Innate Immune Memory and Transcriptional Profiling of Microglia
Heng, Yang
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10.33612/diss.151944032
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Heng, Y. (2021). Innate Immune Memory and Transcriptional Profiling of Microglia. University of Groningen. https://doi.org/10.33612/diss.151944032
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Chapter *
Mouse models of central nervous system ageing
Yang Heng, Bart J.L. Eggen, Erik W.G.M. Boddeke, Susanne M. Kooistra Department Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Published in Drug Discovery Today: Disease Models 2017 25-26:21-34 (review)Abstract
Ageing is a process accompanied by a decrease in overall fitness and performance. Studying brain ageing in humans is challenging due to very limited or no access to healthy tissue, limited opportunities for interventions and complicated confounding factors. The generation of mouse ageing models with uniform genetic backgrounds significantly contributed to our understanding of (brain) ageing at the molecular level. Research has focused on evolutionarily conserved mechanisms or pathways that control ageing to facilitate data extrapolation to humans. Understanding how these pathways contribute to pathological ageing may help us to get a better understanding of human central nervous system (CNS) ageing and assist in the development of possible therapeutic targets. In this review, we focus on the functional consequences and pathological changes in the CNS of ageing mouse models.
2
Introduction
Ageing is the main risk factor for many neurodegenerative diseases. Understanding how normal brain ageing transitions to pathological ageing is of vital importance to develop possible treatment for ageing associated central nervous system (CNS) pathologies.
To investigate CNS ageing, a range of ageing mouse models was developed, in view of the genetic similarity between mice and humans, their relatively short life span and
amenability for genetic manipulation 1. Human and mouse brain ageing exhibit many
common features. On the pathological level, brain atrophy, neuronal loss, neuronal lipofuscinosis and reactive glial cells are observed following ageing in both human and mouse brain 2. On a functional level, both humans and mice show an age-dependent decline in learning and memory and motor performance 3. On a transcriptional level, common sets of genes are affected by ageing in mouse and human 4. On an epigenetic level, DNA methylation is strongly correlated with ageing 5, and age-associated DNA methylation changes are relatively well conserved between humans and mice 6. However, it is worth noting that there is very limited correlation between age regulated gene expression changes in mouse and human, indicating that the ageing process in the CNS of human and mice might be quite different 7,8. Given that age regulation is quite
different in different tissues and species 7, research has focused on evolutionarily
conserved mechanisms that control ageing to facilitate data extrapolation to humans. These conserved pathways or mechanisms include genomic instability, epigenetic alterations, telomere attrition, mitochondrial dysfunction, loss of proteostasis and
nutrient sensing pathways etc. 9,10. In this review, mouse models that have been used to study CNS ageing and ageing-related diseases will be discussed with the main focus on pathological changes during CNS ageing. Mouse models with genomic instability Brain ageing is characterized by loss of genomic integrity 11. Excessive DNA damage and insufficient DNA repair both can contribute to genomic instability during the ageing process 12. Numerous mouse models with genomic instability have been established
and extensively reviewed 13,14. Here, we only focus on models with CNS ageing
phenotypes. Detailed CNS phenotypes of these mice are described in Table 1.
Mouse models with excessive DNA damage
Atm-deficient mice
Ataxia-telangiectasia (AT) is a human genetic disorder caused by mutational
inactivation of the ATM gene 15. ATM plays a major role in maintaining genomic stability
and DNA strand breaks accumulate in the brain of Atm-/- mice 16. ATM dysfunction
resulted in increased reactive oxygen species (ROS) production, which may induce the
degeneration of cerebellar neurons 17. The histological, immunohistochemical and
electrophysiological properties of Purkinje cells (PCs) were not altered in cerebellum, however, these cells showed age-dependent defects in calcium spike bursts and calcium currents 18. Atm deficiency induced progressive loss of dopaminergic neurons in the substantia nigra (SN) and GABAergic neurons in the striatum (STR) 19. Atm deficiency was also shown to impair astrocyte-endothelial cell interactions, which could be the underlying mechanism for neurodegeneration 20. BubR1 deficient mice BubR1 is a mitotic checkpoint protein that is essential for the accurate separation of duplicated chromosomes during cell division. Reduced BubR1 expression induces
aneuploidy, which affects genomic stability 21. BubR1 insufficient mice (BubR1H/H mice)
exhibited various motor deficits, including impaired motor strength, coordination, gait patterns and reduced locomotor activity. BubR1 expression is significantly reduced
with natural ageing in the mouse brain, and BubR1H/H mice exhibit age related decline
in hippocampal neurogenesis 22. The oligodendrocyte progenitor cell proliferation and
oligodendrocyte density were markedly reduced in brain and spinal cord, which further
