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Cited by 398Neuroinflammation and Neurodegeneration MechanismsGenetics, Aging, and Longevity in Model OrganismsTryptophan and brain disorders

Microglia Priming with Aging and Stress

Open access
Niraula, Anzela, Sheridan, John F, Godbout, Jonathan P·2017·Neuropsychopharmacology
DOI 10.1038/npp.2016.185PMC PMC5143497
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Abstract

The population of aged individuals is increasing worldwide and this has significant health and socio-economic implications. Clinical and experimental studies on aging have discovered myriad changes in the brain, including reduced neurogenesis, increased synaptic aberrations, higher metabolic stress, and augmented inflammation. In rodent models of aging, these alterations are associated with cognitive decline, neurobehavioral deficits, and increased reactivity to immune challenges. In rodents, caloric restriction and young blood-induced revitalization reverses the behavioral effects of aging. The increased inflammation in the aged brain is attributed, in part, to the resident population of microglia. For example, microglia of the aged brain are marked by dystrophic morphology, elevated expression of inflammatory markers, and diminished expression of neuroprotective factors. Importantly, the heightened inflammatory profile of microglia in aging is associated with a 'sensitized' or 'primed' phenotype. Mounting evidence points to a causal link between the primed profile of the aged brain and vulnerability to secondary insults, including infections and psychological stress. Conversely, psychological stress may also induce aging-like sensitization of microglia and increase reactivity to secondary challenges. This review delves into the characteristics of neuroinflammatory signaling and microglial sensitization in aging, its implications in psychological stress, and interventions that reverse aging-associated deficits.

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TL;DR

This review proposes that aging and chronic psychological stress converge on a primed/sensitized microglial phenotype that exaggerates neuroinflammatory responses to secondary immune challenges. It also summarizes evidence that young blood, caloric restriction, and exercise can reverse aging-associated neuroimmune and behavioral deficits.

Key findings

  • Aged microglia adopt a primed phenotype marked by dystrophic morphology, elevated MHCII/TLRs/pro-inflammatory cytokines, reduced CX3CR1/CD200R regulatory signaling, impaired mobility, and deficient phagocytosis; microglia number increased by 65% between 3 and 27 months, aged microglia internalized 53% fewer amyloid beta plaques, and hippocampal microglia showed a 30% decline in overall gene expression between 4 and 22 months.
  • Primed microglia produce exaggerated inflammatory responses to immune challenges such as LPS, surgery, and stress; in aged rodents this is linked to prolonged sickness and depressive-like behavior, while minocycline or IL-1 receptor antagonist can reduce these effects.
  • Psychological stress can induce aging-like microglial sensitization: repeated social defeat causes primed microglia, exaggerated IL-1β/TNFα/iNOS/CD14 responses to LPS, and re-establishment of anxiety; chronic stress is also associated with accelerated epigenetic aging and shortened telomeres.
  • Interventions that attenuate aging-associated inflammation—young blood/parabiosis, caloric restriction, and exercise—reverse aspects of aging; caloric restriction in rhesus monkeys was associated with 80% vs 50% survival, 30% caloric restriction for 3 months improved memory by 20% in elderly females, and exercise prevented microglia priming in aged rats.

Methods

  • Narrative review; no primary data are reported. It synthesizes clinical and experimental studies on normal aging, neuroimmune dysregulation, microglial priming, psychological stress, and interventions.
  • Evidence includes human neuroimaging, postmortem histology, CSF/plasma markers, TSPO PET, transcriptomic studies, and rodent models (mice, rats, monkeys).
  • Main analysis is qualitative integration of findings, with figures summarizing the proposed bidirectional aging–stress relationship and reversal of aging-associated deficits via immune alterations.

Limitations

  • The paper states that normal aging lacks a consensus definition, cross-sectional studies may overestimate age-associated cognitive decline, rodent strains and sexes vary substantially in aging and lifespan, TSPO PET findings have methodological and interpretive variability, and the paradox of microglial priming/proliferation alongside senescence remains unclear.
  • The paper also notes inconsistent findings, such as baseline IL-1β being elevated in some aged rodent strains but not others.
  • Evident from the text: as a narrative review, it does not describe a systematic search or quantitative synthesis, and many mechanistic conclusions rely on animal models whose translational relevance to humans is not fully established.

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Integrity signals

Registry

Crossref · 10.1038/npp.2016.185

Cites

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Statistics

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Claims the paper makes

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  • Premisenone given

    The increased inflammation in the aged brain is attributed, in part, to the resident population of microglia.

    “The increased inflammation in the aged brain is attributed, in part, to the resident population of microglia.”
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  • Premisenone given

    The heightened inflammatory profile of microglia in aging is associated with a 'sensitized' or 'primed' phenotype.

    “Importantly, the heightened inflammatory profile of microglia in aging is associated with a 'sensitized' or 'primed' phenotype.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Mounting evidence points to a causal link between the primed profile of the aged brain and vulnerability to secondary insults, including infections and psychological stress.

    “Mounting evidence points to a causal link between the primed profile of the aged brain and vulnerability to secondary insults, including infections and psychological stress.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Cross-sectional analysis overestimated age-associated cognitive decline compared with longitudinal design.

    “For instance, in comparison with longitudinal design, cross-sectional analysis was found to overestimate age-associated cognitive decline (Singh-Manoux et al, 2012).”
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    Life events associated with psychological stress and injury can lead to accelerated aging-associated impairments and dementia.

    “Conversely, life events associated with psychological stress and injury can also lead to accelerated aging-associated impairments and dementia (Epel et al, 2004;Smith et al, 2013).”
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    Aging is a significant risk factor for functional decline, affective impairments, exaggerated response to illnesses, dementia, and overall vulnerability for diseases.

    “Although aging is not a disease, it is a significant risk factor for functional decline, affective impairments, exaggerated response to illnesses, dementia, and overall vulnerability for diseases (Hayflick, 2007;Seals and Melov, 2014).”
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    Clinical and experimental studies on aging have discovered myriad changes in the brain, including reduced neurogenesis, increased synaptic aberrations, higher metabolic stress, and augmented inflammation.

    “Clinical and experimental studies on aging have discovered myriad changes in the brain, including reduced neurogenesis, increased synaptic aberrations, higher metabolic stress, and augmented inflammation.”
    Quote in the paperSubstantial claim

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    Premisenone given

    Microglia of the aged brain are marked by dystrophic morphology, elevated expression of inflammatory markers, and diminished expression of neuroprotective factors.

    “For example, microglia of the aged brain are marked by dystrophic morphology, elevated expression of inflammatory markers, and diminished expression of neuroprotective factors.”
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    Premisenone given

    In rodent models of aging, alterations such as reduced neurogenesis, synaptic aberrations, metabolic stress, and inflammation are associated with cognitive decline, neurobehavioral deficits, and increased reactivity to immune challenges.

