Perspectives for the use of the antidiabetic drug metformin as a strategy to slow biological aging and age-related diseases

Abstract

This review focuses on the use of the antidiabetic drug metformin as one of the most studied geroprotective candidates with a well-established safety profile. The primary theories of aging and the development of age-related diseases, such as type 2 diabetes mellitus (T2DM) and Alzheimer disease, as well as the relationship between T2DM and the development of cognitive impairment, are reviewed. Metformin is hypothesized to improve cognitive function, mitigate the severity of anxiety, and reduce the risk of developing Alzheimer disease. In addition, metformin is able to decelerate the aging process and increase longevity in experiments in mice and rats. Despite being among the most frequently prescribed medications globally, with the ability to cross the blood-brain barrier and distribute to all brain regions, the precise mechanisms underlying its effects on the brain remain unclear. Studies show that metformin is able to activate 5'-adenosine monophosphate-activated protein kinase, reduce the levels of advanced glycation endproducts, and restore mitochondrial function. Moreover, metformin enhances autophagy and exerts a neuroprotective effect on neural stem cells. The findings of numerous studies indicate that metformin has antioxidant and anti-inflammatory properties.

Keywords

metformin / aging / type 2 diabetes mellitus / geroprotective agents / Alzheimer disease

References

[1] United Nations Department of Economic and Social Affairs, Population Division (2022). World Population Prospects 2022: Summary of Results. United Nations, 2022.

[2] Ageing [Internet]. United Nations Population Fund. [cited 2022 Dec 30]. Available from: https://www.unfpa.org/ageing#readmore-expand

[3] Ageing [Internet]. United Nations Population Fund. Режим доступа: https://www.unfpa.org/ageing#readmore-expand Дата обращения: 30.12.2022.

[4] Population of the Russian Federation by gender and age [Internet]. FEDERAL STATE STATISTICS SERVICE (ROSSTAT). [cited 2022 Dec 01]. Available from: https://rosstat.gov.ru/storage/mediabank/Bul_chislen_nasel-pv_01-01-2021.pdf (In Russ.)

[5] Численность населения Российской Федерации по полу и возрасту [Internet]. ФЕДЕРАЛЬНАЯ СЛУЖБА ГОСУДАРСТВЕННОЙ СТАТИСТИКИ (РОССТАТ). Режим доступа: https://rosstat.gov.ru/storage/mediabank/Bul_chislen_nasel-pv_01-01-2021.pdf Дата обращения: 01.12.2022.

[6] Ferrucci L, Gonzalez-Freire M, Fabbri E, et al. Measuring biological aging in humans: A quest. Aging cell. 2020;19(2):e13080. doi: 10.1111/acel.13080

[7] Ferrucci L., Gonzalez-Freire M., Fabbri E., et al. Measuring biological aging in humans: A quest // Aging cell. 2020. Vol. 19, N. 2. P. e13080. doi: 10.1111/acel.13080 EDN: TIPZFN

[8] Li Z, Zhang Z, Ren Y, et al. Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021;22(2):165–187. doi: 10.1007/s10522-021-09910-5

[9] Li Z., Zhang Z., Ren Y., et al. Aging and age-related diseases: from mechanisms to therapeutic strategies // Biogerontology. 2021. Vol. 22, N. 2. P. 165–187. doi: 10.1007/s10522-021-09910-5

[10] Arafa NMS, Marie MA, AlAzimi SA. Effect of canagliflozin and metformin on cortical neurotransmitters in a diabetic rat model. Chemico-Biological Interactions. 2016;258:79–88. doi: 10.1016/j.cbi.2016.08.016

[11] Arafa N.M.S., Marie M.A., AlAzimi S.A. Effect of canagliflozin and metformin on cortical neurotransmitters in a diabetic rat model // Chemico-Biological Interactions. 2016. Vol. 258. P. 79–88. doi: 10.1016/j.cbi.2016.08.016

[12] Ekusheva EV. Cognitive impairment — relevant interdisciplinary problem. Russian Medical Journal. 2018;12(I):32–37. EDN: YOCIRN

