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 âDrug of Miracles and Wonders,â 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.
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 metforminâs 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.
Metformin is a good alternative to berberine if you want to avoid CYP3A4 inhibition. Iâve replaced my morning dose of berberine with extended release metformin.
Avoiding CYP3A4 inhibition is good when using rapamycin as that can make the effects stronger. Some people like inhibiting that but I donât like this as it increases odds of side effects.
Additionally metformin inhibits TGF-β1, which is something that rapamycin activates. This is one of the few potentially bad things about rapamycin that Iâve found so metformin pairs quite well with it. TGF-β1 isnât all bad or good.
âTGF-β signaling is complex and finely regulated fundamental pathway, which has an important role during human development and adult life. It is broadly intertwined with other signaling pathways. Moreover, it is involved in cancerogenesis of solid tumors as well as hematological malignancies. Paradoxically, TGF-β is both a tumor suppressor and tumor promoter. The tumor suppressor activities are widely described as anti-proliferative and apoptotic effects. During cancer progression, tumor frequently avoids tumor suppressive activities of TGF-β either by acquiring mutations of signaling components or by inhibiting its anti-proliferative response. This âswitchâ helps the tumor to use TGF-β as an oncogenic factor inducing tumor motility, invasion, metastasis and epithelial-to-mesenchymal transition. Advances in the study of molecular mechanisms that elucidate oncogenic activities of TGF-β lead to a strong desire to target TGF-β signaling in cancer therapy. However, the exact mechanisms involved in the malignant transformation of TGF-β needs to be clarified. Only then, it will be possible to develop successful therapeutic strategies as well as provide new therapeutic targets to restore the normal TGF-β function.â
Comparative Effectiveness of Metformin vs Sulfonylureas on Exceptional Longevity in Women with Type 2 Diabetes: Target-Trial Emulation
Initiating metformin âwas associated with increased exceptional longevityâ
Key longevity finding
⢠Incidence of death < 90 y: 3.7 vs 5.0 deaths per 100 person-years (metformin vs sulfonylurea)
⢠Hazard ratio: 0.70 (95 % CI 0.56 â 0.88) â â 30 % lower risk of failing to reach age 90 for women who began metformin monotherapy
@adssx what are your latest thoughts on met? Seems like human and NHP data the last year might have increased its attractiveness?
And (@A_User ) nice benefit that it may help again covid and long covid
The paper you shared compared Met to sulfonylureas, a poor class of drugs. When compared to SGLT2i or GLP-1RAs, metformin tends to underperform.
Yes, but interesting how it impacts the probability of living to 90âŚ
Was more that weâve see the primate data in top journal, the human agin clock data, human cancer data, etc, all within the last year and now this other data set - so the holistic picture of multiple new forms of data pointing in the same direction
Metformin is the most commonly prescribed glucose-lowering agent worldwide for the treatment of type II diabetes. Due to evidence of improvements in healthspan and lifespan in model organisms, and mechanistic data relevant to the hallmarks of aging, it has been considered a promising candidate in the search for pharmacological interventions that may attenuate the ageing process in humans. Various epidemiological studies have been influential in generating support for this hypothesis. These include pronounced anticancer and cardioprotective benefits compared to other antidiabetic treatments, and an observation of metformin use in type II diabetes being associated with better survival than that of the general population. Here we discuss recent developments in the evidence underlying the rationale for using metformin to target ageing. We describe the methodological limitations of some of the early and most influential findings and critically assess their scientific follow-up, including replication attempts of key experimental and observational findings, and a range of clinical trials of metformin in individuals without type II diabetes. These developments generally illustrate an emerging uncertainty in the anti-aging potential of metformin.
I havenât read the paper, but it seems to lag quite a bit and just summarizes the potential negative signals that we already have discussed here in the forum and by people like Attia over the last 4-5 years and already has be internalized in our thinking
What it does not seem to do this is discuss/address any of the new, positive human and primate data that we have seen over the last 6-ish months?
For example it does not seem to discuss:
DNAm aging biomarkers are responsive: Insights from 51 longevity interventional studies in humans (bioRxiv pre-print, October 2024) harmonised data from 51 human trials and showed that metformin consistently reduced biological-age scores across mortality-linked clocks such as GrimAge and DunedinPACE. See
Comparative Effectiveness of Metformin vs Sulfonylureas on Exceptional Longevity (J Gerontol A 2025), discussed this weekend above corresponded to a 30 % lower hazard of failing to reach age 90 (HR 0.70, 95 % CI 0.56-0.88), implying metformin may translate into exceptional human longevity benefits.
Or am I missing something?
And upon a skim it may also not fairly discus how impressive the recent primate data is:
Metformin decelerates aging clock in male monkeys (Cell 2024) â Forty months of 20 mg kgâťÂš dayâťÂš oral metformin in 13- to 16-year-old cynomolgus macaques pushed multi-omics epigenetic/transcriptomic/proteomic clocks ~6 âmonkey yearsâ (~15-18 human years) younger than untreated controls. The treatment also preserved frontal-lobe cortical thickness, improved memory tests, and lowered fibrosis & senescent-cell burden across multiple organs, showing whole-body slowing of biological aging.
Very interesting that we know so little even about the most used and most studied drugs. Thatâs why Iâm always skeptical about mechanistic studies. Thereâs so much we donât knowâŚ
