Advertisement

GeroScience

pp 1–8 | Cite as

Taming expectations of metformin as a treatment to extend healthspan

  • Adam R. Konopka
  • Benjamin F. MillerEmail author
Review

Abstract

The anti-hyperglycemic medication metformin has potential to be the first drug tested to slow aging in humans. While the Targeting Aging with Metformin (TAME) proposal and other small-scale clinical trials have the potential to support aging as a treatment indication, we propose that the goals of the TAME trial might not be entirely consistent with the Geroscience goal of extending healthspan. There is expanding epidemiological support for the health benefits of metformin in individuals already diagnosed with overt chronic disease. However, it remains to be understood if these protective effects extend to those free of chronic disease. Within this editorial, we seek to highlight critical gaps in knowledge that should be considered when testing metformin as a treatment to target aging.

Keywords

Metformin Aging Healthspan Slowed aging 

Notes

References

  1. ADVANCE Collaborative Group, Patel A, Macmahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572CrossRefGoogle Scholar
  2. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV (2008) Metformin slows down aging and extends life span of female SHR mice. Cell Cycle Georget Tex 7:2769–2773CrossRefGoogle Scholar
  3. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE (2011) If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging 3:148–157CrossRefGoogle Scholar
  4. Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, Mukherjee J, Currie CJ (2014) 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. Diabetes Obes Metab 16:1165–1173CrossRefGoogle Scholar
  5. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (2016) Metformin as a tool to target aging. Cell Metab 23:1060–1065CrossRefGoogle Scholar
  6. Barzilay JI, Blaum C, Moore T, Xue QL, Hirsch CH, Walston JD, Fried LP (2007) Insulin resistance and inflammation as precursors of frailty: the cardiovascular health study. Arch Intern Med 167:635–641CrossRefGoogle Scholar
  7. Blair SN, Kohl HW, Paffenbarger RS, Clark DG, Cooper KH, Gibbons LW (1989) Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 262:2395–2401CrossRefGoogle Scholar
  8. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, Cacciatori V, Santi L, Targher G, Bonadonna R, Muggeo M (2002) HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 25:1135–1141CrossRefGoogle Scholar
  9. Braun B, Eze P, Stephens BR, Hagobian TA, Sharoff CG, Chipkin SR, Goldstein B (2008) Impact of metformin on peak aerobic capacity. Appl Physiol Nutr Metab 33:61–67CrossRefGoogle Scholar
  10. Bridges HR, Jones AJY, Pollak MN, Hirst J (2014) Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 462:475–487CrossRefGoogle Scholar
  11. Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, Roden M, Gnaiger E, Nohl H, Waldhäusl W, Fürnsinn C (2004) Thiazolidinediones, like metformin, inhibit respiratory complex I a common mechanism contributing to their antidiabetic actions? Diabetes 53:1052–1059CrossRefGoogle Scholar
  12. Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M (2016) The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 39:198–205CrossRefGoogle Scholar
  13. Cabreiro F, Au C, Leung K-Y, Vergara-Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene NDE, Gems D (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153:228–239CrossRefGoogle Scholar
  14. Campbell JM, Bellman SM, Stephenson MD, Lisy K (2017) Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev 40:31–44CrossRefGoogle Scholar
  15. Cartee GD, Hepple RT, Bamman MM, Zierath JR (2016) Exercise promotes healthy aging of skeletal muscle. Cell Metab 23:1034–1047CrossRefGoogle Scholar
  16. Cheng C, Lin C-H, Tsai Y-W, Tsai C-J, Chou P-H, Lan T-H (2014) Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol A Biol Sci Med Sci 69:1299–1305CrossRefGoogle Scholar