caused axonal hypomyelination 23. Besides, BubR1H/H mice also showed cerebral
2 DNA methyltransferase deficient mice DNA methyltransferase 1 (Dnmt1) is the most prevalent DNA methyltransferase that maintains genomic methylation stability. Dnmt1 haploinsufficiency impaired learning and memory function in an age-dependent manner in mice 25. In addition, conditional deletion of Dnmt1 and Dnmt3a in neurons induced abnormal long-term plasticity in CA1 and deficits of learning and memory; however, no neuronal loss was observed 26. DNA damage repair deficient mice DNA damage alters the structure of DNA and most DNA damages undergo repair. Excess DNA damage is associated with ageing and cancer. There are several DNA repair pathways for different types of DNA damage. Deficiencies in DNA repair pathways
cause progeria syndromes in humans and also affect the CNS 27. Several ageing mouse models were established based on deletion or mutation of genes involved in DNA repair pathways. Ercc1 deficient mice Excision repair cross-complementation group 1 (ERCC1) is an essential component of multiple DNA repair pathways: nucleotide excision repair (NER), double-strand break repair and interstrand cross-link repair pathways 28. Mice carrying a knock out and a hypomorpic allele for Ercc1 showed age-dependent motor abnormalities and cognitive decline. Further studies revealed widespread astrogliosis, microgliosis and neuronal degeneration in the brain, and motor neuron loss in the spinal cord 28,29. The mutant
mice did not show altered synapse numbers and dendritic morphology in the
hippocampus. However, Ercc1Δ/− mice did show age-dependent changes in the
proteomic composition and synaptic plasticity in the hippocampus 30
. A similar age-related cognitive decline and neurodegeneration were also observed in conditional
knockout mice (Ercc1f/− CaMKII-Cre+ mice), in which Ercc1 deficiency was directed to
excitatory forebrain neurons 28. For microglia, we have shown that microglia in Ercc1Δ/−
mice exhibit a hypertrophic morphology with thickened primary processes and larger
cell bodies at the age of 16 weeks. Functionally, Ercc1Δ/− microglia displayed increased
exaggerated proinflammatory response to a systemic inflammatory lipopolysaccharide (LPS) challenge, indicative of a “primed” state. Transcriptome analysis also confirmed Ercc1Δ/− microglia were primed, with a clear phagocytic and chemotactic profile and enhanced immune state 31,32. Xpg-/- mice The premature ageing syndrome Cockayne syndrome (CS) is characterized by growth failure, abnormal sensitivity to light and impaired development of the CNS 33. In humans with CS, the DNA repair gene XPG that is involved in NER, homologous recombination
repair and base excision repair (BER) is mutated. Xpg-/- mice exhibit multiple
progressive features of CNS ageing, such as loss of hearing and vision, cognitive decline,
motor deficits and early development of tremors 34. Xpg-/- mice develop wide spread
astrogliosis and microgliosis in brain and spinal cord, starting at 4 weeks of age. At 14 weeks of age, astrogliosis was severe and associated with axonal swellings and loss of PCs in the cerebellum. The genotoxic stress marker p53 was detected in neurons, astrocytes and oligodendrocytes. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed a significant increase in apoptotic cells in the cerebrum at 4
as well as 14 weeks of age 35.
Csa-/- and Csb -/- mice
Csa and Csb are genes involved in transcription-coupled excision repair (TCR) In Csa-/-
and Csb-/- mice, activated microglia and astrocytes are detected in the white matter.
However, microglia activation was not observed in NER-deficient Xpa-/- and Xpc-/- mice.
Therefore, next, TCR-deficient mice were generated with selective NER deficiency
targeted to forebrain neurons. Csb−/−/Xpac/−/CamKIIα-Cre mice displayed dramatic
age-related neuronal loss, behavioral abnormalities, and brain atrophy in the forebrain
36.
Sirt6 deficient mice
Sirtuins (SIRT1–SIRT7) are an evolutionally conserved family of NAD+-dependent
deacetylases, and play a critical role in brain ageing and neurodegenerative diseases 37.
2 expanded life span in male mice 38. Sirt6 knockout mice exhibit an accelerated ageing phenotype and die prematurely. Sirt6 specific depletion in the brain results in increased DNA damage, Tau phosphorylation and learning defects 39. 3xTg/Polβ+/− mice DNA polymerase beta (Polb) is a primary polymerase involved in BER. Disruption of Polb induced growth retardation and post-natal lethality in mice. A 50% reduction in Polb levels (heterozygous for Polβ gene) aggravated the phenotypes of 3xTg Alzheimer’s Disease (AD) mice. Neuronal dysfunction, cell death and memory
impairment were also shown to be more severe than in the 3xTg AD mice or Polβ+/− mice. Pathway comparison analysis of human and mouse microarray data revealed that the combined 3xTg/Polβ+/− transgenic mouse is more similar to human AD patients than the 3xTgAD or Polβ+/− mice 40. Telomere attrition mouse model Telomere shortening is observed in all eukaryotes 41. Mice carrying a homozygous germ line deletion for the telomerase RNA component gene (Terc) showed complete loss of Terc expression and telomerase activity. For the Terc-/- mice, the telomeres become
shorter during successive generations of mating due to the replication end-point problem, usually resulting in phenotypic changes after the third generation. Third
generation Terc-/- mice showed impaired spatial learning memory, and accordingly, the
dentate gyrus (DG) volume and brain weight were decreased in the Terc-/- mice 42.
