Written By Guest User
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White Paper by Kritika Pathak

Reviewed by Ben Kronz 

INTRODUCTION

Metformin, a biguanide, is a well-documented drug used in Type 2 Diabetes Mellitus for over half a century now [1] and is recommended as the drug of choice by the American Diabetes Association [2] and the European Association for the Study of Diabetes [3].

Type 2 Diabetes Mellitus is a chronic disease of adult-onset characterized by high levels of sugar in the blood [4]. Normally, our pancreas produces an important hormone known as insulin, which keeps our blood glucose levels under check [5]. Whenever levels of glucose increase in our blood, for eg after a high carbohydrate meal, insulin synthesis and secretion are accelerated [6] which then acts to increase the uptake of glucose [7] and inhibit biochemical processes involved in the synthesis of glucose [8]. All these actions together help keep our glucose levels in the normal range. However, patients with Type 2 Diabetes Mellitus have a state of ‘insulin resistance’ i.e. their body stops responding to insulin resulting in high blood glucose levels [9]. This excessive glucose gets converted into some toxic products known as advanced glycation end products or AGES [10] which are responsible for the pathogenesis of the various complications associated with diabetes such as cardiovascular disease, nerve damage, kidney disease, eye disease, increased susceptibility to infections etc [11]

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Figure 1 showing Insulin Resistance in Patients with Type 2 Diabetes [12]


Metformin has revolutionised the management of Type 2 Diabetes Mellitus by decreasing glucose production from the liver[13], promoting glucose uptake by various cells in the body[14] and delaying glucose absorption from the gut[14]. It also decreases appetite[15] and has a special weight loss promoting effect[16] making it suitable for patients with obesity and Type 2 DM both[17]. 

MOLECULAR ACTION

Metformin is known to be a potent AMPK (adenosine monophosphate‐activated protein kinase)activator[18]. AMPK is an enzyme involved in cellular energy homeostasis[19] and is also a central regulator of fat and glucose metabolism[20]. Upon activation by Metformin, it acts by inhibiting the genes involved in hepatic gluconeogenesis[13] and increases the expression of a glucose transporter named GLUT 4 in fat and muscle cells thereby increasing the uptake of glucose[21]. It was long thought that Metformin acted primarily by the activation of adenosine monophosphate‐activated protein kinase (AMPK) at the molecular level.[22]

 

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Figure 2 showing Metformin's downstream actions after AMPK activation[23]

 However, Metformin’s exact mechanism of action has been controversial and the perception that it acts only via AMPK dependent mechanism has changed. A couple of studies revealed that the AMPK pathway is neither essential(Foretz et al) [24] nor sufficient enough [25] to be responsible for the reduced hepatic gluconeogenesis. However, it is debated if the suprapharmolocological doses used in one of these studies[24] had a confounding effect or not as Metformin is known to act through different mechanisms in different concentrations[26]. Even then, increasing data has now accumulated which has suggested or rather proved the existence of some AMPK independent mechanisms[27]. For eg two important mitochondrial actions have been described which along with AMPK mechanism which aid in the suppression of hepatic gluconeogenesis.[28] 

 

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Figure 3 illustrating Metformin’s actions to suppress hepatic gluconeogenesis [28]

Interestingly, some studies have strongly indicated that the gut and not the liver is Metformin’s  major site of action unlike what was commonly believed [29 & 30]. This could be supported by the fact that Metformin is known to alter the gut microbiota which leads to increased production of butyrate and propionate, both of which are involved in the maintenance of glucose homeostasis[31]. It also promotes the growth of Akkermansia, an intestinal bacteria, which has been associated with decreased tissue inflammation and improvement in the metabolic profile of diabetics[32]. Moreover, metformin is also known to release incretins such as GLP 1 and also increases the expression of their receptors on the  beta cells of pancreas[33]. Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycemia.[34]

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Figure 4- Metformin’s action on the gut-alters the gut microbiota which leads to increased production of butyrate and propionate both of which are involved in the maintenance of glucose homeostasis, promotes the growth of Akkermansia,induces the release of incretins such as GLP-1,increases expression of GLP-1 receptor on the beta cells of pancreas and retards aging by altering folate and methionine metabolism of intestinal microbiota in C. elegans [35]

Though Metformin’s exact mechanism of action has been a bone of contention, rapid developments are occurring in this regard. Many studies have proposed other novel mechanisms such as inhibition of mitochondrial respiratory-chain complex 1[36], increased FGF21 expression[37], suppression of glucagon signal transduction[38], activation of autophagy[35] , inhibition of  IL‐1β production[39], reduction of terminal endoplasmic reticulum stress[40] to name a few. It is now widely accepted that Metformin brings about its action by acting on various molecular targets and modulating a variety of different pathways and processes. And though we have been using this drug for almost 70 years, new actions continue to be discovered broadening the range of conditions where Metformin could now be used. 

DOSE AND TOXICITY[41] 

Metformin is one of the safest drugs known with a high therapeutic index. Since it has been used for almost half a century now, its safety profile is well documented. FDA recommends a maximum daily dose of 2000mg. Gastric side effects such as nausea and vomiting are common. Lactic acidosis was one of the reasons why there were concerns to approve Metformin initially but now it has been realized that it is a very rare side effect. Contraindications to Metformin include renal failure, hypersensitivity to this drug, and metabolic acidosis.

