Energy Restriction Enhances Adult Hippocampal Neurogenesis-Associated Memory after Four Weeks in an Adult Human Population with Central Obesity; a Randomized Controlled Trial

Curie Kim, Ana Margarida Pinto, Claire Bordoli, Luke Patrick Buckner, Polly Charlotte Kaplan, Ines Maria Del Arenal, Emma Jane Jeffcock, Wendy L Hall, Sandrine Thuret, Curie Kim, Ana Margarida Pinto, Claire Bordoli, Luke Patrick Buckner, Polly Charlotte Kaplan, Ines Maria Del Arenal, Emma Jane Jeffcock, Wendy L Hall, Sandrine Thuret

Abstract

Adult neurogenesis, the generation of new neurons throughout life, occurs in the subventricular zone of the dentate gyrus in the human hippocampal formation. It has been shown in rodents that adult hippocampal neurogenesis is needed for pattern separation, the ability to differentially encode small changes derived from similar inputs, and recognition memory, as well as the ability to recognize previously encountered stimuli. Improved hippocampus-dependent cognition and cellular readouts of adult hippocampal neurogenesis have been reported in daily energy restricted and intermittent fasting adult mice. Evidence that nutrition can significantly affect brain structure and function is increasing substantially. This randomized intervention study investigated the effects of intermittent and continuous energy restriction on human hippocampal neurogenesis-related cognition, which has not been reported previously. Pattern separation and recognition memory were measured in 43 individuals with central obesity aged 35-75 years, before and after a four-week dietary intervention using the mnemonic similarity task. Both groups significantly improved pattern separation (P = 0.0005), but only the intermittent energy restriction group had a significant deterioration in recognition memory. There were no significant differences in cognitive improvement between the two diets. This is the first human study to investigate the association between energy restriction with neurogenesis-associated cognitive function. Energy restriction may enhance hippocampus-dependent memory and could benefit those in an ageing population with declining cognition. This study was registered on ClinicalTrials.gov (NCT02679989) on 11 February 2016.

Keywords: adult hippocampal neurogenesis; ageing; cognition; energy restriction; intermittent fasting; pattern separation; randomized controlled trial; recognition memory.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
CONSORT (Consolidated Standards of Reporting Trials) diagram for the Met-IER study (Metabolic effects of Intermittent Energy Restriction). IER: intermittent energy restriction; CER: continuous energy restriction.
Figure 2
Figure 2
Energy restriction improves pattern separation regardless of method. (a) There is no significant difference between IER and CER in pattern separation and recognition memory performance, as measured by LDI and REC scores, respectively. However, the IER group had a significant reduction in REC score (P = 0.007), which was not observed in the CER group. (b) When the groups are treated as a single cohort, there is a significant increase in LDI score (P = 0.0005). Significance at P < 0.05. ** P < 0.01, *** P < 0.001. IER: intermittent energy restriction; CER: continuous energy restriction LDI: lure discrimination index; REC: recognition.

References

    1. Zamroziewicz M.K., Barbey A.K. Nutritional Cognitive Neuroscience: Innovations for Healthy Brain Aging. Front Neurosci. 2016;10:240. doi: 10.3389/fnins.2016.00240.
    1. Kesby J.P., Kim J.J., Scadeng M., Woods G., Kado D.M., Olefsky J.M., Jeste D.V., Achim C.L., Semenova S. Spatial cognition in adult and aged mice exposed to high-fat diet. PLoS ONE. 2015;10:e0140034. doi: 10.1371/journal.pone.0140034.
    1. Underwood E.L., Thompson L.T. High-fat diet impairs spatial memory and hippocampal intrinsic excitability and sex-dependently alters circulating insulin and hippocampal insulin sensitivity. Biol. Sex Differ. 2016;7:9. doi: 10.1186/s13293-016-0060-3.
    1. Haapala E.A., Eloranta A.M., Venäläinen T., Schwab U., Lindi V., Lakka T.A. Associations of diet quality with cognition in children-the Physical Activity and Nutrition in Children Study. Br. J. Nutr. 2015;114:1080–1087. doi: 10.1017/S0007114515001634.
    1. Kamo T., Nishida Y. Direct and indirect effects of nutritional status, physical function and cognitive function on activities of daily living in Japanese older adults requiring long-term care. Geriatr. Gerontol. Int. 2014;14:799–805. doi: 10.1111/ggi.12169.
