#74

@desertshores What results are you looking for with Jardiance? (I take 12.5 mg)

#75

As an aside, I am having unexpectedly good results from Jardiance. I am taking Jardiance alone because because like regular milk, metformin no longer agrees with me. The Jardiance alone has brought my fasting glucose levels to 85 - 95 mg/dL.
I eat a low carb diet. It took about a month for Jardiance to bring my levels below 95.
I also take Acarbose before any meal that is not low carb.

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#76

This is relevant around why lowering glucose levels and peaks can be helpful for longevity:

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#77

The size of spike probably matters. I see no evidence that eliminating transient post-prandial increases (say around 140 mg/dL or a bit higher) which go back baseline in 2 hours are harmful especially with a blood profile you noted earlier and the youngish age. Probably better to spend time and effort elsewhere. Also, I haven’t looked at the ITP study, but my guess is that it was not carried out on mice in ideal health. Plus, dosage conversion from mice to humans is an ongoing issue.

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#78

I agree about Attia and diet. I prefer experts like Walter Willet and Gary Fraser who have studied diets academically for decades and can show a lot of what I consider to be solid evidence supporting a plant-centric diet. Would prefer if more people, including Attia, would just not say anything, or admit their lack of depth knowledge, rather than trying to pass off an opinion as fact. He should know better considering the apparent pains he goes to analyze things. I will only listen to his podcast when he has a real expert on.

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#79

Do you think about harmful as the same as being not optimal?

Do you see any evidence in the other direction, ie that going up to around 140 vs say just 130 is optimal?

For instance, do you not see this as relevant:

#80

What would be interesting is to see what the normal glucose pattern is for a teenager or someone in their 20s.

As far as I can see keeping below 140ish is a good idea, but one should not particularly worry about post prandial peaks that go up to 140. My CGM charts from early 2022 were much worse than they are now and I often had glucose meandering around the 10mmol/L mark.

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#81

@John_Hemming What are your thoughts on glycation as one key parts of aging?

Seems to me that that is (slowly) accumulating problem that we’d want to address?

#82

Glycation varies. If you take the issue of glycation of haemoglobin, some is labile and then the second step is more permanent. I have not studied glycation more generally, but I would think it is driven by average glucose levels and does not necessarily remain if average glucose levels come down.

Hence if you can get your average glucose levels to below pre-diabetic the level of glycation is probably OK. I have not, however, read up on this.

From an aging perspective the damage that high glucose does to mtDNA is probably far more significant than levels of glycation.

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#83

Thanks for thoughts @John_Hemming

@Olafurpall any comments on above? I thought it was more difficult to reverse any glycation once it has occurred?

#84

Glycation in proteins that turn over quickly (red blood cells) matters less than long lived proteins. Collagen for example.

AGEs is also in the food you eat. “Browning” of food.

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#85

Thanks Joseph.

Is the amount of glucose in our food and blood a part of driving how much glycation there is of such longer lived proteins too?
(Our Blood reaches basically every cell / proteins in the body I think)

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#86

@Neo Here’s a thread where we took a deep dive into the topic around a podcast I did with two scientists studying this topic. These scientists are focused on the AGEs we eat but the conversation touched on both eaten and formed in body from high glucose.

I don’t recall all the details. What I have taken into my lifestyle is to avoid fried / grilled / dry cooked foods. I also add vinegar to my dinners. I have also added the components of glylo into my stack (b6, b1, ALA, nicotinimide) and with unknown AGEs benefit (but these supplements are useful for life in general).

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#87

Yes, there is a distinction between no observed harm and optimal, but is it meaningful in this case? I don’t know. I would have to look back over the available literature if I saw a need to spend time away from other issues to reassess this and still get it wrong or find there is no solid answer - I’m not sure an optimal value (a single number) is known.

You might find the discussions on spikes and CGM data on the Nourished by Science Youtube channel useful, or not. Presented by a PhD in nutrition.

One strategy I employ is to walk after eating. At 70 yo, and WFPB for 12 years, and daily exerciser for same, my HbA1c has stayed at 5%, plus or minus 0.1% for years.

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#88

It’s not ok at all even if you have glucose levels below pre-diabetic levels, unless you consider it ok to experience age-related damages, as long as they are at the rate of someone that takes good care of his health. Fact is, glycation is driven primarily by average the glucose concentration and there is no glucose level that is so low that it will result in no glycation occurring. So even if you have a glucose level of under 100 mg/dL you will still experience a lot of glycation. It will just take you a little longer to reach the same level of glycation you had gotten if you had a considerably higher glucose level.

I strongly disagree with that. I think damages it does to the extracellular matrix, resulting in stiffer tissues all over the body, is probably worse than what it does to mtDNA. I notice that you tend to explain almost everything through the lens of mitochondria being the cause and solution to aging. I think they are very important, but just one piece of a much larger puzzle. mtDNA is just one of thousands of types of molecules damaged by glucose in the body. In addition, damage by glucose is only one of several types of damages that damage mtDNA and not necessarily a substantial contributor of the overall mtDNA damage.

