of hesperetin treatment (Fig. 5K),

the ultrastructural damage to the aged heart had largely disappeared and seem to have been reversed ​

resulting in the ICD features and mitochondria now resembling the situation observed in the hearts of 3-month WT mice​

^ holy ***t

lifespan increase:

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)

8.7% , up to 13.9% lifespan increase (and thats starting supplementation at old age, probably more lifespan increase starting middle age).

amazing study
amazing effects for 1 thing with a great safety profile (as long as you watch out for the CYP450 enzyme inhibition when taking at the same time as some medications)
2 things that stood out on baseline measures after , there's a slight drop in magnesium. and a big increase in fasting insulin.

"The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day" , over 3 to 6 months.

Hesperi tin is harder to find as a supplement than hesperidin. but the body breaks hesperidin down into hesperitin
"Bioavailability Is Improved by Enzymatic Modification of the Citrus Flavonoid Hesperidin in Humans: A Randomized, Double-Blind, Crossover Trial"
~180mg 2.92mg/kg body weight of hesperidin cMax in blood of hesperetin = 1.07
~80mg 1.21mg/kg body weight of hesperitin cMax in blood of hesperetin = 2.66
takes 7 hours to get there taking hesperidin vs hesperetin 30 mins

so assuming thats linear , 80mg hesperetin = 450mg hesperidin for same dose of hesperitin in blood. need 5.5x hesperidin to get same amount of hesperitin.
491mg hesperetin = 2.5g hesperidin.
but not sure about going that high when hesperidin has effects at low doses even. maybe hesperidin could work similar at the same dose ~500mg if high dose is not tolerated.

 

[David PS]

@cs3000 - thank you. This is very interesting.

 

[Beatrix_]

Citrus fiber contains higher amounts of hesperidin, whereas hesperetin occurs in smaller amounts in natural sources

Hesperidin: A Review on Extraction Methods, Stability and Biological Activities

Hesperidin is a bioflavonoid occurring in high concentrations in citrus fruits. Its use has been associated with a great number of health benefits, including antioxidant, antibacterial, antimicrobial, anti-inflammatory and anticarcinogenic properties. The food industry uses large quantities of...

www.mdpi.com

Hesperidin: A Review on Extraction Methods, Stability and Biological Activities

Nutrients 2022, 14(12), 2387; Hesperidin: A Review on Extraction Methods, Stability and Biological Activities


Citrus flavedo (the coloured outer layer of the peel) and albedo (a white soft middle layer part) contain higher amounts of hesperidin in comparison to hand-squeezed juice [4,9]. Commercial juices, squeezed also with peel constituents, are rich in this flavanone. Apart from citrus fruits, hesperidin was also found in mint plants (Mentha) [10,11], honeybush (Cyclopia maculata) [12] and aromatized tea [13]. It is worth mentioning that hesperetin, the aglycone form of hesperidin, is less dominant in nature than its glycosides.

 

[LadyRae]

@Beatrix_
Nice. I just call the white inner peel the "pith", but maybe that's incorrect.

I like to loosely peel an orange with a knife and then slice into 6ths...it seems to retain more juice that way. But it depends on the orange. These "tangelos" I'm currently eating are so juicy it's almost annoying...

 

[Limon9]

Nice, thanks. Hesperidin itself is a glyoxalase type I inducer, improving the clearance of methylglyoxal from the cell. I see methylglyoxal as basically a chalone, an inhibitor of cellular division: there's always too much of it in diabetes & Alzheimer's, but far too little in cancer, so this flavonone's other effects seem to support the conditions for normal growth.

 

[Ben.]

Seems like it also has effects on infections such as fungi and parasites which might contribute to health/longevity effects.

Hesperetin—Between the Ability to Diminish Mono- and Polymicrobial Biofilms and Toxicity

"... Hesperetin is an understudied flavonoid that deserves much more attention due to its wide antifungal potential focused towards both planktonic and biofilm fungal cells. Moreover, its inhibitory effect on the polymicrobial biofilms is of great interest for the further studies and development of novel antimicrobial strategies. On the other hand, its activity towards S. aureus is negligible."