Further study revealed reduced neurogenesis in the DG and loss of neurons in the
hippocampus and frontal cortex in third generation Terc-/- mice 43. Telomere
dysfunction also led to reduced microglial numbers and cell body volume in DG, nevertheless, telomere shortening did not affect microglial proliferation or induce an
ageing phenotype 42,43. Terc-/- microglia also exhibited an enhanced pro-inflammatory
response to peripheral LPS stimulation. However, unlike Ercc1Δ/− microglia, this
enhanced response is correlated with brain infiltration and blood–brain barrier
dysregulation rather than age-related microglia priming 44. Terc deficiency was also
shortening was shown to accelerate the amyotrophic lateral sclerosis (ALS) phenotypes
in SOD1G93A transgenic mice and Parkinson’s disease (PD) phenotypes in
(Thy-1)-h[A30P] α-synuclein transgenic mice 45,46. Surprisingly, telomere shortening reduced
AD amyloid pathology in APP23 transgenic mice 43. Telomerase reverse transcriptase
(TERT) is the catalytic subunit of the telomerase complex. Its deficiency also induced
ageing phenotypes quite similar to Terc -/- mice 47. What differed is that TERT deficiency
induced aggressive and depressive behaviors in a mouse brain structure-specific
manner 48. Tert gene knockout mice also display impaired spatial memory, dendritic
development and neuritogenesis 49. Detailed CNS phenotypes of these mice are
described in Table 1.
Mouse models with mitochondrial dysfunction
It is well accepted that mitochondria play a central role in ageing and
neurodegenerative diseases 50. Commonly used mouse models with mitochondrial
dysfunction include dopaminergic neuron specific Twinkle transgenic mice, mitochondrial late-onset neurodegeneration (MILON) mice, mitochondrial quality control gene Afg3l2, Spg7, Phb2 and HtrA2/Omi-deficient mice, apoptosis-inducing factor Aif deficient mice and mito-PstI transgenic mice all showed substantial brain
ageing and neurodegeneration phenotypes 51. Detailed CNS phenotypes of these mice
are described in Table 1. Due to premature death of HtrA2/Omi deficient mice, this
mouse model is not discussed here 52.
Mouse models with deficits in proteostasis
Loss of proteostasis is observed in many neurodegenerative diseases such as AD and PD. In mammals, proteostasis is maintained by chaperones and two proteolytic systems,
the ubiquitin-proteasome and the lysosome-autophagy systems 10. Autophagy-deficient
mice showed ageing related changes and neurodegenerative changes that resemble
those associated with ageing 53, among them, Becn1, Atg7 and FAK family-interacting
protein of 200 kDa (FIP200) deficient mice showed neurodegeneration phenotypes (see Table 1). Defects in the sphingomyelinases gene Smpd3 resulted in age-dependent
2 phosphorylated Tau (pTau) in neurons. The deficient mice also showed age-dependent
decline of motor activity, coordination and cognitive ability 54. Endoplasmic reticulum
(ER) is important to maintain proteostasis, as approximately 30% of proteins are synthesized and processed there. ER stress is also a common pathological signature in
a variety of diseases, including neurodegenerative disease 55. Binding immunoglobulin
protein (BiP) is central for ER function and mutant BiP mice exhibited motor disabilities during ageing. Degeneration of motoneurons and accumulations of ubiquitinated
proteins were also found in the spinal cord 56.
Mouse models with deficits in nutrient sensing
The insulin/insulin-like growth factor 1 (Insulin/IGF1) signaling pathway is evolutionarily conserved and involved in growth, development, metabolic
homoeostasis and also CNS ageing 57. IGF1 is a neuroprotective hormone that is mainly
produced in the liver. Conditional, liver-specific inactivation of the Igf1 gene induced an age-associated decline in learning memory. Further study identified astrocytosis and
increased neurochemical disturbances in the DG area 58. Reduced hippocampal IGF-1
receptor (IGF1R) expression is associated with age-related decline in learning, and astrocyte-specific knockout of IGF1R was demonstrated to induce impairments in
working memory 59. Forkhead box O (FOXO) transcription factors play a pivotal role in
the IIS/PI3K/Akt signaling pathway. They are important determinants of ageing and
longevity 60. FOXO expression progressively increases in ageing human and mouse
brains 61. Conditional knockout of Foxo 1, 3, and 4 in neurons and glia cells induced an
accelerated ageing phenotype in mice, manifested by axonal tract degeneration and
gliosis 61.
