METFORMIN

(WikiLink: Metformin) - (Last Revision: 6/7/2022)

 
 

[2022] Metformin: Is it a drug for all reasons and diseases?

[7] [2017] Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis

[8] [2019] Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis

⫸The history of metformin for anti-diabetes (36) can date back to the seventeenth century, when the guani- dine compounds were found in extracts from the leaves of French lilac. The anti-glycemic effects of French lilac Galega officinalis were first described in 1653 [155, 156]. Werner and Bell synthesized metformin and related biguanide compounds in 1922, paving the way for its widespread use in humans for type 2 diabetes as a first-line therapeutic agent [157]. In 1957, the drug was approved for the therapy of diabetes through the efforts of Jean Sterne, a French doctor. Observational studies have shown that diabetic patients treated with metformin have improved survival, even compared with non-diabetic controls [158]. Observational data in humans further reinforce metformin’s role in prevent- ing age-related degeneration and cancer [159]. Met- formin has been used as an anti-aging drug in model organisms and humans due to its proven safety record in more than 60 years of clinical use, its efficacy in pro- tecting the heart, and its potential value in preventing and treating cancer [160, 161]. The lifespan-extending effects in C. elegans and mice for metformin have been reported [162–164]. A computational model study pro- vides evidence that SIRT1, an NAD+ related histone deacetylase, may be the target of metformin [165]. Met- formin may also affect the epigenome indirectly by reg- ulating metabolite levels, which are known to change activity of histone and DNA-regulating enzymes. Met- formin is known to impact cellular levels of NAD+, ATP, and tricarboxylic acid intermediates, as well as AMPK, which affect epigenome modification enzyme activity [166]. It was reported that metformin promotes the lifespan of nematodes by altering microbial metab- olism of folate and methionine [167]. The Metformin in Longevity Study, a double-blind, placebo-controlled crossover clinical trial launched in 2014 with 14 human participants, the aim was to determine whether a daily dose of 1700 mg of metformin could improve the expression of the more youthful gene in older adults with impaired glucose tolerance. A larger double- blind, placebo-controlled, multicenter trial targeting aging with metformin plans to enroll 3000 patients between the ages of 65 and 79 as the primary endpoint before any aging-related diseases develop. The sub- jects will take metformin with a dose of 15000 mg daily for 6 years, with an average follow-up of more than 3.5 years [168].

Metformin has been used for diabetes with a good safety record for more than 60 years. There is growing evidence in humans and in preclinical models that it showed beneficial effects to reduce the risk of age-related diseases. These properties of metformin have drawn the attention of a large number of researchers including industry, to develop anti-aging therapies as an indica- tion of metformin for humans. While on the surface this seems reasonable based on the safety and tolerability of the drug, there is still a lot we don’t know about met- formin’s mode of action, especially when it comes to aging. Aging is a heterogeneous phenomenon. Different individuals in the same population respond differently to metformin. Therefore, there is a need for large-scale, multicenter, randomized, placebo-controlled trials to fur- ther elucidate the anti-aging effects of metformin. Rec- ommendations to treat older adults with metformin may require a personalized, precise approach. Once we have better biomarkers of the beneficial effects of metformin on human health and longevity, we can develop these products [155]. ⫷[1]

◉ Metformin was demonstrated to extend lifespan in humans and model organisms [100–102] and have genome-wide impacts on methylation [103–105]. [3]

◉ In a population cohort study, involving 3575 naïve T2D patients, Cameron and coauthors showed that compared to sulfonylurea treatment, metformin reduced the mean neutrophil to lymphocyte ratio, an in"ammation marker and predictor of all cause mortality and cardiac events (Cameron et al. 2016).[2]

Metformin inhibited tumor necrosis factor-α–dependent IκB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1β, and CXCL1/2 (C-X-C motif ligand 1/2). [4]