  17. Crandall J, Barzilai N (2003) Treatment of diabetes mellitus in older people: oral therapy options. J Am Geriatr Soc 51:272–274CrossRefGoogle Scholar
  18. De Haes W, Frooninckx L, Van Assche R, Smolders A, Depuydt G, Billen J, Braeckman BP, Schoofs L, Temmerman L (2014) Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci U S A 111:E2501–E2509CrossRefGoogle Scholar
  19. Dhahbi JM, Mote PL, Fahy GM, Spindler SR (2005) Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics 23:343–350CrossRefGoogle Scholar
  20. Diabetes Prevention Program Research Group, Crandall J, Schade D, Ma Y, Fujimoto WY, Barrett-Connor E, Fowler S, Dagogo-Jack S, Andres R (2006) The influence of age on the effects of lifestyle modification and metformin in prevention of diabetes. J Gerontol A Biol Sci Med Sci 61:1075–1081CrossRefGoogle Scholar
  21. Facchini FS, Hua N, Abbasi F, Reaven GM (2001) Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 86:3574–3578CrossRefGoogle Scholar
  22. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E (2014) Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res Phila 7:867–885CrossRefGoogle Scholar
  23. Goodpaster BH, Carlson CL, Visser M, Kelley DE, Scherzinger A, Harris TB, Stamm E, Newman AB (2001) Attenuation of skeletal muscle and strength in the elderly: the Health ABC Study. J Appl Physiol 90:2157–2165CrossRefGoogle Scholar
  24. Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV, Simonsick EM, Tylavsky FA, Visser M, Newman AB (2006) The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci 61:1059–1064CrossRefGoogle Scholar
  25. Gormsen LC, Sundelin EI, Jensen JB, Vendelbo MH, Jakobsen S, Munk OL, Christensen MMH, Brøsen K, Frøkiær J, Jessen N (2016) In vivo imaging of human 11C-metformin in peripheral organs: dosimetry, biodistribution, and kinetic analyses. J Nucl Med 57:1920–1926CrossRefGoogle Scholar
  26. Hartman MHT, Prins JKB, Schurer RAJ, Lipsic E, Lexis CPH, van der Horst-Schrivers ANA, van Veldhuisen DJ, van der Horst ICC, van der Harst P (2017) Two-year follow-up of 4 months metformin treatment vs. placebo in ST-elevation myocardial infarction: data from the GIPS-III RCT. Clin Res Cardiol 106:939–946CrossRefGoogle Scholar
  27. Iannello S, Camuto M, Cavaleri A, Milazzo P, Pisano MG, Bellomia D, Belfiore F (2004) Effects of short-term metformin treatment on insulin sensitivity of blood glucose and free fatty acids. Diabetes Obes Metab 6:8–15CrossRefGoogle Scholar
  28. Imboden MT, Harber MP, Whaley MH, Finch WH, Bishop DL, Kaminsky LA (2018) Cardiorespiratory fitness and mortality in healthy men and women. J Am Coll Cardiol 72:2283–2292CrossRefGoogle Scholar
  29. Justice JN, Ferrucci L, Newman AB, Aroda VR, Bahnson JL, Divers J, Espeland MA, Marcovina S, Pollak MN, Kritchevsky SB, Barzilai N, Kuchel GA (2018) A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup. GeroScience 40:419–436CrossRefGoogle Scholar
  30. Kaeberlein M (2018) How healthy is the healthspan concept? GeroScience 40:361–364CrossRefGoogle Scholar
  31. Kane DA, Anderson EJ, Price JW, Woodlief TL, Lin C-T, Bikman BT, Cortright RN, Neufer PD (2010) Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med 49:1082–1087CrossRefGoogle Scholar
  32. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403CrossRefGoogle Scholar
  33. Konopka AR, Esponda RR, Robinson MM, Johnson ML, Carter RE, Schiavon M, Cobelli C, Wondisford FE, Lanza IR, Nair KS (2016) Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes. Cell Rep 15:1394–1400CrossRefGoogle Scholar
  34. Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, Musci RV, Safairad OD, Linden MA, Biela LM, Bailey SM, Hamilton KL, Miller BF (2018) Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell e12880Google Scholar
  35. Kristensen JM, Larsen S, Helge JW, Dela F, Wojtaszewski JFP (2013) Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice. PLoS One 8:e53533CrossRefGoogle Scholar
