Abstract
Successful ageing is determined in part by genetic background, but also by experiential factors associated with lifestyle and culture. Dietary, behavioural and pharmacological interventions have been identified as potential means to slow brain ageing and forestall neurodegenerative disease. Many of these interventions recruit adaptive cellular stress responses to strengthen neuronal networks and enhance plasticity. In this Science and Society article, we describe several determinants of healthy and pathological brain ageing, with insights into how these processes are accelerated or prevented. We also describe the mechanisms underlying the neuroprotective actions of exercise and nutritional interventions, with the goal of recruiting these molecular targets for the treatment and prevention of neurodegenerative disease.
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References
Behl, C. Oestrogen as a neuroprotective hormone. Nature Rev. Neurosci. 3, 433–442 (2002).
Burns, J. M., Johnson, D. K., Watts, A., Swerdlow, R. H. & Brooks, W. M. Reduced lean mass in early Alzheimer disease and its association with brain atrophy. Arch. Neurol. 67, 428–433 (2010).
Stone, A. A., Schwartz, J. E., Broderick, J. E. & Deaton, A. A snapshot of the age distribution of psychological well-being in the United States. Proc. Natl Acad. Sci. USA 107, 9985–9990 (2010).
Albert, M. S. The ageing brain: normal and abnormal memory. Phil. Trans. R. Soc. Lond. B 352, 1703–1709 (1997).
Gallagher, M., Burwell, R. & Burchinal, M. Severity of spatial learning impairment in ageing: development of a learning index for performance in the Morris water maze. Behav. Neurosci. 107, 618–626 (1993).
Robitsek, R. J., Fortin, N. J., Koh, M. T., Gallagher, M. & Eichenbaum, H. Cognitive ageing: a common decline of episodic recollection and spatial memory in rats. J. Neurosci. 28, 8945–8954 (2008).
Zyzak, D. R., Otto, T., Eichenbaum, H. & Gallagher, M. Cognitive decline associated with normal ageing in rats: a neuropsychological approach. Learn. Mem. 2, 1–16 (1995).
Mattson, M. P. & Magnus, T. Ageing and neuronal vulnerability. Nature Rev. Neurosci. 7, 278–294 (2006).
Floyd, R. A. & Hensley, K. Oxidative stress in brain ageing. Implications for therapeutics of neurodegenerative diseases. Neurobiol. Ageing 23, 795–807 (2002).
Dei, R. et al. Lipid peroxidation and advanced glycation end products in the brain in normal ageing and in Alzheimer's disease. Acta Neuropathol. 104, 113–122 (2002).
Lovell, M. A., Ehmann, W. D., Mattson, M. P. & Markesbery, W. R. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease. Neurobiol. Ageing 18, 457–461 (1997).
Nicolle, M. M. et al. Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents. Neuroscience 107, 415–431 (2001).
Mattson, M. P. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci. 21, 53–57 (1998).
Guo, Q. et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nature Med. 5, 101–106 (1999).
Mattson, M. P. Roles of the lipid peroxidation product 4-hydroxynonenal in obesity, the metabolic syndrome, and associated vascular and neurodegenerative disorders. Exp. Gerontol. 44, 625–633 (2009).
Kapogiannis, D. & Mattson, M. P. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 10, 187–198 (2011).
Mattson, M. P., Gleichmann, M. & Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron 60, 748–766 (2008).
Gibson, G. E., Starkov, A., Blass, J. P., Ratan, R. R. & Beal, M. F. Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim. Biophys. Acta 1802, 122–134 (2010).
Hyun, D. H., Emerson, S. S., Jo, D. G., Mattson, M. P. & de Cabo, R. Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during ageing. Proc. Natl Acad. Sci. USA 103, 19908–19912 (2006).
Weissman, L. et al. Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. Nucleic Acids Res. 35, 5545–5555 (2007).
Wong, E. & Cuervo, A. M. Autophagy gone awry in neurodegenerative diseases. Nature Neurosci. 13, 805–811 (2010).
Naidoo, N., Ferber, M., Master, M., Zhu, Y. & Pack, A. I. Ageing impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J. Neurosci. 28, 6539–6548 (2008).
Bingol, B. & Sheng, M. Deconstruction for reconstruction: the role of proteolysis in neural plasticity and disease. Neuron 69, 22–32 (2011).
Gleichmann, M., Chow, V. W. & Mattson, M. P. Homeostatic disinhibition in the ageing brain and Alzheimer's disease. J. Alzheimers Dis. 24, 15–24 (2011).
Stranahan, A. M. & Mattson, M. P. Impact of energy intake and expenditure on neuronal plasticity. Neuromolecular Med. 10, 209–218 (2008).
Stranahan, A. M. et al. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nature Neurosci. 11, 309–317 (2008).
Kanoski, S. E., Zhang, Y., Zheng, W. & Davidson, T. L. The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J. Alzheimers Dis. 21, 207–219 (2010).
Inui, A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nature Rev. Neurosci. 2, 551–560 (2001).
Diano, S. et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neurosci. 9, 381–388 (2006).