In vitro and in vivo effects of hesperidin treatment on adult worms of Schistosoma manson

Antifilarial activity in vitro and in vivo of some flavonoids tested against Brugia malayi
"...We evaluated the antifilarial activity of 6 flavonoids against the human lymphatic filarial parasite Brugia malayi using an in vitro motility assay with adult worms and microfilariae, a biochemical test for viability (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT)-reduction assay), and two animal models, Meriones unguiculatus (implanted adult worms) and Mastomys coucha (natural infections). In vitro, naringenin and hesperetin killed the adult worms and inhibited (>60%) MTT-reduction at 7.8 and 31.2 μg/ml concentration, respectively"

Hesperidin Targets Leishmania donovani Sterol C-24 Reductase to Fight against Leishmaniasis

"....Hesperidin, a naturally occurring flavanoid, is present in citrus family of fruits. It was found effective against an array of pathogens including fungi, bacteria, viruses, and protozoa. Here, we evaluated its antileishmanial activity and possible mechanism of action through different in vitro and in silico experiments."

 

[Mauritio]

Very interesting

 

[cs3000]

Very interesting

yeh powerful super-compound in aging
i found something related today , lemon extract is harder to find but
if u want extra hesperetin conversion lemon extract (mostly the eriocitrin content) gives much more than hesperidin from OJ does , in humans at same doses

(but hesperidin also works well)

we have focused on comparing eriocitrin vs. hesperidin metabolisms. In this regard, a remarkable (around 11–fold) increase of hesperetin-derived metabolites was observed after lemon vs. orange extract intake, considering the different amount of hesperidin in both extracts as well as other possible hesperetin precursors, including diosmetin and limocitrin derivatives in the lemon extract (Table 2).

Our results suggest that lemon extract could enhance hesperetin generation in the gut mainly via eriodictyol formation through eriocitrin intake. In this way, the low solubility of hesperidin that severely hampers its metabolism by microbial rhamnosidases could be overcome.
Remarkably, our results describe for the first time in humans the formation of hesperetin (M17) after consuming eriocitrin, likely due to the methylation of eriodictyol in the 4′ position by COMT

Hesperetin increases mitochondrial ATP content 33% - the most potent compound out of 7949 tested for cellular respiration

High throughput screening of mitochondrial bioenergetics in human differentiated myotubes identifies novel enhancers of muscle performance in aged mice Hesperetin (derivative of Hesperidin in orange juice) improves cellular respiration for more ATP which is a key to overall health. increased...

raypeatforum.com

 

[Coderr]

Is hesperidin in the white peel of the orange? If we compare lemon and orange, is the hesperidin ratio high? That's why I'm asking: I can find organic lemons, but I can't find organic oranges.Is hesperidin in the white peel of the orange? If we compare lemon and orange, is the hesperidin ratio high? That's why I'm asking: I can find organic lemons, but I can't find organic oranges.

 

[Mauritio]

To achieve the OP concenctration wouldnt you need several liters of OJ per day ?
...but as you said it might have beneficial effects in much lower doses anyway.

 

[cs3000]

To achieve the OP concenctration wouldnt you need several liters of OJ per day ?
...but as you said it might have beneficial effects in much lower doses anyway.

replicating study would need it as a supplement or eriocitrin which converts well or high dose hesperidin instead of OJ. UK commercial supermarket orange juice avgs ~20mg - 30mg hesperidin (which needs to convert to hesperetin for this study) per 100ml.
but yeh hesperidin from a couple glasses OJ has nice aging reversal & protecting effects also
(bit wary about high dose flavanols tho in terms of mineral depletion. but didnt show up as a problem there)

 

[Mauritio]

replicating study would need it as a supplement or eriocitrin which converts well or high dose hesperidin instead of OJ. UK commercial supermarket orange juice avgs ~20mg - 30mg hesperidin (which needs to convert to hesperitin) per 100ml.
but yeh hesperidin from a couple glasses OJ has nice aging reversal effects also. could be the signalling changes are gained from low doses for the effect instead of dose dependant
(bit wary about high dose flavanols tho in terms of mineral depletion. but didnt show up as a problem there)

Yeah and especially the anti thyroid effects you eluded to in another thread are worrying. IIRC that happened even at a relatively normal consumption of OJ.

