Neo
#101
We also have this new paper by what seems like a legit group?
From the Longevity Interventional Studies Community & lab of Albert Higgins Chen @YaleMed
Full paper (pre-print):
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The Rapamycin doses tested were 3 mg or less in 9 patients only. I guess this shows that higher doses of Rapamycin are needed to show effects.
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It shows that summaries should list drug and dose.
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Neo
#104
And/or that we should skim the actual papers and not just stop with social media 
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Exactly. Whereâs the proof that they DO work?
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Neo
#107
@adssx @Joseph_Lavelle This is more a framework and very early application of it - they say so themselves
Having said that
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while I agree with you on CR (and there are other Nature papers that show even mild CR from the NIH funded human clinical trials run by Yale does positively change epigenetic/biological are
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exercise - while it clearly improves healthspan and health state and probably decreases mortality, does not generally have support in the literature extending lifespan or longevity, so that one might actually be as weâd expect based on other geoscience literature
@Joseph_Lavelle - they are actually proposing this type of framework as a way to refine which clocks and when those clocks work and when they donât - and help the field improve on the clocks
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Neo
#108
Anyone having thoughts on the good scores that Metformin got in this paper?
Any learnings from that?
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cl-user
#109
I would hypothesize reducing inflammation, as itâs what #1 does and we know inflammation is associated with most chronic diseases, as well as reducing blood glucose.
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tj_long
#110
Why wasnât SGLT2i tested?
Neo
#111
Wasnât looking for that in my first skim, you can check in the paper here:
@adssx have you seen any epigentic clock data in any studies with SGLTiâs?
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adssx
#112
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Neo
#113
Thx.
They did not use any third generation epi clock:
Second, we selected 4 epigenetic clock phenotypes (n = 34 710) as another set of outcomes to reflect biological age, which is one of the most plausible candidates of phenotypic aging. Epigenetic clocks are biomarkers of aging developed using DNA methylation-level data at different Cytosine-phosphate-Guanine sites (26), which can predict chronological age with strong accuracy and reflect aging. The first generation of epigenetic aging clocks includes HannumAge (27) and Intrinsic HorvathAge (28), and the second generation includes PhenoAge (29) and GrimAge (30). All the genetic associations with these outcomes were obtained from a GWAS of chronological age (31) and epigenetic clocks (32).
â
Did not seem to find an epi age signal:
The Effect of SGLT2 Inhibition on Aging and Cognitive Outcomes
For chronological age, SGLT2 inhibition showed an effect on longer fatherâs attained age [years of life increase, 6.21, 95% confidence interval (CI) 1.27-11.15, P = .01] (Fig. 2A). But we observed little evidence to support the effect of SGLT2 inhibition on motherâs attained age and combined parental attained age (Supplementary Table S2) (36). For biological age, there was little evidence indicating the causality of SGLT2 inhibition on HannumAge, Intrinsic HorvathAge, PhenoAge, and GrimAge (Fig. 2B and Supplementary Table S2) (36) For all MR results, little evidence was observed to support the existence of heterogeneity (P-value of Cochranâs Q statistic >.05).
Neo
#115
Another (long term and continued) proponent for Metformin (who seems to be doing well with his aging results).
â
Btw: What are peopleâs thoughts on AC-11?
On the âtop listâ
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JKPrime
#116
Very interesting. It is great that at last ART therapy hypothesis is starting to be tested first in mice Inhibition of IL-11 signalling extends mammalian healthspan and lifespan | Nature and now in humans. With respect of the cr and rapamycin it actually may be the case that humans are already long lived species and unlike in mice mtor intervention may not actually do much for lifespan. Metformin looks impressive in this study, though. I wonder how well acarbose and sglt2 inhibitor would perform here.
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Jonas
#117
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This reminded me I needed to provide an update as I am no longer using the galantamine.
To recap; My dosing began on August 1st 2024.
Monday-Friday
AM:
500mg Metformin
2mg of Galantamine
PM:
500mg of Metformin
2mg of Galantamine
I discontinued the galantamine after a measurable decline in my sleep quality. Vivid dreams, horrific nightmares even when discontinuing my night time dosage. I discontinued it November 2nd or 3rd, 2024.
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I know this has been reported before and is well-known, but this is a new paper on the topic:
Metformin targets mitochondrial complex I to lower blood glucose levels
Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metforminâs ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.
https://www.science.org/doi/10.1126/sciadv.ads5466
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