Metformin and aging -
Thus, as an activator of AMP metformin has come under the microscope as a potential anti-aging drug and its potential role as an anti-aging drug promoted 36 , 41 , Worthy of note is that the sensitivity to AMPK declines with age thus promoting the argument that activators of AMPK, such as metformin, could delay aging The lifespan and healthspan of invertebrates are extended by mutations in pathways such as the DAF-2, a gene that encodes for the IGF-1 pathway in the nematode Caenorhabditis elegans C.
elegans , or the mTOR signaling pathways that are linked to accelerating the aging process 60 , 62 — The addition of metformin to the diet can delay aging and increase life span in both C. elegans and rodents 66 — 68 see Table 1. However, in these studies with C. Such doses in humans would be fatal and one would expect the same in C.
elegans where toxicity is offset by the effects of metformin on the microbiome and inhibition of bacterial folate metabolism. Indeed, in the absence of bacteria, metformin shortened lifespan implying that it is the anti-bacterial action of metformin that explains the enhancement of lifespan in C.
elegans Furthermore, in old C. elegans all concentrations of metformin, 10, 25 and 50 mM, proved toxic and reduced lifespan The enhanced toxicity to metformin in the older worms was linked to reduced mitochondria abundance and the reduced ability to generate ATP — see Table 1 for details Table 1 Summaries of studies cited in the review with a focus on the effects of metformin on lifespan.
The same pathways studied in C. As for C. elegans, metformin use in humans will change the microbiome. This action is an important determinant for the anti-hyperglycemic therapeutic effects, the gastrointestinal side effects and possibly the anti-aging effects of metformin 88 , In addition, and also via gut-mediated action, metformin enhances the release of glucagon-like peptide-1 GLP It is the release of GLP-1 that contributes substantially to the antihyperglycemic effects of metformin 26 , 90 , The recognition of the role of both the gut microbiome and the release of GLP-1 as important contributors to the anti-diabetic effects of metformin has been a significant advance in understanding how metformin mediates its therapeutic actions including the contribution to the variable weight loss that is associated with metformin An additional factor in weight loss is the novel cytokine, Growth Differentiation Factor 15 GDF15 , which is a member of the transforming growth factor β superfamily and also known as macrophage inhibitory cytokine-1 MIC As a result of an analysis of data from the ORIGIN trial Outcome Reduction with Initial Glargine Intervention , GDF15 was identified as a biomarker linked to positive CV outcomes and also elevated in those patients receiving metformin 80 , The association between metformin and GDF15 was strengthened by data showing that metformin prevented weight gain in high fat fed mice, but not in mice lacking GDF15, or lacking its receptor, glial cell-derived neurotrophic factor family receptor alpha-like GFRAL , or following treatment with a GRAL antagonist; however, GDF15 was not required for the antihyperglycemic effects of metformin A number of studies have reported a positive correlation between the use of metformin and enhanced levels of GDF15 Of additional interest and based on a proteomic analysis of the plasma from healthy, disease-free, humans in the age range years-old, GDF15 was identified as the protein most positively correlated with chronological age and also known to reduce appetite via an action in the hind-brain 82 , Collectively, these data suggest a link between the putative anti-aging effects of metformin, weight loss and CV benefits that are distinct from the effects of metformin on glucose homeostasis.
GDF15 also signals through the epidermal growth factor EGF family of receptors and the PI3K, and AKT signaling pathways raising the question whether an elevation of GDF15 is necessarily protective 94 , Elevated levels of GDF15 have been linked to tumor growth and poor prognosis in cancer patients raising the question as to whether GDF15 serves as a tumor suppressor or promoter and a target for the treatment of cancer 84 , 85 , See Table 1.
AMPK functions as an energy sensor that coordinates multiple protective and energy-conserving signaling pathways including the pathways activated by caloric restriction and referred to as the fuel gauge of the cell by serving as an energy sensor , Figure 1.
AMPK is activated through metabolic stress and acts as a cellular regulator of lipid and glucose metabolism , Hepatic gluconeogenesis is inhibited by AMPK activation, which also enhances insulin sensitivity, muscle glucose absorption, and fatty acid oxidation , Additionally, metformin inhibits the inflammatory response through nuclear factor κB NFκB inhibition via pathways involving AMPK , Table 2 and Figure 1.
An increase in the activity of AMPK would also explain the protective effects of metformin on endothelial function via the activation of endothelial nitric oxide synthase eNOS thereby countering the negative effects of a diabetic milieu on cardiovascular function AMPK inhibits signaling via mTOR and through this action could contribute to the reduced incidence of some cancers that has been associated with the use of metformin: see Table 2.
Furthermore, reduced sensitivity to AMPK activation with age or disease could result in reduced healthspan and lifespan Although these data support the argument that metformin enhances both healthspan and lifespan, caution is needed because of the high concentrations of metformin, well above therapeutic levels in humans that have been used in some of the pre-clinical in vitro studies.
Figure 1 Metformin inhibits mitochondrial complex 1. In this schematic, metformin is transported into the cell via the organic cation transporters, OCT 1, 2 and 3 and the plasma membrane monoamine transporter PMAT. AMPK activation leads to an inhibition of the mTOR pathway, which would contribute to the antitumor effects of metformin.
Metformin also has been shown to activate AMPK via the serine-threonine liver kinase B1 LKB1 where phosphorylation p activation of AMPK occurs. Table 2 Summaries of studies that focus on cellular actions of metformin to activate AMPK, reduce generation of reactive oxygen species, improve vascular function, mediate anti-inflammatory effects and the potential to treat cancer and neurodegenerative diseases.
Sirtuin-1 is the protein product of the putative anti-aging gene SIRT1, which targets lysine residues in proteins, including histones and the tumor-suppressors, LKB1 and p53 , In endothelial cells, metformin has been shown to enhance phosphorylation and increase the activity of LKB1 Senescence is a major contributor to aging and the development of cardiovascular disease , and sirtuin-1 expression is required for metformin to protect endothelial cells against hyperglycemia-induced senescence Furthermore, in silico analysis suggests that metformin could directly activate SIRT1 Collectively these data provide a link between metformin, AMPK, LKB1, sirtuin-1, and cellular mechanisms that could enhance both healthspan and lifespan by reducing both cellular senescence and the activation of pro-proliferative pathways.
Considerable attention has been placed on the liver and skeletal muscle as the primary sites of action of metformin resulting from the activation of AMPK secondary to an inhibitory action on mitochondrial complex 1. A small increase in the level of AMP enhances AMPK via three mechanisms: i allosteric activation by AMP binding to the Υ subunit ii promotion of phosphorylation of Thr, and iii inhibition of dephosphorylation of Thr Furthermore, an increase in AMP also decreases adenylate cyclase activation and thereby lowers glucagon release This mechanism is an attractive hypothesis to explain how metformin mediates a multitude of cellular effects via AMPK Evidence that metformin targets mitochondrial complex 1 is supported by data from several studies The role of complex 1 inhibition in mediating the effects of metformin is summarized in Figure 1 , and much of the published literature assumes this inhibition is indeed the mechanism whereby the drug mediates its effects via AMPK, and the reduction of the generation of ROS from complex 1 However, several other mechanisms to explain the cellular actions of metformin have also been advanced [see 39 , ].
