Benefits of Metformin in Attenuating the Hallmarks of Aging

Cell Metab.

Author manuscript ; available in PMC 2020 Jul 10. Published in final emended kind as :

department of the interior :10.1016/j.cmet.2020.04.001

PMCID:

PMC7347426

NIHMSID:

NIHMS1582084

PMID : 32333835

Benefits of Metformin in Attenuating the Hallmarks of Aging

, Ph.D., *,1,2, M.D.,3 and, M.D.1,2

Ameya S Kulkarni

1Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York 2Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York Find articles by Ameya S Kulkarni

Sriram Gubbi

3Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland Find articles by Sriram Gubbi

Nir Barzilai

1Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York 2Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York Find articles by Nir Barzilai Author information Copyright and License information Disclaimer 1Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York

2Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 3Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland*Corresponding author: Lead Contact: Ameya Kulkarni, Ph.D., 1300 Morris Park Ave, Belfer 701, Albert Einstein College of Medicine, Bronx, NY 10461, Tel- +1-(919) 561-8761, Corresponding writer : go contact : Ameya Kulkarni, Ph.D., 1300 Morris Park Ave, Belfer 701, Albert Einstein College of Medicine, Bronx, NY 10461, Tel- +1- ( 919 ) 561-8761, moc.liamg @ 522kayema Copyright notice Publisher’s Disclaimer

SUMMARY

biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmark of aging. Metformin- a biguanide that combats age-related disorders and improves healthspan, is the first drug to be tested for its age-targeting effects in the large clinical trial- TAME ( Targeting Aging by MEtformin ). This inspection focuses on metformin ’ second mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient-sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem-cell aging, modulating mitochondrial officiate, regulating transcription, and lowering telomere grinding and agedness. These characteristics make metformin an attractive gerotherapeutic to translate to human trials .

Graphical Abstract

Metformin is the first drug to be tested for its age-targeting effects in a large clinical test. In this Perspective, Kulkarni et alabama. review how metformin acts on its primary and secondary targets to attenuate the hallmarks of aging, highlighting its utility as an effective gerotherapeutic intervention .

Side Effects of Metformin

clearly, the unexpected plus side effects of metformin include increased healthspan and decreased mortality. recently, it was discernible that diabetic patients with liver, kidney and heart diseases, who did not receive metformin could have benefitted from its use with reduce hospitalization and deathrate ( Crowley et alabama. 2017 ). Hence, the ‘ black box ’ warning for metformin has been steadily disappearing, as evidenced by less stern indication for use in patients with reduce kidney officiate ( Bakris and Molitch 2016 ). As in most drugs, child slope effects occur with metformin, but it is authoritative to understand whether they reveal anything about the mechanism of action of this drug. Most of these child side effects include gastrointestinal discomfort such as abdominal or abdomen pain, early repletion, decreased appetite, and diarrhea, which normally subside after one or two weeks of use ( McCreight et aluminum. 2016 ). If diarrhea persists beyond a week ( in ~3 % of users ), the drug is discontinued. These side effects could be the solution of an acute change in the gut microbiome, as evidenced in nematodes and other smaller organisms ( Cabreiro et aluminum. 2013 ). Microbiome changes may besides be secondary to reduced vitamin B12 levels with chronic metformin use, although the mechanism is hush ill-defined and few patients need vitamin B12 replacement ( Aroda et alabama. 2016 ). A circumstance termed Metformin Associated Lactic Acidosis ( MALA ) is associated with metformin function in patients who already have high lactic acidic levels as in severe kidney, liver and heart diseases, while besides taking metformin ( DeFronzo et alabama. 2016 ). few patients may complain about anxiety, wakefulness, fast breathe, and other symptoms soon after taking metformin and will normally stop the drugs on their own. Metformin increases breastfeed levels, while maintaining the normal range, but it is possible that those with dangerous side effects including MALA subjects may be more sensitive to the prohibition of mitochondrial complex-1, attributable to familial mechanisms. The TAME test aims to examine the subjects who stop taking metformin for all the aforesaid reasons and determine if they are prone to different outcomes, with their biological samples available for far mechanistic studies. It is besides important to understand that, consistent with its biological effects since metformin is not a hypoglycemic agentive role it is not likely to cause hypoglycemia unless used in combination with other glucose-lowering drugs in diabetic individuals. therefore, it is very crucial to note that outdoor of its indication for diabetes, the use of metformin is recommended only in the context of clinical trials, under doctor supervision .

