Neo
#104
And/or that we should skim the actual papers and not just stop with social media 
4 Likes
Exactly. Where’s 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 we’d 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 don’t - and help the field improve on the clocks
2 Likes
Neo
#108
Anyone having thoughts on the good scores that Metformin got in this paper?
Any learnings from that?
2 Likes
cl-user
#109
I would hypothesize reducing inflammation, as it’s what #1 does and we know inflammation is associated with most chronic diseases, as well as reducing blood glucose.
3 Likes
tj_long
#110
Why wasn’t SGLT2i tested?
Neo
#111
Wasn’t 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 SGLTi’s?
1 Like
adssx
#112
2 Likes
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).
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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 father’s 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 mother’s 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 Cochran’s Q statistic >.05).
Neo
#115
Another (long term and continued) proponent for Metformin (who seems to be doing well with his aging results).
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Btw: What are people’s thoughts on AC-11?
On the “top list”
1 Like
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.
1 Like
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.
8 Likes
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 metformin’s 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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New paper out of the National University of Singapore and their longevity research group:
Mitochondria and the Repurposing of Diabetes Drugs for Off-Label Health Benefits
This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the “Drug of Miracles and Wonders,” as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2. Metformin leads to the phosphorylation of the AMP-activated protein kinase AMPK, which accelerates the import of glucose into cells via the glucose transporter GLUT4 and switches the cells to the starvation mode, counteracting the virus. Diabetes drugs also stimulate the unfolded protein response and thus mitophagy, which is beneficial for healthy aging and mental health. Diabetes drugs were also found to mimic exercise and help to reduce body weight.
Open access paper:
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Metformin Use and Risk of Non-Melanoma Skin Cancer: A Propensity-Matched Case-Control Study
Our results indicate a reduced risk of non-melanoma skin cancer following exposure to metformin in individuals diagnosed with both SCC or BCC (Tables 2 and 3). This study strengthens the evidence supporting metformin’s potential as a protective agent against non-melanoma skin cancer, especially after adjusting for medications associated with increased risk of skin cancer.
Metformin holds promise as a potential chemopreventive agent for skin cancer, with various proposed biological mechanisms supporting this role. These mechanisms encompass a spectrum of anti-cancer actions.8-12 Firstly, metformin activates AMPactivated protein kinase (AMPK), which acts as a cellular energy sensor, regulating metabolic processes and impeding cancer cell growth by restricting their access to essential energy and nutrients.
Artigo completo: https://jddonline.com/articles/metformin-use-risk-of-non-melanoma-skin-cancer-propensity-matched-case-control-study-S1545961624P8249X/?_page=4&fbclid=IwZXh0bgNhZW0CMTEAAR1s5Z6kM4ivjpyma5uts-dc9oDP1ejKeJUT1ujqPJtNfJkyBvZV4JafumU_aem_SOA_oF8Ohs1eySWaCLeXCA
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Talking Docs talk Metformin.
1 Like