As pointed out by Fontaine, a problem associated with accepting the argument that the therapeutic effects of metformin result from inhibition of complex 1, as depicted in Figure 1 , are the high concentrations used in the cell culture studies described by El Mir et al.
and Owen et al. For instance, activation of AMPK by metformin has been observed at much lower metformin concentrations in comparable cell culture protocols using metformin concentrations that are within the upper limits of its therapeutic plasma levels 4 , On the other hand and based on thermodynamic considerations, Owen et al.
Partial support for this hypothesis has been provided by Chien et al. who used a cell culture protocol with human embryonic kidney HEK cells that were overexpressed with the organic cation transporter 1 OCT1 and exposed for 60 minutes to 5 μM 14 C-metformin Chien et al.
On the basis of this enhanced uptake, Chien et al. argue that metformin can be trapped in intracellular organelles such as microsomes and mitochondria In a similar protocol, the in vitro and in vivo effects of metformin on mitochondria function were investigated in vitro in primary murine hepatocytes and Hepa cells murine hepatoma cells derived from the BW tumor and an in vivo protocol with high-fat diet HFD treated mice It is also worthy of note that the IC50 for metformin to inhibit mitochondrial complex 1 is 19—66 mM , Collectively these data cast doubt as to the contribution of inhibition of complex 1 as the primary target and explanation for the therapeutic effects of metformin both as an anti-diabetic and as an anti-aging drug.
This conclusion is also supported in reviews , , and by clinical data from T2DM patients treated with metformin that show normal mitochondrial complex 1 respiration in skeletal muscle biopsies As discussed below, it is important to consider the pharmacokinetic properties of metformin when extrapolating data from in vitro studies to potential benefits when used clinically.
Mitochondria play a critical role in oxidative metabolism and a link has been made in patients between obesity, insulin resistance, and defective mitochondria oxidative processes that results in a buildup of toxic intermediate metabolites Several studies have also provided evidence that mitochondrial function is impaired in diabetes and thus the additional insult of metformin-induced dysfunction would be detrimental to patients with T2DM , , as was seen with the effects of metformin on old AD10 C.
elegans as previously discussed Complex 1 activity in mitochondria from skeletal muscle biopsies was lower in T2DM and obese subjects compared to diabetic lean subjects Although these data do not entirely negate the argument that metformin mediates its anti-hyperglycemic actions via an inhibitory action on mitochondria complex 1, the evidence strongly suggests that further inhibition of function would worsen, and contribute to, the toxic effects of metformin, such as lactic acidosis, that are, albeit very rare As suggested by Wang et al.
AMPK has also been implicated in the regulation of mitochondrial biogenesis, thus providing another link between metformin, AMPK, and improved mitochondrial function , If metformin can offset the decline in mitochondrial function, as some studies suggest, then this effect could contribute to enhancing both healthspan and lifespan , , Interestingly, both metformin and the anti-oxidant, resveratrol, inhibit ROS-associated mitochondria fission Numerous studies have also reported that resveratrol has anti-aging effects in several species with its effects, as also described for metformin, linked to the deacetylase, sirtuin-1 That said, the concentrations of resveratrol present in the diet, e.
in wines, are far below the amounts that might have any effect on aging. Collectively, these data suggest an important role for metformin in the regulation of mitochondria function that could link to beneficial effects on both healthspan and lifespan. In order to extrapolate data from in vitro studies to in vivo therapeutic effectiveness, it is important to review the pharmacokinetic properties of metformin 34 , , — Metformin is a strongly basic hydrophilic drug with a pKa of approximately 11 is not metabolized and is excreted principally by the kidney.
The expression levels of the saturable organic cation transporters will determine the rate of absorption of metformin from the gut and the subsequent cellular distribution and excretion of metformin.
There are three distinct classes of organic cation-selective transporters that can be utilized by metformin: Organic Cation Transporter OCT 1, 2 and 3 SLC22A1, A2, A3 ; Plasma membrane Monoamine Transporter PMAT; SLC29A4 ; and Multidrug And Toxin Extrusion protein MATE 1 and 2 SLC47A1, A2 , to enter and leave cells Figure 1 A high expression levels of influx transporters in cells might allow a much higher accumulation of metformin resulting in selective toxicity and cell death as has been postulated to explain the anti-cancer effects of the drug However, with a plasma half-life of approximately 3 to 5 hours, and subject to the schedule of dosing, it is unlikely, that other than in gut enterocytes, a significant cellular accumulation of metformin occurs when the drug is used for the treatment of T2DM 34 , , , , It is important that results from in vitro studies using high micromolar and millimolar concentrations of metformin, often for long-exposure times, are looked at critically as such data may not be readily translated to effects when used in humans.
A useful comparison of the doses of metformin used therapeutically versus pre-clinical studies was made by Badrick and Renehan, indicating that for pre-clinical studies done in vivo , the doses ranged from x2 to x45 therapeutic doses and that for studies done in vitro , concentrations ranged from x25 to x higher than those observed in patients Justification for the use of high concentrations of metformin in in vitro studies has been provided.
Thus, Onken and Driscoll 71 reported that the anti-aging actions of metformin in C. elegans has a highly protective cuticle and intestinal lining that generally limit drug uptake such that it is not unusual for polar drugs to be applied at a concentration fold higher than their predicted affinity for the target; physiological levels of drug in animals are anticipated to be much lower.
Although this rationale may be true for C. elegans , the absorption and distribution of metformin in mammals is also dependent on organic cation transporters OCTs and therefore a similar argument should be applied to other species unless it can be shown that C. elegans has a very low expression level of influx transporters and high expression of extrusion transporters thus justifying the use of high mM doses.
Similarly, others have defended drug levels as matching plasma levels in humans and not acknowledged the short half-life of metformin; a drug that is not metabolized, for which plasma levels rapidly drop as metformin is extruded from cellular sites and excreted by the kidney.
Data from multiple studies indicate that patients with T2DM who are prescribed metformin have improved survival rates when compared to non-diabetic controls.
In a study using retrospective observational data from the UK Clinical Practice Research Datalink, T2DM patients on metformin or sulfonylurea monotherapy were compared to non-diabetic control groups that were age and sex matched 69 see Table 1.
Collectively, these data imply a clear mortality benefit associated with the use of metformin. However, the lower survival rate of those in the sulfonylurea-treated group might reflect a negative effect of sulfonylurea drugs on mortality as has been reported in subsequent studies Similarly, a meta-analysis with the objective of determining the cardiovascular benefits of metformin in combination with newer anti-diabetic drugs including incretins GLP-1 agonists , dipeptidyl peptidase-4 DPP-4 inhibitors, and sodium-glucose co-transporter 2 SGLT2 inhibitors revealed both positive and neutral effects of adding metformin , Nonetheless, in the absence of appropriately designed placebo-driven randomized control studies RCTs that include comparison with GLP-1 agonists, DPP-4 and SGLT2 inhibitors, doubt persists if, in fact, metformin does reduce the cardiovascular risk associated with diabetes The endothelium plays a critical role in the regulation of cardiovascular function and not least as a source of the important signaling molecule, nitric oxide NO.
