CoChat
Sign Up
Cited by 1,323Genetics, Aging, and Longevity in Model OrganismsDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Neural mechanisms of ageing and cognitive decline

Open access
Bishop, Nicholas A., Lu, Tao, Yankner, Bruce A.·2010·Nature
DOI 10.1038/nature08983PMC PMC2927852
Open this paper in CoChat — free account

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that brain ageing and cognitive decline are linked to conserved longevity pathways, including mitochondrial function, oxidative stress, autophagy, insulin/IGF signalling, TOR signalling, and sirtuins. It also proposes that the brain may coordinate systemic ageing, while noting that the causal role of these pathways in human neurodegeneration remains unresolved.

Key findings

  • Normal human brain ageing involves less coordinated activity across interacting brain regions and less localized prefrontal activation; delocalization may be compensatory and is associated with better cognitive performance in some older adults. GABA-related inhibitory neurotransmission genes are downregulated in aged human and macaque prefrontal cortex.
  • Conserved ageing signatures include reduced mitochondrial gene expression and increased stress-response gene expression. Apolipoprotein D is the most conserved age-upregulated gene in the cortex of mice, macaques, and humans, but more than 150 genes change with age in all three species, and many neuronal genes increase in mice while decreasing in humans.
  • Caloric restriction extends lifespan in many species, including rhesus macaques, and a three-month caloric restriction in healthy older humans improved verbal memory by approximately 20%. Reduced insulin/IGF signalling, TOR inhibition with rapamycin, and increased autophagy can extend lifespan and reduce neurodegeneration in model organisms.
  • Alzheimer’s disease affects almost 50% of US adults over age 85. Normal ageing and Alzheimer’s disease may be distinguished by metabolic changes in the hippocampal subiculum and dentate gyrus versus the entorhinal cortex, and by patterns of neuronal loss.

Methods

  • Review article synthesizing molecular ageing studies in yeast, worms, flies, mice, rats, macaques, and humans, together with human functional brain imaging and gene expression profiling.
  • No primary experiments, sample, or statistical analysis are reported; the conclusions are a narrative synthesis of published work.

Limitations

  • Stated in the paper: the role of conserved ageing pathways in the onset and progression of human neurodegenerative disorders is still unclear; sirtuin contributions to caloric restriction are controversial and context-dependent; and the mechanisms of lifespan extension in some models are not fully understood.
  • Evident from the text: as a review, it provides no new data and relies heavily on model organisms, so human causal evidence remains limited and future clinical interventions are needed to test these pathways.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nature08983

Cites

102 of 102 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 122 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Expression of BECN1, as well as a number of other key genes in the autophagic pathway, declines with ageing in the human brain.

    “Expression of BECN1, as well as a number of other key genes in the autophagic pathway, declines with ageing in the human brain (T.L. and B.A.Y., unpublished observations), potentially increasing neuronal vulnerability to the toxic effects of protein aggregates.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The higher-order systems biology of the brain is significantly altered by normal ageing in the absence of disease.

    “These observations suggest that the higher-order systems biology of the brain is significantly altered by normal ageing in the absence of disease.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Reduced coordination of brain activity is associated with poor performance in several cognitive domains.

    “Importantly, this reduced coordination of brain activity is associated with poor performance in several cognitive domains (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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. source

      Not checked in the free run.

  • Premisecitation

    Neural activity becomes less localized in some brain regions, particularly the prefrontal cortex, in response to executive level tasks.

    “In addition to being less integrated, neural activity also becomes less localized in some brain regions, particularly the prefrontal cortex, in response to executive level tasks (3,4).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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. source

      Not checked in the free run.

    • cites [4] Park, D. C. & Reuter- Lorenz, P. The adaptive brain: aging and neurocognitive scaffolding. Annu. Rev. Psychol. 60, 173–196 (2009). source

      Not checked in the free run.

  • Premisecitation

    Gene expression profiling studies of ageing mouse, rat, monkey and human brains have shown significant changes in the expression of synaptic genes.

    “Gene expression profiling studies of ageing mouse, rat, monkey and human brains have shown significant changes in the expression of synaptic genes (7–13).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [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. source

      Not checked in the free run.

    • cites [8] Lee, C. K., Weindruch, R. & Prolla, T. A. Gene-expression profile of the ageing brain in mice. Nature Genet. 25, 294–297 (2000). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

    • cites [13] Loerch, P. M. et al. Evolution of the aging brain transcriptome and synaptic regulation. PLoS ONE 3, e3329 (2008). source

      Not checked in the free run.