    “In rodent models of aging, these alterations are associated with cognitive decline, neurobehavioral deficits, and increased reactivity to immune challenges.”
    Quote in the paperSubstantial claim

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    In humans, the distinguishing criteria for normal versus pathological aging are CNS injury, amyloid plaques, neurodegeneration, neuropsychiatric conditions, dementia, and impaired performance on cognitive tests.

    “In humans, the distinguishing criteria for normal vs pathological aging are: central nervous system (CNS) injury, amyloid plaques (based on positron emission tomography (PET)), neurodegeneration, neuropsychiatric conditions, dementia, and impaired performance on cognitive tests (Arani et al, 2015;Fabbri et al, 2016;Tegeler et al, 2016).”
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    New neurons were generated at a rate of 1.75% during adulthood with a modest but significant decline with old age.

    “New neurons were generated at a rate of 1.75% during adulthood with a modest but significant decline with old age.”
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    Aging-associated neuroanatomical changes revealed sexual dimorphism in that males were likely to undergo greater reduction in brain elasticity and stiffness than their female counterparts.

    “Aging-associated neuroanatomical changes also revealed sexual dimorphism in that males were likely to undergo greater reduction in brain elasticity and stiffness than their female counterparts (Arani et al, 2015;Sack et al, 2009).”
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    Neuroimaging studies have confirmed volumetric changes in brain regions of the elderly.

    “Neuroimaging studies have confirmed volumetric changes in brain regions of the elderly (Storsve et al, 2014;Zhang et al, 2016).”
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    Increased number of monocytes, neutrophils, and elevated levels of circulating cytokines have been consistently reported in elderly individuals.

    “For example, increased number of monocytes, neutrophils, and elevated levels of circulating cytokines have been consistently reported in elderly individuals (Leng et al, 2005;Roubenoff et al, 1998;Tan et al, 2007).”
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    Aging-associated immune senescence impairs the ability to fight infections and produce antibodies critical for the efficacy of vaccines.

    “These changes are attributed to aging-associated immune senescence that impairs the ability to fight infections and produce antibodies critical for the efficacy of vaccines (Grubeck-Loebenstein et al, 2009).”
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    Although aging itself is not associated with decline in affective functioning, aged individuals, compared with the young, are more vulnerable to depressive symptoms associated with physical illnesses and life events.

    “Although aging itself is not associated with decline in affective functioning, aged individuals, compared with the young, are more vulnerable to depressive symptoms associated with physical illnesses, and life events (English and Carstensen, 2015;Fiske et al, 2009Fiske et al, , 2013)).”
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    The term 'inflamm-aging' describes the heightened inflammatory status characteristic of the aging process and is attributed to cumulative exposure to antigens and stress.

    “Indeed, the term 'inflamm-aging' has been coined to describe the heightened inflammatory status that is characteristic of the aging process and is attributed to cumulative exposure to antigens and stress (Franceschi et al, 2000).”
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    Microglia originate from yolk sac-derived myeloid progenitors and take up residence in the brain during embryogenesis.

    “During embryogenesis, microglia originate from yolk sac-derived myeloid progenitors and take up residence in the brain (Kierdorf et al, 2012).”
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    Under homeostatic conditions, microglia display a ramified phenotype, marked by numerous processes.

    “Under homeostatic conditions, microglia display a ramified phenotype, marked by numerous processes.”
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    In response to inflammatory insult, microglia undergo morphological alterations, marked by shorter, thicker processes and enhanced expression of inflammatory markers.

    “In response to inflammatory insult, these cells undergo morphological alterations, marked by shorter, thicker processes and enhanced expression of inflammatory markers (Streit et al, 1999).”
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    Microglia are dynamic players in synaptic pruning, maintaining homeostasis, and are primary responders to insult and injury in the CNS.

    “Although initially considered 'quiescent' cells primarily responsible for clearing cellular debris in the brain, microglia are now known as dynamic players in synaptic pruning, maintaining homeostasis and are primary responders to insult and injury in the CNS (Lou et al, 2016;Nimmerjahn et al, 2005;Paolicelli et al, 2011).”
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    Some PET studies have shown increased TSPO ligand-binding activity in the brains of older adults, while other studies did not.

    “Although some PET studies have shown increased TSPO ligand-binding activity in the brains of older adults, other studies did not (Suridjan et al, 2014).”
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    A longevity study performed on 19 strains of specific-pathogen-free mice and rats showed marked differences in lifespan ranging from 312 to 782 days within the mouse strains.

    “For example, a longevity study performed on 19 strains of specificpathogen-free mice and rats showed marked differences in lifespan ranging from 312 to 782 days within the mouse strains (Festing and Blackmore, 1971).”
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    Rodents serve as the most popular animal models owing to their shorter life span, manipulability, convenience, and relative similarities to aging in humans.

    “In particular, rodents serve as the most popular animal models owing to their shorter life span, manipulability, convenience, and relative similarities to aging in humans.”
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    • Rests on an assumption: Animal models, particularly rodents, recapitulate the neurological, inflammatory, and behavioral correlates of human aging sufficiently to support inferences about human aging.

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    An extensive longitudinal and cross-sectional study conducted on 30 most commonly used strains of inbred mice showed strain and sex differences in lifespan, physiological, and histopathological changes.

    “In an extensive longitudinal and crosssectional study conducted on 30 most commonly used strains of inbred mice, the authors showed strain and sex differences in lifespan, physiological, and histopathological changes (Sundberg et al, 2011).”
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    The average lifespan curve for mice is consistent with that of humans, indicating similar patterns of decline in health span between the two species.

    “For instance, the average lifespan curve for mice (Mus musculus) is consistent with that of humans, indicating similar patterns of decline in health span between the two species (Mitchell et al, 2015).”
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    Sex was a strong determinant of lifespan, as females outlived the males in 14 out of the 19 strains, although no significant difference was detected in the remaining 5 strains.

    “Moreover, sex was a strong determinant of lifespan, as females outlived the males in 14 out of the 19 strains, although no significant difference was detected in the remaining 5 strains (Festing and Blackmore, 1971).”
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    Use of higher-affinity TSPO ligands increased vascular binding, in turn masking ligand binding in the microglia.

    “For example, use of higher-affinity TSPO ligands increased vascular binding, in turn masking ligand binding in the microglia (Rizzo et al, 2014).”
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    Animal models have played a significant role in recapitulating the neurological, inflammatory and behavioral correlates of human aging.

    “Animal models have played a significant role in recapitulating the neurological, inflammatory and behavioral correlates of human aging.”
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    TSPO is a peripheral benzodiazepine receptor expressed on the outer mitochondrial layer of microglia, and is believed to be upregulated during microglial activation.

    “TSPO is a peripheral benzodiazepine receptor expressed on the outer mitochondrial layer of microglia, and is believed to be upregulated during microglial activation (Rupprecht et al, 2010).”
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    Elevated IL-1β was reported in some studies and not others; aged Wistar and Fisher 344 rats were reported to show elevated brain IL-1β, whereas other strains did not exhibit increased baseline levels of brain IL-1β.