[13] Екушева Е.В. Когнитивные нарушения — актуальная междисциплинарная проблема // Российский медицинский журнал. 2018. Т. 12, № I. С. 32–37. EDN: YOCIRN

[14] Sanchez-Rangel E, Inzucchi SЕ. Metformin: clinical use in type 2 diabetes. Diabetologia. 2017;60(9):1586–1593. doi: 10.1007/s00125-017-4336-x

[15] Sanchez-Rangel E., Inzucchi S.Е. Metformin: clinical use in type 2 diabetes // Diabetologia. 2017. Vol. 60, N. 9. P. 1586–1593. doi: 10.1007/s00125-017-4336-x

[16] Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–1576. doi: 10.1007/s00125-017-4318-z

[17] Bailey C.J. Metformin: historical overview // Diabetologia. 2017. Vol. 60, N. 9. P. 1566–1576. doi: 10.1007/s00125-017-4318-z

[18] United Nations [internet]. Diabetes is not a death sentence: thousands of Ukrainians tested with UN support. [cited 2023 Dec 01]. Available from: https://news.un.org/ru/story/2021/11/1413872 (In Russ.)

[19] Организация Объединенных Наций [internet]. Диабет — не приговор: тысячи украинцев протестировали при поддержке ООН. Режим доступа: https://news.un.org/ru/story/2021/11/1413872 Дата обращения: 12.01.2023.

[20] Khan MAB, Hashim MJ, King JK, et al. Epidemiology of type 2 diabetes–global burden of disease and forecasted trends. J epidemiol glob health. 2020;10(1):107. doi: 10.2991/jegh.k.191028.001

[21] Khan M.A.B., Hashim M.J., King J.K., et al. Epidemiology of type 2 diabetes–global burden of disease and forecasted trends // J epidemiol glob health. 2020. Vol. 10, N. 1. P. 107. doi: 10.2991/jegh.k.191028.001

[22] Markowicz-Piasecka M, Huttunen MK, Mateusiak L, et al. Is metformin a perfect drug? Updates in pharmacokinetics and pharmacodynamics. Curr Pharmaceut Design. 2017;23(17):2532–2550. doi: 10.2174/1381612822666161201152941

[23] Markowicz-Piasecka M., Huttunen M.K., Mateusiak L., et al. Is metformin a perfect drug? Updates in pharmacokinetics and pharmacodynamics // Current Pharmaceutical Design. 2017. Vol. 23, N. 17. P. 2532–2550. doi: 10.2174/1381612822666161201152941

[24] Kuznik BI, Chalisova NI, Tzibikov NN, et al. Stress, aging and united humoral protective system of the organism. Epigenetic mechanisms of regulation. Advances in the physiological sciences. 2020;51(3):51–68. doi: 10.31857/S030117982002006X

[25] Кузник Б.И., Чалисова Н.И., Цыбиков Н.Н., и др. Стресс, старение и единая гуморальная защитная система организма. Эпигенетические механизмы регуляции // Успехи физиологических наук. 2020. Т. 51, № 3. С. 51–68. doi: 10.31857/S030117982002006X

[26] Pristrom MS, Pristrom SL, Semenenkov II. Physiological and early aging. Modern view of the problem. Meditsinskie novosti. 2017;5–6(28):40–64.

[27] Пристром М.С., Пристром С.Л., Семененков И.И. Старение физиологическое и преждевременное. Современный взгляд на проблему // Международные обзоры: клиническая практика и здоровье. 2017. Т. 5–6, № 28. С. 40–64. EDN: YMPBPN

[28] Savina NV, Nikitchenko NV, Kuzhir TD, Goncharova RI. Polymorphism of genes coding dna helicases: impact on the life span. Molekulyarnaya i prikladnaya genetika. 2016;20:46–54. doi: 10.23888/HMJ201973340-348

[29] Савина Н.В., Никитченко Н.В., Кужир Т.Д., Гончарова Р.И. Полиморфизм генов, кодирующих ДНК-геликазы: влияние на продолжительность жизни // Молекулярная и прикладная генетика. 2016. Т. 20. С. 46–54. doi: 10.23888/HMJ201973340-348

