Skip to main content

Part of the book series: Subcellular Biochemistry ((SCBI,volume 91))

Abstract

With an increasingly ageing population that is expected to double by 2050 in the U.S., it is paramount that we further understand the neurological changes that occur during ageing. This is relevant not only in the context of “pathological” ageing, where the development of many neurodegenerative disorders is typically a feature of only the older population (and indeed, age is the primary risk factor for many conditions such as Alzheimer’s disease), but also for what is considered to be “normal” or “healthy” ageing. Specifically, a significant proportion of the older population are affected by “age-related cognitive decline” (ARCD), which is both independent of dementia and has an incidence 70% higher than dementia alone. However, whilst it is reported that there are pathogenic and phenotypic overlaps between healthy and pathological ageing, it is clear that there is a need to identify the pathways and understand the mechanisms that contribute to this loss of cognitive function with normal ageing, particularly in light of the increasing life expectancy of the global population. Importantly, there is an increasing body of evidence implicating zinc homeostasis as a key player in learning and memory and also potentially ARCD. Further research will ultimately contribute to the development of targeted therapeutics that will promote successful brain ageing. In this chapter we will explore the notion of ARCD, with a perspective on potential key neurochemical pathways that can be targeted for future intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adlard P, Cotman C (2004) Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression. Neuroscience 124:985–992

    Article  CAS  PubMed  Google Scholar 

  • Adlard PA, Perreau VM, Engesser-Cesar C, Cotman CW (2004) The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise. Neurosci Lett 363:43–48

    Article  CAS  PubMed  Google Scholar 

  • Adlard PA, Perreau VM, Cotman CW (2005a) The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiol Aging 26:511–520

    Article  CAS  PubMed  Google Scholar 

  • Adlard PA, Perreau VM, Pop V, Cotman CW (2005b) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci 25:4217–4221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E et al (2008) Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron 59:43–55

    Article  CAS  PubMed  Google Scholar 

  • Adlard PA, Parncutt JM, Finkelstein DI, Bush AI (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J Neurosci 30:1631–1636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adlard PA, Sedjahtera A, Gunawan L, Bray L, Hare D et al (2014) A novel approach to rapidly prevent age-related cognitive decline. Aging Cell 13:351–359

    Article  CAS  PubMed  Google Scholar 

  • Adlard PA, Parncutt J, Lal V, James S, Hare D et al (2015) Metal chaperones prevent zinc-mediated cognitive decline. Neurobiol Dis 81:196–202

    Article  CAS  PubMed  Google Scholar 

  • Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW (2009) Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 85:823–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnold LE, Bozzolo H, Hollway J, Cook A, DiSilvestro RA et al (2005) Serum zinc correlates with parent-and teacher-rated inattention in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 15:628–636

    Article  PubMed  Google Scholar 

  • Assaf S, Chung S-H (1984) Release of endogenous Zn2+ from brain tissue during activity. Nature 308:734

    Article  CAS  PubMed  Google Scholar 

  • Azpurua J, Eaton BA (2015) Neuronal epigenetics and the aging synapse. Front Cell Neurosci 9:208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baker DJ, Dawlaty MM, Wijshake T, Jeganathan KB, Malureanu L et al (2013) Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol 15:96

    Article  CAS  PubMed  Google Scholar 

  • Ballesteros S, Nilsson L-G, Lemaire P (2009) Ageing, cognition, and neuroscience: an introduction. Eur J Cogn Psychol 21:161–175

    Article  Google Scholar 

  • Barnes C, Rao G, Houston F (2000) LTP induction threshold change in old rats at the perforant path–granule cell synapse. Neurobiol Aging 21:613–620

    Article  CAS  PubMed  Google Scholar 

  • Besser L, Chorin E, Sekler I, Silverman WF, Atkin S et al (2009) Synaptically released zinc triggers metabotropic signaling via a zinc-sensing receptor in the hippocampus. J Neurosci 29:2890–2901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bigby C (2004) Ageing with a lifelong disability: a guide to practice, program, and policy issues for human services professionals. Jessica Kingsley, London

