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ANTI-Aging medicine

Cite as: Archiv EuroMedica. 2024. 14; 5. DOI 10.35630/2024/14/5.504

Received 5 August 2024;
Accepted 8 October 2024;
Published 19 October 2024

TAKE AN OLD DRUG AND STAY YOUNG? METFORMIN AS AN ANTI-AGING MEDICATION – A LITERATURE REVIEW.

Konrad Karłowicz1 email orcid id logo, Natalia Małek1 orcid id logo,
Aleksandra Brożyna2 orcid id logo, Sara Emerla2 orcid id logo,
Arkadiusz Bydliński2 orcid id logo, Łukasz Ciulkiewicz3 orcid id logo,
Anita Kwiatkowska4 orcid id logo, Patrycja Figurowska3 orcid id logo,
Maria Hermanowska5 orcid id logo, Julia Lubomirska5 orcid id logo

1Central Clinical Hospital in Warsaw, Warsaw, Poland
2Medical University of Warsaw, Warsaw, Poland
3Independent Public Healthcare Center in Mińsk Mazowiecki, Mińsk Mazowiecki, Poland
4Military Institute of Medicine - National Research Institute, Warsaw, Poland
5Jan Kochanowski University, Collegium Medicum, Kielce, Poland

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  konrad.karlowicz@uckwum.pl

ABSTRACT

AIMS: Metformin is the main drug used in the treatment of type 2 diabetes mellitus, and the most widely prescribed oral antihyperglycemic medication. Its mechanism of action is still not completely understood and research into new uses for the compound is still ongoing, with one possible novel application of the medication being to combat aging on both the cellular and the macroscopic level. The aim of the study is to evaluate the current state of knowledge on metformin’s potential as a lifespan-extending and anti-senescence drug, present evidence on the matter and assess possible lanes of further study into such effects.

METHODS: The literature review was performed using Internet research paper databases (PubMed, Google Scholar, Medline), using articles available in English.

RESULTS: Multiple papers suggest tentative support for the notion that metformin may contribute to slowing cellular senescence, as well as to extending the human lifespan. Theoretical knowledge exists that shows possible routes of action of metformin in this regard.

CONCLUSIONS: There is ample evidence in the literature for metformin’s possible effects as an anti-aging drug. Numerous cellular pathways by which it could exert lifespan-extending effects have been elucidated, and in vivo studies on some non-human animals have shown a measurable decrease in their production of aging markers, as well as an increase in the lifespan. Studies on diabetic patients have also demonstrated a significant reduction in all-cause mortality in that particular group. However, there is a lack of data and a need for more research that would investigate metformin’s potential as a universal anti-senescence agent more directly. Two large-scale studies (MILES and TAME) in the area are currently underway.

KEYWORDS: metformin, anti-aging; senotherapeutic; lifespan.

INTRODUCTION

Metformin is the main oral drug used in the treatment of type 2 diabetes mellitus, recommended as the first-line treatment by multiple international associations. [1,2] A member of the biguanidine class of medications, it is the most commonly prescribed antihyperglycemic drug in the world [3]. It has a pleiotropic and complex mechanism of action, which has not yet been fully elucidated. [4]. It is presumed to exert its antihyperglycemic effect predominantly by decreasing hepatic gluconeogenesis and improving peripheral insulin sensitivity [5]. Having been used since the 1950s, it has recently gained renewed attention due to its possible beneficial (e.g. anti-inflammatory [6] or lifespan-extending [7] properties, described in various scientific studies. In this literature review we are focusing on the latter characteristic, aiming to assess the current drug’s potential to not only extend longevity, but also be used as a cellular aging-modifying agent, also referred to as a senotherapeutic. [8]

METHODS

In order to conduct the review, we have searched multiple Internet-based medical article databases (including PubMed, Medline, Elsevier and Google Scholar) and selected relevant literature available in English. We have used the keywords “metformin”, “anti-aging”, “senotherapeutic”, “senescence-associated secretory phenotype”, “lifespan”. The studies were carefully reviewed and analyzed in order to ensure the presented data was of the highest possible quality.