[30] Bogolepova AN, Vasenina EE, Gomzyakova NA, et al. Clinical Guidelines for Cognitive Disorders in Elderly and Older Patients. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2021;121(10–3):6–137. doi: 10.17116/jnevro20211211036

[31] Боголепова А.Н., Васенина Е.Е., Гомзякова Н.А., и др. Клинические рекомендации «Когнитивные расстройства у пациентов пожилого и старческого возраста» // Журнал неврологии и психиатрии им. С.С. Корсакова. 2021. Т. 121, № 10–3. С. 6–137. doi: 10.17116/jnevro20211211036

[32] Zotkin EG, Dydykina IS, Lila AM. Inflammaging, age-related diseases and osteoarthritis. Russian Medical Journal. 2020;7:33–38. EDN: WUCBVJ

[33] Зоткин Е.Г., Дыдыкина И.С., Лила А.М. Воспалительная теория старения, возраст-ассоциированные заболевания и остеоартрит // Русский Медицинский Журнал. 2020. Т. 7. С. 33–38. EDN: WUCBVJ

[34] Du Y, Gao Y, Zeng B, et al. Effects of anti-aging interventions on intestinal microbiota. Gut Microbes. 2021;13(1):1994835. doi: 10.1080/19490976.2021.1994835

[35] Du Y., Gao Y., Zeng B., et al. Effects of anti-aging interventions on intestinal microbiota // Gut Microbes. 2021. Vol. 13, N. 1. P. 1994835. doi: 10.1080/19490976.2021.1994835

[36] Kim M, Benayoun BA. The microbiome: an emerging key player in aging and longevity. Transl Med Aging. 2020;4:103–116. doi: 10.1016/j.tma.2020.07.004

[37] Kim M., Benayoun B.A. The microbiome: an emerging key player in aging and longevity // Transl Med Aging. 2020. Vol. 4. P. 103–116. doi: 10.1016/j.tma.2020.07.004

[38] Topolyanskaya SV. Interleukin 6 in aging and age–related diseases. The clinician. 2020;14(3–4):10–17. doi: 10.17650/1818-8338-2020-14-3-4-К-633

[39] Тополянская С.В. Роль интерлейкина 6 при старении и возраст-ассоциированных заболеваниях // Клиницист. 2020. Т. 14, № 3–4. С. 10–17. doi: 10.17650/1818-8338-2020-14-3-4-К-633

[40] Li Z, Zhang Z, Ren Y, et al. Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021;22(2):165–187. doi: 10.1007/s10522-021-09910-5

[41] Li Z., Zhang Z., Ren Y., et al. Aging and age-related diseases: from mechanisms to therapeutic strategies // Biogerontology. 2021. Vol. 22, N. 2. P. 165–187. doi: 10.1007/s10522-021-09910-5

[42] Mathews J, Davy PM, Gardner LH, Allsopp RC. Stem cells, telomerase regulation and the hypoxic state. Frontiers in Bioscience. 2016;21(2):303–315. doi: 10.2741/4389

[43] Mathews J., Davy P.M., Gardner L.H., Allsopp R.C. Stem cells, telomerase regulation and the hypoxic state // Front Bioscie. 2016. Vol. 21, N. 2. P. 303–315. doi: 10.2741/4389

[44] Zhu Y, Liu X, Ding X, et al. Telomere, and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction. Biogerontology. 2019;20(1):1–16. doi: 10.1007/s10522-018-9769-1

[45] Zhu Y., Liu X., Ding X., et al. Telomere, and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction // Biogerontology. 2019. Vol. 20, N. 1. P. 1–16. doi: 10.1007/s10522-018-9769-1

[46] Ahmad R, Haque M. Oral Health Messiers: Diabetes Mellitus Relevance. Diabet metab syndr obes. 2021;14:3001–3015. doi: 10.2147/DMSO.S318972

