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Neural mechanisms of ageing and cognitive decline

Abstract

During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.

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Figure 1: Altered functional activation of brain systems during brain ageing.
Figure 2: Evolutionary changes in gene regulation in the brain during ageing.
Figure 3: Conserved pathways that regulate organismal and brain ageing.
Figure 4: The brain as a potential regulator of organismal ageing.

References

  1. 1

    Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A. & Evans, D. A. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol. 60, 1119–1122 (2003).

    PubMed  Google Scholar 

  2. 2

    Andrews-Hanna, J. R. et al. Disruption of large-scale brain systems in advanced aging. Neuron 56, 924–935 (2007). This paper reports that coordination of brain activity between different brain regions becomes less robust in the ageing brain, suggesting a systems-level breakdown of integrated function that correlates with poor cognitive performance.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Cabeza, R. Hemispheric asymmetry reduction in older adults: the HAROLD model. Psychol. Aging 17, 85–100 (2002). This paper shows that spreading activation of the human prefrontal cortex from one hemisphere to both hemispheres may be a compensatory mechanism that preserves function against age-related degenerative changes.

    PubMed  Google Scholar 

  4. 4

    Park, D. C. & Reuter- Lorenz, P. The adaptive brain: aging and neurocognitive scaffolding. Annu. Rev. Psychol. 60, 173–196 (2009).

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Cabeza, R., Anderson, N. D., Locantore, J. K. & McIntosh, A. R. Aging gracefully: compensatory brain activity in high-performing older adults. Neuroimage 17, 1394–1402 (2002).

    PubMed  Google Scholar 

  6. 6

    Yankner, B. A., Lu, T. & Loerch, P. The aging brain. Annu. Rev. Pathol. 3, 41–66 (2008).

    CAS  Google Scholar 

  7. 7

    Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004). This paper shows that the ageing of the human cortex is characterized by a distinct transcriptional signature that includes reduced expression of genes that mediate synaptic plasticity and that correlates with age-dependent DNA damage to the promoters of these genes.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Lee, C. K., Weindruch, R. & Prolla, T. A. Gene-expression profile of the ageing brain in mice. Nature Genet. 25, 294–297 (2000).

    CAS  PubMed  Google Scholar 

  9. 9

    Jiang, C. H., Tsien, J. Z., Schultz, P. G. & Hu, Y. The effects of aging on gene expression in the hypothalamus and cortex of mice. Proc. Natl Acad. Sci. USA 98, 1930–1934 (2001).

    ADS  CAS  PubMed  Google Scholar 

  10. 10

    Blalock, E. M. et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J. Neurosci. 23, 3807–3819 (2003).

    CAS  PubMed  Google Scholar 

  11. 11

    Fraser, H. B., Khaitovich, P., Plotkin, J. B., Paabo, S. & Eisen, M. B. Aging and gene expression in the primate brain. PLoS Biol. 3, e274 (2005).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Erraji-Benchekroun, L. et al. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol. Psychiatry 57, 549–558 (2005).

    CAS  PubMed  Google Scholar 

  13. 13

    Loerch, P. M. et al. Evolution of the aging brain transcriptome and synaptic regulation. PLoS ONE 3, e3329 (2008).

    ADS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Small, S. A., Tsai, W. Y., DeLaPaz, R., Mayeux, R. & Stern, Y. Imaging hippocampal function across the human life span: is memory decline normal or not? Ann. Neurol. 51, 290–295 (2002).

    PubMed  Google Scholar 

  15. 15

    West, M. J., Coleman, P. D., Flood, D. G. & Troncoso, J. C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 344, 769–772 (1994).

    CAS  PubMed  Google Scholar 

  16. 16

    Price, J. L. et al. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol. 58, 1395–1402 (2001).

    CAS  PubMed  Google Scholar 

  17. 17

    Gomez- Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491–4500 (1996).

    Google Scholar 

  18. 18

    Rodrigue, K. M. & Raz, N. Shrinkage of the entorhinal cortex over five years predicts memory performance in healthy adults. J. Neurosci. 24, 956–963 (2004).

    CAS  PubMed  Google Scholar 

  19. 19

    Zahn, J. M. et al. AGEMAP: a gene expression database for aging in mice. PLoS Genet. 3, e201 (2007).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Blalock, E. M. et al. Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc. Natl Acad. Sci. USA 101, 2173–2178 (2004).

    ADS  CAS  PubMed  Google Scholar 

  21. 21

    Liang, W. S. et al. Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc. Natl Acad. Sci. USA 105, 4441–4446 (2008).

    ADS  CAS  PubMed  Google Scholar 

  22. 22

    Miller, J. A., Oldham, M. C. & Geschwind, D. H. A systems level analysis of transcriptional changes in Alzheimer's disease and normal aging. J. Neurosci. 28, 1410–1420 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Walker, D. W., Muffat, J., Rundel, C. & Benzer, S. Overexpression of a Drosophila homolog of apolipoprotein D leads to increased stress resistance and extended lifespan. Curr. Biol. 16, 674–679 (2006).

    CAS  PubMed  Google Scholar 

  24. 24

    Sanchez, D. et al. Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila . Curr. Biol. 16, 680–686 (2006).

    CAS  PubMed  Google Scholar 

  25. 25

    Kalman, J., McConathy, W., Araoz, C., Kasa, P. & Lacko, A. G. Apolipoprotein D in the aging brain and in Alzheimer's dementia. Neurol. Res. 22, 330–336 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Sedensky, M. M. & Morgan, P. G. Mitochondrial respiration and reactive oxygen species in mitochondrial aging mutants. Exp. Gerontol. 41, 237–245 (2006).

    CAS  PubMed  Google Scholar 

  27. 27

    Rea, S. L., Ventura, N. & Johnson, T. E. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans . PLoS Biol. 5, e259 (2007).

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    ADS  CAS  PubMed  Google Scholar 

  29. 29

    Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    ADS  CAS  Google Scholar 

  30. 30

    Schriner, S. E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lin, S. J. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002).

    ADS  CAS  PubMed  Google Scholar 

  32. 32

    Wallace, D. C. et al. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55, 601–610 (1988).

    CAS  PubMed  Google Scholar 

  33. 33

    Holt, I. J., Harding, A. E. & Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717–719 (1988).

    ADS  CAS  Google Scholar 

  34. 34

    Sanchez-Blanco, A., Fridell, Y. W. & Helfand, S. L. Involvement of Drosophila uncoupling protein 5 in metabolism and aging. Genetics 172, 1699–1710 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Branicky, R., Bénard, C. & Hekimi, S. clk-1, mitochondria, and physiological rates. BioEssays 22, 48–56 (2000).

    CAS  PubMed  Google Scholar 

  36. 36

    Lee, S. S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nature Genet. 33, 40–48 (2003).

    CAS  Google Scholar 

  37. 37

    Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002). This paper provided the first systematic demonstration of a role for the electron transport chain in metazoan lifespan control, through RNAi-mediated knockdown of several of the chain's components.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Cristina, D., Cary, M., Lunceford, A., Clarke, C. & Kenyon, C. A. Regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans. PLoS Genet. 5, e1000450 (2009).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598 (2009).

    CAS  Google Scholar 

  40. 40

    Liu, X. et al. Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev. 19, 2424–2434 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Dell'agnello, C. et al. Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444 (2007).

    CAS  PubMed  Google Scholar 

  42. 42

    Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. & Van Remmen, H. Trends in oxidative aging theories. Free Radic. Biol. Med. 43, 477–503 (2007).

    CAS  PubMed  Google Scholar 

  43. 43

    Park, S.-K. et al. Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants. Aging Cell 8, 484–495 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Liu, J. et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-α-lipoic acid. Proc. Natl Acad. Sci. USA 99, 2356–2361 (2002). This paper reports that memory loss in aged rats can be reversed by restoring mitochondrial function with dietary mitochondrial substrates and antioxidants.

    ADS  CAS  PubMed  Google Scholar 

  45. 45

    Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    O' Hagan, H. M., Mohammad, H. P. & Baylin, S. B. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet. 4, e1000155 (2008).