    “For instance, aged (~22 month old) Wistar and Fisher 344 rats (Gemma et al, 2005;Lynch, 1999) were reported to show elevated brain IL-1β, whereas (23-26 month old) Fisher 344 × BN F1 and Fisher 344 rats (Barrientos et al, 2009;Gee, Ding, and Keller, 2006) and (18-22 month old) BALB/c and C57BL/6 mice did not exhibit increased baseline levels of brain IL-1β (Hascup et al, 2016;Huang et al, 2008;Wyn”
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    The primed profile associated with microglia in aging does not refer to an enhanced immune response at baseline, rather it refers to an exaggerated inflammatory response to an immune challenge/stimulus.

    “Nevertheless, it is important to note that the primed profile associated with microglia in aging does not refer to an enhanced immune response at baseline, rather it refers to an exaggerated inflammatory response to an immune challenge/stimulus (Cunningham et al, 2005).”
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    Intraventricular administration of IL-1β was sufficient to induce lipid peroxidation in adult rats, highlighting the causal relationship between inflammatory signaling and metabolic stress.

    “Furthermore, intraventricular administration of IL-1β was sufficient to induce lipid peroxidation in adult rats, highlighting the causal relationship between inflammatory signaling and metabolic stress, the two major characteristics of aging (Giulian et al, 1986).”
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    Interpretationreasoning

    Although rodents serve as an important model for studying aging, the variability in the models demands critical consideration.

    “Therefore, it is important to note that although rodents serve as an important model for studying aging, the variability in the models demands critical consideration.”
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    Microglia depletion in hippocampal culture from aged mice, but not from young mice, promoted formation of neurospheres, suggesting an anti-neurogenic role of microglia in the aged brain.

    “For instance, microglia depletion in hippocampal culture from aged mice, but not from young mice, promoted formation of neurospheres (indicative of neural progenitor cell proliferation), suggesting an anti-neurogenic role of microglia in the aged brain (Vukovic et al, 2012).”
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    Aged mice showed deficits in neurogenesis and memory, corresponding with clinical findings in the human elderly.

    “Corresponding with clinical findings in the human elderly, aged mice showed deficits in neurogenesis and memory (van Praag et al, 2005).”
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    In a neurodegenerative model of ME7 prion disease mice, microglia displayed an ameboid, deramified morphology, distinct from the ramified microglia in the control mice; this morphological alteration was associated with a greater increase in brain IL-1β following LPS injections in the ME7 mice compared with the saline control.

    “Similarly, in a neurodegenerative model of ME7 prion disease mice, microglia displayed an ameboid, deramified morphology, distinct from the ramified microglia in the control mice.This morphological alteration was associated with a greater increase in brain IL-1β following LPS injections in the ME7 mice, compared with the saline control (Cunningham et al, 2005).”
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    The exaggerated expression of cytokines in the aged mice was associated with prolonged sickness and depressive-like behavior.

    “This exaggerated expression of cytokines in the aged mice was associated with the prolonged sickness (Godbout et al, 2005) and depressive-like behavior (Godbout et al, 2008).”
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    Interpretationreasoning

    Central inflammatory signaling in the aged brain can be comprehended in twofolds: microglia take on a primed phenotype as a function of aging, and exhibit an exaggerated inflammatory response when triggered by an immune challenge.

    “Taken together, central inflammatory signaling in the aged brain can be comprehended in twofolds: (i) microglia take on a primed phenotype as a function of aging, (ii) and exhibit an exaggerated inflammatory response when triggered by an immune challenge (Figure 1).”
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    Aged but not young adult rats displayed memory impairments and elevated hippocampal IL-1β levels 4 days after laparotomy.

    “In rodent models, aged but not young adult rats displayed memory impairments and elevated hippocampal IL-1β levels 4 days after laparotomy (Barrientos et al, 2012).”
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    Intracisternal IL-1 receptor antagonist attenuated the laparotomy-induced hippocampal IL-1β and reversed memory deficits.

    “Moreover, intracisternal IL-1 receptor antagonist attenuated the laparotomy-induced hippocampal IL-1β and reversed memory deficits, further highlighting the exaggerated neuroinflammatory response to a peripheral challenge (Barrientos et al, 2012).”
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    LPS-induced increase in brain IL-1β was associated with reduced locomotor activity in the ME7 mice, indicating that microglial priming in the prion disease model induces exaggerated immune response as well as sickness behavior.

    “LPS-induced increase in brain IL-1β was also associated with reduced locomotor activity in the ME7 mice, indicating that microglial priming in the prion disease model induces exaggerated immune response as well as sickness behavior (Combrinck et al, 2002).”
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    Minocycline reduced LPS-induced augmentation of inflammatory mediators, such as IL-1β, indoleamine 2,3 dioxygenase and TLR2, indicating that the neuroinflammatory response and sickness behavior following LPS is mediated by microglial activation.

    “In addition, minocycline, a tetracycline antibiotic with anti-inflammatory actions on microglia, reduced LPS-induced augmentation of inflammatory mediators, such as IL-1β, indoleamine 2,3 dioxygenase and TLR2, indicating that the neuroinflammatory response and sickness behavior following LPS is mediated by microglial activation (Henry et al, 2008).”
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    Microglia of the aged brain also show deficient phagocytic activity and impaired mobility under baseline.

    “Microglia of the aged brain also show deficient phagocytic activity and impaired mobility under baseline (Damani et al, 2011).”
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    Associated with these morphological alterations are biochemical changes, such as elevated expression of antigen presentation molecules (MHCII), Toll-like receptors, pro-inflammatory cytokines (IL-1β), reduced expression of regulatory molecules (CX3CR1 and CD200R), DNA methylation changes and telomere shortening.

    “Associated with these morphological alterations are biochemical changes, such as elevated expression of antigen presentation molecules (MHCII), Toll-like receptors, pro-inflammatory cytokines (IL-1β), reduced expression of regulatory molecules (CX3CR1 and CD200R) (Frank et al, 2006;Maher et al, 2004), DNA methylation changes and telomere shortening (Flanary and Streit, 2003;Zannas et al, 2015).”
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    Primed microglia are vulnerable to subsequent immune stimuli, such as immune challenge, stress, and aging; upon exposure to these stimuli, the primed microglia take on a 'hyperactive' state marked by exaggerated pro-inflammatory response and resistance to regulation.

    “Primed microglia are vulnerable to subsequent immune stimuli, such as immune challenge, stress, and aging.As such, upon exposure to these stimuli, the primed microglia take on a 'hyperactive' state marked by exaggerated pro-inflammatory response and resistance to regulation”
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    A series of studies using a ME7 prion disease model showed dystrophic morphology of microglia and enhanced expression of inflammatory mediators such as IL-1β and COX-2 following in vivo LPS challenge; the exaggerated inflammatory changes in ME7 mice were also associated with impairments in spatial learning.