 

[YourUniverse]

Have been really enjoying lemonade recently, and tastes incredible

 

[Mauritio]

Posting this part from a thread i wrote on Hesperidins beneficial effects on toxic metal protection, diabetes, wound healing etc

Great study on the life promoting effects of hesperitin (the derivative of hesperidin found in orange juice):

*Reverses effects of aging / restores youth
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00838-7
(hesperidin breaks down to some hesperitin in the body)

^ that makes it sound like a superpower compound lol.
changes their genetic expression to match that seen in youth more closely. it wasnt profound enough to move them back completely to youth of course. but shifted them more towards that across many measures
its actually a great effect. some measures were profound enough to match or exceed youthful measures.
glycogen synthesis restored completely, reversal of otherwise increased glycolysis.
it improved muscle function, lymphocyte count,

their metabolism completely restored and even EXCEEDED youthful levels in oxygen consumption, CO2 production and basal energy expenditure during light period, & all measures went up significantly higher than non treated aged rats. their mitochondria is thriving again

View attachment 47807


their lean body mass % went way up.
and their muscle performance went up a lot. their heart function improved.


^ holy ***t

lifespan increase:

8.7% , up to 13.9% lifespan increase (and thats starting supplementation at old age, probably more lifespan increase starting middle age).

amazing study
amazing effects for 1 thing with a great safety profile (as long as you watch out for the CYP450 enzyme inhibition when taking at the same time as some medications)
2 things that stood out on baseline measures after , there's a slight drop in magnesium. and a big increase in fasting insulin.

"The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day" , over 3 to 6 months.

Hesperi tin is harder to find as a supplement than hesperidin. but the body breaks hesperidin down into hesperitin
"Bioavailability Is Improved by Enzymatic Modification of the Citrus Flavonoid Hesperidin in Humans: A Randomized, Double-Blind, Crossover Trial"
~180mg 2.92mg/kg body weight of hesperidin cMax in blood of hesperetin = 1.07
~80mg 1.21mg/kg body weight of hesperitin cMax in blood of hesperetin = 2.66
takes 7 hours to get there taking hesperidin vs hesperetin 30 mins

so assuming thats linear , 80mg hesperetin = 450mg hesperidin for same dose of hesperitin in blood. need 5.5x hesperidin to get same amount of hesperitin.
491mg hesperetin = 2.5g hesperidin.
but not sure about going that high when hesperidin has effects at low doses even. maybe hesperidin could work similar at the same dose ~500mg if high dose is not tolerated.

CISD2 seem like an interesting gene. Has anybody looked into that?

This is a very interesting study and again it retards aging a lot. It increases median life span by about 19%, which I thought woud be more, given that the mice were transgenic, meaning high in CISD2, from birth, but on the other hand it basically abolished muscle,mitochondria, brain and skin aging, so still great results.
An interesting observation was that genes related to oxidative stress like GSH or CAT were not changed. This shows that the anti-aging effects of the CISD2 gene were not because it reduces oxidative stress. This leaves open an opportunity for a combination of CISD2 promoters and anti aging substances like selegiline that mainly work through reducing oxidative stress. A combination might be very effective.
- A persistent level of Cisd2 extends healthy lifespan and delays aging in mice

CISD2 deletion massively increases cortisol, so that might have to do with the anti-aging effects ascribed to CISD2.
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355079/

It seems to prevent iron accumulation:
"Taken together, our findings suggest that CISD2 protects cardiomyocytes from overaccumulation of iron..."
- The [2Fe-2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes - PubMed