Furchgott and Zawadski were the first to report that an intact and undamaged endothelium was essential in order for acetylcholine to mediate a vasodilator response We now refer to acetylcholine as an endothelium-dependent vasodilator, and we also recognize that endothelial dysfunction, which can be defined as a reduced vasodilator response to acetylcholine, is an early prognostic indicator for the onset of cardiovascular disease — Remarkably it was the much earlier microscopy work of Dr.
Rudolf Altschul in Saskatoon Canada that recognized the link between hypercholesterolemia and the pathological changes in the endothelium. Based on his comparisons of blood vessels of patients who died from cardiovascular disease versus other causes Dr.
Blood vessels, however, are primarily endothelial tubes with secondary, accessorial walls, and, therefore, it may be postulated that the endothelium has a great importance in our life and that its failure will cause the death of many of us. There is an extensive literature based on data from pre-clinical and clinical studies that indicates metformin protects endothelial function from the effects of diabetes Positive clinical data have been provided by Mather et al.
who used forearm strain-gauge plethysmography to assess the effects of metformin on forearm blood flow following the intra-brachial artery administration of acetylcholine versus responses to the endothelium-independent vasodilators, sodium nitroprusside and verapamil, in patients with T2DM The patients, prior to the start of the week trial, were metformin naïve and either received metformin mg, twice each day or placebo Mather et al.
reported that compared to placebo, metformin improved endothelium-dependent, but not endothelium-independent vasodilation thus highlighting the primary dysfunction in blood flow was not the vascular smooth muscle response but was secondary to endothelial dysfunction A larger randomized placebo-controlled study with patients receiving daily doses of between and mg metformin focused on changes in biomarkers of endothelial dysfunction and patients were followed for 52 months The results complement the plethysmography data reported by Mather et al.
The metabolomics data can links the lowering of citrulline to the increase in NO generation from arginine and improved eNOS activity, thus providing support to the literature that metformin protects the cardiovascular system via promoting the generation of NO As previously discussed, metformin directly protects the endothelium from hyperglycemia-induced dysfunction and premature senescence and implicates a crucial role for the SIRT1-derived deacetylase, sirtuin-1 , Sirtuin-1 plays an essential role in the regulation of angiogenesis, a protective role against oxidative stress and cardiovascular disease and higher expression levels of sirtuin-1 are associated with reducing disease — Sirtuin-1 also has been reported to promote endothelial cell proliferation and suppress senescence of porcine primary aortic endothelial cells via a signaling mechanism requiring the expression of the serine-threonine kinase, LKB1, the upstream regulator of AMPK Sirtuin-1 plays a positive role in regulating endothelium-dependent vasodilation via the deacetylation of lysines and on endothelial nitric oxide synthase eNOS The positive effects of metformin to offset hyperglycemia-induced endothelial dysfunction reflect an increase in the generation of NO , In both studies, Arunachalam et al.
Of significance is that much lower concentrations of metformin, between 1 and 10 μM, have also been shown to protect endothelium-dependent vasodilation in murine aortae In their study, Triggle et al.
Furthermore, at the low micromolar concentrations used in this study, neither mitochondrial complex-I nor complex-III oxygen consumption rates were inhibited, but were when μM metformin was used. Collectively, these data suggest that a novel mechanism of action is responsible for mediating the protective effects of metformin in the vasculature Figure 2.
Figure 2 Metformin protects endothelial function. Pre-clinical and clinical data indicates that metformin has direct effects to protect the endothelium from diabetes-induced dysfunction and treatment results in improved function of endothelial nitric oxide synthase eNOS , the generation of nitric oxide NO and improved blood flow that facilitates glucose disposal.
The latter has important links to the regulation of metabolism. OCT3 transporter expression in nuclear membrane facilitates metformin transport into the nucleus To unravel the precise signaling pathway linking metformin to the NR4A nuclear receptor family requires further studies, but it is worthy of note that the orphan receptor, Nur77, regulates LKB1 localization and is also important for the regulation of glucose uptake into C mouse muscle cells , Additional evidence that metformin protects mitochondrial function has been provided by Wang et al.
Wang et al. have reported that metformin protects complex 1 activity in a cell culture protocol in hepatocytes but enhances mitochondria fission, thereby promoting healthy mitochondrial function via mitophagy Metformin and other drugs used for T2DM, like the SGLT2 inhibitors, may also reduce hyperglycemia-induced elevated endothelial ROS, independent of negative effects on complex 1, such as via inhibition of NADPH oxidase or blocking the entry of glucose into the endothelium 32 , — , , Table 2.
Thus, based on both pre-clinical and clinical data, we can conclude that metformin elicits important protective effects on vascular function that help offset the advance of vascular-related diseases and thereby improves healthspan. Hyperglycemic memory was first described in humans as the resistance to preventing the development of diabetic retinopathy despite achieving good glycemic control in patients Hyperglycemic memory contributes to the pathophysiology of diabetes despite the initiation of intensive glycemic control , Data from studies of tissues from streptozotocin-induced diabetic rats and also of endothelial cells in culture indicate that glucose-elevated fibronectin expression is not reversed when normal glycaemia is restored Metformin has been shown to reverse hyperglycemic memory.
In bovine retinal capillary endothelial cells BRECs and retinas from diabetic rats, hyperglycemia-induced elevated levels of NF-κB, and Bax, a pro-apoptotic gene, were sustained even after returning to normoglycemia BRECs where SIRT1 was knocked down with siRNA knockdown demonstrated an increased sensitivity to hyperglycemic stress, whereas SIRT1 overexpression, or exposure to metformin, inhibited the increase of mitochondrial ROS by upregulation of LKB1, and suppressed the expression of NF-B and the apoptosis regulator protein, Bax Several other studies using a variety of different cell types have reported that metformin inhibits NF-κB activation, decreases the production of inflammatory cytokines and the genes that code for the inflammatory response thus supporting the healthspan benefits of metformin , — Exercise activates AMPK, which in turn enhances glucose uptake into muscle and improves insulin sensitivity thus helping to offset the negative effects of obesity, diabetes and cardiovascular disease and thereby reducing morbidity and improving healthspan It is important to note that exercise has been shown to have positive effects on the endothelium and, via improved eNOS function, enhances endothelium-dependent vasodilation.
Metformin has also been reported to offset the effects of aging in the elderly and in cardiovascular disease , — On the other hand data from the Diabetes Prevention Program study of pre-diabetic subjects over an average of 2. Since both exercise and metformin can improve glycemic control and since both mediate their effects via the activation of AMPK, this suggests that there should be at least an additive effect when metformin use is combined with exercise.