    “A series of studies using a ME7 prion disease model showed dystrophic morphology of microglia and enhanced expression of inflammatory mediators such as IL-1β and COX-2 following in vivo LPS challenge.The exaggerated inflammatory changes in ME7 mice were also associated with impairments in spatial learning (Cunningham et al, 2009).”
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    Acute challenge, such as Escherichia coli in aged rats, induced exaggerated neuroinflammatory response and memory impairments that were completely resolved by 14 days.

    “Acute challenge, such as Escherichia coli in aged rats (discussed above) induced exaggerated neuroinflammatory response and memory impairments that were completely resolved by 14 days (Barrientos et al, 2009).”
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    Microglia under normal aging showed upregulation of genes associated with antigen presentation, such as MHCII, CD86, and CIITA, and suppression of anti-inflammatory genes, such as IL-10 and CD200.

    “Microglia under normal aging (ie, aging in absence of neurodegeneration) showed upregulation of genes associated with antigen presentation, such as MHCII, CD86, and CIITA (Frank et al, 2006;Godbout et al, 2005;VanGuilder et al, 2011), and suppression of anti-inflammatory genes, such as IL-10 and CD200 (Frank et al, 2006).”
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    Premisecitation

    Microglia from the aged brain internalized 53% fewer amyloid beta plaques compared with the young brain, suggesting inefficient phagocytosis in aged microglia.

    “Furthermore, compared with the young brain, microglia from the aged brain were found to internalize 53% fewer amyloid beta plaques, suggesting inefficient phagocytosis in aged microglia (Njie et al, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Njie et al, 2012 source

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  • May combine two claims.

    Premisecitation

    In response to in vivo focal laser injury, microglia from both young and aged mice accumulated around the injury site 4 days post injury; however, microglia in the young mice, but not in the aged, showed disaggregation at 16 days post injury, suggesting prolonged accumulation of the aged microglia and impaired ability for disaggregation.

    “In response to in vivo focal laser injury, microglia from both young and aged mice accumulated around the injury site 4 days post injury.However, microglia in the young mice, but not in the aged showed disaggregation at 16 days post injury, suggesting prolonged accumulation of the aged microglia and impaired ability for disaggregation (Damani et al, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Damani et al, 2011 source

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  • May combine two claims.

    Premisecitation

    Although microglia from young mice responded to extracellular ATP by extension of old processes and formation of new, aged microglia were found to withdraw and even eliminate their existing processes.

    “For example, although microglia from young mice responded to extracellular ATP by extension of old processes and formation of new, aged microglia were found to withdraw and even eliminate their existing processes (Damani et al, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Damani et al, 2011 source

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  • May combine two claims.

    Interpretationreasoning

    Aging-associated changes vary across brain regions and sexes; these changes are associated with an overall increase in neuroinflammatory signaling that can be attributed to the primed profile of microglia.

    “Together, these findings indicate aging-associated changes that vary across brain regions and sexes.Furthermore, these changes are associated with an overall increase in neuroinflammatory signaling that can be attributed to the primed profile of microglia.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Neuronal signals regulating microglial activation have been categorized as Off signals and On signals; Off signals are constitutively expressed signals (such as CX3CL1 and CD200) that maintain homeostatic functions of microglia, whereas On signals are inducible signals (such as ATP and TREM2 ligand) that trigger pro- and anti-inflammatory activation in microglia.

    “Neuronal signals regulating microglial activation have been categorized as Off signals and On signals.The former refer to constitutively expressed signals (such as, CX3CL1 and CD200) that maintain the homeostatic functions of microglia, whereas the latter refer to inducible signals (such as, ATP and TREM2 ligand) that trigger pro-and anti-inflammatory activation in microglia (Biber et al, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Biber et al, 2007 source

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  • May combine two claims.

    Premisecitation

    Aging induced an overall increase in the expression of immunoreceptor tyrosine-based activation motif (ITAM) with no change in immunoreceptor tyrosine-based inhibitory motif.

    “Notably, aging induced an overall increase in the expression of immunoreceptor tyrosine-based activation motif (ITAM) with no change in immunoreceptor tyrosine-based inhibitory motif.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grabert and Michoel, 2016 source

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  • May combine two claims.

    Premisecitation

    Gene expression profile changes in aging occurred in a region-dependent and sexually dimorphic manner.

    “Interestingly, gene expression profile changes in aging occurred in a region-dependent and sexually dimorphic manner.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Berchtold et al, 2008 source

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  • May combine two claims.

    Premisecitation

    Male brains showed greater alterations in overall gene expression, although increased immune activation was characteristic of both sexes.

    “Moreover, the male brains showed greater alterations in overall gene expression, altough increased immune activation was characteristic of both sexes (Berchtold et al, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Berchtold et al, 2008 source

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  • May combine two claims.

    Premisecitation

    There was an age-dependent increase in the expression of amplifying receptors (such as TREM1, SIRPB1a, etc), and a corresponding reduction (eg, CD200 receptor) or stable expression (eg, CD300a) of inhibitory receptors in microglia.

    “For example, there was an age-dependent increase in the expression of amplifying receptors (such as, TREM1, SIRPB1a, etc), and a corresponding reduction (eg, CD200 receptor) or stable expression (eg, CD300a) of inhibitory receptors in microglia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grabert and Michoel, 2016 source

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  • May combine two claims.

    Premisecitation

    Microglia are the only CNS cells to express the fractalkine receptor CX3CR1, a constitutively expressed marker that serves a critical role in postnatal synaptic development and behavioral outcomes.

    “Microglia are the only CNS cells to express the fractalkine receptor CX 3 CR 1 , a constitutively expressed marker that serves a critical role in postnatal synaptic development and behavioral outcomes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Paolicelli et al, 2011 source

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    • cites Zhan et al, 2014 source

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  • May combine two claims.

    Premisecitation

    Most notable increases occurred in cytokines, complement components and cell adhesion-related genes, although remarkable decreases were observed in genes involved in synaptic transmission, vesicular transport, and protein signaling.

    “Most notable increases occurred in cytokines, complement components and cell adhesion-related genes, although remarkable decreases were observed in genes involved in synaptic transmission, vesicular transport, and protein signaling (Lu et al, 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lu et al, 2004

      Not checked in the free run.

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

    Premisenone given

    Neurons and microglia are engaged in constant interaction via secreted and membrane-bound ligands and receptors.

    “For example, neurons and microglia are engaged in constant interaction via secreted and membrane-bound ligands and receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Aged mice show deficient IL-4Rα expression, reduced arginase production, and impaired functional recovery following spinal cord injury compared with adult mice.

