High FGF21, Low Insulin And Glucose: A Pro-Longevity Strategy?
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- Опубліковано 29 тра 2021
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Papers referenced in the video:
FGF21 and Chronic Kidney Disease: www.sciencedirect.com/science...
The starvation hormone, fibroblast growth factor-21, extends lifespan in mice:
www.ncbi.nlm.nih.gov/pmc/arti...
Inhibition of growth hormone signaling by the fasting-induced hormone FGF21:
pubmed.ncbi.nlm.nih.gov/18585...
Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice:
pubmed.ncbi.nlm.nih.gov/32877...
Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression:
pubmed.ncbi.nlm.nih.gov/31773...
Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice:
www.ncbi.nlm.nih.gov/pmc/arti...
Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses:
pubmed.ncbi.nlm.nih.gov/28552...
Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer's disease in comparison with healthy aging:
pubmed.ncbi.nlm.nih.gov/33131...
Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue:
pubmed.ncbi.nlm.nih.gov/30043...
Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals:
pubmed.ncbi.nlm.nih.gov/26042...
Lower All-Cause, Cardiovascular, and Cancer Mortality in Centenarians' Offspring:
pubmed.ncbi.nlm.nih.gov/15571...
Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome in Offspring without Diabetes Mellitus of Nonagenarian Siblings: The Leiden Longevity Study:
pubmed.ncbi.nlm.nih.gov/20398... - Наука та технологія
Soon as a healthy 90 year old has increased blood pressure they are put on warfarin in in Aus. Consequently calcification of blood vessels and heart increases and increases blood pressure. Your protocols to increase Vit K from gut bacteria is pro reduction in calcification of blood vessels. Some minor interventions could increase number of centenarians. Low levels of medical intervention seems a prolongevity stance.
This guy is off the charts. In an area that feels full of frauds and people with bad information having this channel is like throwing a drowning man a luxury yacht. The subscriber count on this channel is unacceptable. Please tell all your people. I know I tell mine.
This study shows that FGF-21 increases with insulin, but not glucose:
"FGF21 Is an Insulin-Dependent Postprandial Hormone in Adult Humans"
The effect is attenuated on a high fat diet.
I now think there's a lot more to the story than I presented, so thanks for that.
Fascinating and confusing. It appears to be worthy of further study. Great video, thanks!
Thanks Neil, but why is it confusing? High FGF21 in the context of relatively low insulin and glucose may be a pro-longevity strategy, at least based on the data in centenarian offspring and FGF21 over-expressing mice.
great video you really do a great job explaining data and helping the viewer understand data
Thanks for sharing this valuable data
Great video!
Thanks Olya!
I seem to remember reading that FGF21 activity is dependent on Klotho. I think Klotho falls with age.
Possible FGF21 agonists: cold exposure, berberine, Acetyl L Carnitine, betaine, stearic acid, palmitic acid, Butyrate and alpha lipoic acid
Hibiscus sabdariffa possibly reduces FGF21 resistance.
I think FGF21 is essentially catabolic, and there are studies that show excessive FGF21 expression is associated with bone loss/weak bones.
high leucine, low iso leucine & low valine seems to trigger FGF21. Leucine to iso leucine ratio seems important
high tryptophan & threonine reduce FGF21 expression
Thank you for your research and work. I love the way that you analyse / present the data that the non science savvy people can understand. I imagine that takes a lot of time and thinking. I really appreciate it.
Thanks Ariel Hu!
Resveratrol is said to increase FGF21, if I'm not mistaken. It has increased lifespan of multiple species from yeast to fish. Although some studies failed to lengthen normal mice lifespan other studies have supposedly succeeded in lengthening normal mice lifespan as well.
I'm not impressed by the resveratrol data. It extends lifespan on an obesogenic diet in mice, but not mice on a normal diet.
@@conqueragingordietrying1797 there was another study in which it also extended lifespan of mice in a normal diet, iirc. It has extended mice lifespan on normal diet, iirc, also lifespan of mice with various types of mitochondrial mutations as well as senescent accelerated mice lifespan too. Also resveratrol optimal dosing in those earlier experiments was not properly known.
@@diamond_s If you can find the paper where resveratrol increased lifespan in mice on a normal diet, please post it.