[47] Ahmad R., Haque M. Oral Health Messiers: Diabetes Mellitus Relevance // Diabetes Metab Syndr Obes. 2021. Vol. 14. P. 3001–3015. doi: 10.2147/DMSO.S318972

[48] Markowicz-Piasecka M, Sikora J, Szydłowska A, et al. Metformin – a future therapy for neurodegenerative diseases. Pharmaceutical research. 2017;34(12):2614–2627. doi: 10.1007/s11095-017-2199-y

[49] Markowicz-Piasecka M., Sikora J., Szydłowska A., et al. Metformin–a future therapy for neurodegenerative diseases // Pharmaceutical research. 2017. Vol. 34, N. 12. P. 2614–2627. doi: 10.1007/s11095-017-2199-y

[50] Du Y, Gao Y, Zeng B, et al. Effects of anti-aging interventions on intestinal microbiota. Gut Microbes. 2021;13(1):1994835. doi: 10.1080/19490976.2021.1994835

[51] Du Y., Gao Y., Zeng B., et al. Effects of anti-aging interventions on intestinal microbiota // Gut Microbes. 2021. Vol. 13, N. 1. P. 1994835. doi: 10.1080/19490976.2021.1994835

[52] Paltsev MA, Polyakova VO, Linkova NS, et al. Molecular and cellular mechanisms of Alzheimer’s disease. Molecular medicine. 2016;14(6):3–10. EDN: XHLYSV

[53] Пальцев М.А., Полякова В.О., Линькова Н.С., и др. Молекулярно–клеточные механизмы болезни Альцгеймера // Молекулярная медицина. 2016. Т. 14, № 6. С. 3–10. EDN: XHLYSV

[54] Kandimalla R, Thirumala V, Reddy PH. Is Alzheimer’s disease a type 3 diabetes? A critical appraisal. Biochim Biophys Acta Mol Basis Dis. 2017;1863(5):1078–1089. doi: 10.1016/j.bbadis.2016.08.018

[55] Kandimalla R., Thirumala V., Reddy P.H. Is Alzheimer’s disease a type 3 diabetes? A critical appraisal // Biochim Biophys Acta Mol Basis Dis. 2017. Vol. 1863, N. 5. P. 1078–1089. doi: 10.1016/j.bbadis.2016.08.018

[56] De Sousa RAL, Harmer AR, Freitas DA, et al. An update on potential links between type 2 diabetes mellitus and Alzheimer’s disease. Molecular Biology Reports. 2020;47(8):6347–6356. doi: 10.1007/s11033-020-05693-z

[57] De Sousa R.A.L., Harmer A.R., Freitas D.A., et al. An update on potential links between type 2 diabetes mellitus and Alzheimer’s disease // Mol Biol Rep. 2020. Vol. 47, N. 8. P. 6347–6356. doi: 10.1007/s11033-020-05693-z

[58] Zhang J, Chen C, Hua S, et al. An updated meta-analysis of cohort studies: diabetes and risk of Alzheimer’s disease. Diabetes research and clinical practice. 2017;124:41–47. doi: 10.1016/j.diabres.2016.10.024

[59] Zhang J., Chen C., Hua S., et al. An updated meta-analysis of cohort studies: diabetes and risk of Alzheimer’s disease // Diabetes research and clinical practice. 2017. Vol. 124. P. 41–47. doi: 10.1016/j.diabres.2016.10.024

[60] Ostroumova OD, Surkova EV, Goloborodova IV, et al. Hypoglycemia and the risk of cognitive impairment and dementia in elderly and senile patients with type 2 diabetes. Diabetes. 2020;23(1):72–87. doi: 10.14341/DM10202

[61] Остроумова О.Д., Суркова Е.В., Голобородова И.В., и др. Гипогликемии и риск когнитивных нарушений и деменции у больных пожилого и старческого возраста с сахарным диабетом 2 типа // Сахарный диабет. 2020. Т. 23, № 1. С. 72–87. doi: 10.14341/DM10202

[62] Kim WJ, Lee SJ, Lee E, et al. Risk of Incident Dementia According to Glycemic Status and Comorbidities of Hyperglycemia: A Nationwide Population–Based Cohort Study. Diabetes care. 2022;45(1):134–141. doi: 10.2337/dc21-0957

[63] Kim W.J., Lee S.J., Lee E., et al. Risk of Incident Dementia According to Glycemic Status and Comorbidities of Hyperglycemia: A Nationwide Population–Based Cohort Study // Diabetes care. 2022. Vol. 45, N. 1. P. 134–141. doi: 10.2337/dc21-0957

[64] Khan S, Barve KH, Kumar MS. Recent advancements in pathogenesis, diagnostics, and treatment of Alzheimer’s disease. Current Neuropharmacology. 2020;18(11):1106–1125. doi: 10.2174/1570159X18666200528142429

[65] Khan S., Barve K.H., Kumar M.S. Recent advancements in pathogenesis, diagnostics, and treatment of Alzheimer’s disease // Curr Neuropharmacol. 2020. Vol. 18, N. 11. P. 1106–1125. doi: 10.2174/1570159X18666200528142429

[66] Cassano V, Leo A, Tallarico M, et al. Metabolic and cognitive effects of ranolazine in Type 2 Diabetes Mellitus: Data from an in vivo Model. Nutrients. 2020;12(2):382. doi: 10.3390/nu12020382

[67] Cassano V., Leo A., Tallarico M., et al. Metabolic and cognitive effects of ranolazine in Type 2 Diabetes Mellitus: Data from an in vivo Model // Nutrients. 2020. Vol. 12, N. 2. P. 382. doi: 10.3390/nu12020382

[68] Shcherbakova EM. Population aging and sustainable development. Demoscope Weekly. 2016;(709–710):15–30. (In Russ.) EDN: XDYGPX

[69] Щербакова Е.М. Старение населения и устойчивое развитие // Демоскоп Weekly. 2016. № 709–710. С. 15–30. EDN: XDYGPX

[70] Moskalev АA, Guvatova Z, Lopes IDA, et al. Targeting aging mechanisms: pharmacological perspectives. Trends in Endocrinology & Metabolism. 2022;33(4):266–280. doi: 10.1016/j.tem.2022.01.007

[71] Moskalev А.A., Guvatova Z., Lopes I.D.A., et al. Targeting aging mechanisms: pharmacological perspectives // Trends in Endocrinology & Metabolism. 2022. Vol. 33, N. 4. P. 266–280. doi: 10.1016/j.tem.2022.01.007

[72] Rayson A, Boudiffa M, Naveed M, et al. Geroprotectors and Skeletal Health: Beyond the Headlines. Front Cell Dev Biol. 2022;10:682045. doi: 10.3389/fcell.2022.682045

[73] Rayson A., Boudiffa M., Naveed M., et al. Geroprotectors and Skeletal Health: Beyond the Headlines // Front Cell Dev Biol. 2022. Vol. 10. P. 682045. doi: 10.3389/fcell.2022.682045

[74] Moskalev AА, Chernyagina E, Kudryavtseva A, Shaposhnikov MV. Geroprotectors: A Unified Concept and Screening Approaches. Aging and Disease. 2017;8(3). doi: 10.14336/AD.2016.102

[75] Moskalev A.А., Chernyagina E., Kudryavtseva A., Shaposhnikov M.V. Geroprotectors: A Unified Concept and Screening Approaches // Aging and Disease. 2017. Vol. 8, N. 3. doi: 10.14336/AD.2016.102

[76] Moskalev AА, Shaposhnikov MV, Solovev IA. Studying the geroprotective effects of inhibitors suppressing aging-associated signaling cascades in model organisms. Medical News of North Caucasus. 2017;12(3):342–7. doi: 10.14300/mnnc.2017.12090

[77] Moskalev A.А., Shaposhnikov M.V., Solovev I.A. Studying the geroprotective effects of inhibitors suppressing aging-associated signaling cascades in model organisms // Medical News of North Caucasus. 2017. Vol. 12, N. 3. P. 342–7. doi: 10.14300/mnnc.2017.12090