Unfortunately, based on a prospective, double-blinded, randomized, controlled study additive effects of benefits were not observed In addition, metformin blunted the exercise-induced increase in VO 2peak The authors suggest that the negative effect of metformin on exercise results from metformin lowering ROS levels, thus reducing the effects of ROS to activate AMPK.
Additional doubts about the benefits of combining metformin and exercise come from two studies with older adults. Konopka et al. Comparable conclusions were reached based on the data from the Look AHEAD randomized intensive lifestyle intervention trial that metformin provided minimal additional benefit But the negative effects of metformin on exercise-induced benefits raise concerns about the use of metformin for anything other than for approved diseases such as T2DM.
Several genetic mutations, such as in the C. elegans DAF transcription signaling pathway, involving nutrient-sensing pathways have been described and linked to a role in extending lifespan. The data infer the mutations cause a physiological state similar to that experienced during periods of reduced calorie intake Furthermore, caloric restriction has been found to extend the life span of several organisms including S.
cerevisiae yeast , C. elegans, fish, rodents, and rhesus monkeys , Caloric restriction reduces the generation of growth hormone, insulin, IGF1, and other growth factors, all of which have been shown to hasten aging and increase mortality in a number of species see Figure 3 Figure 3 Potential cellular targets for metformin that affect healthspan and lifespan.
The figure depicts how metformin may affect cell aging and indicates a potential action in the gut where, prior to absorption, merformin modulates the microbiome as well as enhances release of glucagon-like factor 1 GLP Important links are also indicated to the insulin IRS: Insulin Receptor Substrate and insulin-like growth factor-1 IGF-1 signaling pathways as well as to tumor suppressors including p53, and inflammation and cytokine signaling.
PI3K: Phosphatidylinositol 3-kinase ; AKT: protein kinase B ; FOXO: Forkhead Box O3 ; SIRT1: NAD-dependent deacetylase sirtuin-1 ; Bax: Bclassociated X protein. As a result of metformin moderating the cellular signaling pathways mediated by insulin, IGF-1, and cytokines, both, healthspan and lifespan are increased.
Metformin also, inhibits the inflammatory pathway and increases AMPK activation, which inhibits mTOR, a primary target for cell aging modulation. Inflammation, apoptosis, autophagy, cell survival, and protein synthesis are all affected by these mechanisms and are all linked to accelerated aging.
Apart from lifespan extension, caloric restriction also reduces the risk factors for major diseases including diabetes and cardiovascular disease in rodents , Studies by the Calorie Restriction Society, a group of people who chose to limit their calorie consumption with the intention of extending their life span, included adult men and women mean BMI, Those on the calorie-restricted diet demonstrated a number of metabolic improvements including body fat, lower blood pressure, and improved insulin sensitivity, and lipid profile — Meta-analysis has also demonstrated that dietary restrictions decreased levels of circulating IGF-1 in humans ; however, although much of the evidence indicates that lower levels of IGF-1 benefit enhanced lifespan, IGF-1 does play important roles in homeostasis and not just during childhood thus raising the concern of potential negative effects of excessive lowering of the growth hormone.
Collectively, these observations support the benefits of calorie restriction and heighten the interest in pharmacologic agents, such as metformin, as calorie restriction mimetics; however, there are questions and limitations to address that include [see , ]: For instance: 1. What level of calorie restriction is required and is acceptable for optimal benefit?
How to avoid the effects of severe calorie restriction that can result in malnutrition and adversely affect health particularly in those with low BMI? These questions are important as not all studies have demonstrated a clear relationship between BMI, being overweight, obese and mortality although the risk of CVD is elevated The cellular processes that mediate the benefits of calorie restriction on lifespan in mammalian species remain controversial and although it is tempting to assume an important role for AMPK as a key nutrient sensor, there are a number of caveats that limit a positive correlation in mammalian species versus more convincing evidence in lower eukaryotic organisms, such as C.
For instance, as discussed in the next section, despite activating AMPK, metformin has not reproducibly been shown to enhance lifespan in rodents and notably less, or not effective in older animals, including C.
In addition, applying data obtained from studies with C. elegans and rodents to intervention studies in a diverse human population raises obvious limitations.
The National Institute on Aging Interventions Testing Program has investigated the effectiveness of a variety of pharmacologic agents, including aspirin, metformin, nordihydroguaiaretic acid NDGA , and rapamycin to determine whether they prolong lifespan in mice Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C.
elegans , S. cerevisiae, and Drosophila melanogaster fruit fly — The lifespan-extending effects of metformin have been investigated by Martin-Montalvo et al. in male mice, and indicate that long-term treatment with 0. The effects of metformin were reported to be similar to those of calorie restriction, including improved insulin sensitivity and lower cholesterol levels However, Strong et al.
were unable to reproduce the positive lifespan data with the 0. Strong et al. provided the explanation that the insulin-sensitizing effect of metformin offsets the negative effects of rapamycin on glucose homeostasis Smith et al.
Collectively, these results demonstrated that the mTOR pathway has a role in lifespan extension in mammals, but raise the question as to why, with the exception of the study by Martin-Montalvo et al.
Blagosklonny argued that the metabolic side effects of rapamycin are a consequence of it acting as a CRM and are required to mediate its positive effects on lifespan If we accept this argument and also accept that metformin, despite inhibiting mTOR, is not a CRM 77 , 78 then metformin would not be expected to extend lifespan.
One caveat to consider for all ageing studies using rodent models relates to the marked genomic differences between rodents and humans in terms of the response to inflammatory disease No doubt, both the innate and adaptive immune responses to inflammation play a key role in the ageing process, and differences in these responses between rodents and humans merit attention.
In this regard, metformin may play an important role, due to its potential impact on the innate immune response and the generation of ROS caused by inflammatory cytokines. Autophagy is a process necessary for the removal of damaged proteins and organelles and plays an important role in the regulation of cell aging, providing a supply of nutrients to maintain cellular function during starvation, and inhibition of autophagy mimics accelerated aging 52 , , Furthermore, calorie restriction is a strong inducer of autophagy and increases the lifespan in C.
Xie et al. investigated the role of chronic AMPK activation by metformin in restoring cardiomyocyte autophagy in OVE26 diabetic mice, a model for type one diabetes Isolated hearts, from the diabetic mice showed a substantial reduction in AMPK function and cardiomyocyte autophagy as well as mitochondria aggregations dispersed between poorly organized myofibrils and increased apoptosis that was reversed following chronic treatment with metformin Song et al.
have reported a link between SIRT1, AMPK, and metformin-induced autophagy thereby supporting a synergistic relationship between the deacetylase, sirtuin-1, and metformin-mediated effects on aging In mice, overexpression of Atg5, the protein product of the essential gene for the autophagosome, boosts autophagy and, more importantly, induces anti-aging phenotypes including enhanced insulin sensitivity and motor control Additionally, embryonic fibroblasts cultured from Atg5 transgenic mice are less affected by oxidative stress-induced cell death, a tolerance reversible by an autophagy inhibitor Collectively, data from these studies suggest a link between metformin, autophagy, and extension of lifespan.