Conclusions and Perspectives

Metformin ’ s efficacy in attenuating hallmarks of biological ripening is reflective of its persuasiveness and electric potential as a curative that can target all-important mechanistic pathways involved in aging. The metabolic effects of metformin are chiefly through its metabolic weapon via activation of AMPK and oxidative arm through prohibition of complex I of the mitochondrial ETC. There are extra direct effects on mTORC1, PGC1-α, Insulin-IGF1 bespeak, SIRT1, NF-κB sign, and proinflammatory cytokines thereby allowing us to classify the four hallmarks ( deregulated nutrient-sensing, altered intercellular communication, genomic instability and loss of proteostasis ) as the primary coil targets of metformin. The effects on mitochondrial function, DNA and histone modifications, shank cell rejuvenation, preventing telomere shorten and downregulation of aging and SASP are downriver of the primary coil targets ( ) .An external file that holds a picture, illustration, etc.
Object name is nihms-1582084-f0006.jpgOpen in a separate window several clinical trials are presently afoot to assess the reaction of metformin as a monotherapy and in combination with life style interventions like drill, on clinical and molecular outcomes of person hallmarks of aging. These are particularly involved in measuring metformin ’ mho consequence on frailty and associate incendiary and SASP candidate biomarkers ( { “ type ” : ” clinical-trial ”, ” attrs ” : { “ text ” : ” NCT03451006 ”, ” term_id ” : ” NCT03451006 ” } } NCT03451006 ), pro-autophagy effects by measuring LC3 levels ( { “ character ” : ” clinical-trial ”, ” attrs ” : { “ text ” : ” NCT03309007 ”, ” term_id ” : ” NCT03309007 ” } } NCT03309007 ), changes in muscle size ( { “ type ” : ” clinical-trial ”, ” attrs ” : { “ text ” : ” NCT03107884 ”, ” term_id ” : ” NCT03107884 ” } } NCT03107884 ), improvements in immune answer via the catgut microbiota ( { “ type ” : ” clinical-trial ”, ” attrs ” : { “ textbook ” : ” NCT03713801 ”, ” term_id ” : ” NCT03713801 ” } } NCT03713801 ), and effective influenza vaccine responses ( { “ type ” : ” clinical-trial ”, ” attrs ” : { “ text ” : ” NCT03996538 ”, ” term_id ” : ” NCT03996538 ” } } NCT03996538 ). An authoritative limitation to studying metformin ’ mho legal action on age is its tissue-specificity, dose-dependency and the function of mitochondrial inhibition in contributing to any of its effects. No doubt, further studies will potentially shed more abstemious on each of these limitations. But as the accumulation of attest links metformin to all hallmarks of aging, it is identical authoritative to remember that metformin ’ s impact on any of these hallmarks has steer consequences on systemic attenuation across several other hallmarks of aging ( ). For exemplar, as highlighted above, evidence suggests that targeting autophagy impacts mitochondrial function, nutrient-sensing, and macromolecular wrong. With this note of think, we suggest that targeting aging at any of the primary or secondary levels, will ultimately make the cells, tissues, and systems more youthful, with a direct impression on the systemic biology of aging ( ). Thus, some effects that are observed are a resultant role of achieving systemic youth and not directly targets of the drug. In fact, reviewing the effects of other interventions like rapalogs and sirtuins besides shows that they may be impacting many of the like hallmarks of aging ( Lamming et alabama. 2013, Grabowska et aluminum. 2017 ). however, for any biotechnology or pharmaceutical firm that wants to design metformin-like drugs, it is besides potential that all effects of metformin need to be combined for the optimum effect. For example, targeting complex I is reasonable for the development of anti-cancer drugs and a drug that does not depend on tissue selectivity and gets to the mitochondrion in all tissues ( that is besides relevant for aging ) is warranted. But to show that it is superior to metformin in preventing age-related diseases may be hazardous, not to mention-expensive for patients. In conclusion, there is extensive epidemiologic, basic science, and clinical data highlighting the potency of metformin in targeting respective age-related morbidities in humans. Studies in model organisms and cell lines provide compelling evidence on metformin ’ s beneficial effects against crucial pathways in aging. In summation to its known safety profile and long-run habit in humans, metformin-induced attenuation of the major hallmarks of biological aging and their interconnectivity makes it a very attractive campaigner against aging, which the TAME discipline is set to prove and change the landscape of healthspan around the global .

Acknowledgments

This employment is supported by the grants from the National Institutes of Health ( P01AG021654 ) ( N.B. ), Nathan Shock Center of Excellence in the Basic Biology of Aging ( P30AG038072 ) ( N.B. ), Paul F. Glenn Center for the Biology of Aging Research at the Albert Einstein College of Medicine ( N.B. ). A.S.K. is supported by the Albert Einstein College of Medicine ’ s Ph.D. in Clinical Investigation program .

Footnotes

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announcement of Interests The authors declare no competing interests

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