    1. Kempermann G., Gage F.H., Aigner L., Song H., Curtis M.A., Thuret S., Kuhn H.G., Jessberger S., Frankland P.W., Cameron H.A., et al. Human Adult Neurogenesis: Evidence and Remaining Questions. Cell Stem Cell. 2018;23:25–30. doi: 10.1016/j.stem.2018.04.004.
    1. Lee H., Thuret S. Adult Human Hippocampal Neurogenesis: Controversy and Evidence. Trends Mol. Med. 2018;24:521–522. doi: 10.1016/j.molmed.2018.04.002.
    1. Eriksson P.S., Perfilieva E., Björk-Eriksson T., Alborn A.M., Nordborg C., Peterson D.A., Gage F.H. Neurogenesis in the adult human hippocampus. Nat. Med. 1998;4:1313–1317. doi: 10.1038/3305.
    1. Spalding K.L., Bergmann O., Alkass K., Bernard S., Salehpour M., Huttner H.B., Boström E., Westerlund I., Vial C., Buchholz B.A., et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219. doi: 10.1016/j.cell.2013.05.002.
    1. Sorrells S.F., Paredes M.F., Cebrian-Silla A., Sandoval K., Qi D., Kelley K.W., James D., Mayer S., Chang J., Auguste K.I., et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555:377–381. doi: 10.1038/nature25975.
    1. Boldrini M., Fulmore C.A., Tartt A.N., Simeon L.R., Pavlova I., Poposka V., Rosoklija G.B., Stankov A., Arango V., Dwork A.J., et al. Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell. 2018;22:589–599. doi: 10.1016/j.stem.2018.03.015.
    1. Moreno-Jiménez E.P., Flor-García M., Terreros-Roncal J., Rábano A., Cafini F., Pallas-Bazarra N., Ávila J., Llorens-Martín M. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nature Medicine. Nat. Publ. Group. 2019;25:554–560.
    1. Gonçalves J.T., Schafer S.T., Gage F.H. Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. Cell Cell Press. 2016;167:897–914. doi: 10.1016/j.cell.2016.10.021.
    1. Toda T., Gage F.H. Review: Adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res. 2018;373:693–709. doi: 10.1007/s00441-017-2735-4.
    1. Anacker C., Luna V.M., Stevens G.S., Millette A., Shores R., Jimenez J.C., Chen B., Hen R. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature. 2018;559:98–102. doi: 10.1038/s41586-018-0262-4.
    1. Cameron H.A., Glover L.R. Adult Neurogenesis: Beyond Learning and Memory. Annu. Rev. Psychol. 2015;66:53–81. doi: 10.1146/annurev-psych-010814-015006.
    1. Fanselow M.S., Dong H.W. Are the Dorsal and Ventral Hippocampus Functionally Distinct Structures? Neuron. 2010;65:7–19. doi: 10.1016/j.neuron.2009.11.031.
    1. Stark S.M., Yassa M.A., Lacy J.W., Stark C.E.L. A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment. Neuropsychologia. 2013;51:2442–2449. doi: 10.1016/j.neuropsychologia.2012.12.014.
    1. Bakker A., Kirwan C.B., Miller M., Stark C.E.L. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science. 2008;319:1640–1642. doi: 10.1126/science.1152882.
    1. Lacy J.W., Yassa M.A., Stark S.M., Muftuler L.T., Stark C.E.L. Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using highresolution fMRI and variable mnemonic similarity. Learn. Mem. 2011;18:15–18. doi: 10.1101/lm.1971111.
    1. Clelland C.D., Choi M., Romberg C., Clemenson G.D., Fragniere A., Tyers P., Jessberger S., Saksida L.M., Barker R.A., Gage F.H., et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–213. doi: 10.1126/science.1173215.
    1. Sahay A., Scobie K.N., Hill A.S., O’Carroll C.M., Kheirbek M.A., Burghardt N.S., Fenton A.A., Dranovsky A., Hen R. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466–470. doi: 10.1038/nature09817.
    1. Gould E., Reeves A.J., Fallah M., Tanapat P., Gross C.G., Fuchs E. Hippocampal neurogenesis in adult Old World primates. Proc. Natl. Acad. Sci. USA. 1999;96:5263–5267. doi: 10.1073/pnas.96.9.5263.
    1. Clark R.E. Recognition memory: An old idea given new life. Curr. Biol. 2013;23:725–727. doi: 10.1016/j.cub.2013.07.037.
    1. Bird C.M. The role of the hippocampus in recognition memory. Cortex. 2017;93:155–165. doi: 10.1016/j.cortex.2017.05.016.