    Google Scholar 

  • Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Black MM (2003) The evidence linking zinc deficiency with children’s cognitive and motor functioning, 2. J Nutr 133:1473S–1476S

    Article  CAS  PubMed  Google Scholar 

  • Buckner C, Fridland E (2017) What is cognition? angsty monism, permissive pluralism (s), and the future of cognitive science. Springer, Heidelberg

    Book  Google Scholar 

  • Canas PM, Duarte JM, Rodrigues RJ, Köfalvi A, Cunha RA (2009) Modification upon aging of the density of presynaptic modulation systems in the hippocampus. Neurobiol Aging 30:1877–1884

    Article  CAS  PubMed  Google Scholar 

  • Celsis P (2000) Age-related cognitive decline, mild cognitive impairment or preclinical Alzheimer’s disease? Ann Med 32:6–14

    Article  CAS  PubMed  Google Scholar 

  • Chen WQ, Viidik A, Skalicky M, Höger H, Lubec G (2007) Hippocampal signaling cascades are modulated in voluntary and treadmill exercise rats. Electrophoresis 28:4392–4400

    Article  CAS  PubMed  Google Scholar 

  • Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD (1999) Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci 96:1716–1721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deary IJ, Corley J, Gow AJ, Harris SE, Houlihan LM et al (2009) Age-associated cognitive decline. Br Med Bull 92:135–152

    Article  PubMed  Google Scholar 

  • Fjell AM, Walhovd KB (2010) Structural brain changes in aging: courses, causes and cognitive consequences. Rev Neurosci 21:187–222

    Article  PubMed  Google Scholar 

  • Fontana L, Partridge L, Longo VD (2010) Extending healthy life span—from yeast to humans. Science 328:321–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frederickson CJ, Koh J-Y, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449

    Article  CAS  PubMed  Google Scholar 

  • Froestl W, Muhs A, Pfeifer A (2012) Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors. J Alzheimers Dis 32:793–887

    Article  CAS  PubMed  Google Scholar 

  • Froestl W, Muhs A, Pfeifer A (2013a) Cognitive enhancers (nootropics). Part 2: Drugs interacting with enzymes. J Alzheimers Dis 33:547–658

    Article  CAS  PubMed  Google Scholar 

  • Froestl W, Pfeifer A, Muhs A (2013b) Cognitive enhancers (nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. disease-modifying drugs. J Alzheimers Dis 34:1–114

    Article  CAS  PubMed  Google Scholar 

  • Guan J-S, Haggarty SJ, Giacometti E, Dannenberg J-H, Joseph N et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hancock SM, Finkelstein DI, Adlard PA (2014) Glia and zinc in ageing and Alzheimer’s disease: a mechanism for cognitive decline? Front Aging Neurosci 6:137

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hara Y, Morrison JH (2014) Synaptic correlates of aging and cognitive decline. In: The synapse: structure and function. Elsevier Inc, Amsterdam, pp 301–342

    Google Scholar 

  • Hara Y, Park CS, Janssen WG, Punsoni M, Rapp PR, Morrison JH (2011) Synaptic characteristics of dentate gyrus axonal. boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J Neurosci 31:7737–7744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harada CN, Love MCN, Triebel KL (2013) Normal cognitive aging. Clin Geriatr Med 29:737–752

    Article  PubMed  PubMed Central  Google Scholar 

  • Head D, Buckner RL, Shimony JS, Williams LE, Akbudak E et al (2004) Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging. Cereb Cortex 14:410–423

    Article  PubMed  Google Scholar 

  • Hedden T, Gabrieli JD (2004) Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci 5:87

    Article  CAS  PubMed  Google Scholar 

  • Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM (1998) Neuropathological and neuropsychological changes in “normal” aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J Neuropathol Exp Neurol 57:1168–1174

    Article  CAS  PubMed  Google Scholar 

  • Jagust W (2013) Vulnerable neural. systems and the borderland of brain aging and neurodegeneration. Neuron 77:219–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kambe T, Tsuji T, Hashimoto A, Itsumura N (2015) The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol Rev 95:749–784