METFORMIN AND AGING

The world is on the brink of a demographic milestone.The number of people aged 65 or older is projected to grow from an estimated 524 million in 2010 to nearly 1.5 billion in 2050[42].Chronic diseases and illnesses related to this unprecedented aging of humans are a global challenge that poses a risk to handicap world economies and deteriorates the quality of life.[43]Many researchers believe that aging is by far the best predictor of whether people will develop a chronic disease like atherosclerotic heart disease, stroke, cancer, dementia or osteoarthritis.[44]

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Figure 5 shows an increase in the incidence of various age-related diseases with increasing age[45]


THE TAME TRIAL

Conventionally, aging has been considered as a debilitating physiological phenomenon that is inevitable.[46] It is believed to be a ‘natural process’ which is bound to happen to all of us. Some researchers believe otherwise and efforts are underway to classify ‘aging’ as a disease and target it as a whole instead of trying to devise treatments for different age-related diseases individually.[47] Targeting this biology of aging, is the famous TAME TRIAL led by the American Federation for Aging Research (AFAR) Scientific Director Nir Barzilai, MD.

The researchers at the TAME trial believe that “The TAME Trial will establish a clinical trial to provide proof-of-concept that aging can be treated, just as we treat diseases. We hope the FDA will approve aging as an indication, to signify that aging can be “treated.” In medical terms, an “indication” for a drug refers to the use of that drug for treating a particular condition.

If aging is made an indication, the TAME Trial will mark a paradigm shift: from treating each age-related medical condition separately, to treating these conditions together, by targeting aging per se.”[47]

The TAME Trial plans to engage around 3,000 adults within the age group of 65-79 all over the US[48]. Though many drugs have shown promising results with respect to aging, Metformin is the main focus because it has been used for over a century as the drug of choice in Type 2 Diabetes Mellitus, has a wide therapeutic window and its safety profile has been very well documented, low cost and, most importantly, various studies have shown the beneficial effects of Metformin in retarding aging and it is also known to modulate key processes that are involved in the pathogenesis of various age-related conditions.[48]

MECHANISM BY WHICH METFORMIN BRINGS ABOUT ITS ANTI AGING EFFECTS

Remarkable progress has taken place in the past few decades in the science and biology of aging. Key pathways implicated in this aging process have been discovered and extensively studied, which have now become a target for intervention.[48] One such pathway is the mTOR pathway (mechanistic target of rapamycin kinase), which has garnered great attention in the anti-aging community. Though the exact mechanism is unknown, mTOR is known to accelerate aging by modulating the hallmarks of aging such as nutrient availability (represented by amino acid availability), energy homeostasis, cellular senescence, cell stemness, and proteostasis.[49]

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Figure 6 illustrates the role of the mTOR pathway in the regulation of the hallmarks of aging(black arrows).The depicted hallmarks of aging are also interconnected (grey arrows), suggesting that aging is a coordinated process in which mTOR plays a significant role. [49]

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Figure 7 - Growth factors and nutrients activate mTOR which inhibits autophagy and promotes protein synthesis which contributes to cellular stress which might lead to altered cell function, DNA damage,mitochondrial dysfunction etc and induces stem cell exhaustion, which reduces tissue repair and promotes tissue dysfunction which further contribute to the development of age-related diseases. (blue and red) indicates activation,   indicates inhibition.[50]

 Moreover, some studies have suggested Metformin to be a powerful caloric restriction mimetic[51] which acts by activating AMPK [52](known to promote the catabolic reaction and suppresses anabolic reactions).In accordance, studies in C.elegans have shown similar results [53]. Metformin is also known to counteract hyperinsulinemia and reduce IGF-1 levels[54], inhibit mTOR (through both AMPK independent and dependent pathways [55,56], reduce ROS production[57] and even reduce DNA damage[58]. Recent studies have identified some new processes Metformin effects such as the mitohormesis pathway involving PRDX-2 [59]. It also modulates key processes known to have a close association with aging 

and the onset of age-related disorders- inflammation[60], autophagy[61], and even cellular senescence[62]. Metformin has also known to affect two kinases- PKD and MK2, [63] which have an important role to play in cellular stress. 

ANIMAL STUDIES

The unique set of actions that Metformin brings to the table have known to affect aging directly or indirectly. However, most of them have been only reproduced in animal models and not in humans till date and even these animal studies have not shown consistent results. Studies in invertebrate models have shown contrasting results with models such as C.elegans[64] demonstrating positive effects whereas studies in D. [65] have shown quite the opposite. Some review papers have discussed the various confounding factors such as light exposure etc possibly affecting these results[66]. Even the developmental stage at which Metformin was supplemented may also have some effects on the prolongevity.[67]

Figure 8- Summary of the effects of metformin supplementation in invertebrate (Caenorhabditis elegans and Drosophila melanogaster) and vertebrate models (rodents, mainly mice) [68]

CLINICAL STUDIES

Data collected from various animal models have shown promising results. But keep in mind that findings in most animal models may not always translate into humans, more clinical studies are required to come up with definitive results. However, various randomized trials, observational and retrospective studies have shown affirmative results providing evidence for a prolongevity effect which cannot be attributed to glucose-lowering alone. This further substantiates the fact that there are some nonglycemic benefits of Metformin which may hold the key to prolongevity. Various clinical studies have shown improvements in cardiovascular disease [69], stroke[70],cancer[71],autoimmune diseases[72] and neurocognitive disorders[73]. In addition to this, a meta-analysis by Camp et al showed a reduction in all-cause mortality[70]. In fact, a retrospective observational study (Bannister et al) showed that patients with type 2 diabetes initiated with metformin monotherapy had longer survival than their non‐diabetic controls , despite the fact that the diabetic patients were more obese and had greater co-morbidities at baseline.[74]

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Figure 9- Metformin and its benefits in various diseases with their proposed mechanism of action[75]

CONCLUSION

Metformin has been used safely for over half a century now and is a drug that the scientific community is well versed with . This makes it the perfect drug to be used and tested for its potential actions in modulating aging and age-related diseases. However, most studies have been done in prediabetics and more clinical trials are required with appropriate controls.[66]

Correlation Is Not Causation, but It’s the Way to Bet

 

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