    “For example, compared with adult mice, the aged mice showed deficient IL-4Rα expression, that corresponded with reduced arginase production and impaired functional recovery following spinal cord injury (Fenn et al, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fenn et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged mice fail to upregulate IL-4Rα in response to LPS and do not elicit an alternative (regulatory) immune response to ex vivo IL-4.

    “Aged mice failed to upregulate IL-4Rα in response to LPS, and did not elicit an alternative (regulatory) immune response to ex vivo IL-4 (Fenn et al, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fenn et al, 2012 source

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  • May combine two claims.

    Premisecitation

    Mice lacking CX3CR1 undergo deficient synaptic pruning and brain development, subsequently resulting in abnormal social behavior.

    “Indeed, mice lacking CX 3 CR 1 undergo deficient synaptic pruning and brain development, subsequently resulting in abnormal social behavior (Paolicelli et al, 2011;Zhan et al, 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Paolicelli et al, 2011 source

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    • cites Zhan et al, 2014 source

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  • May combine two claims.

    Premisecitation

    Aged mice, but not adults, showed reduced baseline levels of CX3CL1 that remained unaltered after a systemic LPS challenge.

    “Aged mice, but not adults, showed reduced baseline levels of CX 3 CL 1 that remained unaltered after a systemic LPS challenge (Wynne et al, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wynne et al, 2010 source

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  • May combine two claims.

    Premisecitation

    IL-4 knockout mice have reduced baseline expression of CD200 at mRNA and protein levels, associated with enhanced glial production of IL-1β, TNFα, and IL-6 following LPS treatment.

    “Moreover, IL-4 knockout mice had reduced baseline expression of CD200 at mRNA and protein levels, which was associated with enhanced glial production of IL-1β, TNFα, and IL-6 following LPS treatment (Lyons et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lyons et al, 2009 source

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  • May combine two claims.

    Premisecitation

    IL-4 treatment of cultured neurons and intracerebroventricular administration of IL-4 markedly increase CD200 expression in hippocampal neurons.

    “IL-4 treatment of cultured neurons and intracerebroventricular administration of IL-4 markedly increased CD200 expression in hippocampal neurons (Lyons et al, 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lyons et al, 2007 source

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  • May combine two claims.

    Premisecitation

    LPS-injected aged mice showed protracted downregulation of CX3CR1 and reduced social behavior, which was accompanied by elevated IL-1β and reduced TGFβ.

    “LPS-injected aged mice, however, showed protracted downregulation of CX 3 CR 1 and reduced social behavior, which was accompanied by elevated IL-1β and reduced TGFβ (Wynne et al, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wynne et al, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD200-knockout mice have deramified microglia with upregulated levels of CD11b and CD45 at baseline, indicative of an activated phenotype.

    “Indeed, despite normal lifespan and no obvious behavioral abnormalities, CD200-knockout mice have deramified microglia with upregulated levels of CD11b and CD45 at baseline, overall indicative of an activated phenotype (Hoek et al, 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoek et al, 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The heightened inflammatory profile in IL-4 knockout mice is associated with exacerbated sickness behavior, lack of social exploration, and enhanced anxiety-like behavior.

    “Furthermore, this heightened inflammatory profile was associated with exacerbated sickness behavior, lack of social exploration, and enhanced anxiety-like behavior (Lyons et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lyons et al, 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-associated increase in telomerase activity and reduction in telomere length has been reported in the rat brain, indicating that microglia of the aged brain have a reduced potential for proliferation.

    “Indeed, ageassociated increase in telomerase activity and reduction in telomere length has been reported in the rat brain (Flanary and Streit, 2003), indicating that microglia of the aged brain have a reduced potential for proliferation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Flanary and Streit, 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, these reports indicate that microglial activation may present as a problem or as a resolution to a problem.

    “Overall, these reports indicate that microglial activation may present as a problem or as a resolution to a problem.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These therapeutic interventions were tested on naive animals, and therefore may not reflect the effects that may occur in animals with depressive-like behavior.

    “However, it is important to note that these therapeutic interventions were tested on naive animals, and therefore, may not reflect the effects that may occur in animals with depressive-like behavior.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Some individuals diagnosed with major depression may show reduced levels of inflammatory markers, whereas others may show elevated levels.

    “For example, some individuals diagnosed with major depression may show reduced levels of inflammatory markers, whereas others may show elevated levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Repeated nerve crush injury results in increased microglial proliferation in young rats, but not in aged rats.

    “For example, repeated nerve crush injury resulted in the increased microglial proliferation in young rats, but not in the aged (Miller and Streit, 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miller and Streit, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These reports of senescence are suggestive of functional deficiency and reduced proliferation of microglia with age.

    “Overall, these reports of senescence are suggestive of functional deficiency and reduced proliferation of microglia with age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These findings revealed the heterogeneous nature of microglia activation, in which microglia may be functionally hyperactive for cytokine production, whereas hypoactive for clearance of plaques and debris.

    “Although this disease model is not representative of normal aging, these findings overall revealed the heterogeneous nature of microglia activation, in which the microglia may be functionally hyperactive for cytokine production, whereas hypoactive for clearance of plaques and debris.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Gene expression analysis of the choroid plexus revealed an aging-induced upregulation of IFN-I and downregulation of interferon-II response genes.

    “Indeed, gene expression analysis of the choroid plexus, a brain region marked by epithelial lining that serves as a neurovascular interface, revealed an aging-induced upregulation of interferon-I (IFN-I) and downregulation of interferon-II response genes (Baruch et al, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Baruch et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Replenishing the circulatory system with young blood has been shown to rejuvenate peripheral organs and reverse functional deficits in animals.

    “Replenishing the circulatory system with young blood has been shown to rejuvenate peripheral organs and reverse functional deficits in animals (Sinha et al, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sinha et al, 2014 source

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  • May combine two claims.

    Premisecitation

    Aging-associated increase in systemic levels of CCL11 is associated with impaired neurogenesis and learning deficits, which are reversed by systemic and intrahippocampal administration of neutralizing anti-CCL11 antibody in aged mice.

    “In particular, aging-associated increase in systemic levels of CCL11 was associated with impaired neurogenesis and learning deficits, which were reversed by systemic and intrahippocampal administration of neutralizing anti-CCL11 antibody in the aged mice (Villeda et al, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Villeda et al, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Plasma transfer from younger mice into aged mice was sufficient to replicate the findings from parabiosis experiments, elucidating the role of blood-borne soluble factors, and not blood cells, in reversing aging-associated impairments in the brain.

    “Furthermore, plasma transfer from younger mice into the aged was sufficient to replicate the findings from the parabiosis experiments, elucidating the role of blood-borne soluble factors, and not blood cells, in reversing aging-associated impairments in the brain (Villeda et al, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Villeda et al, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutralizing antibodies against IFN-I restored growth factor levels and cognitive functioning in aged mice, demonstrating the role of blood-derived factors in aging-induced neurological deficits.