    Google Scholar 

  47. 47

    Guarente, L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 14, 1021–1026 (2000).

    CAS  PubMed  Google Scholar 

  48. 48

    Curran, S. P. & Ruvkun, G. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet. 3, e56 (2007).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L. H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007). This paper shows that memory loss may be related to altered chromatin structure in a mouse model of neurodegeneration and can be reversed in part with histone deacetylase inhibitors. This raises the possibility of epigenetic approaches to the treatment of human neurodegenerative disorders.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans . Science 301, 1387–1391 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans . PLoS Genet. 4, e24 (2008).

    PubMed  PubMed Central  Google Scholar 

  52. 52

    Simonsen, A. et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila . Autophagy 4, 176–184 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Juhasz, G., Erdi, B., Sass, M. & Neufeld, T. P. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila . Genes Dev. 21, 3061–3066 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    ADS  CAS  PubMed  Google Scholar 

  55. 55

    Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006). References 54 and 55 describe mouse models deficient in key autophagy regulatory genes that demonstrate the essential role of autophagy in protection against age-related neurodegeneration and protein aggregation.

    ADS  CAS  PubMed  Google Scholar 

  56. 56

    Shibata, M. et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474–14485 (2006).

    CAS  PubMed  Google Scholar 

  57. 57

    Schieke, S. M. & Finkel, T. Mitochondrial signaling, TOR, and life span. Biol. Chem. 387, 1357–1361 (2006).

    CAS  PubMed  Google Scholar 

  58. 58

    Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004).

    CAS  Google Scholar 

  60. 60

    Fischer, D. F. et al. Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol. Aging 30, 847–863 (2009).

    CAS  PubMed  Google Scholar 

  61. 61

    Broughton, S. & Partridge, L. Insulin/IGF-like signalling, the central nervous system and aging. Biochem. J. 418, 1–12 (2009).

    CAS  PubMed  Google Scholar 

  62. 62

    Flachsbart, F. et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA 106, 2700–2705 (2009).

    ADS  CAS  PubMed  Google Scholar 

  63. 63

    Suh, Y. et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl Acad. Sci. USA 105, 3438–3442 (2008).

    ADS  CAS  Google Scholar 

  64. 64

    Willcox, B. J. et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13987–13992 (2008).

    ADS  CAS  PubMed  Google Scholar 

  65. 65

    Libina, N., Berman, J. R. & Kenyon, C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489–502 (2003).

    CAS  PubMed  Google Scholar 

  66. 66

    Iser, W. B., Gami, M. S. & Wolkow, C. A. Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs. Dev. Biol. 303, 434–447 (2007).

    CAS  PubMed  Google Scholar 

  67. 67

    Broughton, S. J. et al. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc. Natl Acad. Sci. USA 102, 3105–3110 (2005).

    ADS  CAS  PubMed  Google Scholar 

  68. 68

    van der Heide, L. P., Ramakers, G. M. J. & Smidt, M. P. Insulin signaling in the central nervous system: learning to survive. Prog. Neurobiol. 79, 205–221 (2006).

    PubMed  Google Scholar 

  69. 69

    Taguchi, A., Wartschow, L. M. & White, M. F. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369–372 (2007).

    ADS  CAS  PubMed  Google Scholar 

  70. 70

    Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006).

    ADS  CAS  PubMed  Google Scholar 

  71. 71

    Freude, S. et al. Neuronal IGF-1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J. 23, 3315–3324 (2009).

    CAS  PubMed  Google Scholar 

  72. 72

    Cohen, E. et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157–1169 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    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. Aging 31, 224–243 (2008).

    Google Scholar 

  74. 74

    Haigis, M. C. & Guarente, L. P. Mammalian sirtuins — emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009). This paper reports that caloric restriction increases longevity in primates, delays the onset of age-related diseases and reduces age-related brain atrophy.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Ingram, D. K., Weindruch, R., Spangler, E. L., Freeman, J. R. & Walford, R. L. Dietary restriction benefits learning and motor performance of aged mice. J. Gerontol. 42, 78–81 (1987).