Its positive effects seem to largely depend on SIRT7 expression. @David PS
- https://www.sciencedirect.com/science/article/pii/S0167488921000082?via=ihub#bb0130

 

[Mauritio]

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice - PubMed

Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for...

pubmed.ncbi.nlm.nih.gov

 

[High_Prob]

Posting this part from a thread i wrote on Hesperidins beneficial effects on toxic metal protection, diabetes, wound healing etc

Great study on the life promoting effects of hesperitin (the derivative of hesperidin found in orange juice):

*Reverses effects of aging / restores youth
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00838-7
(hesperidin breaks down to some hesperitin in the body)

^ that makes it sound like a superpower compound lol.
changes their genetic expression to match that seen in youth more closely. it wasnt profound enough to move them back completely to youth of course. but shifted them more towards that across many measures
its actually a great effect. some measures were profound enough to match or exceed youthful measures.
glycogen synthesis restored completely, reversal of otherwise increased glycolysis.
it improved muscle function, lymphocyte count,

their metabolism completely restored and even EXCEEDED youthful levels in oxygen consumption, CO2 production and basal energy expenditure during light period, & all measures went up significantly higher than non treated aged rats. their mitochondria is thriving again

View attachment 47807


their lean body mass % went way up.
and their muscle performance went up a lot. their heart function improved.


^ holy ***t

lifespan increase:

8.7% , up to 13.9% lifespan increase (and thats starting supplementation at old age, probably more lifespan increase starting middle age).

amazing study
amazing effects for 1 thing with a great safety profile (as long as you watch out for the CYP450 enzyme inhibition when taking at the same time as some medications)
2 things that stood out on baseline measures after , there's a slight drop in magnesium. and a big increase in fasting insulin.

"The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day" , over 3 to 6 months.

Hesperi tin is harder to find as a supplement than hesperidin. but the body breaks hesperidin down into hesperitin
"Bioavailability Is Improved by Enzymatic Modification of the Citrus Flavonoid Hesperidin in Humans: A Randomized, Double-Blind, Crossover Trial"
~180mg 2.92mg/kg body weight of hesperidin cMax in blood of hesperetin = 1.07
~80mg 1.21mg/kg body weight of hesperitin cMax in blood of hesperetin = 2.66
takes 7 hours to get there taking hesperidin vs hesperetin 30 mins

so assuming thats linear , 80mg hesperetin = 450mg hesperidin for same dose of hesperitin in blood. need 5.5x hesperidin to get same amount of hesperitin.
491mg hesperetin = 2.5g hesperidin.
but not sure about going that high when hesperidin has effects at low doses even. maybe hesperidin could work similar at the same dose ~500mg if high dose is not tolerated.

Now if only Pure Encapsulations would take the D-Aspartic Acid out of their formula…

https://www.pureencapsulationspro.com/tribulus-formula.html

Supplement Facts
Serving size 3 capsules
Servings per container 30
Amount Per Serving
Tribulus (Tribulus terrestris)
extract (fruit)
(standardized to contain 20% protodioscin) 250 mg
D-Aspartic acid 1000 mg
Chrysin 100 mg
Hesperetin 50 mg

 

[Badger]

Posting this part from a thread i wrote on Hesperidins beneficial effects on toxic metal protection, diabetes, wound healing etc

Great study on the life promoting effects of hesperitin (the derivative of hesperidin found in orange juice):

*Reverses effects of aging / restores youth
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00838-7
(hesperidin breaks down to some hesperitin in the body)

^ that makes it sound like a superpower compound lol.
changes their genetic expression to match that seen in youth more closely. it wasnt profound enough to move them back completely to youth of course. but shifted them more towards that across many measures
its actually a great effect. some measures were profound enough to match or exceed youthful measures.
glycogen synthesis restored completely, reversal of otherwise increased glycolysis.
it improved muscle function, lymphocyte count,

their metabolism completely restored and even EXCEEDED youthful levels in oxygen consumption, CO2 production and basal energy expenditure during light period, & all measures went up significantly higher than non treated aged rats. their mitochondria is thriving again

View attachment 47807


their lean body mass % went way up.
and their muscle performance went up a lot. their heart function improved.


