#42

Interesting discussion about epigenetic clocks, in the context of hearing loss.

(Frontiers | Epigenetic Age Acceleration and Hearing: Observations From the Baltimore Longitudinal Study of Aging)).

" Our results suggest that not all commonly cited epigenetic clocks may correlate with sensory function. Although these clocks have been shown to be associated with mortality, as well as physical and cognitive function, they may not capture the same aspects of aging (Oblak et al., 2021). The epigenetic clocks were constructed using different phenotype information in populations of varying ages. Previously it has been observed that the correlation between clocks is not always strong. Indeed, among BLSA (Baltimore Longitudinal Study of Aging) participants who are typically healthier than general population, we observe younger epigenetic age (Hannum clock, Horvath clock, GrimAge, and PhenoAge) but the mean epigenetic measurement of pace of aging is 1.02, a value consistent with slightly accelerated aging. One potential explanation is that many age-related functional and phenotypic changes in fact accelerates at mid-to-late life, which the pace of aging may be unable to acknowledge because this epigenetic measure is established using only young adults ([Belsky et al., 2020]"

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#43

Took the Maxx herb Ca-AKG for about two months. Did not notice anything. Am not taking plain AKG from Double Wood. I take it in the morning with the calcium pantothenate. There seems to be more energy, but that is subjective.

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#44

I was taking Rejuvant for 3 months earlier this year, and now switched to AKG supplement from Amazon.

#45

The powder has no taste or very little taste. Depending on how sensitive your taste buds are. I use the powder in hot chocolate and I do not notice any flavour change. I also add it to my dogs food and he does not seem to notice it.

The 1000 mg powdered ca-akg is taken in the evening after dinner. I also take 500 mg in a capsule in the morning. The capsules are from Pro Health Longevity.

I have been taking ca-akg for just over 2 years and the only noticable change has been in my hair colour. It has darked and there is less grey. This has been noticed by friends and relatives as well.

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#46

I added it to my stack today. This starts tomorrow. I will report back.

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#47

A slight cautionary tale: Too much calcium especially without vitamin D and vitamin K2 supplementation increases the risk of myocardial infarction. The upper daily safe dose of a calcium supplement is around 1200mg.
ā€œA meta-analysis of trials totaling 12 000 participants found that calcium supplements
increase the risk of myocardial infarction by about 30%ā€

I take AKG in the form of potassium AKG because my potassium intake is on the low side and the potassium in the supplement lowers my blood pressure by about 10 mm Hg. The main downside is it nasty. It is extremely hygroscopic and I dissolve it in about 1/2 ounce of water and take it like a shot of tequila.

An old supplement Para-aminobenzoic acid (PABA) was a popular supplement for a while back in the '50s. It was used to increase the bodyā€™s ability to get a suntan without burning. It is still widely available as a supplement

ā€œPABA, also known as vitamin B10, is an organic compound found in some foods and supplements. In the past, it was a common ingredient in sunscreen, as it blocks UVB rays. Limited research also suggests that PABA supplements may help darken grey hair and improve skin issues that involve tissue buildup and hardening. Aug 31, 2020ā€

It is a chemical that occurs naturally in the body. It is also found in several foods including grains, eggs, milk, and meat.

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#48

I am trying to understand if, and how, AKG could or should, be taken together with rapamycin.

According to this article AKG seem to indirectly lower mTOR activation.

I would really appreciate if someone more knowledgeable, based on this article, could make some educated guesses about how AKG and rapa could interact? And if they should be taken together or in different stages of a rapa cycle.

Its proposed that AKG mimics caloric restriction. Could AKG serve as the ā€œlazy manā€™s fastingā€?

mTOR/Ī±-ketoglutarate-mediated signaling pathways in the context of brain neurodegeneration and neuroprotection

https://www.sciencedirect.com/science/article/pii/S2667160322000266

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#49

I donā€™t think you are going to get a satisfactory answer to your question. As I am the original poster, you should refer to the original clincal study. In any case, in MOUSE studies AKG ā€œincreases lifespan by reducing the level of systemic inflammatory cytokines and inducing anti-inflammatory cytokine IL-10.ā€

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#50

Sorry for kidnapping tour thread. I thought it would be better to revive your thread, than starting a similar one on the same topic.