The answer to this is a bit complicated. In general, yes, it’s hard to reverse glycation once it has occurred and there are no good interventions that are effective at doing so and are commercially available. The more detailed answer is that glycation is a process usually involving several steps, the first of which is the attachment of the glucose to the amino group of proteins and other compounds. The last step is the formation of various compounds. In some cases these compounds are harmful AGEs (advanced glycated endproducts). The first steps can spontaneously reverse, but once you are far enough to have formed AGEs it’s too late. AGEs are generally irreversible.

Btw on top of my head, I recall that carnosine has been found to be able to reverse the first stages of glycation (the formation of a Shiff base), but I doubt it’s effective enough to have significant effects on glycation after ingestion, unless perhaps one were to take very large doses of it. See this study:

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#89

Very helpful @Olafurpall

Besides diet/exercise do you take any medicines to help lower glucose?

Any thoughts on SGLTi’s and especially Canagliflozin in metabolically fit and healthy individuals?

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#90

I see mtDNA and senescence as being at the centre of the cause of the failure of somatic renewal. The biochemistry of glycation is the same in all species. I dont see it affecting healthspan.

#91

I agree. Constantly striving for a perfectly flat glucose line on a CGM, or panicking over spikes, can be more harmful to mental health than the occasional rise in glucose from food. This hyperfocus on avoiding any peaks, leading to restrictive food choices and labeling foods like rice as “bad,” is likely to have detrimental long-term effects.

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#92

If you need any more convincing as to why to take Acarbose, I suggest looking at these charts:

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#93

Yes, the main ones are that I take metformin (1500 mg daily), acarbose (with starch rich meals), high dose chromium, vinegar, cinnamon, and also a little bit of R-ALA. The only one of these that made an obvious difference in my blood glucose was the chromium, and it only made a difference when I increased the dose from a few hundred micrograms daily to 1000 mcg daily.

I haven’t researched SGLTi’s, but based on their mechanism of action I would think they are likely beneficial for most people, even those that are fit and healthy. However, people must be careful to make sure they don’t experience hypoglycemia when taking SGLTI’s. Hypoglycemic episodes can be harmful for the brain and they are not always easy to notice.

I see. Even if you were right (which I don’t necessarily think you are), lack of somatic renewal is still only a part of the causes of aging. There are lots of things that are of major importance for aging that cannot be renewed at all and therefore have other causes than somatic renewal problems. Glycation is one such problem.

I think this is very wrong. Yes, technically the process of glycation is the same in all species, since glycation is a stochastic process between molecules, and a such does not depend on the species and happens even in dead things. However, as far as being the same in all species, and therefore not effecting lifespan or healthspan, that’s not quite true. Longer lived species have evolved in ways to tolerate more glycation over their lifespan (and yes, improved renewal abilities would be a part of that) but I’m pretty sure most mammals end up having enough glycation damage at older ages that it contributes strongly to their aging and poor health. This is even more true for long lived mammals like humans because glycation damage accumulates slowly and poses more of a problem in long lived species.

As far as glycation effecting healthspan. The impact of glycation and AGE formation on healthspan is very obvious. You only have to look at how much stiffer all tissues in the body get with aging. A lot of that is most likely caused by glycation. For most of that damage, the body has no capacity to repair it, so even with cellular rejuvenation with epigenetic reprogramming the stiffness would remain. In fact, the stiffness makes cellular rejuvenation more difficult because it influences the programming of the cells.

A very clear example of the glycation damage, and the rejuvenation that can occur when you reverse that damage, is cataracts. As an example, you will see cataracts in old dogs as well as in old humans. It takes a lot more years to effect the healthspan of humans than dogs, because dogs live shorter and it occurs faster in them, but the effect is the same. Also while the body has no mechanisms to effectively reverse cataracts, it can be reversed partially with eyedrops containing n-acetyl-l-carnosine (NALC). This can be observed in various animals and even in lenses in vitro. Yellowish cataractic lenses become more clear in vitro after treatment with NALC, and regain some of their youthful flexibility. Also eyedrops containing NALC have been found to prevent and partially reverse cataracts in animals and humans. I think that’s just a glimpse of the rejuvenation that would occur if glycation damage could be reversed in the whole body. Also I’m almost certain that mitochondrial rejuvenation will not reverse glycation damage, although it would help slow it down. If you could replace all the mitochondria in your body of an old person with perfectly healthy young mitochondria, their cataracts would not disappear, neither would the glycation damage in most of the rest of their body. The body is fine with you getting cataracts at 80 years of age so it never needed to develop mechanisms to repair it. The same is true for all kinds of damages in the rest of the body. It doesn’t have mechanisms to repair them because it never needed it. Evolution only requires you to live to middle age to pass your genes along to the next generation.

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