While all the other health-related improvements are interesting, I care most about lifespan. Also, high dose resveratrol may be bad for health in people, at least based on this RCT:
pubmed.ncbi.nlm.nih.gov/31891746/
@@diamond_s The NIA ITP showed no (or very small 3%) life extension from resveratrol in 3 mice trials.
@@conqueragingordietrying1797 www.lifeextension.com/newsletter/2013/3/resveratrol-increases-life-span-in-mice That is the news regards the study, iirc, though haven't found link to actual paper, it links to journal. It comments that both senescent accelerated as well as senescent resistant normal aging mice both received lifespan extension from resveratrol.
Thanks again for your in-depth knowledge and information! Fasting intermittently, does in the long run, help with longevity!
but i think they (not in this study), are finding that intermittent fasting Without caloric restriction, does not help in humans)
@@robertnewton5343 what if you just restrict your calories and don't intermittent fast? Same results?
@@reviewgodusa9613 he has a more recent video that indicates that intermittent fasting must be included with CR to extend lifespan
Low bcaa high FGF21
These videos are wonderful and I admire your dedication to longevity.
As I understand it, the activity of FGF21 depend on sufficient Klotho being present. Could it be that the increasing FGF21 levels in older people are an attempt by the aging body to compensate for each unit of FGF21 being less effective due to lack of Klotho?
Could excessive FGF21 then be a driver for bone loss and osteoporosis?
A high carbohydrate diet raises fgf21 with moderate adjustments to protein intake as long as it doesn't exceed calorie limitations.
But the issue is, are higher FGF21 levels good or bad for health, as aging and obesity increase it too. If higher carb raises FGF21, it should be within the context of lower insulin and glucose to potentially gain the lifespan extending effect.
@@conqueragingordietrying1797 If the heart undergoes physiological stress, FGF21 production is increased as a protective response therefore it has to contribute to longevity as stress in older age is a very critical threat to mortality.
Very interesting subject and thank you for your dedication to this field.
It also correlates with each individuals genes as to the response to carbs etc so It's important to monitor your glucose and insulin as you are aware It's all a matter of tweaking your individual markers but all the literature on this is definitely pointing to be beneficial to longevity,interestingly it looks like activation and over expession is extremely beneficial from very early age.
Some doctor like Jason Fung has recommended to reduce carbohydrates in diet to reduce the insulin level.
What to follow
@@shivaprasadj1888 main thing to consider is daily intake of carbs,protein and fats, if you are eating a balanced diet and not gorging on food, there's many experts that will give advice to sell more books,best advice is to read studies and stick to the basic protocols don't smoke, exercise,and eat a balanced diet.
data also showed that a LPD (lowprotein diet) resulted in the improvement in glucose and T-CHO levels in diabetic rats; however, the addition of methionine (MET) to the LPD attenuated its effects on the diabetic state in LPD-fed diabetic rats, which was possibly associated with changes in plasma FGF21 levels. Plasma FGF21 levels were markedly increased by the LPD; however, the LP + Met diet suppressed it.
Nice, thanks for that!
@@conqueragingordietrying1797 Forgive me if my comments are a distraction.
I am pleased to follow your efforts and do not want to distract your many viewers.
Great work.
PS: Do not forget to continue to emphasize the Red Corvette Fallacy. ;-)
i.e. the *failure(s)* of the multimillion dollar HDL elevating drugs to improve outcomes. It is not the HDL that saves lives, the HDL is sign of something else and elevating HDL in and of it self is worthless.
Peace, out.
@@drrutledgemd It's not a distraction, I appreciate and read all comments, good, bad, critical (or not). I'm open to ideas from everywhere.