^ holy ***t

lifespan increase:

8.7% , up to 13.9% lifespan increase (and thats starting supplementation at old age, probably more lifespan increase starting middle age).

amazing study
amazing effects for 1 thing with a great safety profile (as long as you watch out for the CYP450 enzyme inhibition when taking at the same time as some medications)
2 things that stood out on baseline measures after , there's a slight drop in magnesium. and a big increase in fasting insulin.

"The dose used in this study is an achievable dose in humans and is a human equivalent dose of 491 mg/60 kg/day" , over 3 to 6 months.

Hesperitin is harder to find as a supplement than hesperidin. but the body breaks hesperidin down into hesperitin
"Bioavailability Is Improved by Enzymatic Modification of the Citrus Flavonoid Hesperidin in Humans: A Randomized, Double-Blind, Crossover Trial"
~180mg 2.92mg/kg body weight of hesperidin cMax in blood of hesperetin = 1.07
~80mg 1.21mg/kg body weight of hesperitin cMax in blood of hesperetin = 2.66
takes 7 hours to get there taking hesperidin vs hesperetin 30 mins

so assuming thats linear , 80mg hesperetin = 450mg hesperidin for same dose of hesperitin in blood. need 5.5x hesperidin to get same amount of hesperitin.
491mg hesperetin = 2.5g hesperidin.
but not sure about going that high when hesperidin has effects at low doses even. maybe hesperidin could work similar at the same dose ~500mg if high dose is not tolerated.

Fantastic post, CS3000, thanks for sharing!!!

 

[Badger]

Where to buy Hesperetin (with a T) and NOT Hesperedin (with a D):

1. **Santa Cruz Biotechnology** offers hesperetin (CAS 69097-99-0) as a powder, with a purity of ≥95% according to HPLC analysis. It is soluble in ethanol and has a melting point of 250 - 254 °C. This product is intended for research use.

Hesperetin | CAS 69097-99-0 | SCBT - Santa Cruz Biotechnology

Hesperetin, CAS: 69097-99-0, is a dietary flavanone with chemopreventive effect. MF: C16H14O6, MW: 302.28. Cited in 13 publications

www.scbt.com

2. **Sigma-Aldrich** also provides hesperetin (CAS 69097-99-0) with a purity of ≥95%. This product is available for purchase on their website.

https://www.sigmaaldrich.com/US/en/product/aldrich/w431300?utm_source=google&utm_medium=organicshopping&srsltid=AfmBOoqaRePx-eP8H4NFiAnrNCZ2XZLLUlaNWKnLvmYp3ETPKk7xAE_vn4s

3. **Biorbyt** lists hesperetin with a CAS number of 520-33-2, indicating a high purity level of >98%. This product is categorized under small molecules and is intended for research purposes.

Biorbyt

Hesperetin

www.biorbyt.com

4. **Sussex Research** offers a variant of hesperetin, hesperetin-d3 (CAS 1346605-26-2), with a purity of >95% (HPLC) and isotopic enrichment of >98%. This product is designed for research applications and has a molecular weight of 305.3

https://sussex-research.com/products/si080040?

5. **Sigma-Aldrich** also has hesperidin (CAS 520-26-3) as an analytical standard with a purity of ≥97.0% (HPLC). This product is suitable for food and beverage testing and has a limited shelf life with the expiry date indicated on the label.

https://www.sigmaaldrich.com/US/en/product/sial/50162?utm_source=google&utm_medium=organicshopping&srsltid=AfmBOop-wW6n_8Ey1AcLN_N9-4kix4S0_vKXgCb-5qmpJB5OTlUitMnrJCo

 

[Ben.]

It is high in peppermint?

 

[Aad]

I offer this in quantities of 25 grams/unit. Enough for roughly 50 days. Purity > 99 %.

Let me know if you guys are interested.