Johansson, I. et al. Proliferative and protective effects of growth hormone secretagogues on adult rat hippocampal progenitor cells. Endocrinology 149, 2191–2199 (2008).
Debette, S. et al. Midlife vascular risk factor exposure accelerates structural brain ageing and cognitive decline. Neurology 77, 461–468 (2011).
Sturman, M. T. et al. Body mass index and cognitive decline in a biracial community population. Neurology 70, 360–367 (2008).
Molteni, R., Barnard, R. J., Ying, Z., Roberts, C. K. & Gómez-Pinilla, F. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112, 803–814 (2002).
Stranahan, A. M. et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 18, 1085–1088 (2008).
McNay, E. C. et al. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol. Learn. Mem. 93, 546–553 (2010).
Morrison, C. D. et al. High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J. Neurochem. 114, 1581–1589 (2010).
Greenwood, C. E. & Winocur, G. Learning and memory impairment in rats fed a high saturated fat diet. Behav. Neural. Biol. 53, 74–87 (1990).
Kanoski, S. E., Meisel, R. L, Mullins, A. J. & Davidson, T. L. The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat. Behav. Brain Res. 182, 57–66 (2007).
Mielke, J. G. et al. Longitudinal study of the effects of a high-fat diet on glucose regulation, hippocampal function, and cerebral insulin sensitivity in C57BL/6 mice. Behav. Brain Res. 175, 374–382 (2006).
Goodrick, C. L. Effects of lifelong restricted feeding on complex maze performance in rats. Age 7, 1–2 (1984).
Fontán-Lozano, A. et al. Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor. J. Neurosci. 27, 10185–10195 (2007).
Lee, J., Duan, W. & Mattson, M. P. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 82, 1367–1375 (2002).
Halagappa, V. K. et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease. Neurobiol. Dis. 26, 212–220 (2007).
Wu, P. et al. Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice. Neurobiol. Ageing 29, 1502–1511 (2008).
Duan, W. & Mattson, M. P. Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J. Neurosci. Res. 57, 195–206 (1999).
Maswood, N. et al. Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc. Natl Acad. Sci. USA 101, 18171–18176 (2004).
Duan, W. et al. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc. Natl Acad. Sci. USA 100, 2911–2916 (2003).
Mattson, M. P. Hormesis defined. Ageing Res. Rev. 7, 1–7 (2008).
Arumugam, T. V. et al. Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann. Neurol. 67, 41–52 (2010).
Yang, J. L., Tadokoro, T., Keijzers, G., Mattson, M. P. & Bohr, V. A. Neurons efficiently repair glutamate-induced oxidative DNA damage by a process involving CREB-mediated up-regulation of apurinic endonuclease 1. J. Biol. Chem. 285, 28191–28199 (2010).
Son, T. G., Camandola, S. & Mattson, M. P. Hormetic dietary phytochemicals. Neuromolecular Med. 10, 236–246 (2008).
Kanoski, S. E. & Davidson, T. L. Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol. Behav. 103, 59–68 (2011).
Parachikova, A., Green, K. N., Hendrix, C. & LaFerla, F. M. Formulation of a medical food cocktail for Alzheimer's disease: beneficial effects on cognition and neuropathology in a mouse model of the disease. PLoS ONE 5, e14015 (2010).
Kruman, I. I. et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J. Neurosci. 22, 1752–1762 (2002).
Karuppagounder, S. S. et al. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model. Neurobiol. Ageing 30, 1587–1600 (2009).
Ma, Q. L. et al. β-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J. Neurosci. 29, 9078–9089 (2009).
Obregon, D. F. et al. ADAM10 activation is required for green tea (–)-epigallocatechin-3-gallate-induced α-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 281, 16419–16427 (2006).
Son, T. G. et al. Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia. J. Neurochem. 112, 1316–1326 (2010).
Vingtdeux, V. et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J. Biol. Chem. 285, 9100–9113 (2010).
Park, S. S. et al. Cortical gene transcription response patterns to water maze training in aged mice. BMC Neurosci. 12, 63 (2011).
Stranahan, A. M. et al. Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice. Neurobiol. Ageing 31, 1937–1949 (2010).
Garcia, C., Chen, M. J., Garza, A. A., Cotman, C. W. & Russo-Neustadt, A. The influence of specific noradrenergic and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts following voluntary physical activity. Neuroscience 119, 721–732 (2003).
Heneka, M. T. et al. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J. Neurosci. 26, 1343–1354 (2006).
Barrientos, R. M. et al. Little exercise, big effects: reversing ageing and infection-induced memory deficits, and underlying processes. J. Neurosci. 31, 11578–11586 (2011).
Lazarov, O., Mattson, M. P., Peterson, D. A., Pimplikar, S. W. & van Praag, H. When neurogenesis encounters ageing and disease. Trends Neurosci. 33, 569–579 (2010).
Bremner, J. D. Stress and brain atrophy. CNS Neurol. Disord. Drug Targets. 5, 503–512 (2006).