However, under conditions when tumor microvascular endothelial cells in culture are exposed to glucose starvation, metformin inhibits autophagy via inhibition of the mTOR pathway and a partially AMPK-independent mechanism in The effects of metformin to inhibit autophagy were only seen following a hour incubation with 2 mM metformin, and lower concentrations that are in the therapeutic range, including 50 μM, were ineffective Thus, again the question is raised as to whether effects reported from in vitro studies with mM concentrations of metformin can be translated to a therapeutic effect in humans.
Diabetes has been associated with an enhanced risk for the development of various cancers A retrospective study published in reported that patients with diabetes who had been treated with metformin for T2DM had a lower risk of cancer and highlighted the possible link between metformin and the serine-threonine tumor suppressor, LKB1, as a mechanism for the reduced risk see Table 2.
Similarly, the link between metformin and the activation of AMPK has been emphasized as the basis for the anti-proliferative effects of metformin Extensive support for a protective effect of metformin against cancer has been provided by numerous, but not all studies , For instance, no association has been shown between the use of metformin and a lower incidence of bladder cancer and concerns have also been expressed how data from observational studies are analyzed , Examples include a Phase II study, NCT, designed to determine whether metformin reduces obesity-associated breast cancer risk and due to be completed in mid A logical target whereby metformin could mediate its putative antiproliferative effects in cancer is via inhibition of mTOR and the serine-threonine kinase, ribosomal S6K pS6K , either via activation of AMPK or via an AMPK-independent pathway , It has also been argued that the inhibition of mitochondrial complex 1 is an important contributor to the cytotoxic effects of metformin and has been observed in cancer cells and supported by data showing reduced inhibition of tumor growth in cancer cells expressing a metformin-resistant yeast complex 1, NDI1 , The metabolic changes that occur as a result of diabetes hyperinsulinemia, hyperglycemia, and dyslipidemia potentiate signaling pathways and may increase the oncogenic nature of breast tissue through accelerating cell growth and migration, angiogenesis, increasing metastasis, and decreasing the response to chemotherapy , — These metabolic pathways, rather than a direct anti-proliferative action, may be the target as Metformin decreases hepatic gluconeogenesis, improves insulin sensitivity, reduces insulin and blood glucose levels, and these effects, which also will reduce tumor growth, rather than a direct anti-proliferative action may be the primary target of metformin 55 , As previously stated when used to treat diabetes peak plasma concentrations of metformin are usually less than 20 μM , However, many in vitro studies have used mM concentrations of metformin to demonstrate an anti-proliferative action in tumor cells in culture [see , ; Table 2 ].
Chandel et al. argue that higher concentrations of metformin are necessary in in vitro cell culture protocols because the abundance of growth factors and nutrients, such as glucose, reduces the sensitivity to the inhibitory effects of metformin thus reflecting the importance of glucose and the Warburg effect for cancer cell growth as well as the importance of glycemic control in diabetes Studies of the effects of glucose concentration on the anti-proliferative effects of metformin on breast cancer cell growth in different human cancer lines In vitro studies reveal that triple negative breast cancer cells TNBC are particularly sensitive to the pro-proliferative effects of glucose, and TNBC cells are more sensitive to metformin at lower levels of glucose Zordoky et al.
reported that metformin significantly inhibited growth in cells cultured in normoglycemic conditions, and only for the cells grown in normoglycemic conditions did metformin induce significant AMPK activation Samuel et al. have also demonstrated using a cell culture protocol that higher levels of glucose reduce the ability of metformin to inhibit cancer cell proliferation In contrast to the data from in vitro studies, a retrospective analysis of patients with T2DM and TNBC by Bayraktar et al.
indicated that treatment with adjuvant metformin was not associated with a significantly improved survival and concluding the need for data from prospective Phase III randomized studies An argument to explain the selective action of metformin in some cancers but not all is that there is a differential expression of the influx and efflux transporters in tumor cells that allows for the intracellular accumulation of metformin in the cancer cell and resultant selective toxicity Cai et al.
who compared metformin uptake levels and inhibiting activity on cancer cell growth in a human breast cancer cell line BT deficient in OCTs and a BT cell line overexpressing organic cation transporter 3 OCT3 , OCT3-BH20 cells: OCT3 is also a predominant transporter in human breast neoplasms Comparable data has also been reported from a study with a high-fat diet rat model of breast cancer showing a positive association with the expression of OCT2 and accumulation of [D 6 ]-metformin isotope In contrast and although LnCaP, a prostate cancer line, proved to be particularly sensitive to metformin and in a concentration range that was within that expected clinically and correlated with a high expression of mRNA for OCT3 and low expression of MATE2 for the other cell lines, very high concentrations, up to 10mM, of metformin were required to see significant inhibition, and a strong significant correlation between inhibition of proliferation and MATE2 expression was not seen A limitation of the studies investigating expression levels of the cation transporters is that in the absence of adequate specific transporter antibodies quantification of transporter protein was not possible, and correlations were based entirely on mRNA data.
Collectively, these data suggest that expression levels of the uptake and extrusion transporters are not necessarily the limiting factors determining the anti-proliferative effects of metformin and that genetically determined variations in signaling pathways are variably important as are nutrient levels in the tumor microenvironment , In conclusion, since beneficial effects of metformin are not seen in all cancers further studies are required to determine whether the anti-cancer actions are direct or are secondary to the positive effects of metformin on healthspan that are apparent in obese patients such as improved glucose homeostasis, enhanced insulin sensitivity and reduced signaling through the IGF-1—mTOR pathway , , Table 2.
Diabetes-associated hyperglycemia, hyperinsulinemia, elevated oxidative stress, vascular disease, and inflammation are all linked to cognitive decline and, as reflected by a meta-analysis, it was concluded that metformin reduces cognitive decline and dementia in T2DM subjects In another clinical trial, 58 participants who had both depression and T2DM received either metformin or placebo for 24 weeks concluded that metformin improved cognitive performance A molecular basis for the effects of metformin on cognitive function is suggested by data using adult murine neural stem cells in culture that shows metformin in the concentration range nM to 1 μM enhanced proliferation and self renewal dependent on the transcription factor, Tap73, and enhanced neuronal differentiation via the AMPK-atypical protein kinase C aPKC -CREB-binding protein CBP pathway [ : Table 2 ].
An overlooked hypothesis is that the ability of metformin to enhance CNS vascular function, as it does in the periphery , may also contribute to improved CNS function. Designed as a crossover study, the Metformin in Longevity Study MILES is a double-blinded study where the subjects act as their own placebo control group [ 79 Table 1 ].
Data from the MILES trial indicate that metformin modified multiple pathways associated with aging including metabolic pathways, collagen trimerization and extracellular matrix ECM remodeling, adipose tissue and fatty acid metabolism, mitochondria, and the MutS genes, MSH2 and MSH3, which play a role in DNA mismatch repair, a process that declines with age However, it is important to note a concluding sentence from Kulkarni et al.