    1. Bachevalier J., Nemanic S., Alvarado M.C. The influence of context on recognition memory in monkeys: Effects of hippocampal, parahippocampal and perirhinal lesions. Behav. Brain Res. 2015;285:89–98. doi: 10.1016/j.bbr.2014.07.010.
    1. Cohen S.J., Stackman R.W. Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 2015;285:105–117. doi: 10.1016/j.bbr.2014.08.002.
    1. Lafenêtre P., Leske O., Ma-Högemeie Z., Haghikia A., Bichler Z., Wahle P., Heumann R. Exercise can rescue recognition memory impairment in a model with reduced adult hippocampal neurogenesis. Front Behav. Neurosci. 2010;3:34. doi: 10.3389/neuro.08.034.2009.
    1. Kim J.I., Lee J.W., Lee Y.A., Lee D.H., Han N.S., Choi Y.K., Hwang B.R., Kim H.J., Han J.S. Sexual activity counteracts the suppressive effects of chronic stress on adult hippocampal neurogenesis and recognition memory. Brain Res. 2013;1538:26–40. doi: 10.1016/j.brainres.2013.09.007.
    1. Zainuddin M.S.A., Thuret S. Nutrition, adult hippocampal neurogenesis and mental health. Br. Med. Bull. 2012;103:89–114. doi: 10.1093/bmb/lds021.
    1. Mattson M.P. Neuroprotective signaling and the aging brain: Take away my food and let me run. Brain Res. 2000;886:47–53. doi: 10.1016/S0006-8993(00)02790-6.
    1. Horne B.D., Muhlestein J.B., Anderson J.L. Health effects of intermittent fasting: Hormesis or harm? A systematic review. Am. J. Clin. Nutr. 2015;102:464–470. doi: 10.3945/ajcn.115.109553.
    1. Murphy T., Dias G.P., Thuret S. Effects of diet on brain plasticity in animal and human studies: Mind the gap. Neural Plast. 2014;2014:563160. doi: 10.1155/2014/563160.
    1. Mattson M.P., Longo V.D., Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. 2017;39:46–58. doi: 10.1016/j.arr.2016.10.005.
    1. Pinto A.M., Bordoli C., Buckner L.P., Kim C., Kaplan P.C., Del Arenal I.M., Jeffcock E.J., Hall W.L. Intermittent energy restriction is comparable to continuous energy restriction for cardiometabolic health in adults with central obesity: A randomized controlled trial; the Met-IER study. Clin. Nutr. 2019 doi: 10.1016/j.clnu.2019.07.014.
    1. Stark S.M., Stevenson R., Wu C., Rutledge S., Stark C.E.L. Stability of age-related deficits in the mnemonic similarity task across task variations. Behav. Neurosci. 2015;129:257–268. doi: 10.1037/bne0000055.
    1. Brownlow M.L., Joly-Amado A., Azam S., Elza M., Selenica M.L., Pappas C., Small B., Engelman R., Gordon M.N., Morgan D. Partial rescue of memory deficits induced by calorie restriction in a mouse model of tau deposition. Behav. Brain Res. 2014;271:79–88. doi: 10.1016/j.bbr.2014.06.001.
    1. Carter C.S., Leeuwenburgh C., Daniels M., Foster T.C. Influence of calorie restriction on measures of age-related cognitive decline: Role of increased physical activity. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2009;64:850–859. doi: 10.1093/gerona/glp060.
    1. Wu P., Jiang C., Shen Q., Hu Y. Systematic gene expression profile of hypothalamus in calorie-restricted mice implicates the involvement of mTOR signaling in neuroprotective activity. Mech. Ageing Dev. 2009;130:602–610. doi: 10.1016/j.mad.2009.07.005.
    1. Kaptan Z., Akgün-Dar K., Kapucu A., Dedeakayoʇullari H., Batu Ş., Üzüm G. Long term consequences on spatial learning-memory of low-calorie diet during adolescence in female rats; Hippocampal and prefrontal cortex BDNF level, expression of NeuN and cell proliferation in dentate gyrus. Brain Res. 2015;1618:194–204. doi: 10.1016/j.brainres.2015.05.041.
    1. Li L., Wang Z., Zuo Z. Chronic intermittent fasting improves cognitive functions and brain structures in mice. PLoS ONE. 2013;8:e66069. doi: 10.1371/journal.pone.0066069.
    1. Ahn J.H., Shin B.N., Song M., Kim H., Park J.H., Lee T.K., Park C.W., Park Y.E., Lee J.C., Yong J.H. Intermittent fasting increases the expressions of SODs and catalase in granule and polymorphic cells and enhances neuroblast dendrite complexity and maturation in the adult gerbil dentate gyrus. Mol. Med. Rep. 2019;19:1721–1727. doi: 10.3892/mmr.2019.9822.