[78] Gilmutdinova IR, Kudryashova IS, Kostormina EY, et al. Modern Approaches to Diagnostic and Correction of Aging Biomarkers. Bulletin of Rehabilitation Medicine. 2021;20(6):96–102. doi: 10.38025/2078-19

[79] Гильмутдинова И.Р., Кудряшова И.С., Костромина Е.Ю., и др. Современные подходы диагностики и коррекции биомаркеров старения // Вестник восстановительной медицины. 2021. Т. 20, № 6. С. 96–102. doi: 10.38025/2078-19

[80] Wang C, Liu C, Gao K, et al. Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury. Biochem Biophys Res Commun. 2016;477(4):534–540. doi: 10.1016/j.bbrc.2016.05.148

[81] Wang C., Liu C., Gao K., et al. Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury // Biochem Biophys Res Commun. 2016. Vol. 477, N. 4. P. 534–540. doi: 10.1016/j.bbrc.2016.05.148

[82] Chiang MC, Cheng YC, Chen SJ, et al. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cell agains amyloid-betainduced mitochodrial dysfunction. Experimental Cell Research. 2016;347(2):322–31. doi: 10.1016/j.yexcr.2016.08.013

[83] Chiang M.C., Cheng Y.C., Chen S.J., et al. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cell agains amyloid-betainduced mitochodrial dysfunction // Exp Cell Res. 2016. Vol. 347, N. 2. P. 322–31. doi: 10.1016/j.yexcr.2016.08.013

[84] Chung MM, Chen YL, Pei D, et al. The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent. Biochim Biophys Acta. 2015;1852(5):720–31. doi: 10.1016/j.bbadis.2015.01.006

[85] Chung M.M., Chen Y.L., Pei D., et al. The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent // Biochim Biophys Acta. 2015. Vol. 1852, N. 5. P. 720–31. doi: 10.1016/j.bbadis.2015.01.006

[86] Benito-Cuesta I, Ordonez-Gutierrez L, Wandosell F. AMPK activation does not enhance autophagy in neurons in contrast to MTORC1 inhibition: Different impact on beta-amyloid clearance. Autophagy. 2021;17:656–671. doi: 10.1080/15548627.2020.1728095

[87] Benito-Cuesta I., Ordonez-Gutierrez L., Wandosell F. AMPK activation does not enhance autophagy in neurons in contrast to MTORC1 inhibition: Different impact on beta-amyloid clearance // Autophagy. 2021. Vol. 17. P. 656–671. doi: 10.1080/15548627.2020.1728095

[88] Guangli Lu, Zhen W, Jia S, et al. The effects of metformin on autophagy. Biomed Pharmacother. 2021;137:111286. doi: 10.1016/j.biopha.2021.111286

[89] Guangli L., Zhen W., Jia S., et al. The effects of metformin on autophagy // Biomed Pharmacother. 2021. Vol. 137. P. 111286. doi: 10.1016/j.biopha.2021.111286

[90] Chung MM, Nicol CJ, Cheng YC, et al. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Experimental Cell Research. 2017;352:75–83. doi: 10.1016/j.yexcr.2017.01.017

[91] Chung M.M., Nicol C.J., Cheng Y.C., et al. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs // Exp Cell Res. 2017. Vol. 352. P. 75–83. doi: 10.1016/j.yexcr.2017.01.017

[92] Oliveira WH, Nunes AK, RochaFrança ME, et al. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Research. 2016;1644:149–60. doi: 10.1016/j.brainres.2016.05.013

[93] Oliveira W.H., Nunes A.K., RochaFrança M.E., et al. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice // Brain Res. 2016. Vol. 1644. P. 149–60. doi: 10.1016/j.brainres.2016.05.013

[94] Thies W, Bleile L. Alzheimer’s disease facts and figures. Alzheimers Dementia. 2022;18(4):700–789. doi: 10.1002/alz.12638