    “Moreover, neutralizing antibodies against IFN-I restored growth factor levels and cognitive functioning in aged mice, thus demonstrating the role of blood-derived factors in aging-induced neurological deficits (Baruch et al, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Baruch et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Older mice that share a blood supply with younger mice show increased neurogenesis, enhanced LTP and improved cognitive functioning.

    “Additional evidence for the role of blood-borne systemic factors in aging-induced impairments was provided by Villeda et al (2011) who showed that older mice that share a blood supply with younger mice show increased neurogenesis, enhanced LTP and improved cognitive functioning.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Villeda et al, 2011 source

      Not checked in the free run.

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

    Premisenone given

    Aging-associated decline in physiology and function also occurs beyond the brain in peripheral organs such as muscles, heart, and bone.

    “Aging-associated decline in physiology and function also occurs beyond the brain in peripheral organs such as muscles, heart, and bone.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Younger mice heterochronically paired with older mice show reduced cell proliferation in the dentate gyrus and impaired neurogenesis.

    “Conversely, younger mice heterochronically paired with older mice showed reduced cell proliferation in the dentate gyrus and impaired neurogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Villeda et al, 2011 source

      Not checked in the free run.

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

    Premisenone given

    Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress.

    “Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Caloric restriction is associated with prolonged life, increased gray matter volume, improved motor function, and reduced chronic pathology and inflammatory markers in rodents, non-human primates, and humans.

    “Caloric restriction (middle) is associated with prolonged life, increased gray matter volume, improved motor function, and reduced chronic pathology (eg, neoplasia) and inflammatory markers (complement proteins, antigen presentation markers, and pro-inflammatory cytokines) in rodents, non-human primates, and humans (Colman et al, 2009;Willette et al, 2012;Witte et al, 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Colman et al, 2009 source

      Not checked in the free run.

    • cites Willette et al, 2012 source

      Not checked in the free run.

    • cites Witte et al, 2009 source

      Not checked in the free run.

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

    Premisenone given

    Clinical trials involving plasma and plasma protein transfer from younger individuals are already underway for the treatment of aging-associated diseases such as Alzheimer's disease.

    “Indeed, clinical trials involving plasma and plasma protein transfer from younger individuals are already underway for the treatment of aging-associated diseases such as, Alzheimer's disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A low-calorie diet for 12 weeks in post-menopausal obese females led to significant weight reduction that corresponded with improved memory, enhanced gray matter volume and functional connectivity in the hippocampus and inferior frontal gyrus.

    “According to a recent study on post-menopausal obese females, a lowcalorie diet for 12 weeks led to a significant weight reduction that corresponded with improved memory, enhanced gray matter volume and functional connectivity in the hippocampus and inferior frontal gyrus (Prehn et al, 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Prehn et al, 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aerobic exercise in humans and voluntary running in rodents is associated with enhanced neurogenesis, improved learning and memory, increased hippocampal BDNF, and dampened inflammatory response to immune challenge and microglia proliferation.

    “Clinical and animal reports show that aerobic exercise (right) in humans and voluntary running in rodents is associated with enhanced neurogenesis, improved learning and memory, increased hippocampal BDNF, and dampened inflammatory response to immune challenge and microglia proliferation (Barrientos et al, 2011;Colcombe et al, 2003;Gebara et al, 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Barrientos et al, 2011 source

      Not checked in the free run.

    • cites Colcombe et al, 2003 source

      Not checked in the free run.

    • cites Gebara et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Emerging evidence supports that alterations in systemic factors in aging drive neurogenic and functional impairments, and that manipulation of these factors may allow for reversal of aging-induced dysregulation.

    “Taken together, emerging evidence supports that alterations in systemic factors in aging drive neurogenic and functional impairments, and that manipulation of these factors may allow for reversal of aging-induced dysregulation (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Caloric restriction is known to enhance longevity and improve cognitive functioning via immunological alterations.

    “In addition to exposure to young blood, caloric restriction has also been known to enhance longevity and improve cognitive functioning via immunological alterations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The role of blood-borne factors in aging-associated physiological and behavioral alterations in the brain has garnered further credence and offers therapeutic promise.

    “Although the definitive role of GDF11 in aging-induced vascular deficits was challenged by subsequent studies, the role of blood-borne factors in aging-associated physiological and behavioral alterations in the brain has garnered further credence and offers therapeutic promise (Castellano et al, 2015;Egerman et al, 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Castellano et al, 2015 source

      Not checked in the free run.

    • cites Egerman et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Functional neuroimaging results showed that caloric restriction in older monkeys reduced iron deposition in the brain and improved motor performance on multiple measures.

    “In a separate study, functional neuroimaging results showed that caloric restriction in older monkeys reduced iron deposition in the brain and improved motor performance on multiple measures (Kastman et al, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kastman et al, 2012 source

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  • May combine two claims.

    Premisecitation

    Prolonged life in the 40% caloric restriction rats, but not in 10%, was accompanied by significant reduction in aging-associated pathology, such as neoplasia, indicating that higher caloric restriction induces longevity while delaying chronic pathology.

    “Interestingly however, prolonged life in the 40% caloric restriction rats, but not in 10%, was accompanied by significant reduction in aging-associated pathology, such as neoplasia, indicating that higher caloric restriction induces longevity while delaying chronic pathology (Richardson et al, 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Richardson et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Findings of increased longevity have been reported in several species and have been corroborated by multiple studies.

    “Taken together, findings of increased longevity have been reported in several species and have been corroborated by multiple studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Monkeys under the caloric restriction condition had delayed onset of aging-associated pathology, such as neoplasia, cardiovascular diseases, and glucose-associated impairments, and showed higher gray matter volume in subcortical regions.

    “Furthermore, monkeys under the caloric restriction condition had delayed onset of aging-associated pathology, such as, neoplasia, cardiovascular diseases, and glucose-associated impairments, and showed higher gray matter volume in subcortical regions (Colman et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Colman et al, 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caloric restriction-associated reversal of aging-induced brain atrophy was also associated with reduced IL-6 levels, thus highlighting the role of immune mediators.

    “Furthermore, caloric restriction-associated reversal of aging-induced brain atrophy was also associated with reduced IL-6 levels, thus highlighting the role of immune mediators (Willette et al, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Willette et al, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rejuvenation of the aged brain by caloric restriction and by exposure to young blood are both mediated by overall attenuation of inflammatory signaling in the aged brain.

    “Overall, studies reveal that rejuvenation of the aged brain by caloric restriction and by exposure to young blood are both mediated by overall attenuation of inflammatory signaling in the aged brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The rejuvenating effects of caloric restriction and exercise indicate that aging, a natural and progressive phenomenon, is susceptible to environmental factors and lifestyle, of which stress is an example.