Senescence accelerated mouse-prone (SAM-P) mice
The SAM-P mice are naturally occurring mouse lines that display a series of accelerated ageing phenotypes. At present, there are eight strains of SAM-P. It is noteworthy that
each SAM-P strain has relatively strain-specific pathological phenotypes 62
. Since SAM-P/8 and SAM-P/10 display deficits in learning and memory, these strains were extensively used to investigate CNS ageing. A variety of age-associated alterations
involving neurons, glia and blood brain barriers have been identified in SAM-P/8 and SAM-P/10 mice brain. SAM-P/8 could also serve as an animal model for AD and other dementias as age-related increases in pTau and amyloid accumulation were also
observed in the hippocampus of SAMP8 mouse brains 63. The 3xTg-AD transgenes in a
SAM-P/8 background showed deficits in spatial memory and female-specific aggravation of AD pathology characterized by activation of astrocytes and increased
accumulation of pTau and amyloid in the brain 64. Some epigenetic alternations
associated with ageing and neurodegeneration were also identified in the SAMP-P/8 brain 65,66. Promising therapeutic targets Although ageing itself is an inevitable process, interventions could be applied to extend both lifespan and health-span. A longevity study in monozygotic twins indicated that life span is determined largely by environmental factors rather than genetic factors 67. Work on mouse models of ageing has not only contributed to the identification of many of the molecular pathways involved in ageing, but also have provided possible targets for the treatment of age-related CNS decline. Epigenetic signatures are proposed to function as biomarkers of ageing, for example, the DNA methylome can help to measure
human ageing rates 5. Epigenetic modifications are considered to be dynamic and
reversible, making it an attractive therapeutic target. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors are thought to provide a
promising treatment for neurodegenerative diseases 68,69.
In recent years, senescent cells are recognized as a new target for age-related disease.
In mouse, clearance of p16Ink4a-positive senescent cells was shown to delay ageing-associated phenotypes in BubR1H/H mice 70. Fuhrmann-Stroissnigg et al. established a
drug-screening platform to identify senolytic compounds using Ercc1-/- primary murine
embryonic fibroblasts. Through this platform, they successfully identified an HSP90
inhibitor, 17-DMAG, which could extend health-span and delay the onset of several age-related symptoms in Ercc1Δ/− mice 71. Microglia are shown to undergo age-dependent
degeneration, increasingly displaying a primed or hyperreactive, pro-inflammatory phenotype and a deficiency in phagocytosis and chemotaxis. Senescent microglia are
2
believed to be involved in switching normal brain ageing to pathological ageing 72. The
rejuvenation of senescent microglia was already shown to be a potential druggable
target 73. However, so far, there is no evidence whether microglia senolysis could
restore normal function and revert or halt CNS ageing phenotypes.
Dietary restriction increases lifespan or health-span in all investigated eukaryote
species 10. A similar effect is seen when the activity of nutrient-sensing pathways is
reduced by mutations or chemical inhibitors 74, indicating that nutrient-sensing
pathways could provide promising targets to slow ageing. For example, the Insulin- and IGF-1-signaling pathway, the mammalian target of rapamycin (mTOR) pathway and the AMPK pathway are involved in nutrient sensing. And, manipulation of these pathways
could increase lifespan and delay multiple aspects of ageing 10,75,76.
Conclusions
Studying brain ageing in humans is challenging due to very limited or no access to healthy tissue, limited opportunities for interventions and human ageing in general is complicated by confounding factors like environment, nutrition, medical history, medication, education etc. The generation of mouse models with uniform genetic backgrounds significantly contributed to our understanding of ageing at the molecular level. However, conclusions must be drawn with caution because the results obtained from inbred mice may not represent the species as a whole 77. Also, the mouse models cannot recapture all the brain ageing phenotypes in human, nor reliably predict age-related changes in humans owing to differences in the ageing process in human and mouse.
Though the mouse models described here have been used to identify molecular mechanisms of ageing, and to identify possible therapeutic targets, their use in the development of therapies and in particular the translation to the human situation is still
not well developed 78. In case of AD, for example, gene mutations that lead to AD-like
phenotypes in young animals do not fully mimic human AD in older patients and
therefore the predictive value of testing drugs in such models is limited 79.