    CAS  PubMed  Google Scholar 

  77. 77

    Stewart, J., Mitchell, J. & Kalant, N. The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes. Neurobiol. Aging 10, 669–675 (1989).

    CAS  PubMed  Google Scholar 

  78. 78

    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).

    ADS  CAS  PubMed  Google Scholar 

  79. 79

    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).

    CAS  PubMed  Google Scholar 

  80. 80

    Mair, W. & Dillin, A. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727–754 (2008).

    CAS  Google Scholar 

  81. 81

    Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae . Science 289, 2126–2128 (2000).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Rogina, B. & Helfand, S. L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl Acad. Sci. USA 101, 15998–16003 (2004).

    ADS  CAS  PubMed  Google Scholar 

  83. 83

    Boily, G. et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3, e1759 (2008).

    ADS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Chen, D., Steele, A. D., Lindquist, S. & Guarente, L. Increase in activity during calorie restriction requires Sirt1. Science 310, 1641 (2005).

    CAS  PubMed  Google Scholar 

  85. 85

    Kaeberlein, M., Kirkland, K. T., Fields, S. & Kennedy, B. K. Sir2-independent life span extension by calorie restriction in yeast. PLoS. Biol. 2, e296 (2004).

    PubMed  PubMed Central  Google Scholar 

  86. 86

    Chen, D. et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 22, 1753–1757 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Araki, T., Sasaki, Y. & Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010–1013 (2004).

    ADS  CAS  PubMed  Google Scholar 

  88. 88

    Kim, D. et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 8, 38–48 (2008).

    PubMed  PubMed Central  Google Scholar 

  90. 90

    Apfeld, J. & Kenyon, C. Regulation of lifespan by sensory perception in Caenorhabditis elegans . Nature 402, 804–809 (1999).

    ADS  CAS  PubMed  Google Scholar 

  91. 91

    Alcedo, J. & Kenyon, C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41, 45–55 (2004).

    CAS  PubMed  Google Scholar 

  92. 92

    Bishop, N. A. & Guarente, L. Two neurons mediate diet-restriction-induced longevity in C. elegans . Nature 447, 545–549 (2007). This paper demonstrates the essential role of two C. elegans neurons in coordinating the organismal response to caloric restriction and argues for a central role of the nervous system in this form of increased longevity.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Flurkey, K., Papaconstantinou, J., Miller, R. A. & Harrison, D. E. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA 98, 6736–6741 (2001).

    ADS  CAS  Google Scholar 

  94. 94

    Conti, B. et al. Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825–828 (2006).

    ADS  CAS  PubMed  Google Scholar 

  95. 95

    Jankord, R. & Herman, J. P. Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann. NY Acad. Sci. 1148, 64–73 (2008).

    ADS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Conrad, C. D. Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis. Rev. Neurosci. 19, 395–411 (2008).

    PubMed  PubMed Central  Google Scholar 

  97. 97

    Bao, A. M., Meynen, G. & Swaab, D. F. The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res. Rev. 57, 531–553 (2008).

    CAS  PubMed  Google Scholar 

  98. 98

    Zahn, J. M. et al. Transcriptional profiling of aging in human muscle reveals a common aging signature. PLoS Genet. 2, e115 (2006).

    PubMed  PubMed Central  Google Scholar 

  99. 99

    Rodwell, G. E. et al. A transcriptional profile of aging in the human kidney. PLoS Biol. 2, e427 (2004).

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Maalouf, M., Rho, J. M. & Mattson, M. P. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res. Rev. 59, 293–315 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We apologize for the many studies and references that could not be included owing to space limitations. Our work is supported by the National Institute on Aging of the US National Institutes of Health, the Ellison Medical Foundation and the Glenn Foundation for Medical Research.

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Reprints and permissions information is available at http://www.nature.com/reprints. The authors declare no competing financial interests. Correspondence should be addressed to B.A.Y. (bruce_yankner@hms.harvard.edu).

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Bishop, N., Lu, T. & Yankner, B. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010). https://doi.org/10.1038/nature08983

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