  36. Kulkarni AS, Brutsaert EF, Anghel V, Zhang K, Bloomgarden N, Pollak M, Mar JC, Hawkins M, Crandall JP & Barzilai N (2018) Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 17Google Scholar
  37. Larsen S, Rabøl R, Hansen CN, Madsbad S, Helge JW, Dela F (2011) Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration. Diabetologia 55:443–449CrossRefGoogle Scholar
  38. Lee H, Ko G (2014) Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol 80:5935–5943CrossRefGoogle Scholar
  39. Lexis CPH, van der Horst ICC, Lipsic E, Wieringa WG, de Boer RA, van den Heuvel AFM, van der Werf HW, Schurer RAJ, Pundziute G, Tan ES, Nieuwland W, Willemsen HM, Dorhout B, Molmans BHW, van der Horst-Schrivers ANA, Wolffenbuttel BHR, ter Horst GJ, van Rossum AC, Tijssen JGP, Hillege HL, de Smet BJGL, van der Harst P, van Veldhuisen DJ, Investigators GIPS-III (2014) Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA 311:1526–1535CrossRefGoogle Scholar
  40. Linden MA, Lopez KT, Fletcher JA, Morris EM, Meers GM, Siddique S, Laughlin MH, Sowers JR, Thyfault JP, Ibdah JA, Rector RS (2015) Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats. Appl Physiol Nutr Metab Physiol Appl Nutr Metab 40:1038–1047CrossRefGoogle Scholar
  41. Long DE, Peck BD, Martz JL, Tuggle SC, Bush HM, McGwin G, Kern PA, Bamman MM & Peterson CA (2017) Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial. Trials 18. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405504/ [Accessed January 25, 2019]
  42. Madiraju AK, Erion DM, Rahimi Y, Zhang X-M, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez J-P, Lee H-Y, Cline GW, Samuel VT, Kibbey RG, Shulman GI (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–546CrossRefGoogle Scholar
  43. Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang X-M, Zhang D, Camporez J-PG, Cline GW, Butrico GM, Kemp BE, Casals G, Steinberg GR, Vatner DF, Petersen KF, Shulman GI (2018) Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med Available at: http://www.nature.com/articles/s41591-018-0125-4 [Accessed August 22, 2018] 24:1384–1394CrossRefGoogle Scholar
  44. Malin SK, Gerber R, Chipkin SR, Braun B (2012) Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care 35:131–136CrossRefGoogle Scholar
  45. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin M-J, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192CrossRefGoogle Scholar
  46. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66:191–201CrossRefGoogle Scholar
  47. Miller ME, Williamson JD, Gerstein HC, Byington RP, Cushman WC, Ginsberg HN, Ambrosius WT, Lovato L, Applegate WB (2014a) Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD Trial. Diabetes Care 37:634–643CrossRefGoogle Scholar
  48. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R (2014b) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13:468–477CrossRefGoogle Scholar
  49. Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, Peralba JM, Harrison DE (2008) Design of aging intervention studies: the NIA interventions testing program. Age Dordr Neth 30:187–199CrossRefGoogle Scholar
  50. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B (2014) Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis 41:61–68CrossRefGoogle Scholar
  51. Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One 5:e8758CrossRefGoogle Scholar
  52. Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348:607–614CrossRefGoogle Scholar
  53. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142CrossRefGoogle Scholar
  54. Peterson C, Grace Walton R, Craig Tuggle S, Kulkarni A (2018) Metformin to augment strength training effective response in seniors: the masters trial. Innov Aging 2:544–545CrossRefGoogle Scholar
  55. Physical Activity Committee (2018) Scientific Report - 2018 Physical Activity Guidelines - health.gov. Available at: https://health.gov/paguidelines/second-edition/report/
  56. Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P, Fisher M, Packard CJ, Sattar N (2014) Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol 2:116–124CrossRefGoogle Scholar