Targeting Aging with Metformin TAME trial is a double-blinded, placebo-controlled, multicenter trial that is planned to involve 14 research centers in the USA, and subject to funding and approval, will enroll ethnically diverse, non-diabetic subjects aged 65—80 60 , The objectives of TAME are: 1.
Clinical outcomes as measured by the appearance of new age-related chronic diseases; 2. Functional outcomes such as changes in mobility as measured by gait speed over 10 meters [also see ], as well as measures of cognitive impairment; 3.
Biomarkers of aging such as for inflammation and senescence The study plan for TAME is that patients will be given a daily dose of metformin mg for 6 years, with an estimated follow-up period of more than 3.
It is argued that TAME trial outcomes will give more insight on whether metformin decreases the risk of developing age-dependent diseases, excluding diabetes, in non-diabetic individuals, and potentially provide a tool to target aging itself and not related diseases individually 60 , However, as expressed both in this review and by others there are concerns about the age —dependent effects of metformin and in older organisms, including C.
elegans, rodents and humans, the effects of metformin are variable and may be detrimental [see ]. It is also worthy of citing a concluding statement and caution by Pyrkov et al. A number of other clinical trials are underway that address some of the concerns noted in this review: NCT Does Insulin Sensitivity Impact the Potential of Metformin to Slow Aging due to be completed in April , which is a randomized, placebo driven, double-blinded Phase 3 study with participants and the objective to compare the effects of metformin on insulin sensitivity and mitochondria function in patients who are insulin-sensitive versus those who are insulin resistant.
Frailty will be determined using a standardized assessment Collectively the results from these studies will be valuable in better assessing the benefits of metformin on healthspan and also fine-tuning future larger studies such as TAME.
Based on a year history of use as an anti-diabetic drug for the treatment of T2DM, metformin is accepted as a comparatively safe drug. Metformin is no longer protected by patents and thus is comparatively inexpensive.
Collectively, these attributes together with an extensive literature supportive of benefits in the settings of diabetes, obesity, cardiovascular disease and, arguably, cancer and dementia could justify its wider use as a prophylactic to offset the effects of aging and enhance healthspan and lifespan.
In this review we have also highlighted and critiqued some of the key clinical and laboratory-based studies that provide data supportive of the hypothesis that metformin, independent of its anti-hyperglycemic actions, has benefits that in principle can slow cellular aging and enhance healthspan and lifespan.
Metformin, via its direct protective effects on vascular function, may slow the aging process via improved blood flow and provide protection against age-related cognitive decline.
However, not all of the data is supportive and metformin, as shown in C. elegans and mice, may be less effective, or ineffective, in older humans. We have also stressed that, based on the pharmacokinetic properties of metformin, caution is needed before extrapolating from in vitro cell-based studies done with comparatively high metformin concentrations to clinical effectiveness with plasma concentrations in the range of 20 micromolar or lower.
Furthermore, a dependence on the use of metformin as a prophylactic to delay aging could serve to decrease the incentive to pursue the proven benefits of lifestyle changes such as improved diet and exercise. Moreover, the long-term chronic use of metformin would require attention to the potential occurrence of vitamin B12 deficiency.
Indeed, the use of metformin may negate some of the positive effects of exercise and lifestyle and less favorable effects in older subjects as was also emphasized by the Diabetes Prevention Program , On the more positive side, we do accept that the use of metformin in the treatment of patients with T2DM is associated with a positive benefit on healthspan.
By lowering plasma glucose levels and body weight, metformin improves the metabolic profile of the patient and thereby reduces the severity and risk of other diseases associated with diabetes such as cardiovascular, cancer, and also neurodegenerative diseases The importance of the gut-brain axis in mediating the therapeutic effects of metformin is also emphasized, as are the potential beneficial effects of metformin to protect against neurodegenerative disorders.
Finally, although the evidence for lifespan expansion in mammalian species is not conclusive, a full analysis and follow-up of clinical trials, including MILES and TAME, may provide more definitive answers as to whether metformin should be promoted beyond its use to treat T2DM, as a drug that enhances both healthspan and lifespan.
Of particular importance is the need for evidence from prospective studies of the effects of metformin on subjects of different age groups, free of chronic diseases, which will help determine if metformin has benefits beyond those of reducing pre-existing disease burden.
IM and CT participated in the manuscript conceptualization and writing the first draft. HD, MH, IM, and CT contributed equally to literature and manuscript review and revisions of the manuscript.
All authors contributed to the article and approved the submitted version. The publication of this article was funded by the Department of Medical Education, Weill Cornell Medicine.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Loss of Metabolic Plasticity Underlies Metformin Toxicity in Aged Caenorhabditis Elegans. It also offers them cardiovascular benefits , including lower rates of death due to cardiovascular disease.
And it sometimes helps people with diabetes lose excess weight. Metformin may also have health benefits for people who don't have diabetes. Doctors have long prescribed it off-label — that is, to treat conditions outside its approved use, including:.
Because the vast majority of research regarding metformin included only people with diabetes or prediabetes, it's unclear whether these potential benefits are limited to people with those conditions, or whether people without diabetes may derive benefit as well.
The safety profile for metformin is quite good. Side effects include nausea, stomach upset, or diarrhea; these tend to be mild. More serious side effects are rare. They include severe allergic reactions and a condition called lactic acidosis , a buildup of lactic acid in the bloodstream.
The risk for this is higher among people with significant kidney disease, so doctors tend to avoid prescribing metformin for them. Metformin is a first-line treatment for type 2 diabetes, according to current diabetes guidelines.
It's relatively inexpensive and its potential side effects are well understood. If you have diabetes and need metformin to help lower your blood sugar, its other potential health benefits are a wonderful — not harmful — side effect.
And if you don't have diabetes? Well, its role in preventing or treating diseases, and possibly even slowing aging and extending life expectancy, is much less clear. While the research so far is promising, we need more compelling evidence before endorsing its widespread use for people without diabetes.
Metdormin it's because of the tremendous health benefits the Germ-elimination systems provides for a particular condition, like insulin for type Hydration and weight loss diabetes Dark chocolate energy antibiotics for Dark chocolate energy. Qging, it might be because the drug is good agjng Metformin and aging different conditions: aspirin has often been called a wonder drug because it can relieve pain, treat or prevent cardiovascular disease, and even prevent cancer. Could metformin be joining this list? It's approved in the US to treat type 2 diabetes when used with diet and exercise by people ages 10 and older. But in recent years, interest has grown regarding its potential to prevent or treat a variety of other conditions, including aging. Yes, aging.Metformin and aging -
Moreover, top hits from the Gene Ontology GO included HIF-1α pathways. Corresponding Email: gens stanford. Keywords: metformin, longevity, diabetes, epigenetics, aging, inflammation, methylation.
Launched in , Aging Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways e.