    1. Geng Y.Q., Guan J.T., Xu M.Y., Xu X.H., Fu Y.C. Behavioral Study of Calorie-restricted Rats from Early Old Age; Proceedings of the 2007 29th Annual International Conference of the IEEE Engineering in Medicine and Biology Society; Lyon, France. 22–26 August 2007; pp. 2393–2395.
    1. Wu P., Shen Q., Dong S., Xu Z., Tsien J.Z., Hu Y. Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice. Neurobiol. Aging. 2008;29:1502–1511. doi: 10.1016/j.neurobiolaging.2007.03.028.
    1. Longo V.D., Mattson M.P. Fasting: Molecular Mechanisms and Clinical Applications. Cell Metab. 2014;19:181. doi: 10.1016/j.cmet.2013.12.008.
    1. Lee J., Seroogy K.B., Mattson M.P. Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J. Neurochem. 2002;80:539–547. doi: 10.1046/j.0022-3042.2001.00747.x.
    1. Michael Anson R., Guo Z., de Cabo R., Iyun T., Rios M., Hagepanos A., Ingram D.K., Lane M.A., Mattson M.P. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc. Natl. Acad. Sci. USA. 2003;100:6216–6220. doi: 10.1073/pnas.1035720100.
    1. Maruszak A., Pilarski A., Murphy T., Branch N., Thuret S. Hippocampal neurogenesis in Alzheimer’s disease: Is there a role for dietary modulation? J. Alzheimer’s Dis. 2014;38:11–38. doi: 10.3233/JAD-131004.
    1. Manzanero S., Erion J.R., Santro T., Steyn F.J., Chen C., Arumugam T.V., Stranahan A.M. Intermittent fasting attenuates increases in neurogenesis after ischemia and reperfusion and improves recovery. J. Cereb. Blood Flow Metab. 2014;34:897–905. doi: 10.1038/jcbfm.2014.36.
    1. Komatsu T., Chiba T., Yamaza H., Yamashita K., Shimada A., Hoshiyama Y., Henmi T., Ohtani H., Higami Y., de Cabo R., et al. Manipulation of caloric content but not diet composition, attenuates the deficit in learning and memory of senescence-accelerated mouse strain P8. Exp. Gerontol. 2008;43:339–346. doi: 10.1016/j.exger.2008.01.008.
    1. Wei M., Brandhorst S., Shelehchi M., Mirzaei H., Cheng C.W., Budniak J., Groshen S., Mack W.J., Guen E., Di Biase S., et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci. Transl. Med. 2017;9:8700. doi: 10.1126/scitranslmed.aai8700.
    1. Madeo F., Carmona-Gutierrez D., Hofer S.J., Kroemer G. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metab. 2019;29:592–610. doi: 10.1016/j.cmet.2019.01.018.
    1. Vallejo E. Hunger diet on alternate days in the nutrition of the aged. Prensa Med. Argent. 1957;44:119–120.
    1. Redman L.M., Ravussin E. Caloric restriction in humans: Impact on physiological, psychological, and behavioral outcomes. Antioxid. Redox Signal. 2011;14:275–287. doi: 10.1089/ars.2010.3253.
    1. Stekovic S., Hofer S.J., Tripolt N., Aon M.A., Royer P., Pein L., Stadler J.T., Pendl T., Prietl B., Url J., et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans. Cell Metab. 2019;30:462–476. doi: 10.1016/j.cmet.2019.07.016.
    1. Anton S.D., Lee S.A., Donahoo W.T., McLaren C., Manini T., Leeuwenburgh C., Pahor M. The effects of time restricted feeding on overweight, older adults: A pilot study. Nutrients. 2019;11:1500. doi: 10.3390/nu11071500.
    1. Tinsley G.M., La Bounty P.M. Effects of intermittent fasting on body composition and clinical health markers in humans. Nutr. Rev. 2015;73:661–674. doi: 10.1093/nutrit/nuv041.
    1. Sutton E.F., Beyl R., Early K.S., Cefalu W.T., Ravussin E., Peterson C.M. Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metab. 2018;27:1212–1221. doi: 10.1016/j.cmet.2018.04.010.
    1. Prehn K., Jumpertz von Schwartzenberg R., Mai K., Zeitz U., Witte A.V., Hampel D., Szela A.M., Fabian S., Grittner U., Spranger J., et al. Caloric Restriction in Older Adults—Differential Effects of Weight Loss and Reduced Weight on Brain Structure and Function. Cereb. Cortex. 2016;27:1765–1778. doi: 10.1093/cercor/bhw008.
