Research Article: Metformin in obesity, cancer and aging: addressing controversies

Date Published: May 30, 2012

Publisher: Impact Journals LLC

Author(s): Lev M. Berstein.

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Abstract

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender- and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous. Here we discuss whether the discrepancies in different studies are merely methodological or inherently related to individual differences in responsiveness to the drug.

Partial Text

Weight-reducing effects of biguanides may explain in part their antitumor activity [13, 17]. Obesity is associated with increased mortality and, hence, decreased lifespan [2, 4]. Therefore, first of all, we will discuss whether biguanides reduce weight and affect body composition (fat vs. lean mass and visceral vs. subcutaneous fat). Two meta-analyses published in 2005 and 2011 summarized the use of metformin to treat adults having excessive body mass (fat) and showed that, among more than fifty potentially relevant studies, only less than ten satisfied all criteria. Only two or three of the latter confirmed that metformin had moderate weight-reducing effects, which, however, were inferior to the effects of behavioral interventions and gastrointestinal fat absorption inhibitor orlistat [18, 19]. Nevertheless, more scrutiny in treating the data accumulated so far, a part of which reproduces earlier results, suggests that it is reasonable to dissect the evidence into several subsections.

Potential antiaging drugs are expected to prevent or eliminate age-related diseases [7]. Evidence that metformin is more beneficial that other antidiabetic drugs in reducing all-cause mortality and, therefore, increasing life expectancy in diabetic patients was presented earlier. This important feature is believed to be associated with the ability of metformin to influence the rate of macrovascular complications of diabetes [67, 68] rather than the basic mechanisms of aging. Such mechanisms as potential targets of metformin are under increasing scrutiny in the recent years. Among proximal targets under discussion are those involved in insulin resistance, insulin/IFG-1 system, and fatty acid oxidation and utilization [7, 69-71], which were considered earlier with regard to the antiaging effects of phenformin [3, 14, 72]. Among the most discussed targets of metformin are AMPK activity and AMP-related signaling, glycation reactions and glycation end-products, mitochondrial membranes, reactive oxygen species generation, epigenetic mechanisms, pluripotent stem cells, cell proliferative senescence and mTOR pathway [7, 71, 73-77]. Without digging into all possible mechanistic details, the only endpoints used to assess metformin as an antiaging agent will be considered below.

The main and uniform conclusion presented herein is that metformin acts ‘selectively’ and its effects on obesity, cancer, and lifespan experiments vary depending on gender [90], age [24, 25, 51, 88] and other factors, including tumor location (tissue specificity). It has been pointed out earlier [36, 55] that, in order to make use of the potential antitumor and/or weight-reducing activities of metformin, it is necessary to consider its direct and indirect effects, the presence or absence of glucose intolerance, and impairments in the insulin/IGF-1 system and tissue responsiveness, which are determined, among others, by pharmacogenetic factors (see also [53, 63]). This can be true as well for antiaging applications where, in particular, the evaluation of mTOR-related pathways and gene-expression markers is recommended as a means for the choice of geroprotectors [77, 94]. With all the known benefits of metformin in different areas, including reducing the rate of certain complications in diabetic patients [67, 68], only further studies will allow the specific molecular targets of metformin to be elucidated fully with respect to treatment and prevention of obesity, cancer, other age-related pathology and lifespan as discussed above.

 

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