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Key points on metformin as an anti-aging drug Metformin is often the first line of treatment for the management of type 2 diabetes, but emerging research shows it may improve some signs of aging. Research is ongoing to understand how exactly metformin influences aging to extend lifespan and improve healthspan.
Intermittent fasting, engaging in strength-based exercise, managing stress, and maintaining good blood glucose levels may help reverse aging and encourage longevity.
Metformin and cognition. Metformin and cardiovascular events. Metformin and incidence of cancer. Metformin and all-cause mortality. If that's true, "wonder drug" might be an understatement.
The history of metformin goes back hundreds of years. In Europe, the medicinal herb Galega officinalis was popular for digestive health and to treat urinary problems and other ailments.
Then in , a scientist discovered that one of its ingredients, guanidine, could lower blood sugar. Medicines containing guanidine, such as metformin and phenformin, were developed to treat diabetes.
But they fell out of favor due to serious side effects caused by phenformin, and by the discovery of insulin. Metformin was rediscovered decades later and approved as a treatment for diabetes in Europe in the s. It wasn't until that the FDA approved it for use in the US.
It has since become the most widely prescribed medication for people with diabetes who cannot control their blood sugar through diet and exercise alone. For decades we've known that metformin does more than just help lower blood sugar in people with diabetes.
It also offers them cardiovascular benefits , including lower rates of death due to cardiovascular disease.
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Medicines annd guanidine, such Energy-boosting formulas metformin anx phenformin, were developed to treat eMtformin.
But Metcormin fell out of favor due an serious side effects caused by phenformin, and by the discovery of insulin. Metformin was rediscovered decades later and approved as a treatment for diabetes in Europe in the s. It wasn't until that the FDA approved it for use in the US. It has since become the most widely prescribed medication for people with diabetes who cannot control their blood sugar through diet and exercise alone.
For decades we've known that metformin does more than just help lower blood sugar in people with diabetes. It also offers them cardiovascular benefitsincluding lower rates of death due to cardiovascular disease. And it sometimes helps people with diabetes lose excess weight. Metformin may also have health benefits for people who don't have diabetes.
Doctors have long prescribed it off-label — that is, to treat conditions outside its approved use, including:. Because the vast majority of research regarding metformin included only people with diabetes or prediabetes, it's unclear whether these potential benefits are limited to people with those conditions, or whether people without diabetes may derive benefit as well.
The safety profile for metformin is quite good. Side effects include nausea, stomach upset, or diarrhea; these tend to be mild.
More serious side effects are rare. They include severe allergic reactions and a condition called lactic acidosisa buildup of lactic acid in the bloodstream. The risk for this is higher among people with significant kidney disease, so doctors tend to avoid prescribing metformin for them.
Metformin is a first-line treatment for type 2 diabetes, according to current diabetes guidelines. It's relatively inexpensive and its potential side effects are well understood. If you have diabetes and need metformin to help lower your blood sugar, its other potential health benefits are a wonderful — not harmful — side effect.
And if you don't have diabetes? Well, its role in preventing or treating diseases, and possibly even slowing aging and extending life expectancy, is much less clear. While the research so far is promising, we need more compelling evidence before endorsing its widespread use for people without diabetes.
But, for clinical researchers hoping to repurpose an old medicine as a new wonder drug, metformin would seem like a great place to start.
: Metformin and aging| Animal Studies Have Been Promising | The Inflammatory disease prevention Prevention Dark chocolate energy Research Agingg. Well, eMtformin role in preventing Dark chocolate energy Metfornin diseases, and possibly even slowing aging and extending life expectancy, is much less clear. Remarkably it was the much earlier microscopy work of Dr. Am J Physiol Endocrinol Metab E49— In a paper he coauthored in the journal Cell MetabolismBarzilai lays out the ways in which metformin can improve the way cells behave in an aging body. |
| Could the Diabetes Drug Metformin Slow the Aging Process? | Caloric Restriction and Aging: Studies in Mice and Monkeys. Metformin influences multiple physiological processes related to aging. Blood vessels, however, are primarily endothelial tubes with secondary, accessorial walls, and, therefore, it may be postulated that the endothelium has a great importance in our life and that its failure will cause the death of many of us. Long-Term Metformin Usage and Cognitive Function Among Older Adults With Diabetes. He's lost 10 pounds so far, and he'd like to lose 10 more. Zordoky et al. |
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Toxicol Pathol — Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, et al. Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys. Science —4. Guo Z, Mitchell-Raymundo F, Yang H, Ikeno Y, Nelson J, Diaz V, et al. Dietary Restriction Reduces Atherosclerosis and Oxidative Stress in the Aorta of Apolipoprotein E-Deficient Mice. Mech Ageing Dev — Fontana L, Klein S, Holloszy JO, Premachandra BN. Effect of Long-Term Calorie Restriction With Adequate Protein and Micronutrients on Thyroid Hormones. J Clin Endocrinol Metab —5. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-Term Calorie Restriction Is Highly Effective in Reducing the Risk for Atherosclerosis in Humans. Proc Natl Acad Sci USA — Meyer TE, Kovács SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L. Long-Term Caloric Restriction Ameliorates the Decline in Diastolic Function in Humans. It also offers them cardiovascular benefits , including lower rates of death due to cardiovascular disease. And it sometimes helps people with diabetes lose excess weight. Metformin may also have health benefits for people who don't have diabetes. Doctors have long prescribed it off-label — that is, to treat conditions outside its approved use, including:. Because the vast majority of research regarding metformin included only people with diabetes or prediabetes, it's unclear whether these potential benefits are limited to people with those conditions, or whether people without diabetes may derive benefit as well. The safety profile for metformin is quite good. Side effects include nausea, stomach upset, or diarrhea; these tend to be mild. More serious side effects are rare. They include severe allergic reactions and a condition called lactic acidosis , a buildup of lactic acid in the bloodstream. The risk for this is higher among people with significant kidney disease, so doctors tend to avoid prescribing metformin for them. Metformin is a first-line treatment for type 2 diabetes, according to current diabetes guidelines. Metformin has some qualities that make it stand out among the many medications being investigated, she says. And while other drugs appear to target aging or disease via a single mechanism, metformin appears to positively impact many key pathways, says Justice. But the results of these animal studies have been modest, and usually only significant when metformin is started at a young age. That may be relevant to the research on healthspan and lifespan in humans, she adds. Lower levels of oxidative stress allow cells to repair any damage more effectively. Research in humans suggests that metformin can impact mortality. A meta-analysis published in that included 53 different studies concluded that metformin reduces all-cause mortality and diseases of aging, independent of its effect on diabetes. The analysis found that the use of metformin lowers the risk of cancer, cardiovascular disease, stroke, and death, says Justice. Researchers have known for some time that metformin does more than just help lower blood sugar, says Chris Triggle, PhD , a researcher and professor of pharmacology at Weill Cornell Medicine in Doha, Qatar. On average, most people lose about six pounds after being on metformin for a year, according to research. In the Diabetes Prevention Program study , participants without diabetes were prescribed exercise, metformin, or placebo to delay diabetes. At the end of the study, metformin appeared to reduce the incidence of diabetes by 30 percent. io, an organization dedicated to raising funds to research aging and age-related diseases. Barzilai pointed out. The problem is the lack of research to back it up. |