    Article  CAS  PubMed  Google Scholar 

  • Kinsella K, Velkoff VA (2002) The demographics of aging. Aging Clin Exp Res 14:159–169

    Article  PubMed  Google Scholar 

  • Kirkwood TB (2005) Understanding the odd science of aging. Cell 120:437–447

    Article  CAS  PubMed  Google Scholar 

  • Kramer JH, Mungas D, Reed BR, Wetzel ME, Burnett MM et al (2007) Longitudinal MRI and cognitive change in healthy elderly. Neuropsychology 21:412

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee Y-S, Silva AJ (2009) The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 10:126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lepping P, Huber M (2010) Role of zinc in the pathogenesis of attention-deficit hyperactivity disorder. CNS Drugs 24:721–728

    CAS  PubMed  Google Scholar 

  • Levenson C, Tassabehji N (2007) Role and regulation of copper and zinc transport proteins in the central nervous system. In: Handbook of neurochemistry and molecular neurobiology. Springer, New York, pp 257–284

    Chapter  Google Scholar 

  • Levenson JM, O'Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279:40545–40559

    Article  CAS  PubMed  Google Scholar 

  • Linkous DH, Flinn JM, Koh JY, Lanzirotti A, Bertsch PM et al (2008) Evidence that the ZNT3 protein controls the total amount of elemental zinc in synaptic vesicles. J Histochem Cytochem 56:3–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lunenfeld B (2008) An Aging World – demographics and challenges. Gynecol Endocrinol 24:1–3

    Google Scholar 

  • Madden DJ, Spaniol J, Costello MC, Bucur B, White LE et al (2008) Cerebral white matter integrity mediates adult age differences in cognitive performance. J Cogn Neurosci 21:289–302

    Article  Google Scholar 

  • Maggio M, Dall’Aglio E, Lauretani F, Cattabiani C, Ceresini G et al (2012) The hormonal pathway to cognitive impairment in older men. J Nutr Health Aging 16:40–54

    Article  CAS  PubMed  Google Scholar 

  • Mather M (2006) Why memories may become more positive as people age. Blackwell Publishing, Malden

    Book  Google Scholar 

  • McQuail JA, Frazier CJ, Bizon JL (2015) Molecular aspects of age-related cognitive decline: the role of GABA signaling. Trends Mol Med 21:450–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meijer WA, de Groot RH, van Gerven PW, van Boxtel MP, Jolles J (2009) Level of processing and reaction time in young and middle-aged adults and the effect of education. Eur J Cogn Psychol 21:216–234

    Article  Google Scholar 

  • Meunier D, Stamatakis EA, Tyler LK (2014) Age-related functional reorganization, structural changes, and preserved cognition. Neurobiol Aging 35:42–54

    Article  PubMed  Google Scholar 

  • Mocchegiani E, Costarelli L, Giacconi R, Cipriano C, Muti E et al (2006) Zinc homeostasis in aging: two elusive faces of the same “metal”. Rejuvenation Res 9:351–354

    Article  CAS  PubMed  Google Scholar 

  • Morisson JH, Baxter MG (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240

    Article  CAS  Google Scholar 

  • Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A et al (2013) The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev 12:661–684

    Article  CAS  PubMed  Google Scholar 

  • Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301–334

    Article  CAS  PubMed  Google Scholar 

  • Palmiter RD, Cole TB, Quaife CJ, Findley SD (1996) ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci 93:14934–14939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paoletti P, Vergnano A, Barbour B, Casado M (2009) Zinc at glutamatergic synapses. Neuroscience 158:126–136

    Article  CAS  PubMed  Google Scholar 

  • Park DC, Polk TA, Park R, Minear M, Savage A, Smith MR (2004) Aging reduces neural specialization in ventral visual cortex. Proc Natl Acad Sci U S A 101:13091–13095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756

    Article  CAS  PubMed  Google Scholar 

  • Peters R (2006) Ageing and the brain. Postgrad Med J 82:84–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petralia RS, Mattson MP, Yao PJ (2014) Communication breakdown: the impact of ageing on synapse structure. Ageing Res Rev 14:31–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR et al (2007) Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29:125–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR et al (2008) Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med 148:427–434