  • May combine two claims. 23
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Premisecitation

    Aged individuals who exhibit delocalized activity show better cognitive performance than aged individuals with more localized activity, consistent with the idea that delocalization may be a compensatory response.

    “Aged individuals who exhibit delocalized activity show better cognitive performance than aged individuals with more localized activity, consistent with the idea that delocalization may be a compensatory response (3,5).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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. source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increased neural activity in the prefrontal cortex of aged individuals may initially be compensatory but could predispose the individuals to excitotoxicity and neurodegenerative pathology.

    “This may contribute to increased neural activity in the prefrontal cortex of aged individuals, a systems-level change that may initially be compensatory but could predispose the individuals to excitotoxicity and neurodegenerative pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mice that have been engineered to accumulate mitochondrial DNA mutations at an elevated rate show reduced electron transport chain function, signs of accelerated ageing and shortened lifespan.

    “Mice that have been engineered to accumulate mitochondrial DNA mutations at an elevated rate show reduced electron transport chain function, signs of accelerated ageing and shortened lifespan (28,29).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004). source

      Not checked in the free run.

    • cites [29] Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Normal ageing is associated with reduced metabolic activity in the subiculum and the dentate gyrus, whereas reduced activity in the entorhinal cortex may be an early indicator of Alzheimer's disease.

    “Normal ageing is associated with reduced metabolic activity in the subiculum and the dentate gyrus, whereas reduced activity in the entorhinal cortex may be an early indicator of Alzheimer’s disease (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A modest reduction in electron transport chain activity can increase lifespan, whereas a more severe reduction shortens it.

    “This effect seems to be crucially dose dependent, because a modest reduction in electron transport chain activity can increase lifespan, whereas a more severe reduction shortens it (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial function seems to be an important modulating influence on the ageing process in all species tested, and it can have either positive or negative effects on lifespan, depending on the context.

    “Mitochondrial function seems to be an important modulating influence on the ageing process in all species tested, and it can have either positive or negative effects on lifespan, depending on the context (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Sedensky, M. M. & Morgan, P. G. Mitochondrial respiration and reactive oxygen species in mitochondrial aging mutants. Exp. Gerontol. 41, 237–245 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apolipoprotein D expression extends lifespan in Drosophila, and the protein functions as a lipid antioxidant conferring resistance to oxidative stress.

    “Apo lipoprotein D expression extends lifespan in Drosophila, and the protein functions as a lipid antioxidant conferring resistance to oxidative stress (23,24).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In flies, increasing autophagy in neurons alone is sufficient to extend lifespan, and reducing autophagy shortens lifespan and gives rise to neurodegeneration.

    “In flies, increasing autophagy in neurons alone is sufficient to extend lifespan (52), and reducing autophagy shortens lifespan and gives rise to neurodegeneration (52,53).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Given that human brain ageing is accompanied by memory loss and reduced synaptic connectivity, but not significantly by neuronal loss, it is probable that loss of the ability to access stored memories underlies age-dependent memory deficits.

    “Given that human brain ageing is accompanied by memory loss and reduced synaptic connectivity, but not significantly by neuronal loss, it is probable that loss of the ability to access stored memories underlies age-dependent memory deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Caloric restriction was found to reduce amyloid-β deposition and improve learning and memory in transgenic mouse models of Alzheimer's disease.

    “There is also evidence that caloric restriction may confer resistance to Alzheimer’s-disease-type pathology: caloric restriction was found to reduce amyloid-β deposition and improve learning and memory in transgenic mouse models of Alzheimer’s disease (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The signalling pathway of the kinase TOR is a central regulator of protein homeostasis that acts to inhibit autophagy and messenger RNA translation.

    “The signalling pathway of the kinase TOR is a central regulator of protein homeostasis that acts to inhibit autophagy and messenger RNA translation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Schieke, S. M. & Finkel, T. Mitochondrial signaling, TOR, and life span. Biol. Chem. 387, 1357–1361 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caloric restriction prevents many age-dependent gene expression changes in the mouse brain, reduces age-related brain atrophy in rhesus macaques, and has significant beneficial effects on the age-dependent impairment of learning and memory in rodents and humans.

    “It prevents many age-dependent gene expression changes in the mouse brain (8,43), reduces age-related brain atrophy in rhesus macaques (75) and has significant beneficial effects on the age-dependent impairment of learning and memory in rodents (76,77) and humans (78).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [8] Lee, C. K., Weindruch, R. & Prolla, T. A. Gene-expression profile of the ageing brain in mice. Nature Genet. 25, 294–297 (2000). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

    • cites [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. source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Environmental enrichment promoted the recovery of lost memories, which was accompanied by increased synaptic plasticity and the induction of activating histone acetylation marks.