  57. Reed RL, Pearlmutter L, Yochum K, Meredith KE, Mooradian AD (1991) The relationship between muscle mass and muscle strength in the elderly. J Am Geriatr Soc 39:555–561CrossRefGoogle Scholar
  58. Reid KF, Fielding RA (2012) Skeletal muscle power: a critical determinant of physical functioning in older adults. Exerc Sport Sci Rev 40:4–12CrossRefGoogle Scholar
  59. Reid KF, Naumova EN, Carabello RJ, Phillips EM, Fielding RA (2008) Lower extremity muscle mass predicts functional performance in mobility-limited elders. J Nutr Health Aging 12:493–498CrossRefGoogle Scholar
  60. Seals DR, Justice JN, LaRocca TJ (2016) Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity. J Physiol 594:2001–2024CrossRefGoogle Scholar
  61. Sharoff CG, Hagobian TA, Malin SK, Chipkin SR, Yu H, Hirshman MF, Goodyear LJ, Braun B (2010) Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals. Am J Physiol-Endocrinol Metab 298:E815–E823CrossRefGoogle Scholar
  62. Smith DL, Elam CF, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB (2010) Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 65:468–474CrossRefGoogle Scholar
  63. Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, Javors MA, de Magalhães JP, Marinez PA, McCord JM, Miller BF, Müller M, Nelson JF, Ndukum J, Rainger GE, Richardson A, Sabatini DM, Salmon AB, Simpkins JW, Steegenga WT, Nadon NL, Harrison DE (2016) Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872–884CrossRefGoogle Scholar
  64. UKPDS Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet Lond Engl 352:854–865CrossRefGoogle Scholar
  65. Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L, Keller GM, Frankland PW, Kaplan DR, Miller FD (2012) Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 11:23–35CrossRefGoogle Scholar
  66. Weiss R, Fernandez E, Liu Y, Strong R, Salmon AB (2018) Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice. Aging 10:386–401CrossRefGoogle Scholar
  67. Wessels B, Ciapaite J, van den Broek NMA, Nicolay K & Prompers JJ (2014) Metformin impairs mitochondrial function in skeletal muscle of both lean and diabetic rats in a dose-dependent manner. PLoS One 9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065055/ [Accessed April 15, 2015]
  68. Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS, Chandel NS (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 3:e02242CrossRefGoogle Scholar
  69. Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11(4):398–411. http://doi.org/jstor.org/stable/2406060
  70. Williams PT (2001) Physical fitness and activity as separate heart disease risk factors: a meta-analysis. Med Sci Sports Exerc 33:754–761CrossRefGoogle Scholar
  71. Wu JW, Boudreau DM, Park Y, Simonds NI, Freedman AN (2014) Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: a review of the literature. Expert Opin Drug Saf 13:1071–1099CrossRefGoogle Scholar
  72. Zampieri S, Pietrangelo L, Loefler S, Fruhmann H, Vogelauer M, Burggraf S, Pond A, Grim-Stieger M, Cvecka J, Sedliak M, Tirpáková V, Mayr W, Sarabon N, Rossini K, Barberi L, De Rossi M, Romanello V, Boncompagni S, Musarò A, Sandri M, Protasi F, Carraro U, Kern H (2015) Lifelong physical exercise delays age-associated skeletal muscle decline. J Gerontol A Biol Sci Med Sci 70:163–173CrossRefGoogle Scholar
  73. Zhou K, Donnelly L, Yang J, Li M, Deshmukh H, Van Zuydam N, Ahlqvist E, Wellcome Trust Case Control Consortium 2, Spencer CC, Groop L, Morris AD, Colhoun HM, Sham PC, McCarthy MI, Palmer CNA, Pearson ER (2014) Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. Lancet Diabetes Endocrinol 2:481–487CrossRefGoogle Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Department of Kinesiology and Community HealthUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  2. 2.Institute for Genomic BiologyUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  3. 3.Aging and Metabolism Research ProgramOklahoma Medical Research FoundationOklahoma CityUSA

Personalised recommendations