Nonhuman primates are more similar to humans in how they experience ageing processes, which include ageing related pathologies like cancer, diabetes, arthritis,
cardiovascular disease, and neurological decline. However, their substantial size, long lifespan, and the associated expense are prohibitive factors in their large scale-use for research into ageing. Nonetheless, they could provide a crucial component between the
bench and the bedside 80. In this review, we mainly focused on the functional
consequences and pathological changes resulting from conserved pathways dysfunction in brain ageing. Understanding how these conserved pathways contribute to pathological ageing may help us to get a better understanding of brain ageing and develop possible treatment strategies. Finally, it is worth noting that the ageing process involves multiple organs and tissues, and the influence of peripheral organs on CNS
2 Ta b le 1 . S el ec te d C N S ag ei n g p h en ot yp es o f a ge in g m ou se m od el s Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) At m Kn oc ko ut ( KO ) Im pa ir ed mo to r co or di n at io n; ir re gu la r ga it pa tt er ns ; re duc ed lo co m ot or ac ti vi ty 81 Sm al le r br ai n 82 Pr og re ssi ve lo ss of DA n eu ro ns in th e SN a nd G A B A er gi c ne ur ons in th e ST R 19; n o ne ur on al lo ss in th e ce re be llu m ; ag e-de pe nde nt de fe ct s in c al ci um sp ik e bu rst s an d ca lci um cu rr en ts in PC s 18 Pr og re ssi ve st ru ct ur al al ter at io ns in as tr oc yt es o f th e re ti na 20 ,83; as tr oc yt es ac ti vat io n in ce re be llu m 84 At ax ia -te la ng ie cta si a (AT ) Bu bR 1 Ho m oz yg ou s hy po m or pi c mu ta io n Im pa ir ed mo to r st re ng th , co or di n at io n an d bal an ce; ir re gu la r ga it pa tt er ns ; re duc ed lo co m ot or ac ti vi ty 23 Sm al le r br ai n 23 Re duc ed in de ndr it ic s pi n e de ns it y in th e mo to r co rt ex a nd ce re be llu m 23; de fi ci ts in n eu ra l pr og en it or pr ol if er at io n an d ma tu ra ti on in hi pp oc am pus 22 Ag e de pe nd en t in cr ea se o f GF A P-po si ti ve as tr oc yt es in co rt ex a nd th al am us 24 Ag e d ep en de nt in cr ea se o f CD 11 b-po si ti ve mi cr og li a in c or te x, h ip po ca m pu s an d th al am us 24 Re duc ed ol ig od en dr oc yt e pr og en it or c el l pr ol if er at io n an d ol ig od en dr oc yt e de ns it y in b ra in a nd sp in al c or d 23 Ly nc h sy nd ro m e; mo sa ic va ri eg at ed an eu pl oi dy sy nd ro m e Dn m t1 an d Dn m t3 a Co nd it io na l Dn m t1 an d Dn m t3 a KO in ne ur on Ag e-de pe nde nt de cl in e in le ar ni ng a nd me mo ry 26 Sm al le r hi pp oc am pi 26 Im pa ir ed n eu ra l pl as ti ci ty in C A 1 26 Ce re be lla r at ax ia , de af ne ss , a nd na rc ol ep sy ; he re di ta ry se nso ry ne ur op at hy Er cc 1 Hy po m or p hi c mu ta ti on Cl as pi ng o f t he hi nd -li m bs , fi ne tr em or s an d ky ph os is , re duc ed m ot or pe rf or ma nc e an d co gn it iv e de cl in e 29 Sm al le r br ai n 29 Ag e-de pe nde nt ch an ge s in th e pr ot eo mi c co m po si ti on a nd sy na pt ic p la st ic it y in h ip po ca m pu s 28 ,85; p ro gr es si ve mo to r ne ur on lo ss in s pin al c or d 29 Ag e-re la te d in cr ea se in GF A P po si ti ve as tr oc yt es in sp in al c or d an d br ai n 29 Ag e-re la te d in cre as e in Ma c2 -po si ti ve mi cr og lia in sp in al c or d a nd b ra in 29; hy pe rt ro phi c m orp h ol og y wi th th ic ke ne d p ri m ar y pr oc es se s an d la rg er c el l bo di es ; i nc re as ed ph ag oc yt os is , pr ol if er at io n an d R O S pr od uc ti on ; pr imi ng s ta te 31 ,32 Ce re br o-oc ul o-fa ci o-sk el et al (C O FS ) sy nd ro m e; xe ro de rm a pi gme nt os um (X P )
Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Xp g KO Lo ss o f h ea ri n g an d vi si on , co gn it iv e de cl in e, m ot or de fi ci ts a nd ear ly de ve lo pm en t of tr em or s 34 Sm al le r br ai n 86 Lo ss o f P Cs ; ab no rm al d en dr it ic mo rph ol og ie s an d sw ol le n pr ox im al ax on o f P Cs 35 Ag e-re la te d in cr ea se in GF A P po si ti ve as tr oc yt es in sp in al c or d an d br ai n 35 Ag e-re la te d in cre as e in Ib a-1 p os it iv e m ic ro gl ia in sp in al c or d a nd b ra in 35 X P; C O FS sy nd ro m e Cs a KO In cr ea se of p 5 3-po si ti ve n eu ro ns in ne oc or te x, ce re be lla r co rt ex an d sp in al c or d; no n-de te ct ab le le ve ls o f n eu ro na l de ge n er at io n at 2 6 we ek s of a ge 36 In cr ea se of p5 3-po si ti ve as tr oc yt es in ne oc or te x, ce re be lla r co rt ex a nd sp in al c or d; in cr ea se o f GF A P-po si ti ve as tr oc yt es in th e me du lla ry re ti cul ar fo rm at io n 36 In cr ea se of M ac 2-po si ti ve mi cr og lia in th e w hi te ma tt er 36 Ma c2 -po si ti ve mi cr og lia w er e fr eq ue nt ly in cl os e pr ox imi ty o f ol ig od en dr oc yt es in sp in al c or d 36 Co ck ay ne sy nd ro m e (C S) Cs b KO Mi ld m ot or co or di n at io n de fi ci ts ; re duc ed lo co m ot io n 87 CS ; CO F S sy nd ro m e Xp d Kn oc ki n; G6 02 D p oi nt mu ta ti on in Xp d lo cu s Le ss a ct iv e wi th in th e fi rs t mi nu te o f a n op en fi el d te st ; no rm al m ot or co or di n at io n an d lea rn in g ca pa ci ty 88 XP c om bi ne d wi th C S (X P CS ); tr ic ho th io dy st ro phy (T TD ) Cs b an d Xp a Ne ur on -sp ec if ic K O Xp a in Cs b -/ - mi ce Se iz ur e be ha vi or ; re duc ed lo co m ot or ac ti vi ty ; re duc ed am bu lat or y be ha vi or in op en fi le d te st 36 Co rt ex at ro ph y 36 Ch ro ni c ne ur on al de ge n era ti on in fo re br ai n n eu ro ns 36 In cr ea se of GF A P-po si ti ve as tr oc yt es in ne oc or te x, hi pp oc am pu s an d am yg dal a 36 CS; X P
2 Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Si rt 6 Br ai n-sp ec if ic Si rt 6 KO Im pa ir ed n on -as so ci at iv e (o pe n fi el d te st) a nd as so ci at iv e (c on te xt ua l fe ar co nd it io ni ng ) le ar ni ng 39 Te rc KO Im pa ir ed sp at ia l l ea rn in g an d m em or y 42 De cr ea se d DG vo lu m e 42 Lo ss o f n eu ro ns in th e CA 1 an d fr on ta l co rt ex ; r ed uce d sy na pt ic d en si ty in fr on ta l co rt ex ; im pa ir ed d en dr it ic de ve lo pm en t a nd ne ur it oge ne si s in hi pp oc am pus 43 Un ch an ge d GF A P po si ti ve as tr oc yt es de ns it y in co rt ex 43 Ag e d ep en de nt d ec re as e of CD 11 b po si ti ve m ic ro gl ia l nu m be r and c el l b od y vo lu m e in D G ; i nc re as ed mi cr og lia l d en si ty in D G 42; i nc re ase d Ib a-1 p os it iv e mi cr og lia d en si ty ; r ed uc ed de ndr it ic le ng th a nd br an ch p oi nt s of m ic ro gli a in c or te x an d CA 1 43 Dy ske ra to si s co ng en it a (D K C) Te rt KO Im pa ir ed sp at ia l l ea rn in g an d m em or y 49; ag gr es si ve an d de pr es si ve be ha vi or 48 Im pa ir ed d en dr it ic de ve lo pm en t a nd ne ur it og ene si s in hi pp oc am pus 49 DK C Tw nk Ov er ex pr es si o n of Tw in kl e du p3 53 – 36 5 in D A ne ur ons Im pa ir ed mo to r co or di n at io n 89 Lo ss o f D A n eu ro ns in th e SN 89 Pr og re ssi ve ex ter nal op ht ha lm op le gi a; inf ant ile -on se t sp in oc er eb el l ar at ax ia; Pe rr au lt sy nd ro m e
Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Tf am Co nd it io na l K O Tf am in fo re br ai n ne ur ons (M IL O N m ic e) De cr ea se d sp on ta ne ou s mo to r ac ti vi ty ; wo bb ly wa lk in g; ag gr es si ve be ha vi or an d/ or hy pe ra ct iv it y in r es po ns e to st re ss 90 Ma ss iv e ne ur od eg en er at io n in th e hi pp oc am pus , t he so m at ose nso ry co rt ex a nd th e pi ri fo rm c or te x 90; ex ten si ve ax on al de ge n er at ion in ne oc or te x and hi pp oc am pus 91 In cr ea se of GF A P-po si ti ve c el ls in c or pu s ca llo su m 91 Mi to ch on dr ia l DN A de pl et io n sy nd ro m e Af g3 l2 Ha pl oi ns uf fi ci e nc y of Af g3 l2 Im pa ir ed mo to r co or di n at io n; ab no rm al g ai t; cl as pi ng o n ta il su sp en si on 92 Pr og re ssi ve lo ss of PC s; m or ph ol og ic al ch an ge s of P Cs 92 