    “Environmental enrichment promoted the recovery of lost memories, which was accompanied by increased synaptic plasticity and the induction of activating histone acetylation marks.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A transient period of p25 expression in the adult mouse resulted in some degree of neurodegeneration and synapse loss in the hippocampus, together with memory loss.

    “A transient period of p25 expression in the adult mouse resulted in some degree of neurodegeneration and synapse loss in the hippocampus, together with memory loss (49).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sirtuins' involvement in caloric restriction is debated and depends on context, differing between yeast genetic backgrounds and mouse tissues.

    “It is important to note, however, that the potential roles of sirtuins in caloric restriction are controversial and context dependent (see page 480), differing markedly across genetic backgrounds in yeast (85) and tissue types in mice (86).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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). source

      Not checked in the free run.

    • cites [86] Chen, D. et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 22, 1753–1757 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SIR2, an NAD+-dependent deacetylase, was among the first genes linked to the response to caloric restriction, initially in yeast.

    “The NAD+-dependent deacetylase SIR2 was one of the earliest genes to be implicated in the response to caloric restriction, initially in a yeast model (81).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    This may partly reflect gene expression changes affecting synaptic function, axonal integrity and myelination.

    “This may reflect, in part, gene expression changes that affect synaptic function, axonal integrity and myelination.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    This loss of integration might lead to age-related physiological changes like hypertension and insulin resistance, and increase susceptibility to pathological brain changes with age.

    “Such a loss of integrated function may contribute to age-related physiological changes, such as hypertension and insulin resistance, and predispose individuals to age-related pathological changes in the brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The ASI neurons regulate energy metabolism in C. elegans and may therefore be a functional analogue of the mammalian hypothalamus.

    “Interestingly, the ASI neurons regulate energy metabolism in C. elegans and may thus represent a functional analogue of the mammalian hypothalamus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SIRT1 protects against amyloid-β toxicity in cell culture and against neurodegeneration in the p25/CDK5 mouse model, which mimics aspects of Alzheimer's disease pathology and tauopathy.

    “SIRT1 also protects against amyloid-β toxicity in cell culture and neurodegeneration in the p25/CDK5 mouse model, which recapitulates aspects of Alzheimer’s disease pathology and tauopathy (88).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic or severe stress can cause excessive glucocorticoid production, which may harm hippocampal neurons and make the organism more susceptible to neurodegeneration, potentially breaking the regulatory circuit between hippocampus and hypothalamus.

    “However, excessive glucocorticoid production associated with chronic or severe stress may impair hippocampal neuronal function and predispose the organism to neurodegeneration (96), potentially disrupting the regulatory circuit that connects the hippocampus and the hypothalamus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Conrad, C. D. Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis. Rev. Neurosci. 19, 395–411 (2008). source

      Not checked in the free run.

    • Rests on an assumption: The hippocampus directly senses glucocorticoids and then suppresses hypothalamic stimulation of further glucocorticoid release through a negative feedback loop.

  • May combine two claims.

    Premisecitation

    The lifespan increase depended on SKN-1 activity specifically in ASI neurons; SKN-1 is a transcription factor homologous to mammalian NFE2L2 and is known to activate defences against oxidative and xenobiotic stress.

    “Lifespan extension required ASI-neuron-specific activity of the transcription factor SKN-1, a homologue of the mammalian NF-E2 related factor (NFE2L2), with known functions in activating cellular defences against oxidative and xenobiotic stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Evolutionarily conserved ageing-control pathways, including insulin/IGF signalling and mitochondrial function, can influence pathology and cognitive decline in mouse, fly and worm models of Alzheimer's disease and other neurodegenerative disorders.

    “Conserved pathways and mechanisms that control organismal ageing, such as insulin/IGF signalling and mitochondrial function, can modulate pathology and cognitive decline in mouse, fly and worm models of Alzheimer’s disease and other neurodegenerative disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ablating specific neurons can increase lifespan in worms and flies.

    “Furthermore, ablation of specific neurons can increase lifespan in worms (91) and flies (67).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Alcedo, J. & Kenyon, C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41, 45–55 (2004). source

      Not checked in the free run.

    • cites [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). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Recent findings suggest that higher-order brain systems become less efficient with age, with some disconnection between brain areas that normally function together in young adults.

    “Recent findings suggest that higher-order brain systems become less efficient with age, with some degree of disconnection between brain areas that normally function together in young adults.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sirt1 knockout mice show less oxidative stress and more neuroprotection in the ageing brain, yet their lifespan is shortened.