    Article  PubMed  PubMed Central  Google Scholar 

  • Portbury SD, Adlard PA (2017) Zinc signal in brain diseases. Int J Mol Sci 18:2506

    Article  PubMed Central  CAS  Google Scholar 

  • Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991

    Article  CAS  PubMed  Google Scholar 

  • Reuter-Lorenz PA (2002) New visions of the aging mind and brain. Trends Cogn Sci 6:394–400

    Article  PubMed  Google Scholar 

  • Robertson DA, Savva GM, Kenny RA (2013) Frailty and cognitive impairment—a review of the evidence and causal mechanisms. Ageing Res Rev 12:840–851

    Article  PubMed  Google Scholar 

  • Rocha TJ, Blehm CJ, Bamberg DP, Fonseca TLR, Tisser LA et al (2014) The effects of interactions between selenium and zinc serum concentration and SEP15 and SLC30A3 gene polymorphisms on memory scores in a population of mature and elderly adults. Genes Nutr 9:377

    Article  PubMed  CAS  Google Scholar 

  • Rogalski E, Stebbins G, Barnes C, Murphy C, Stoub T et al (2012) Age-related changes in parahippocampal white matter integrity: a diffusion tensor imaging study. Neuropsychologia 50:1759–1765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rozycka A, Liguz-Lecznar M (2017) The space where aging acts: focus on the GABAergic synapse. Aging Cell 16(4):634–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saito T, Takahashi K, Nakagawa N, Hosokawa T, Kurasaki M et al (2000) Deficiencies of hippocampal Zn and ZnT3 accelerate brain aging of Rat. Biochem Biophys Res Commun 279:505–511

    Article  CAS  PubMed  Google Scholar 

  • Salthouse TA (2011) Neuroanatomical substrates of age-related cognitive decline. Psychol Bull 137:753

    Article  PubMed  PubMed Central  Google Scholar 

  • Scarr E, Udawela M, Greenough MA, Neo J, Seo MS et al (2016) Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia. NPJ Schizophrenia 2:16002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shing YL, Rodrigue KM, Kennedy KM, Fandakova Y, Bodammer N et al (2011) Hippocampal subfield volumes: age, vascular risk, and correlation with associative memory. Front Aging Neurosci 3:2

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith TD, Adams MM, Gallagher M, Morrison JH, Rapp PR (2000) Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J Neurosci 20:6587–6593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stanley EM, Fadel JR, Mott DD (2012) Interneuron loss reduces dendritic inhibition and GABA release in hippocampus of aged rats. Neurobiol Aging 33:431. e1–31. e13

    Article  PubMed  CAS  Google Scholar 

  • Takahashi S, Takahashi I, Sato H, Kubota Y, Yoshida S, Muramatsu Y (2001) Age-related changes in the concentrations of major and trace elements in the brain of rats and mice. Biol Trace Elem Res 80:145–158

    Article  CAS  PubMed  Google Scholar 

  • United Nations, Department of Economic and Social Affairs, Population Division (2017) World population prospects: the 2017 revision, key findings and advance tables. Working Paper No. ESA/P/WP/248

    Google Scholar 

  • VanGuilder H, Freeman W (2011) The hippocampal neuroproteome with aging and cognitive decline: past progress and future directions. Front Aging Neurosci 3:8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vincent GK, Velkoff VA (2010) The next four decades: the older population in the United States: 2010 to 2050. US Department of Commerce, Economics and Statistics Administration, US Census Bureau

    Google Scholar 

  • Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE (2010) High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic mild cognitive impairment. NeuroImage 51:1242–1252

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul A. Adlard .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Juan, S.M.A., Adlard, P.A. (2019). Ageing and Cognition. In: Harris, J., Korolchuk, V. (eds) Biochemistry and Cell Biology of Ageing: Part II Clinical Science. Subcellular Biochemistry, vol 91. Springer, Singapore. https://doi.org/10.1007/978-981-13-3681-2_5

Download citation

Publish with us

Policies and ethics