I think the article I posted, is more a review artikel that summarizes the gathered knowledge as of -22. And that it could be of relevance for the title of the thread.

If you or rapadmin think its better, I donā€™t mind starting a new thread. :blush:

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#51

There is reasearch that points to il10 causing senescence.

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#52

Not concerned about thread, merely pointing out that the action of AKG in humans is not known so I donā€™t think you will get a satisfactory answer to your question. Furthermore, the company primarily selling AKG supplements is making a lot of claims about life extension that are unfounded

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#53

is it AKG working for you? If so, how? Thanks

#54

I dont know. Given the arguments about il10 i may stop it.

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#55

I have been eating 3-5 grams AAKG a day during the last month. As expected I canā€™t say that I feel any different than I did before.

I soon intend to start rapa, and since drug interaction, good and bad, is a real thing, i try to get a better understanding of possible interactors.

Good candidates for interaction, as I understand it, are supplements that indirectly and directly are sharing some mechanisms of action.

AKGs and rapamycins common suppression of mTOR is one. Does anyone have a rough comparison of effect magnitude compared to Rapa? Understand that it would have to be from animal studiesā€¦

There also seem to be some overlapping effects between AKG and caloric restriction. AKG doesnā€™t prolong life in calorie restricted C. Elegans, and also seem to be secreted in humans after vigorous exercise.

I understand that quiet a few members on this forum are MDs, or have quite deep understanding of biochemistryā€¦ but agreed, interpretations of bad data never get very good.

So, Rapadmins ā€œrule of thumbā€ not to take them on the same day is out best bet, based on lacking data?

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#56

Curious if:

  1. anyone is still taking AKG (Ca or otherwise)

  2. does it have any impact anyone has noticed? Blood levels? Age tests? Feeling?

  3. is it superfluous if taking rapamycin? (Both appear to impact MTOR so same pathway)

  4. worth seriously considering?

Thanks.

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#57

The last I saw on the ITP for AKG:

alpha-ketoglutarate (AKG)
2020
20,000 ppm
18 mo
In Progress

So we have no idea. Thereā€™s the old 2014 study that showed 40% life extension in C Elegans.

Clearly the Bucks Institute research 2020 suggests thereā€™s something here:

https://www.science.org/content/article/bodybuilding-supplement-promotes-healthy-aging-and-extends-life-span-least-mice

Mice given the substanceā€”alpha-ketoglutarate (AKG)ā€”were healthier as they aged, and females lived longer than mice not on the supplement.

ā€¦

Some differences jumped out within a few months: ā€œThey looked much blacker, shinier, and youngerā€ than control mice, says Azar Asadi Shahmirzadi, a postdoc at the Buck Institute who did the experiments as a graduate student. In addition, the AKG-fed mice scored an average of more than 40% better on tests of ā€œfrailty,ā€ as measured by 31 physiological attributes including hair color, hearing, walking gait, and grip strength. And female mice lived a median of 8% to 20% longer after AKG treatment began than control mice, the group reports today in Cell Metabolism.

The AKG-eating mice did not perform better on tests of heart function or treadmill endurance, however, and the tests did not include cognitive performance.

ā€¦

The effects on life span and health were smaller for AKG than for some other antiaging compounds, notes aging researcher Matt Kaeberlein of the University of Washington, Seattle, who was not involved with the work.

Thereā€™s a 1g per day human clinical trial starting 2023.

So the question is: is this something that could be taken WITH Rapamycin? Or is it superfluous if taking Rapamycin. Or (dare I say) taken INSTEAD OF Rapamycin?

Body builders have been taking the stuff for years and see ancillary benefits aside from longevity (wound healing, recovery). Am I crazy to want to try this (1g daily)?

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#58

Sorry, @John_Hemming : is this the research on il10 you mentioned?

Abstract

Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.