    “By contrast, SIRT1 may also have some detrimental effects, as Sirt1 knockout mice show reduced oxidative stress and increased neuroprotection in the ageing brain even though lifespan is shortened (89).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Whether these conserved pathways contribute to the onset and progression of neurodegenerative disorders in humans is still uncertain.

    “However, the role of these conserved pathways in the onset and progression of neurodegenerative disorders in humans is still unclear.”
    Quote in the paperSubstantial claim
27 of 27

  • The paper relies on this without support.

    Age itself is the greatest risk factor for cognitive decline and Alzheimer's disease in older adults.

    “The greatest risk factor for cognitive decline and Alzheimer’s disease in older adults is age itself.”

  • The paper relies on this without support.

    The prevalence of cognitive decline and dementia has increased as life expectancy has increased.

    “As the life expectancy of the population has increased, so too has the prevalence of cognitive decline and dementia, largely in the form of Alzheimer’s disease, which now affects almost 50% of adults over the age of 85 in the United States (1).”

  • The paper relies on this without support.

    The hypothalamus acts as a central regulator of metabolism and energy use, coordinating whole-organism physiological responses via hormonal signalling.

    “The hypothalamus functions as a central regulator of metabolism and energy use, and it coordinates the physiological responses of the entire organism through hormonal signalling.”

  • The paper relies on this without support.

    The hippocampus directly senses glucocorticoids and then suppresses hypothalamic stimulation of further glucocorticoid release through a negative feedback loop.

    “Glucocorticoids can be sensed directly by another part of the brain, the hippocampus, which then suppresses hypothalamic stimulation of further glucocorticoid release in a negative feedback loop (Fig. 4).”

  • The paper relies on this without support.

    Ageing of the brain is the major risk factor for neurodegeneration and cognitive decline.

    “The major risk factor for neurodegeneration and cognitive decline is the ageing of the brain.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Decreased cognitive performance begins around midlife from 45 years and increases with age due to structural and functional brain changes.

    “The decreased cognitive performance begins around midlife from 45 years [173] and increases with age due to structural and functional changes in the brain (for instance, regional brain volumes and integrity of the white matter, reduction in the fluidity of brain membranes, and changes in lipid composition) [163,174,175,176].”

    From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [174]

  • Genome wide expression profiling studies have identified several genes and biological pathways affected by aging.

    “Genome wide expression profiling studies have identified several genes and biological pathways affected by aging (Bishop et al. 2010, Lopez-Otin et al. 2013, Kenyon 2010, Yankner et al. 2008).”

    From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as Bishop et al. 2010

  • The hypothalamo-pituitary axis connects brain and endocrine function and regulates metabolism and energy through homeostatic hormones.

    “The brain and endocrine system are intrinsically linked through the hypothalamo-pituitary axis, which controls metabolism and energy use via the signaling action of a series of homeostatic hormones (23).”

    From Frailty in elderly people (2013) · cites this paper as [23]

  • Most cortical areas lose few individual neurons, yet metabolically demanding cells like hippocampal pyramidal neurons may suffer disproportionately from changes in synapses, protein transport and mitochondria.

    “The loss of individual neurons in the majority of cortical regions is minimal (23), but neurons with high metabolic demands, for example the hippocampal pyramidal neurons, may be disproportionally affected by altered synaptic function, protein transport and mitochondrial function (23).”

    From Frailty in elderly people (2013) · cites this paper as [23]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Bishop, N. A., Lu, T., & Yankner, B. A.
Affiliations
Harvard University (US)
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2010-03-24
Volume
464
Issue
7288
Pages
529-535
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature08983
PMC
PMC2927852
OpenAlex
W1992842030
Cited by
1,323
References
102
Citations by year
2026: 41 · 2025: 75 · 2024: 64 · 2023: 77 · 2022: 91 · 2021: 107 · 2020: 98 · 2019: 89 · 2018: 98 · 2017: 92 · 2016: 62 · 2015: 91 · 2014: 68 · 2013: 76 · 2012: 81
FWCI
7.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Ellison Medical Foundation
  • Glenn Foundation for Medical Research
  • National Institutes of Health
  • National Institute on Aging (R01AG027040, P01AG027916, RC1AG036106, DP1AG044161, R01AG026651)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
brain aging, cognitive decline, Alzheimer's disease, model organisms
MeSH terms
Aging, Animals, Autophagy, Brain, Cognition Disorders, Humans, Insulin, Insulin-Like Growth Factor I, Mitochondria, Signal Transduction, Oxidative Stress, Epigenesis, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review