    “The rejuvenating effects of caloric restriction and exercise indicate that aging, a natural and progressive phenomenon, is yet susceptible to environmental factors and lifestyle, of which stress is an example.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Overall, exercise increases neurogenesis and improves cognitive functioning in aged animals, while reducing microglia priming associated with aging.

    “Overall, these findings indicate that exercise increases neurogenesis and improves cognitive functioning in aged animals, while reducing microglia priming associated with aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Six months of aerobic exercise was associated with significant increases in brain oxygen uptake, and cortical gray and white matter volume in older adults.

    “For example, 6 months of aerobic exercise was associated with significant increases in brain oxygen uptake, and cortical gray and white matter volume in older adults (Colcombe et al, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Colcombe et al, 2006 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Clinical findings supporting the benefits of caloric restriction are in line with animal studies, which revealed that the resulting delay in mortality and neuroprotective effects are mediated by reversal of inflammatory and metabolic changes associated with aging.

    “Taken together, clinical findings supporting the benefits of caloric restriction are in line with animal studies, which revealed that the resulting delay in mortality and neuroprotective effects are mediated by reversal of inflammatory and metabolic changes associated with aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Older mice that engaged in voluntary running showed significant improvement in spatial memory and increased neurogenesis compared to non-runners.

    “Older mice that engaged in voluntary running showed significant improvement in spatial memory and increased neurogenesis compared to non-runners (van Praag et al, 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites van Praag et al, 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In aged rats, exercise prevented learning impairments following peripheral immune challenge, and this effect was associated with increased expression of hippocampal BDNF.

    “In aged rats, exercise prevented learning impairments following peripheral immune challenge, and this effect was associated with increased expression of hippocampal BDNF (Barrientos et al, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Barrientos et al, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Findings from caloric restriction experiments have shown that reduction in caloric intake can significantly prolong lifespan and prevent microglia priming associated with age.

    “Indeed, findings from caloric restriction experiments have shown that reduction in caloric intake can significantly prolong lifespan and prevent microglia priming associated with age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Higher caloric expenditure via exercise and reduced caloric intake via caloric restriction both confer their benefits by attenuating the enhanced inflammatory profile of the aged brain.

    “Overall, (i) higher caloric expenditure via exercise and (ii) reduced caloric intake via caloric restriction both confer their benefits by attenuating the enhanced inflammatory profile of the aged brain (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hippocampal IL-1β levels were reduced in old runners, but not in old sedentary rats.

    “For example, hippocampal IL-1β levels were reduced in old runners, but not in old sedentary rats.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Barrientos et al, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Psychological stress is known to trigger inflammatory response and premature shortening of telomere length, leading to cellular senescence, which is characteristic of aging.

    “Psychological stress is known to trigger inflammatory response and premature shortening of telomere length, leading to cellular senescence, which is characteristic of aging (Lindqvist et al, 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lindqvist et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The inflammatory and metabolic correlates of chronic stress in adults are similar to those in older individuals, indicating that adults exposed to chronic stress are vulnerable to premature aging.

    “Taken together, the inflammatory and metabolic correlates of chronic stress in adults are similar to those in older individuals, indicating that adults exposed to chronic stress are vulnerable to premature aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chronic stress associated with long-term caregiving for a demented spouse was associated with shortened telomere length, lower levels of telomerase activity, and increased oxidative stress.

    “A recent study showed that chronic stress associated with long-term caregiving for demented spouse was associated with shortened telomere length, lower levels of telomerase activity, and increased oxidative stress (Epel et al, 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Epel et al, 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Primed microglia from the stress-exposed mice, but not naive mice, elicited an exaggerated inflammatory response to acute social defeat stress, and this response was sufficient for the recurrence of anxiety-like behavior.

    “For example, primed microglia from the stressexposed mice, but not naive mice, elicited an exaggerated inflammatory response to acute social defeat stress, and this response was sufficient for the recurrence of anxiety-like behavior (Wohleb et al, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wohleb et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial activation and inflammatory signaling following psychological stress has been reported in mice and rats alike, and has also been recapitulated in other models, such as restraint stress and foot-shock stress.

    “Microglial activation and inflammatory signaling following psychological stress has been reported in mice and rats alike, and has also been recapitulated in other models, such as restraint stress and foot-shock stress (Frank et al, 2007;Hinwood et al, 2012;Kreisel et al, 2014;Tynan et al, 2010;Voorhees et al, 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Frank et al, 2007 source

      Not checked in the free run.

    • cites Hinwood et al, 2012 source

      Not checked in the free run.

    • cites Kreisel et al, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Older adults were found to display higher levels of circulating corticosterone at baseline that was associated with hippocampal atrophy and memory deficits.

    “Indeed, older adults were found to display higher levels of circulating corticosterone at baseline that was associated with hippocampal atrophy and memory deficits (Lupien et al, 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lupien et al, 1998 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This age-associated increase in corticosterone was also reported in rats, and was associated with a decline in hippocampal neurogenesis.

    “This age-associated increase in corticosterone was also reported in rats, and was associated with a decline in hippocampal neurogenesis (Cameron and McKay, 1999;Sapolsky, 1992).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cameron and McKay, 1999 source

      Not checked in the free run.

    • cites Sapolsky, 1992 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These effects were not observed in monkeys placed on 30% caloric restriction, suggesting that caloric restriction may attenuate the stress-induced behavioral and anatomical impairments associated with aging.

    “These effects were not observed in monkeys placed on 30% caloric restriction, suggesting that caloric restriction may attenuate the stress-induced behavioral and anatomical impairments associated with aging (Willette et al, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Willette et al, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Psychological stress leads to activation of the microglia, which then take on a primed profile, and elicit an exaggerated inflammatory response when exposed to subsequent immune challenge.

    “Taken together, psychological stress leads to activation of the microglia, which then take on a primed profile, and elicit an exaggerated inflammatory response when exposed to subsequent immune challenge.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Natural killer cell and lymphocyte activity, which are reported to diminish with age in monkeys and mice, were further attenuated following restraint stress in aged mice.

    “For example, natural killer cell and lymphocyte activity, which are reported to diminish with age in monkeys and mice, were further attenuated following restraint stress in aged mice (Coe, 2004;Padgett, 1998).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Coe, 2004 source

      Not checked in the free run.

    • cites Padgett, 1998 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although stress can accelerate and mimic aspects of aging, the converse also holds true: the effects of stress in older adults are more pronounced than in younger adults.

    “Although stress can accelerate and mimic aspects of aging, the converse also holds true.In other words, the effects of stress in older adults are more pronounced than in younger adults.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The heightened inflammatory signaling observed in humans under stress and aging has been well recapitulated in animal models.

    “The heightened inflammatory signaling observed in humans under stress and aging has been well recapitulated in animal models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    As GC receptors reside in the cytoplasm in their inactive form and in the nucleus in their active form, the increased presence of nuclear GC receptors is indicative of increased GC receptor signaling.