As tr oc yt es ac ti vat io n in gr an ul e la ye r of ce re be llu m 92 Sp as ti c a ta xi a; sp in oc er eb el l ar at ax ia Co nd it io na l KO Af g3 l2 in P Cs Un ste ad y ga it 93 Pr og re ssi ve lo ss of PC s; im pa ir ed mi to ch on dr ia l pr ot ei n s yn th es is in P Cs 93 As tr oc yt es act iv at io n in ce re be llu m ; ac ti vat ed as tr oc yt es ar e hy pe rt ro phi c an d ex pr es s in cr ea se d le ve ls o f GF A P 93 Pr og re ssi ve a ct iv at io n of mi cr og lia in c er ebe llu m ; ce llu la r hy pe rt ro ph y an d re tra ct io n of c yt op la sm ic pr oc es se s of a ct iv at ed mi cr og lia 93 Co nd it io na l KO Af g3 l2 in fo re br ai n ne ur ons De ge n er at io n of co rt ica l n eu ro ns ; in cr ea se d pT au le ve ls in c or ti ca l ne ur on 94 Co nd it io na l KO Af g3 l2 in ol ig od en dr oc yt es Mi ld b ut si gn if ic an t im pa ir m en t in mo to r co or di n at io n 95 Ax on al de ge n er at io n ch ar act er iz ed b y my el in th ic ke ni ng , va cu ol iz at io n an d di sr up ti on in s pi n al co rd 95
2 Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Af g3 l1 an d Af g3 l2 Co nd it io na l K O Af g3 l2 an d Af g3 l1 in ol ig od en dr oc yt es Im pa ir ed mo to r co or di n at io n 95 Up re gu la ti on of G FA P pr ot ei n le ve l in th e br ain an d sp in al co rd , as tr oc yt es ac ti vat io n in co rp us ca llo su m 95 Ac tiv at ed a m oe bo id -li ke mi cr og lia w it h th ic k pr oc es se s in c or p us ca llo su m 95 Pr og re ssi ve a xo n al de m ye lin at io n in th e sp in al c or d an d br ai n; d ea th o f ma tu re ol ig od en dr oc yt es fo llo w ed b y co m pe ns at or y re po pul at io n 95 Sp as ti c a ta xi a; sp in oc er eb el l ar at ax ia Sp g7 KO Ab no rm al g ait ch ar act er iz ed by un co ord in at ed mo ve me nt o f th e hi nd lim bs ; pr og re ss iv e im pa ir ed mo to r co or di n at io n 96 Pr og re ssi ve de ge n er at io n of lo ng s pi na l a xo ns , op ti c ne rv es a nd sc ia ti c ne rv es; mi to ch on dr ia l ab no rm al it ies in sy na pt ic te rm in al s in s pin al c or d 96 Sp as ti c pa ra pl eg ia Sp g7 an d Af g3 l2 Sp g7 KO a nd Af g3 l2 ha pl oi ns uf fi ci e nc y Re duc ed c ag e ac ti vi ty ; al ter ed co or di n at io n o f th e hi nd lim bs du ri ng g ai t; lo ss o f ba la nc e, un co ord in at ed ga it , t re m or an d dy st on ic mo ve me nt s of th e he ad 97 Pr og re ssi ve de ge n er at io n an d ab no rm al de ndr it og en es is o f PC s; d eg en er at io n of h ip p oc am p al CA 3 py ra m id al ne ur ons 97 As tr oc yt es ac ti vat io n in hi pp oc am pu s 97 Sp as ti c pa ra pl eg ia ; sp ast ic a ta xi a; sp in oc er eb el l ar at ax ia
Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Ph b2 Co nd it io na l K O Ph b2 in fo re br ai n Im pa ir ed le ar ni ng a nd me mo ry ; im pa ir ed in na te fe ar be ha vi or a nd mo to r co or di n at io n; ex ces si ve pa th ol og ic al gr oo m in g be ha vi or 98 Sm al le r br ai n; fo re br ai n at ro ph y 98 Lo ss of n eu ro ns in DG a nd c or nu am m on is ( CA ); in cr ea se d pT au in hi pp oc am pus ; sh ri nk ag e of th e ce ll bo dy a nd lo ss of p roc es se s of co rt ex n eu ro n 98 Pr og re ssi ve de ve lo pm en t of as tr og lio si s in D G 98 Ai f Ai f hy po m or phi c ha rl eq ui n mu ta ti on Al te re d ga it pa tt er n an d rhy thm ; l ow er lo co m ot io n sp ee d 99 Sm al le r ce re be lla 10 0 Pr og re ssi ve lo ss of ce re be lla r gr an ul e ce lls a nd P Cs 100 Pr og re ssi ve as tr og lio si s in th al am us , ce re be llu m an d th e ST R 10 1 Mi cr og lia a ct iv at io n 101 Co w ch oc k sy nd ro m e; X -lin ke d de af ne ss -5 Ps tI Sp ec if ic ex pr es si on o f mi to -Ps tI ge ne in D A n eu ro ns Re duc ed ex pl or at or y be ha vi or a nd sp on ta ne ou s ac ti vi ty ; im pa ir ed mo to r co or di n at io n 10 2 Pr og re ssi ve lo ss of DA n eu ro ns in S N ; re duc ed D A n euro n pr oj ec ti on a nd al ter ed ne ur ot ra ns m it te r pr od uc ti on in th e ST R 102 He re di ta ry pa nc re at it is Ex pr es si on o f mi to -Ps tI in fo re br ai n ne ur ons Ab no rm al lim b-cl as pi ng ; im pa ir ed mo to r co or di n at io n; im pa ir ed sp at ia l l ea rn in g an d m em or y 10 3 Sm al le r br ai n; co rt ica l at ro ph y 10 3 Ma ss iv e ne ur od eg en er at io n in th e ST R 103 In cr ea se d GF A P p ro te in le ve l i n ST R , hi pp oc am pu s an d co rt ex 10 3