RESULTS OF SELECTION & CONTENT OF THE REVIEW

Nowadays, metformin is a cheap and widely available medication, making its possible new applications potentially capable of expanding the lifespans and improving the HLY (Healthy Life Years) indicator for patients across the world, with notably few economic barriers.

Gerontology, the field of research dedicated to studying aging and diseases related to it has seen significant advancements in the recent years. [20] The drugs used to combat senescence are referred to as senotherapeutics [21], and can be further divided into narrower subcategories [22], such as senolytics, agents that target aging cells and induce their apoptosis in a process called senolysis, and senomorphics, compounds that modify cellular metabolism and counteract SASP (senescence-associated secretory phenotype), a phenomenon implicated in cellular aging via producing various inflammatory cytokines [23]. The latter term is related to inflammaging, a concept that frames aging as an extended process largely caused by accrued periods of low-grade inflammation [24]

mTOR (mammalian target of rapamycin) is one of the most crucial proteins in aging research, and decreasing its activity has been connected to increased lifespan in multiple studies on numerous organisms, ranging from S. cerevisiae [31] to mice [32]. There have been numerous drug trials for new agents targeting the mTOR pathways, but there is also growing evidence that metformin can be a potent inhibitor [33], providing strong theoretical foundation for its possible role as a senomorphic.

Metformin has been postulated to inhibit the formation of reactive oxygen species [34, 35], which are also thought to be implicated in cellular aging in the free radical theory, with posits aging as a result of accrued oxidative damage to cells and organelles [36].

Metformin is also considered to be a ‘calorie-restriction mimetic’, but the research on its efficacy in preventing aging in this manner appears to be inconclusive [37, 38].

Numerous studies have found an association between metformin use and increased longevity in humans and non-human animals, resulting in part from a reduced risk of cancer and cardiovascular events.

A study by Cabreiro et al. [39] examined metformin’s effects of the lifespan of C. elegans worms and found that they depended heavily on the accompanying microbes (different strains of E. coli and B. subtilis). In the presence of metformin-sensitive E. coli, whose methionine metabolism was restricted by the drug, the worm’s longevity was extended by up to 36% (concentration-dependent). However, the presence of metformin-resistant E. coli strains or an axenic C. elegans culture both led to reduced lifespans with metformin’s use, likely due to the drug’s toxicity. The findings suggest that the potential lifespan-prolonging effect of metformin may be indirect and mediated by the gut microbiota, but there are no human studies that would validate the claim.

While metformin’s beneficial effects on longevity and its potential to reduce mortality in diabetic patients are well-documented, there is a notable lack of quality date on the drug’s possible use for prolonging the human lifespan in non-diabetic patients [40]. The research remains ongoing, however and there are, in particular, two clinical trials underway: MILES (Metformin in Longevity Study) and TAME (Targeting Aging with Metformin).

CONCLUSIONS

Since its introduction to the diabetes treatment guidelines many decades ago, metformin has proven to be a safe, reliable and effective medication to improve the health span of diabetes patients. While many of the drug’s effects and detailed mechanisms of action remain elusive, the growing body of data gives tentative support to the notion that it may contribute to slowing the aging process and extending the healthy lifespan. The most noteworthy issue at the moment is the insufficient amount of data about metformin’s effects from prospective studies on the topic. With two such trials (MILES and TAME) in progress, the situation is without a doubt worth following up on in the years to come.

Disclosures

Author contributions:

Conceptualization: Konrad Karłowicz, Aleksandra Brożyna;

Methodology: Patrycja Figurowska, Arkadiusz Bydliński;

Formal analysis: Natalia Małek, Sara Emerla, Łukasz Ciulkiewicz;

Investigation: Patrycja Figurowska, Maria Hermanowska;

Writing - rough preparation: Konrad Karłowicz, Julia Lubomirska;

Writing - review and editing: Konrad Karłowicz, Anita Kwiatkowska, Sara Emerla;

Supervision: Konrad Karłowicz.

All authors have read and agreed with the published version of the manuscript.

Funding Statement:

This research received no external funding.

Conflicts of Interests:

The authors declare no conflict of interest.

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