This article suggests suppressing il10 is a positive. You imply it is a negative: what are your thoughts here?

#59

The research on IL-10 was a where it caused senescence. It does inhibit NF kappa B, but that reduces cytosolic citrate.

All of the Krebs metabolites have some effect.

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#60

So to be clear and summarizing this multi year thread thus far:

  1. Over the past several years many of us here have tried AKG in the 1-3g per day dose, over 1 month to greater than this (I believe I saw six months)

  2. it sounds like one person saw ā€œgreater energy over the first weekā€ and another saw ā€œgray hair darkenā€ but then all noticeable impacts became unnoticeable. No one else noticed any impact of AKG

  3. no-one had any tests done to show there were any impacts?

  4. @John_Hemming has concerns about IL-10, and my initial literature reading this morning on this topic trying to understand what the risks are led me down such a deep dark rabbit hole of immune response being both positive and negative that Iā€™m not sure what to make of it now: reducing inflammaging? ā€” good. Reducing immune response against threats (probably including cancer) ā€” bad. And articles on both sides suggesting reducing IL-10 fights aging, and enhancing it fights aging. So Iā€™m now more confused than when I started.

  5. no-one continued it?

Is anyone still taking it?

Did anyone else see their hair darken?

For those that stopped, was it simply ā€œno noticeable effectsā€? Or was there a noticeable negative effect? Or was it just not worth potential risks given no noticeable effects?

Iā€™m very curious if it is a replacement to rapamycin. It sounds like no one wants to take it WITH rapamycin. Also if ā€œhair darkenedā€ is a normal response to taking it, obviously an aesthetic benefit but far more importantly it may be an indication of actual biological age ā€” this is what I think many interventions are solely lacking. For instance, has anyoneā€™s hair darkened on rapamycin? ā€” this concerns me that this isnā€™t happening (even though life extension is well documented) as it suggests biological aging is not being reduced, only slowed (hypothesis).

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#61

This is the paper I found. It was not in a journal.

https://repositorium.sdum.uminho.pt/handle/1822/54794

Chronic inflammation is present in several diseases from autoimmunity to cancer, neurodegenerative diseases and others. A chronic state of low-grade inflammation, known as inflammaging, has also been linked to aging. To counteract this chronic inflammation, the anti- inflammatory cytokine interleukin (IL)-10 appears as a potential candidate. IL-10 has a broad role in regulating the immune system and has several distinct actions in different cells. Due to its great therapeutic potential in inflammatory and autoimmune diseases, understanding the impact of IL-10 in the organism homeostasis is fundamental. Our group has been investigating this issue, by resorting to a novel mouse model of inducible IL-10 over-expression (pMT-10). Previous results indicated that pMT-10 mice over-expressing IL-10 for 30 days develop a myeloproliferative phenotype, which is similar to that of animal models and patients with myeloproliferative neoplasms and is compatible with an aged hematopoietic system. The main aim of this thesis was to extensively characterize at the organism level the effects of 75 days of sustained IL-10 over-expression. Interestingly, we found that pMT-10 mice die prematurely and present hair depigmentation, along with an histological phenotype suggestive of an aged skin. This skin phenotype is marked by a reduction of dermal and skin fat thickness, wound healing delay and alterations at the hair follicle (HF) level, including the frequency, length and melanin content. Resorting to an ex vivo model, we found the cellular phenotype of fibroblasts retrieved from pMT-10 mice that over-expressed IL-10 for 75 days to be compatible to that of elderly fibroblasts. Finally, using an in vitro system, we gained evidence that IL-10 triggers cellular senescence in mouse adult fibroblasts. Together, these data disclosed IL-10 over- expression to induce multiple phenotypes that parallel premature aging and age-related diseases. In all, this thesis brings novel insight on the biology of IL-10, which might shed light into novel targets involved in aging and into the importance of immune-driven aging, showing that immune balances, rather than inflammaging play a role in this process.

Finally, using an in vitro system, we gained evidence that IL-10 triggers cellular senescence in mouse adult fibroblasts.

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