#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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#94

I think the issue of the renewal of the extra cellular matrix is the key thing here. This can be seen in both the flexibilty of the skin and the ability of the individual to bend.

I have found personally that enhancing my own systems of renewal makes my body more flexible so that I bend in ways I could not a few years ago.

Hence I think this is a renewal issue rather than a glycation issue. I accept, however, that this is a good issue to discuss.

Humans do have deglycation enzymes. It could be that in older people these enzymes are not functioning properly.

What is clear is that in older people different things don’t function properly for whatever reason (obviously I have explained what I think the reason is).

I accept, however, that some damage may be irreversible. Glycation from high glucose levels may be partially irreversible as it arises from a metabolic failure rather than a failure of enzymes.

#95

We do have some deglycation enzymes, that’s a great point. However, as most enzymes, they are only found in specific places and only work on specific types of damages. It would be interesting to see what happens if they were upregulated, but I expect that to only cause minimal improvements in health. The reason I think so, which is also the main reason rejuvenation theories are cannot account for aging fully, is that even in young animals, damages still accumulate. How can people expect rejuvenation therapies to fix glycation damage fully when glycation accumulates even in healthy young children or animals that have all these rejuvenation pathways at perfectly youthful levels? Secondly, these deglycating enzymes only work on specific glycation products, not all of them. There are plenty for which no known rejuvenation pathways exist. How do you expect to upregulate a rejuvenation pathway that doesn’t exist? I think that refusal to accept that lots of things in the body have no mechanisms for repair is a coping strategy by those that strongly believe in evolutionoary theories of aging. They always just hope that the rest is going to somehow magically fix itself, even when it’s very obvious that evolution does not require species to be able to fix all damages and in fact it makes evolutionary sense to not fix everything.

Fortunately we are seeing companies work on epigenetic rejuvenation and also companies working on mitochondrial transplant therapies. I predict that once these become much more advanced, such that we can replace all the mitochondria in animals with young and healthy mitochondria, and rejuvenate their epigenetic programming, we will see that this leads to a large increase in healthspan and lifespan, yet leaves a lot left to be fixed and does in no way solve aging.

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#96

Yes, I think the ageing of the skin ( and agerelated changes in the ECM) is a mirror of a general ageing process. We have a few threads that bring up the importance of the ECM in ageing (even in the brain.)

I like Colin Ewald’s research in this field

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#97

Thank you for incredibly valuable posts above

One place to partially start, is this thread - it’s one of the best and richest discussions, anchored in a lot of papers, within the entire RapaNew forum:

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#98

100% agree and think a larger acceptance and realization of that with lead to more focus on replacement approaches to aging.

Every mammalian mother’s egg is able to create tissues, organs and whole bodies with everything reset to an age of ~0. (Even the mitochondria and and the extra cellular matrix, etc, etc, is reset to 0 age). This machines could be used to replace cells, tissues, organs and eventually whole bodies to truly rejuvenate older people.

See for example this thread: Regenerative Medicine, Growing New Organs, Etc

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#99

I’m very optimistic on transplant therapies. I think in many ways it’s going to be a lot simpler to grow a healthy young organ and transplant it than to rejuvenate and fix all the damages in an old organ. Eventually, it won’t be so difficult to have yourself cloned and then get your head transplanted onto a young body. The big concern is of course the brain, since you can’t replace the brain obviously, althouth some have hypothesized that we will be able replace tiny parts of it at a time without losing our identity. The closer we get to growing organs for replacement, or to full body replacement, the more important it is to put the main focus on the health of the brain.

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#100

I am absolutely NOT looking forward to the day that my head can be cut and placed into a cloned body. I much rather clone myself (including my head) and then take care of mini me as if it were my child and that would be very interesting, since you’d be able to avoid things you know were detrimental for your wellbeing, while focusing on doing things that you really liked and enjoyed LOL.

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#101

I think you are right in principle in this. My view on my own thesis on aging (mitochondria and senescence) is that when that is fixed it will leave other things to be fixed and glycation may be part of this.

It is clear that glycation may be something with more permanent effects. Hence I am happy to say I am drinking a bottle of wine which will have the effect of driving down my glucose levels which have been pushed up by yesterdays high dose (effective 77mg) of rapamycin.

Cheers.

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#102

Yikes!..return of the headless horseman/headless clone…hope he’s not one of the 4 horseman…but aside from that tangent, great discussion!

I agree that blood glucose control is critical. My top 5 systems to optimize for longevity would be 1) Cardiovascular 2) Blood Glucose Control 3) Inflammation 4) Mitochondrial Health and 5) Epigenetics with maybe Microbiome as runner up.
**I need to do more research on glycation and AGEs (and extracellular matrix). I am taking metformin and acarbose in low doses and still looking at GLP-1 and SGLT2 for longevity in perfectly fit and healthy individuals.

That sounds a lot like lipids and plaque formation, that starts early, accumulates over time and then is very difficult to reverse.

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#103

:point_up_2: 100% on all accounts

We also have this dynamic

  • If body replacement becomes widely used, there will be much less need to study most non-brain disease processes - as most of them can be solved by a body replacement. Perhaps that is too extreme, but it would absolutely shift the incentives and funding and market dynamics to reward work focus on neurological health and neurological aging - probably by several orders of magnitude!!!
  • Think about it…. no need to invest in liver, pancreas, colon, breast, prostate cancer… no need to invest in type 1 and 2 diabetes…, no need to investment organ impairment of kidney, liver, pancreas, lung and heart…, no need to invest in things like Crohn’s or any other digestive tract type of disease…, no need to invest in thing like sarcopenia, osteoporosis…, and so on and so forth…
  • Above is further accelerated by the fact that people will (a) be living longer lives and (b) care much more about their brain specifically, so the willingness for both the government and individuals to invest in brain health would go up by a lot
  • So beyond a mass shift in resources, government founding, investor and industry funding to Alzheimer’s and other dementia, etc, etc, any of the other longevity therapies that show promise, like partial reprogramming, CRISPR editing - your stuff - can now in a more focused way target brain health and rejuvenation without having to be diluted towards every other system and disease process in our body
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#104

Yes, is very interesting - that seems to be on the path to some good funding, see for example

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#105

Still not sure I follow @ng0rge - what is the issue?

Sounds very similar to people who felt that it was Frankenstein to transplant bone marrow or an organ from one human to another or to use a defibrillator to bring back from after their heart stopped?

Would love to hear what you feel or think any actual issues are so I can understand and perhaps reply with some thoughts if I have.

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#106

No serious issues scientifically or theoretically…but remember that we are still also emotional creatures ( at least I am) with dark irrational fears - like spiders and snakes, poisonous or not…and deeply repressed superstitions. You act like everyone should be perfectly comfortable with images of headless creatures…I think that’s far from reality. That’s why I feel like the “headless clone” concept will face many social/political obstacles. In no way is it in the same category as bone marrow or organ transplants or defibrillators. We’ve already seen the social resistance to head transplants in monkeys and dogs…let’s see how the public reacts to mice ( apparently on the near horizon).

The US island ruled by alien snakes and spiders

https://www.bbc.com/future/article/20241030-the-island-ruled-by-alien-snakes-and-spiders

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