Stranahan, A. M., Khalil, D. & Gould, E. Social isolation delays the positive effects of running on adult neurogenesis. Nature Neurosci. 9, 526–533 (2006).
Rothman, S. M. et al. 3xTgAD mice exhibit altered behavior and elevated Aβ after chronic mild social stress. Neurobiol. Ageing 19 Aug 2011 (doi:10.1016/j.neurobiolaging.2011.07.005).
Lindvall, O. & Kokaia, Z. Stem cells in human neurodegenerative disorders — time for clinical translation? J. Clin. Invest. 120, 29–40 (2010).
Olanow, C. W., Kordower, J. H., Lang, A. E. & Obeso, J. A. Dopaminergic transplantation for Parkinson's disease: current status and future prospects. Ann. Neurol. 66, 591–596 (2009).
Hargus, G. et al. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc. Natl Acad. Sci. USA 107, 15921–15926 (2010).
Nagahara, A. H. & Tuszynski, M. H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nature Rev. Drug Discov. 10, 209–219 (2011).
Moloney, A. M. et al. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Ageing 31, 224–243 (2010).
Massa, S. M. et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J. Clin. Invest. 120, 1774–1785 (2010).
Harvey, J. Leptin regulation of neuronal excitability and cognitive function. Curr. Opin. Pharmacol. 7, 643–647 (2007).
Mirescu, C. & Gould, E. Stress and adult neurogenesis. Hippocampus 16, 233–238 (2006).
Mattson, M. P., Perry, T. & Greig, N. H. Learning from the gut. Nature Med. 9, 1113–1115 (2003).
Stranahan, A. M. et al. Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus 19, 951–961 (2009).
Witte, A. V., Fobker, M., Gellner, R., Knecht, S. & Flöel, A. Caloric restriction improves memory in elderly humans. Proc. Natl Acad. Sci. USA 106, 1255–1260 (2009).
Porter, D. W., Kerr, B. D., Flatt, P. R., Holscher, C. & Gault, V. A. Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance. Diabetes Obes. Metab. 12, 891–899 (2010).
Calabrese, E. J. et al. Biological stress response terminology: integrating the concepts of adaptive response and preconditioning stress within a hormetic dose–response framework. Toxicol. Appl. Pharmacol. 222, 122–128 (2007).
Xu, X. et al. Gene expression atlas of the mouse central nervous system: impact and interactions of age, energy intake and gender. Genome Biol. 8, R234 (2007).
Calabrese, V., Cornelius, C., Dinkova-Kostova, A. T., Calabrese, E. J. & Mattson, M. P. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox Signal. 13, 1763–1811 (2010).
Kraft, A. D., Johnson, D. A. & Johnson, J. A. Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J. Neurosci. 24, 1101–1112 (2004).
Kim, S. J. et al. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J. Biol. Chem. 283, 14497–14505 (2008).
Spencer, J. P. The impact of fruit flavonoids on memory and cognition. Br. J. Nutr. 104 (Suppl. 3), 40–47 (2010).
Roriz-Cruz, M. et al. Cognitive impairment and frontal-subcortical geriatric syndrome are associated with metabolic syndrome in a stroke-free population. Neurobiol. Ageing 28, 1723–1736 (2007).
Gunstad, J. et al. Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr. Psychiatry 48, 57–61 (2007).
van den Berg, E., Biessels, G. J., de Craen, A. J., Gussekloo, J. & Westendorp, R. G. The metabolic syndrome is associated with decelerated cognitive decline in the oldest old. Neurology 69, 979–985 (2007).
Li, Y., Dai, Q., Jackson, J. C. & Zhang, J. Overweight is associated with decreased cognitive functioning among school-age children and adolescents. Obesity (Silver Spring) 16, 1809–1815 (2008).
Huizinga, M. M., Beech, B. M., Cavanaugh, K. L., Elasy, T. A. & Rothman, R. L. Low numeracy skills are associated with higher BMI. Obesity (Silver Spring) 16, 1966–1968 (2008).
Sabia, S., Kivimaki, M., Shipley, M. J., Marmot, M. G. & Singh-Manoux, A. Body mass index over the adult life course and cognition in late midlife: the Whitehall II Cohort Study. Am. J. Clin. Nutr. 89, 601–607 (2009).
Volkow, N. D. et al. Inverse association between BMI and prefrontal metabolic activity in healthy adults. Obesity (Silver Spring) 17, 60–65 (2009).
Fergenbaum, J. H. et al. Obesity and lowered cognitive performance in a Canadian First Nations population. Obesity (Silver Spring) 17, 1957–1963 (2009).
Granholm, A. C. et al. Effects of a saturated fat and high cholesterol diet on memory and hippocampal morphology in the middle-aged rat. J. Alzheimers Dis. 14, 133–145 (2008).
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This work was supported by the Intramural Research Program of the National Institute on Aging.
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Stranahan, A., Mattson, M. Recruiting adaptive cellular stress responses for successful brain ageing. Nat Rev Neurosci 13, 209–216 (2012). https://doi.org/10.1038/nrn3151
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DOI: https://doi.org/10.1038/nrn3151
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