| Metformin Could Help To Promote Healthy Aging | In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Studies suggest the drug delays stem-cell aging, encourages more autophagy, and reduces telomere shortening, all of which deter the effects of aging. The paper also provides evidence that metformin can prevent processes that encourage disease, like oxidative stress. For all these reasons, metformin has become a daily routine not just among Silicon Valley biohackers — many well-heeled doctors are now taking the drug, too. David Boulware, an infectious disease expert who conducts research on metformin with Bramante in Minnesota, says he started taking the drug "off and on" about six months ago. He'd contracted COVID, and he knew — based on his own team's research , published in the New England Journal of Medicine in — that there was a real possibility it could have antiviral benefits. He hoped it would reduce the odds he'd have a severe case of the coronavirus and end up in the hospital. Then he "researched it a bit more" and decided to stay on metformin for weight management. He's lost 10 pounds so far, and he'd like to lose 10 more. Boulware isn't yet convinced there's good scientific evidence that metformin on its own can help people live longer, healthier lives. Most scientific studies of metformin for age-related issues like blurry eyesight or cancer suggest it's possible that the drug might have decent anti-aging properties, but they tend to have boilerplate language in them about how the evidence is inconclusive, or stressing that more research is needed. The drug has shown anti-aging effects on roundworms, mice , and fruit flies, but that doesn't automatically translate to good news for humans. And almost all of the evidence for metformin's benefits for people has been done on patients with type 2 diabetes, not those with normal blood sugar. But at the very least, Boulware thinks that maintaining a healthy weight is good for aging — and metformin can help with that. Yes," he said. Barzilai is currently working to launch a first-of-its-kind study that he's dubbed "Targeting Aging with Metformin," or TAME. He wants to conduct a large, randomized, controlled trial of 3, older adults at 14 medical centers around the country, to finally answer the question: Can metformin help people stay healthy and sharp in late life? And that's a wonderful indication. At the moment, insurance companies and FDA scientists don't recognize aging as a condition, and big pharmaceutical companies, as a result, aren't that interested in "treating" it. If successful, Barzilai's study would be the first for the FDA to consider as evidence for a new class of anti-aging drugs, called "geroprotectors," which have never been medically approved in the US before. The regenerative-medicine scientist and aging expert Marco Quarta said that TAME could be an exciting first step toward establishing credibility for the field, as the first large clinical trial "really looking at aging as a syndrome. But until there are clearer studies, Quarta thinks people should be careful with metformin for anti-aging. Some people lose lots of weight on metformin; others don't see an impact. It can cause rare issues like liver damage and lactic-acid buildup in the bloodstream. And it's been shown to lower testosterone and inhibit muscle growth. One study also suggests it can harm men's sperm in a way that increases the risk of birth defects. Barzilai himself believes that for now, off-label metformin for longevity should be limited to those already experiencing the effects of aging. Investigators hope that the people taking metformin will experience a delay in major age-related events and associated beneficial changes in biomarkers of aging. If found to be effective, the low cost and availability of metformin means it could have a population-wide effect, adds Justice. That depends on who you talk to, though experts agree that before taking metformin or any prescription drug, for that matter , you should talk with your doctor. Unless you are participating in a clinical study, it would not be advisable to use metformin except to treat type 2 diabetes or polycystic ovary syndrome PCOS , says Triggle, despite metformin being a generally well-tolerated and safe drug. Besides, metformin is not an over-the-counter dietary supplement: You need a prescription from a doctor, says Dr. Although there are cases of doctors prescribing it off-label, right now most doctors are waiting for more proof — such as the kind TAME could provide — before recommending this to patients, she says. Health Conditions A-Z. Best Oils for Skin Complementary Approaches Emotional Wellness Fitness and Exercise Healthy Skin Online Therapy Reiki Healing Resilience Sleep Sexual Health Self Care Yoga Poses See All. Atkins Diet DASH Diet Golo Diet Green Tea Healthy Recipes Intermittent Fasting Intuitive Eating Jackfruit Ketogenic Diet Low-Carb Diet Mediterranean Diet MIND Diet Paleo Diet Plant-Based Diet See All. 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| Let Us Help You Pick Your Next Workout | It may also be a key to slow aging, mitigate age-related diseases, extend lifespan and increase health span. All in a pill that costs pennies a day, is safe, and has been scientifically shown to impact age-related biological changes. Many studies show that metformin targets these age-related cell changes. The result: Not only does it help control type 2 diabetes, but over time, people with diabetes taking the drug had lower death rates, better health, and longer lives compared with both diabetic and non-diabetics not taking metformin. Metformin also has anti-inflammatory effects , which may contribute to its ability to slow aging. Since chronic inflammation is one hallmark of aging and age-related diseases, reducing inflammation can improve health and life span. And it has a domino effect; if you target one hallmark, it will affect the others. Nir Barzilai, director of the Einstein Institute for Aging Research and a professor of medicine and genetics at Albert Einstein College of Medicine in New York. After about age 60, many of us start to accumulate age-related diseases like heart disease, diabetes, many forms of cancer, and dementia. The goal is to help people not only live longer, but live with less disease, resulting in greater health span—the period of time spent free from disabling disease. They looked at 4 targets of metformin — AMP-activated protein kinase AMPK , electron transfer flavoprotein dehydrogenase ETFDH , glycerolphosphate dehydrogenase 1 GPD1 and presenilin enhancer 2 PEN2 , and their associated genes, and how they might influence aging. The research team found that HbA1c lowering — induced by the metformin target GPD1 — was associated with younger phenotypic age and longer LTL, while AMPKγ2 — a variant of AMPK — was associated only with younger phenotypic age. This proof-of-concept work suggests that metformin might promote healthy aging via targets GPD1 and AMPKγ2 and supports further clinical research into the repurposing of metformin in healthy longevity. The findings may foreshadow results from the TAME Targeting Aging with Metformin trial, the first anti-aging study approved by the US Food and Drug Administration to evaluate the role of metformin in longevity. Reference: Luo S, Wong ICK, Chui CSL, et al. Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomization study using data from the UK Biobank. Lancet Healthy Longev. doi: This article is a rework of a press release issued by the University of Hong Kong. Material has been edited for length and content. I Understand. Metformin Could Help To Promote Healthy Aging News Published: July 25, Sarah Whelan, PhD. Sarah is a science writer and editor at Technology Networks. Learn about our editorial policies. Moreover, top hits from the Gene Ontology GO included HIF-1α pathways. Corresponding Email: gens stanford. Keywords: metformin, longevity, diabetes, epigenetics, aging, inflammation, methylation. Launched in , Aging Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways e. Please visit our website at www. |
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