    “As GC receptors reside in the cytoplasm in their inactive form and in the nucleus in their active form, the increased presence of nuclear GC receptors is indicative of increased GC receptor signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Together, these findings provide the evidence of increased corticosterone in psychological stress, as well as in aging.

    “Together, these findings provide the evidence of increased corticosterone in psychological stress, as well as in aging.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Although historically characterized as anti-inflammatory, GCs exert dynamic actions on the immune system.

    “Although historically characterized as anti-inflammatory, GCs exert dynamic actions on the immune system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Prior exposure to GCs can instead promote NF-κB activity and increase the pro-inflammatory response to subsequent LPS, indicating that GCs can exert a priming effect to subsequent immune challenge.

    “However, accumulating evidence indicates that prior exposure to GCs can instead promote NF-κB activity and increase the pro-inflammatory response to subsequent LPS, indicating that GCs can exert a priming effect to subsequent immune challenge (Frank et al, 2010;Munhoz et al, 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Frank et al, 2010

      Not checked in the free run.

    • cites Munhoz et al, 2006 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    As GCs are the primary responders in stress regulation, these reports reveal a dynamic and bidirectional relationship between psychological stress and aging, in which one may exacerbate the effects of the other.

    “More importantly, as GCs are the primary responders in stress regulation, these reports reveal a dynamic and bidirectional relationship between psychological stress and aging, in which one may exacerbate the effects of the other (Lupien et al, 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lupien et al, 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increased lifespan is accompanied by increased exposure to lifetime stress, which in turn leads to accelerated aging, primarily marked by premature senescence, diseases, and poor quality of life.

    “Furthermore, increased lifespan is accompanied by increased exposure to lifetime stress, which in turn leads to the accelerated aging, primarily marked by premature senescence, diseases, and poor quality of life.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Microglia of the aged brain take on a 'primed' or 'sensitized' phenotype, characterized by dystrophic morphology, progressive accumulation of metabolic stress, increased cell-surface expression of antigen recognition molecules, and an exaggerated inflammatory response to immune challenge.

    “Microglia of the aged brain take on a 'primed' or 'sensitized' phenotype, characterized by dystrophic morphology, progressive accumulation of metabolic stress, increased cell-surface expression of antigen recognition molecules, and an exaggerated inflammatory response to immune challenge.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Exercise, physical activity, and caloric restriction in humans and animals have also been shown to promote healthy aging.

    “Furthermore, exercise, physical activity, and caloric restriction in humans and animals have also been shown to promote healthy aging.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Recent findings in animals indicating that manipulation of the peripheral immune system may restore cognitive functioning and cellular activity in the brain have generated the idea of blood-induced rejuvenation of the aged brain.

    “Recent findings in animals indicating that manipulation of the peripheral immune system may restore cognitive functioning and cellular activity in the brain have generated the idea of blood-induced rejuvenation of the aged brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    This augmented inflammatory profile of microglia in the aged brain is associated with impairments in synaptic plasticity, neurogenesis, and emotional and cognitive deficits.

    “This augmented inflammatory profile of microglia in the aged brain is associated with impairments in synaptic plasticity, neurogenesis, and emotional and cognitive deficits.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Caloric restriction is associated with prolonged life in rodents, non-human primates, and humans.

    “Caloric restriction (middle) is associated with prolonged life, increased gray matter volume, improved motor function, and reduced chronic pathology (eg, neoplasia) and inflammatory markers (complement proteins, antigen presentation markers, and pro-inflammatory cytokines) in rodents, non-human primates, and humans(Colman et al, 2009;Willette et al, 2012;Witte et al, 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Colman et al, 2009 source

      Not checked in the free run.

    • cites Willette et al, 2012 source

      Not checked in the free run.

    • cites Witte et al, 2009 source

      Not checked in the free run.

126 of 126

  • The paper relies on this without support.

    Psychological stress can induce aging-like sensitization of microglia and increase reactivity to secondary challenges.

    “Conversely, psychological stress may also induce aging-like sensitization of microglia and increase reactivity to secondary challenges.”

  • The paper relies on this without support.

    Animal models, particularly rodents, recapitulate the neurological, inflammatory, and behavioral correlates of human aging sufficiently to support inferences about human aging.

    “Animal models have played a significant role in recapitulating the neurological, inflammatory and behavioral correlates of human aging.”

  • The paper relies on this without support.

    Caloric restriction and young blood-induced revitalization reverse the behavioral effects of aging in rodents.

    “In rodents, caloric restriction and young blood-induced revitalization reverses the behavioral effects of aging.”

  • The paper relies on this without support.

    Aging is a progressive phenomenon and not a disease by itself.

    “Aging is a progressive phenomenon and not a disease by itself.”

  • The paper relies on this without support.

    Aging is associated with reduced neurogenesis.

    “Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress.”

  • The paper relies on this without support.

    Aging is associated with impaired learning and memory.

    “Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress.”

  • The paper relies on this without support.

    Aging is associated with increased pro-inflammatory markers.

    “Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress.”

  • The paper relies on this without support.

    Aging is associated with increased antigen presentation molecules.

    “Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress.”

  • The paper relies on this without support.

    Aging is associated with increased oxidative stress.

    “Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress.”
9 of 9

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Human hormone named corticosterone instead of cortisol

    Minor

    The text attributes a finding about circulating corticosterone in older adults to Lupien et al (1998), while its reference list identifies that study as measuring cortisol. These are different hormones.

  • 2014 study called first despite an earlier 2011 finding

    Minor

    The review calls the 2014 young-blood findings the first to implicate blood-borne factors in reversing brain aging, but later describes a 2011 study reporting improved neurogenesis and cognitive function in old mice sharing young mice's blood supply.

2 of 2

Cites

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1 of the 174 references couldn’t be matched to a known paper.

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Related

Authors
Niraula, A., Sheridan, J. F., & Godbout, J. P.
Affiliations
The Ohio State University (US)
Corresponding author
Godbout, Jonathan P
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2016-09-08
Volume
42
Issue
1
Pages
318-333
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2016.185
PMC
PMC5143497
OpenAlex
W2516246660
Semantic Scholar
343c8b9c48d795de1ef40a024b321b7b35a05bfb
Cited by
398
References
174
Citations by year
2026: 52 · 2025: 39 · 2024: 41 · 2023: 44 · 2022: 53 · 2021: 55 · 2020: 44 · 2019: 30 · 2018: 23 · 2017: 14 · 2016: 2 · 2015: 1
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (R01AG051902, R01AG033028)
  • National Institute of Mental Health (R01MH097243, R01MH093473)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
microglia, brain aging, microglial priming, neuroinflammation, psychological stress, caloric restriction, young blood, cognitive decline, neurodegeneration, neuroprotection, neurogenesis, synaptic dysfunction, brain energy metabolism
MeSH terms
Aging, Animals, Humans, Inflammation, Stress, Psychological, Microglia

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 2026-10-10.

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

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