⫸ Metformin (16) is an anti-diabetic drug, which works through enhancing the sensitivity of cell surface insulin receptors of muscle and fat cells to insulin involved in gluconeogenesis in the liver and thus reduce the risk of glycation and other age-related damage[43,44]. Metformin also modulates stress responses through activation of adenosine monophosphate-activated protein kinase (AMPK) that exerts its effect through switching on pathways capable of preventing and repairing cell damage by producing a sudden bout of energy production concomitant with suppressing those energy demanding processes not directly essential for the survival of the organism [45]. This is exactly what happens during calorie restriction when the body is in ‘survival mode’ and when nutritional stress of a low calorie diet activates pathways that increase cell repair. Therefore, metformin can act as a calorie restriction mimic ⫷ [46].

[2009] Synthetic drugs with anti-ageing effects

43 Wiernsperger, N.F. and Bailey, C.J. (1999) The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 58, 31–33

44 Fulgencio, J.P. et al. (2001) Effect of metformin on fatty acid and glucose metabolismin freshly isolated hepatocytes and on specific gene expression in culturedhepatocytes. Biochem. Pharmacol. 62, 439–446

45 Zakikhani, M. et al. (2006) Metformin is an AMP Kinase-dependent growth inhibitorfor breast cancer cells. Cancer Res. 66, 10269–10273

46 Dean, W. (2000) Metformin: the weight-loss drug. IAS Bull. 4, 3–5

Metformin is inexpensive, safe and widely prescribed glucose-lowering drug, being the !rst-line treatment for patients with T2D, it was proven to effectively reduce risk of cardiovascular diseases and death (Chamberlain et al. 2017; Palmer et al. 2016). In older patients, use of metformin is accompanied by reduced risk of hypoglycaeglia and non-fatal cardiovascular events, compared to other antidiabetic drugs (Schlender et al. 2017). Apart from its direct hypoglycemic effects and prevention of target-organ damage in T2D patients it has shown numerous advantageous effects in patients with diverse conditions such as impaired glucose tolerance (Hostalek et al. 2015), obesity (Bouza et al. 2012; Siskind et al. 2016), metabolic syndrome (Zimbron et al. 2016), polycystic ovary syndrome (PCOS) (Patel and Shah 2017) and nonalcoholic fatty liver disease (Li et al. 2013). [2]

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Source: Metformin Chemistry Click [√] Image for Additional Information

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Dosage for anti-aging

A dose of 250 mg to 850 mg twice a day with meals is recommended for anti-aging purposes. For healthy non-diabetic patients dosage of 500mg twice a day is recommended but its long-term effects in healthy patients are not well known yet. It is important to keep in mind that Metformin has not been FDA approved, yet as an anti-aging drug. Nothing else has been either!

Source: Metformin and aging; Science and Technology 2021

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News Release: 6/8/2022

The Saudi royal family has started a not-for-profit organization called the Hevolution Foundation that plans to spend up to $1 billion a year of its oil wealth supporting basic research on the biology of aging and finding ways to extend the number of years people live in good health, a concept known as “health span.”

Hevolution has reached a preliminary agreement to fund a test of the diabetes drug metformin in several thousand elderly people.

That trial, known as “TAME” (for “Targeting Aging with Metformin”), has been touted as the first major test of any drug to postpone aging in humans, but the study has languished for years without anyone willing to pay for it.

Nir Barzilai, a researcher at the Albert Einstein School of Medicine in New York who conceived of the TAME trial, told an audience in London this April that Hevolution had agreed to fund one-third of its cost.

That agreement, if it’s finalized, would be an endorsement of what’s called the “geroscience hypothesis”—the still unproven idea that some drugs, by altering basic aging processes inside cells, may able to delay the onset of many diseases, including cancer and Alzheimer’s.

The term “geroscience” was popularized by Felipe Sierra, the former head of the division of aging biology at the US National Institutes of Health, who was recently hired to be Hevolution’s chief scientific officer. Reached by email, Sierra declined to comment, but he has previously called geroscience the observation “that aging is by far, and I mean by far, the major risk factor for all chronic diseases.”