[95] Thies W., Bleile L. Alzheimer’s disease facts and figures // Alzheimers Dementia. 2022. Vol. 18, N. 4. P. 700–789. doi: 10.1002/alz.12638

[96] Ashrostaghi Z, Ganji F, Sepehri H. Effect of metformin on the spatial memory in aged rats. National Journal of Physiology Pharmacy and Pharmacology. 2015;5:416–420. doi: 10.5455/njppp.2015.5.1208201564

[97] Ashrostaghi Z., Ganji F., Sepehri H. Effect of metformin on the spatial memory in aged rats // National Journal of Physiology Pharmacy and Pharmacology. 2015. Vol. 5. P. 416–420. doi: 10.5455/njppp.2015.5.1208201564

[98] Qin Z, Zhou C, Xiao X, Guo C. Metformin attenuates sepsis-induced neuronal injury and cognitive impairment. BMC Neuroscience. 2021;22(1):78. doi: 10.1186/s12868-021-00683-8

[99] Qin Z., Zhou C., Xiao X., Guo C. Metformin attenuates sepsis-induced neuronal injury and cognitive impairment // BMC Neuroscience. 2021. Vol. 22, N. 1. P. 78. doi: 10.1186/s12868-021-00683-8

[100] Le Douce J, Maugard M, Veran J, et al. Impairment of glycolysis–derived l–serine production in astrocytes contributes to cognitive deficits in Alzheimer’s disease. Cell metabolism. 2020;31(3):503–517. doi: 10.1016/j.cmet.2020.02.004

[101] Le Douce J., Maugard M., Veran J., et al. Impairment of glycolysis–derived l–serine production in astrocytes contributes to cognitive deficits in Alzheimer’s disease // Cell metabolism. 2020. Vol. 31, N. 3. P. 503–517. doi: 10.1016/j.cmet.2020.02.004

[102] Ruyatkina LA, Ruyatkin DS. Multidimensional effects of metformin in patients with type 2 diabetes. Diabetes mellitus. 2017;20(3):210–219. doi: 10.14341/DM2003458-64

[103] Руяткина Л.А., Руяткин Д.С. Многоплановые эффекты метформина у пациентов с сахарным диабетом 2 типа // Сахарный диабет. 2017. Т. 20, № 3. С. 210–219. doi: 10.14341/DM2003458-64

[104] Wang CP, Lorenzo C, Habib SL, et al. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complications. 2017;31:679–686. doi: 10.1016/j.jdiacomp.2017.01.013

[105] Wang C.P., Lorenzo C., Habib S.L., et al. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes // J Diabetes Complications. 2017. Vol. 31. P. 679–686. doi: 10.1016/j.jdiacomp.2017.01.013

[106] Samaras K, Makkar S, Crawford JD, et al. Metformin Use Is Associated with Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults with Type 2 Diabetes: The Sydney Memory and Ageing Study. Diabetes Care. 2020;43:2691–2701. doi: 10.2337/dc20-0892

[107] Samaras K., Makkar S., Crawford J.D., et al. Metformin Use Is Associated with Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults with Type 2 Diabetes: The Sydney Memory and Ageing Study // Diabetes Care. 2020. Vol. 43. P. 2691–2701. doi: 10.2337/dc20-0892

[108] Kuan YC, Huang KW, Lin CL, et al. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog. Neuropsychopharmacol. Progress in Neuro-Psychopharmacology and Biological Psychiatry.2017;79:77–83. doi: 10.1016/j.pnpbp.2017.06.002

[109] Kuan Y.C., Huang K.W., Lin C.L., et al. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog. Neuropsychopharmacol // Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2017. Vol. 79. P. 77–83. doi: 10.1016/j.pnpbp.2017.06.002

[110] Ou Z, Kong X, Sun X, et al. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behavior and Immunity. 2018;69:351–363. doi: 10.1016/j.bbi.2017.12.009

[111] Ou Z., Kong X., Sun X., et al. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice // Brain Behavior and Immunity. 2018. Vol. 69. P. 351–363. doi: 10.1016/j.bbi.2017.12.009

[112] Farr SA, Roesler E, Niehoff ML, et al. Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer’s Disease. Journals of Alzheimer’s Disease. 2019;68:1699–1710. doi: 10.3233/JAD-181240

[113] Farr S.A., Roesler E., Niehoff M.L., et al. Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer’s Disease // Journals of Alzheimer’s Disease. 2019. Vol. 68. P. 1699–1710. doi: 10.3233/JAD-181240

[114] Levin OS, Chimagomedova ASh, Arefieva AP. Anxiety in the elderly. Korsakov Journal of Neurology and Psychiatry. 2019;119(6):113–118. doi: 10.17116/jnevro2019119061113

[115] Левин О.С., Чимагомедова А.Ш., Арефьева А.П. Тревожные расстройства в пожилом возрасте // Журнал неврологии и психиатрии им. С.С. Корсакова. 2019. Т. 119, № 6. С. 113–118. doi: 10.17116/jnevro2019119061113

[116] Gribanov AV, Dzhos YuS, Deryabina IN, et al. An aging brain: morphofunctional aspects. Korsakov Journal of Neurology and Psychiatry. 2017;117(1–2):3–7. doi: 10.17116/jnevro2017117123-7

[117] Грибанов А.В., Джос Ю.С., Дерябина И.Н., и др. Старение головного мозга человека: морфофункциональные аспекты // Журнал неврологии и психиатрии им. С.С. Корсакова. 2017. Т. 117, № 1–2. С. 3–7. doi: 10.17116/jnevro2017117123-7

[118] Fang W, Zhang J, Hong L, et al. Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. Journal of Affective Disorders. 2020;260:302–313. doi: 10.1016/j.jad.2019.09.013

[119] Fang W., Zhang J., Hong L., et al. Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation // Journal of Affective Disorders. 2020. Vol. 260. P. 302–313. doi: 10.1016/j.jad.2019.09.013

[120] Fan J, Di Li, Hong-Sheng C, et al. Metformin produces anxiolytic-like effects in rats by facilitating GABAA receptor trafficking to membrane. British Journal of Pharmacology. 2019;176:297–316. doi: 10.1111/bph.14519

[121] Fan J., Di L., Hong-Sheng C., et al. Metformin produces anxiolytic-like effects in rats by facilitating GABAA receptor trafficking to membrane // British Journal of Pharmacology. 2019. Vol. 176. P. 297–316. doi: 10.1111/bph.14519

[122] Owen MD, Baker BC, Scott EM, Forbes K. Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. Int J mol sci. 2021;22(11):5759. doi: 10.3390/ijms22115759

[123] Owen M.D., Baker B.C., Scott E.M., Forbes K. Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies // International Journal of molecular scientist. 2021. Vol. 22, N. 11. P. 5759. doi: 10.3390/ijms22115759

[124] Connelly PJ, Lonergan M, Soto-Pedre E, et al. Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study. Diabetes Obes Metab. 2017;19(11):1579–1586. doi: 10.1111/dom.12978

[125] Connelly P.J., Lonergan M., Soto-Pedre E., et al. Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: a GoDarts study // Diabetes Obes Metab. 2017. Vol. 19, N. 11. P. 1579–1586. doi: 10.1111/dom.12978

[126] Madsen KS, Kähler P, Kähler LKA, et al. Metformin and second-or third generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2019;4(4). doi: 10.1002/14651858.CD012368.pub2

[127] Madsen KS, Kähler P, Kähler LKA, et al. Metformin and second-or third generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev // 2019. Vol. 4, N. 4. doi: 10.1002/14651858.CD012368.pub2

[128] Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front Endocrinol. 2021;12:718942. doi: 10.3389/fendo.2021.718942

[129] Mohammed I., Hollenberg M.D., Ding H., Triggle C.R. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan // Front Endocrinol. 2021. Vol. 12. P. 718942. doi: 10.3389/fendo.2021.718942

Funding

Russian Science FoundationРоссийский Научный Фонд(23-25-00333)

RIGHTS & PERMISSIONS

Eco-Vector