The percentage ranges of FGF21 levels can vary widely based on different stages or conditions such as fasting, diet, exercise, age, and health conditions. However, specific percentages are not commonly provided in literature as FGF21 levels are usually discussed in terms of absolute concentrations (e.g., pg/mL or ng/mL) rather than percentages. That said, I can provide a general idea of how FGF21 levels change in response to different factors:Basal (Normal) Levels:Approximately 50-300 pg/mL in healthy individuals.This represents the baseline level (100%).Fasting and Caloric Restriction:FGF21 levels can increase by 2-10 times compared to basal levels during prolonged fasting or significant caloric restriction.This means a potential increase to 200%-1000% of the baseline level.Low-Protein, High-Carbohydrate Diets:Levels can increase by 2-5 times compared to a normal diet.This means a potential increase to 200%-500% of the baseline level.Ketogenic Diet:Levels can increase by approximately 2-3 times.This means a potential increase to 200%-300% of the baseline level.Exercise:Endurance exercise can increase levels by 1.5-2 times.This means a potential increase to 150%-200% of the baseline level.Cold Exposure:Cold exposure can increase levels by approximately 1.5-2 times.This means a potential increase to 150%-200% of the baseline level.Age and Health Conditions:In conditions such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, levels can be chronically elevated by 1.5-3 times.This means a potential increase to 150%-300% of the baseline level.These values are approximate and can vary between individuals. For precise information tailored to your specific situation, consulting a healthcare professional and conducting appropriate blood tests is recommended.
Crazy how much variation there is in genetically similar mice (20 - 28mo) between different studies- it is on the same scale as the interventions.
Yep, and that's a big factor. Did the intervention extend lifespan in naturally long-lived mice that are short-lived in the study, like berberine? Or, did the intervention (FGF21) extend lifespan in mice that lived their normal lifespan (30, 40 months for average, maximal)? That's important to consider.
@@conqueragingordietrying1797 Mr. Lustgarden. Can you please give me any insight if Intermittent fasting (20 hour fasts), even help longevity in humans if no calories are restricted? For example, my basal metabolic rate is 1600 calories daily. I have done intermitten fasting for years eating 1600 to 1800 daily.... I saw Brad Stanfield having a video saying data shows IF in humans Without a reduction in calories yields no benefits. Can you eleaborate whether this is true or not?
@@robertnewton5343 Whether it's true depends on your physiology. On my channel, I don't promote any dietary ideology, but instead, blood testing to see if any approach, including CR or IF actually works at the individual level. Do you have any recent blood test data?
@@conqueragingordietrying1797 unfortunately I am incredibly poor so I cannot afford that. But perhaps I can err on the side of caution and do calorie restriction even when doing IF
@@conqueragingordietrying1797 Also, why dont people do bigger CR? If 20% CR is so effective, why not do 30 or 40%?
Since methionine is the starting amino acid of proteins it does make sense that a methionine restricted diet would slow metabolism, increase autophagy, and inhibit cancers, thus increasing life-spans.
It works in life-long caged, sedentary mice, but we'll see how it plays out in humans...
@@conqueragingordietrying1797 Also I often wonder what people mean by caloric restricted and unrestricted? Are the unrestricted just diabetic? I've just looked up a few recent reports on humans that seem to confirm the methionine basics. But, some on the carnivore diet side object, while some on the plant based diet side cheer. This adds more fuel to that fire. Obviously there are missing elements. Thanks for the heads up on methionine! Looking forward to the food fights!
@@Earwaxfire909 Calorie restricted = eating less calories than your usual body weight maintenance intake. For ex., without CR, I average ~2800 calories/d. I've been averaging ~2500 for the past month, so I'm ~11% calorie restricted.
Being calorie restricted is the opposite of being diabetic, as insulin sensitivity improves with less calories, and generally gets worse with more.
@@conqueragingordietrying1797 Thanks. I'm not sure if the caloric restriction calculations are universal, but glad to know what they are based on. Also I was noting that the unrestricted mice might be diabetic, if honestly unrestricted. But now I understand that unrestricted is just a standard calculation, that perhaps holds for mice more so than men. Thanks again!
@@Earwaxfire909 The unrestricted mice are not diabetic in youth, but insulin sensitivity worsens with age including in people. But, CR mice have improved insulin sensitivity at older ages when compared with unrestricted mice.
Two observations: (1) a ketogenic diet is already low-glucose & low insulin and is associated with higher FGF21.
Could it be that high insulin signalling lowers FGF21? That would make sense as insulin and IGF-1 can upregulate mTOR via AKT/TSC2/Rheb and lower mTOR expression is associated with longevity.
This seems consistent with the observation in the video that a low-protein diet increases FGF21 as high protein diets tend to upregulate mTOR via leucine/mTORC1 signalling.
Could this mean there’s a connection between FGF21 upregulation and AMPK upregulation especially as fasting increases FGF21?