    1. Hussin N.M., Shahar S., Teng N.I.M.F., Ngah W.Z.W., Das S.K. Efficacy of Fasting and Calorie Restriction (FCR) on mood and depression among ageing men. J. Nutr. Health Aging. 2013;17:674–680. doi: 10.1007/s12603-013-0344-9.
    1. Fitzgerald K.C., Vizthum D., Henry-Barron B., Schweitzer A., Cassard S.D., Kossoff E., Hartman A.L., Kapogiannis D., Sullivan P., Baer D.J., et al. Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis. Mult. Scler. Relat. Disord. 2018;23:33–39. doi: 10.1016/j.msard.2018.05.002.
    1. Jamshed H., Beyl R.A., Manna D.L.D., Yang E.S., Ravussin E., Peterson C.M. Early time-restricted feeding improves 24-hour glucose levels and affects markers of the circadian clock, aging, and autophagy in humans. Nutrients. 2019;11:1234. doi: 10.3390/nu11061234.
    1. Hullinger R., Puglielli L. Molecular and cellular aspects of age-related cognitive decline and Alzheimer’s disease. Behav. Brain Res. 2017;322:191–205. doi: 10.1016/j.bbr.2016.05.008.
    1. Nakashiba T., Cushman J.D., Pelkey K.A., Renaudineau S., Buhl D.L., McHugh T.J., Rodriguez Barrera V., Chittajallu R., Iwamoto K.S., McBain C.J., et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell. 2012;149:188–201. doi: 10.1016/j.cell.2012.01.046.
    1. Oreopoulos A., Kalantar-Zadeh K., Sharma A.M., Fonarow G.C. The obesity paradox in the elderly: Potential mechanisms and clinical implications. Clin. Geriatr. Med. 2009;25:643–659. doi: 10.1016/j.cger.2009.07.005.
    1. Sellbom K.S., Gunstad J. Cognitive function and decline in obesity. J. Alzheimers Dis. 2012;30:89–95. doi: 10.3233/JAD-2011-111073.
    1. Kuo H.-K., Jones R.N., Milberg W.P., Tennstedt S., Talbot L., Morris J.N., Lipsitz L.A. Cognitive function in normal-weight, overweight, and obese older adults: An analysis of the Advanced Cognitive Training for Independent and Vital Elderly cohort. J. Am. Geriatr. Soc. 2006;54:97–103. doi: 10.1111/j.1532-5415.2005.00522.x.
    1. Memel M., Bourassa K., Woolverton C., Sbarra D.A. Body Mass and Physical Activity Uniquely Predict Change in Cognition for Aging Adults. Ann. Behav. Med. 2016;50:397–408. doi: 10.1007/s12160-015-9768-2.
    1. Skinner J.S., Abel W.M., McCoy K., Wilkins C.H. Exploring the “obesity paradox” as a correlate of cognitive and physical function in community-dwelling black and white older adults. Ethn. Dis. 2017;27:387–394. doi: 10.18865/ed.27.4.387.
    1. Hariton E., Locascio J.J. Randomised controlled trials—The gold standard for effectiveness research: Study design: Randomised controlled trials. Int. J. Obstet. Gynaecol. 2018;125:1716. doi: 10.1111/1471-0528.15199.
    1. Stark S.M., Kirwan C.B., Stark C.E.L. Mnemonic Similarity Task: A Tool for Assessing Hippocampal Integrity. Trends Cogn. Sci. 2019;23:938–951. doi: 10.1016/j.tics.2019.08.003.
    1. Ho N.F., Hooker J.M., Sahay A., Holt D.J., Roffman J.L. In vivo imaging of adult human hippocampal neurogenesis: Progress, pitfalls and promise. Mol. Psychiatry. 2013;18:404–416. doi: 10.1038/mp.2013.8.
    1. Rounds T., Harvey J. Enrollment Challenges: Recruiting Men to Weight Loss Interventions. Am. J. Mens Health. 2019;13 doi: 10.1177/1557988319832120.
    1. Snyder J.S., Soumier A., Brewer M., Pickel J., Cameron H.A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011;476:458–462. doi: 10.1038/nature10287.
    1. Kempermann G. Environmental enrichment, new neurons and the neurobiology of individuality. Nat. Rev. Neuroscience. 2019;20:235–245. doi: 10.1038/s41583-019-0120-x.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir