A TAME Attempt to Slow Aging Part 4: Mixed Messages on Metformin and the Mind

Metformin has been proposed as an “anti-aging drug,” and a major clinical trial is about to get underway to test the idea.
Metformin-Books-2.0-o

Short summary: Metformin has been proposed as an “anti-aging drug,” and a major clinical trial to test the idea is about to begin. In earlier posts in the series, we’ve reviewed the animal data on metformin and outcomes relevant to intervention in aging (especially metformin lifespan studies); human studies on metformin’s effects on a variety of health outcomes, including a flawed observational study suggesting that people with diabetes on metformin live longer than people with diabetes; and clinical trials of metformin to prevent or treat cancer. This post is focused on whether metformin might plausibly be protective against cognitive decline and dementia, some of the most feared effects of degenerative aging.

The most perplexing findings on metformin’s effects in nondiabetic people come from studies on the drug’s effects on age-related cognitive decline and dementia — the health outcome that is least likely to be captured in an animal lifespan study, and that is never truly well-modeled in animal studies of any kind. The animal and test-tube data are all over the place on this question, with some studies suggesting that metformin might slow down[1],[2],[3] and others implying that it will exacerbate[4],[5],[6],[7],[8] the slide into cognitive decline and dementia with age.[9]

One important signal coming out of the noise of these contradictory studies comes from noticing that most of them don’t actually test the effects of metformin on age-related cognitive decline and dementia. Instead, most were carried out in cells in Petri dishes, or in young animals that were genetically engineered to produce very high levels of proteins that are key players in neurodegenerative disease, like beta-amyloid and different forms of abnormal tau protein. But things look clearer when we zero in on the only two studies of the effect of metformin on truly age-related cognitive decline in otherwise-normal aging lab animals. In both of these two studies, metformin made the progressive loss of memory and brain function with age worse, not better.[5],[8]

In humans with diabetes, both clinical trials and observational studies of metformin’s effect on age-related neurodegenerative disease have also been inconsistent, with different studies showing that metformin has a protective effect, a harmful effect (on the risk of Alzheimer’s[10],[11] and Parkinson’s[11] diseases), or no effect at all. But when all the evidence from such studies has been systematically combined, the bottom line is that metformin appears to have no effect one way or the other on the rate of cognitive function decline or on the risk of dementia,[12],[13] except for the possibility that metformin may increase the risk of Alzheimer’s in people in Asian countries but not in other national groups.[13]

Additionally, the most recent systematic review of all of the observational studies on the association between metformin use and dementia risk in people with diabetes has found that
all of the published studies either certainly have, or can’t exclude, the kind of methodological errors that are generated when researchers misclassify people depending on when a person
they start and stop taking metformin. [19] This creates the same kinds of artifacts that underlay the supposed survival advantage of diabetic people taking metformin that we discussed in the
second blog post in this series. [20],[21]

One additional data point to consider. Remember that in a previous installment in this series, we discussed the evidence that metformin may blunt the body’s beneficial adaptations to exercise. Something similar may happen with the protective effect of a healthy diet against cognitive decline. A substudy within a major clinical trial of the Mediterranean diet high in extra-virgin olive oil (EVOO) found that it not only protected against age-related cognitive decline as compared to a healthy but lower-fat control diet, but that it improved people’s scores on multiple cognitive tests as well.[14] But then the researchers looked for possible interactions between the diet and metformin use in people with well-controlled diabetes. And there they found that metformin users gained less improvement in memory and decision-making abilities from the diet than did people using other drugs, despite having equivalent adherence to the Mediterranean diet for nearly the entire trial.[15]

The result isn’t clear-cut because of several complicating factors: most notably, diabetics who did not use metformin tended to score lower on cognitive tests before the diet trial began, and then improved substantially on the high-EVOO Mediterranean diet. But along with the exercise studies, this analysis of the trial data tends to undermine the idea that metformin is one more tool that one can throw in on top of a healthy lifestyle to gain even more benefits.

A Mediterranean diet with extra-virgin olive oil was protective against cognitive decline — but metformin use appeared to blunt the effect. Credit: USDA Agricultural Research Service, Food Components and Health Laboratory.

The most promising evidence on metformin and the risk of developing the dementias of aging in people who don’t have diabetes comes from three small pilot studies.[16],[17],[18] In these trials, metformin seemed to improve aspects of cognitive function in nondiabetic people who had already suffered significant cognitive impairment: they either had so-called “mild” cognitive impairment (MCI — which is not “mild” at all, although it is not yet full-blown dementia) or they were in the earliest stages of dementia per se.

There are several reasons to be skeptical of these trials, however. For one thing, these were all small studies: in one case, just 20 people were involved.[16] For another, in one of the studies,[17] there was a substantial difference in cognitive functioning between the group assigned to take metformin and those who were given placebo pills even before the trial even got started. This kind of pre-existing difference between groups can distort a trial’s later results for the same reason that letting one runner in a race start off several yards ahead of the others can create an undeserving champion. And finally, each of these studies ran the subjects through a whole battery of mental functioning tests, but each of them reported that metformin improved a different test from the one it was found to improve in each of the other two studies. This divergence suggests the possibility that, after testing so many independent domains, each study randomly hit upon one false positive result just by chance (the so-called “problem of multiple comparisons”). The fact that such a thing can happen randomly would explain why the apparent improvement was observed on a different test in each study.

Another notable thing about these three trials[16],[17],[18] is that nearly all the observational studies on metformin and cognitive function (which find no effect) have studied people who were diabetic and aging, but who did not yet have dementia. By contrast, as we mentioned, the subjects in these three trials already had MCI or early-stage AD dementia before they started taking metformin as part of the trial. A plausible explanation for the difference is that metformin seemed to work in these trials because it can correct some metabolic dysfunction that only occurs in the brain once it’s already been so compromised as to qualify for a disease diagnosis. If that were true, metformin could benefit these patients but have no protective effect on people whose brains have not yet undergone enough damage for this hypothetical metabolic derangement to emerge.

Happily, by the TAME is really rolling, we are likely to already know the results of additional trials that will help answer some of the most essential questions. One trial will test the Metformin Effect on Brain Function in Insulin Resistant Elderly People, looking at the drug’s effects on cognitive scores and measures of mitochondrial energy production in the brain. And the Metformin in Alzheimer’s Dementia Prevention (MAP) trial will see if metformin can indeed slow the accelerated cognitive decline and accumulation of Alzheimer’s-driving cellular and molecular aging damage in overweight or obese nondiabetic people aged 55 to 90 years who are not already being treated with the drug.

In the last two installments of this series, we’ll look at TAME itself: how it came to be, how it’s designed, and in what way it might ultimately help us to develop working longevity therapeutics — even if almost in spite of itself.

Citations:

[1] Lu XY, Huang S, Chen QB, Zhang D, Li W, Ao R, Leung FC, Zhang Z, Huang J, Tang Y, Zhang SJ. Metformin Ameliorates Aβ Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer’s Disease. Oxid Med Cell Longev. 2020 Apr 19;2020:2315106. doi: 10.1155/2020/2315106. PMID: 32377293; PMCID: PMC7191377.

[2] Ou Z, Kong X, Sun X, He X, Zhang L, Gong Z, Huang J, Xu B, Long D, Li J, Li Q, Xu L, Xuan A. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun. 2018 Mar;69:351-363. doi: 10.1016/j.bbi.2017.12.009. Epub 2017 Dec 15. PMID: 29253574.

[3] Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology. 2011 May;60(6):910-20. doi: 10.1016/j.neuropharm.2011.01.033. Epub 2011 Jan 26. PMID: 21277873.

[4] Picone P, Vilasi S, Librizzi F, Contardi M, Nuzzo D, Caruana L, Baldassano S, Amato A, Mulè F, San Biagio PL, Giacomazza D, Di Carlo M. Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates. Aging (Albany NY). 2016 Aug;8(8):1718-34. doi: 10.18632/aging.101004. PMID: 27509335; PMCID: PMC5032692.

[5] Allard JS, Perez EJ, Fukui K, Carpenter P, Ingram DK, de Cabo R. Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res. 2016 Mar 15;301:1-9. doi: 10.1016/j.bbr.2015.12.012. Epub 2015 Dec 14. PMID: 26698400; PMCID: PMC4823003.

[6] Barini E, Antico O, Zhao Y, Asta F, Tucci V, Catelani T, Marotta R, Xu H, Gasparini L. Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol Neurodegener. 2016 Feb 9;11:16. doi: 10.1186/s13024-016-0082-7. PMID: 26858121; PMCID: PMC4746897.

[7] Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation. Neuron. 2013 Apr 10;78(1):94-108. doi: 10.1016/j.neuron.2013.02.003. PMID: 23583109; PMCID: PMC3784324.

[8] Li W, Chaudhari K, Shetty R, Winters A, Gao X, Hu Z, Ge WP, Sumien N, Forster M, Liu R, Yang SH. Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice. Aging Dis. 2019 Oct 1;10(5):949-963. doi: 10.14336/AD.2019.0120. PMID: 31595194; PMCID: PMC6764722.

[9] Liao W, Xu J, Li B, Ruan Y, Li T, Liu J. Deciphering the Roles of Metformin in Alzheimer’s Disease: A Snapshot. Front Pharmacol. 2022 Jan 27;12:728315. doi: 10.3389/fphar.2021.728315. PMID: 35153733; PMCID: PMC8829062.

[10] Ha J, Choi DW, Kim KJ, Cho SY, Kim H, Kim KY, Koh Y, Nam CM, Kim E. Association of metformin use with Alzheimer’s disease in patients with newly diagnosed type 2 diabetes: a population-based nested case-control study. Sci Rep. 2021 Dec 15;11(1):24069. doi: 10.1038/s41598-021-03406-5. PMID: 34912022; PMCID: PMC8674300.

[11] Kuan YC, Huang KW, Lin CL, Hu CJ, Kao CH. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):77-83. doi: 10.1016/j.pnpbp.2017.06.002. Epub 2017 Jun 3. PMID: 28583443.

[12] Tabatabaei Malazy O, Bandarian F, Qorbani M, Mohseni S, Mirsadeghi S, Peimani M, Larijani B. The effect of metformin on cognitive function: A systematic review and meta-analysis. J Psychopharmacol. 2022 Jun;36(6):666-679. doi: 10.1177/02698811211057304. Epub 2022 Mar 17. PMID: 35297284.

[13] Luo A, Ning P, Lu H, Huang H, Shen Q, Zhang D, Xu F, Yang L, Xu Y. Association Between Metformin and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Clinical Observational Studies. J Alzheimers Dis. 2022 Jun 28. doi: 10.3233/JAD-220180. Epub ahead of print. PMID: 35786654.

[14] Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martínez-González MÁ, Martínez-Lapiscina EH, Fitó M, Pérez-Heras A, Salas-Salvadó J, Estruch R, Ros E. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. JAMA Intern Med. 2015 Jul;175(7):1094-1103. doi: 10.1001/jamainternmed.2015.1668. Erratum in: JAMA Intern Med. 2018 Dec 1;178(12):1731-1732. PMID: 25961184.

[15] Soldevila-Domenech N, Cuenca-Royo A, Babio N, Forcano L, Nishi S, Vintró-Alcaraz C, Gómez-Martínez C, Jiménez-Murcia S, Fernández-Carrión R, Gomis-González M, Alvarez-Sala A, Carlos S, Pintó X, Corella D, Díez-Espino J, Castañer O, Fernández-Aranda F, Salas-Salvadó J, de la Torre R. Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention. Front Nutr. 2021 Oct 5;8:742586. doi: 10.3389/fnut.2021.742586. PMID: 34676236; PMCID: PMC8523839.

[16] Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L, Detre JA, Wolk DA, Arnold SE. Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study. Alzheimer Dis Assoc Disord. 2017 Apr-Jun;31(2):107-113. doi: 10.1097/WAD.0000000000000202. PMID: 28538088; PMCID: PMC5476214.

[17] Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14. doi: 10.3233/JAD-150493. PMID: 26890736; PMCID: PMC5079271.

[18] Lin Y, Wang K, Ma C, Wang X, Gong Z, Zhang R, Zang D, Cheng Y. Evaluation of Metformin on Cognitive Improvement in Patients With Non-dementia Vascular Cognitive Impairment and Abnormal Glucose Metabolism. Front Aging Neurosci. 2018 Jul 27;10:227. doi: 10.3389/fnagi.2018.00227. Erratum in: Front Aging Neurosci. 2018 Oct 12;10:322. PMID: 30100873; PMCID: PMC6074058.

[19] Dai J, Ports KD, Corrada MM, Odegaard AO, O'Connell J, Jiang L. Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases. J Alzheimers Dis Rep. 2022 Aug 3;6(1):443-459. doi: 10.3233/ADR-220002. PMID: 36186728; PMCID: PMC9484147.

[20] McConway K. Expert reaction to study looking at type 2 diabetes, metformin and lifespan. Science Media Centre. 2014 Aug 8. Online resource: http://www.sciencemediacentre.org/expert-reaction-to-study-looking-at-type-2-diabetes-metformin-and-lifespan/ . Accessed 2023-01-11.

[21] Margulis MV, Pladevall M, Riera-Guardia N, Seeger J, Patorno E, Varas-Lorenzo C. Comment on: Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. PubPeer. 2016 Mar. Online resource:
https://pubpeer.com/publications/4E29C6C9E32D2C24662AED78A59AC5 Accessed 2023-01-11.

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