(2) beta-hydroxybutyrate from a ketogenic diet is a Class I HDAC inhibitor that upregulates FOXO3 (the so-called master regulator of longevity). Perhaps there’s a mechanistic connection between this aspect of ketones and FGF21 in longevity?
Seems like obesity affects the effectiveness of a lot of longevity strategies, what exactly would be the sweet spot in terms of Body-fat % before it becomes starts becoming unhealthy and affects other biomarkers negatively. Or is that always going to be specific based on the strategy you're trying to use.
That's relatively easy to answer with blood testing, and with measurement of other objective biomarkers like blood pressure.
Hi Michael!
What food nutrition tracking app are you using?
Hey Maxim Pankratov, cronometer.com
I have no idea what you are talking about! I get the gist through the comments.
Ha, no worries Duncan Cross. When I encounter a challenging subject, I read it/watch it a few times and look up key concepts, which helps a lot!
first heard fiberglass and was like wut
Haha, "fiberglass" instead of FGF21?
Appears that most people are going to want to rely on future gene therapies for increasing FGF21. Diet and exercise are fine and I exercise regularly, but I have trouble sticking with keto and reports show my genetic profile prefers high protein. At some point therapies should be available to help boost FGF21, probably not in the U.S. where these things are so over-regulated that nothing gets done.
I understand that position, but based on the data in the video, increasing FGF21 in the context of low insulin and glucose may improve lifespan. If FGF21 is increased without the context of low insulin and glucose (i.e. aging, obesity), it's likely there wouldn't be a lifespan extension.
@@conqueragingordietrying1797 So in that case, then it's probably not a good target for future rejuvenation therapies or worthwhile interventions unless they also combine it with some as yet unknown treatment for insulin and glucose levels that don't have the side effect problems metformin and berberine have. Plus if levels are lower at younger ages across the board, as I noticed in some of your graphs, I'm not sure if FGF isn't increasing with age as a result of some other upstream issue to compensate.
@@natesofamerica Reducing insulin and glucose isn't difficult-leanness (having a low body fat %) and a prudent diet (which varies from person to person) contribute.
@@natesofamerica what are the side effects of berberine?
@@Avital4414 Side effects include diarrhea, constipation, gas, stomach upset, and headache.
hi there,
i suggest that the chart at 5:38 is wrongly interpreted. You can not compare absolute you need to compare against controls. What we can see is that the % of increase of life span is greater in Berberine than in FGF21. Obviously, the experiments were somehow very different.
Categorical misinterpretation also of the chart at14:35, correlation of fgf21 with BMI. You cite it from Conte, but you should indicate that calculating a regression on such data and then with such a crisp conclusion is utter nonsense.
Now, also the aging argument is wrongly placed. Obviously, you can not investigate positive influence on life span, if there would be an independent influence of age... which is called selection bias, particularly in the light of very diverse functional contexts for FGF21.
@13:35: the difference in glucose and insulin between centenarians and their partners: small absolute difference, and fasting insulin of 5.6 is anyway way too high, hence not of relevance when comparing to fasted Ins of 6.6.
(edited:) I found a review study relating FGF21 to nutrition: www.degruyter.com/document/doi/10.1515/hmbci-2016-0034/html. here, obesity is interpreted as fgf21 resistance. in non-obese, FGF21 is enhancing insulin sensitivity.
Your final strategy needs an extra proof: (1) does life style influence FGF21 in such a way that glucose is lowered by that? (2) is life style in humans (CR, Exercise) the prime determinant of longevity, or i.a.w., does CR and its effect reduce the correlation of FGF21 expression in various tissues, and circulation?
Finally, transgenic mice obviously overexpress FGF21 in all of their tissues, sth you can not achieve by life style.
The key to the understanding of physiology is the functional context. Pointing to singularized gene is the opposite.
For me, based on further other sci papers, FGF21 is an adaptation to a strong seasonal pattern of feeding with meat in spring and fruits in autumn, helping to mitigate stressful situations. Whether it is a causal, independent factor for stress-independent longevity, see : www.frontiersin.org/articles/10.3389/fphys.2019.00419/full ... remains questionable.
I don't think comparing data between trials is valid. Were the cages the same? Was the diet the same? ETC.