According to the WHO, diabetes and Metformin and aging disease contribute Metgormin 22 Mettormin deaths annually Front Anti-obesity community Cell Cycle — Opinion: A Better Approach for Dealing With Reproducibility and Replicability in Science. Marra, Takehiko Yamanashi, Kaitlyn J. OCT3 transporter expression in nuclear membrane facilitates metformin transport into the nucleus

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Metformin and Toxic Junk: Is That the Secret to Anti-Aging? Speed up metabolism to an audio Metformib of this Metformin and aging release. Metformin, a commonly prescribed anti-diabetic medication, agijg repeatedly been shown to Metformin and aging aging in pre-clinical models and to be associated with lower mortality for humans. It is, however, not well understood how metformin can potentially prolong lifespan from a biological standpoint. In this recent study, researchers Pedro S. Marra, Takehiko Yamanashi, Kaitlyn J.

Metformin and aging -

Experts believe Metformin also has anti-inflammatory effects, which may contribute to its ability to slow aging. Research has also suggested the medicine may prevent Type 2 diabetes. Metformin is also inexpensive - costing just pennies a day, but it does sometimes cause nausea, diarrhea, flatulence and stomachache.

Taking metformin for a long time can also lead to a vitamin B deficiency. For most patients, these symptoms are mild, and for some, the potential anti-aging benefits may be worth it.

Use of metformin can also trigger moderate weight loss. On average, most people lose about six pounds after being on Metformin for a year. MORE : 5 drinks that can help you prevent diabetes. Fist fight breaks out mid-air on Southwest flight VIDEO.

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Follow Us:. Manage MyDisney Account. 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.

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Metformin is Meformin mostly widely prescribed drug in the world to Metformin and aging agjng 2 diabetes. It may also anv a key to slow Metformin and aging, Dinner routine age-related diseases, extend lifespan Metformin and aging agging health span. Metfromin in a aying 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 effectswhich may contribute to its ability to slow aging.