2 Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Ps tI Sp ec if ic ex pr es si on o f mi to -Ps tI ge ne in ol ig od en dr oc yt es Im pa ir ed mo to r co or di n at io n; re duc ed sp on ta ne ou s ac ti vi ty ; g ai t al ter at io ns ; tr un k in st ab ilit y; lo ss of ta il ton e; st if f a nd wo bb ly wa lk in g; re duc ed re ari ng be ha vi or 104 As tr og lio sis in s pin al co rd 104 Mi cr og lio si s in s pi na l c or d 10 4 ol ig od en dr oc yt e lo ss , d em ye lin at io n, an d ax on al d am ag e in th e sp in al c or d 10 4 Be cn 1 He te ro zy go us KO Be cn 1 in AP P tr an sg en ic mi ce Re duc ed n euro na l au to ph ag y; sy na pt od en dr it ic de ge n er at io n; ne ur on lo ss 105 In cr ea se d CD 68 e xp re ss ion an d un ch an ged Ib a-1 ex pr es si on in fr on tal co rt ex 105 Co nd it io na l K O Be cn 1 in P Cs Ab no rm al g ait an d at ax ic be ha vi or 106 Sw ol le n d ys tr op hi c ax on s of th e PC s; ra pi d de ge ne ra ti on of P Cs 106 Co nd it io na l K O Be cn 1 in co rt ica l a nd hi pp oc am pa l ne ur ons Re duc ed n euro n de ns it y in C A 1 106 At g7 Co nd it io na l K O At g7 in C N S Ab no rm al lim b-cl as pi ng re fl exe s; tr em or ; im pa ir ed mo to r co or di n at io n 10 7 Co rt ex at ro ph y 10 7 Lo ss o f P Cs ; n eu ro n lo ss in hi pp oc am pus 107 Inc re as ed GF A P ex pr es si on in th e ce re br al co rt ex 107
Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) At g7 Co nd it io na l K O At g7 in m ot or ne ur ons o f SO D 1 G9 3A mi ce Hi nd lim b tr em or 108 Pr og re ssi ve lo ss of mo to r ne ur on s 108 D ec reas ed GF A P ex pr es si on in sp in al c or d co m pa re d to SO D 1 G9 3A mi ce 108 De cr ea se d Ib a-1 ex pr es si on in s pi nal c or d co m pa re d to S O D 1 G9 3A mi ce 108 Co nd it io na l K O At g7 in P Cs Im pa ir ed lo co m ot io n an d m ot or co or di n at io n 10 9 Ax on al d ys tr op hic sw el lin g; de ge n er at io n of PC s 10 9 Co nd it io na l K O At g7 in fo re br ai n ne ur ons Im pa ir ed co nt ex tu al fe ar me mo ry a nd cu ed fe ar me mo ry 110 Pr og re ssi ve de ge n er at io n of CA 1 n eu ro ns ; in cr ea se d pT au -po si ti ve in cl us io ns in n eu ro ns 110 Co nd it io na l K O At g7 in D A ne ur ons Im pa ir ed lo co m ot io n 111 De la ye d D A n eu ro n de ge n er at io n in mi db ra in ; e ar ly de ge n er at io n of ni gr os tr ia ta l a xo ns ; re du ce d st ri at al DA le ve ls ; dy st ro ph ic de ndr it es ; ac cu mu la ti on o f al ph a-sy nu cl ei n in pr es yn apt ic te rm in al s 111 FI P 20 0 Co nd it io na l K O FI P 20 0 in C N S Im pa ir ed mo to r co or di n at io n; tr em or s an d st if f mo ve me nt ; ab no rm al li m b- cl as pi ng re fl exe s 112 Sm al le r ce re be lla 11 2 Pr og re ssi ve lo ss of ne ur ons , sp on gi osi s, a nd ne ur it e de ge n er at io n in th e ce re be llu m 112 He re di ta ry br ea st -ov ar ia n ca nce r sy nd ro m e
2 Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Sm pd 3 KO Ag e-de pe nde nt de cl in e of mo to r, co or di n at io n, an d co gn it iv e ab ili ty 54 In cr ea se d ne ur on -sp ec if ic m ar ke r Ma pt an d Tt bk ex pr es si on ; a ge -de pe nd en t ne ur on al dy sp ro te os ta si s ch ar act er iz ed b y in cr ea se d AP P, am yl oi d-be ta a nd pT au p ro te in le ve ls ; a ge -de pe nd en t i nc re as e of n eu ron al ap op to si s 54 Un ch an ge d as tr oc yt es -sp ec if ic ma rk er s Ea ac 1 an d Gl as t1 ge ne ex pr es si on le ve l i n br ai n 54 In cr ea se d ol ig od en dr oc yt e-sp ec if ic Pl p ge ne ex pr es si on in b rai n 54 Bi p Kn oc k-in ; Bi p he te ro zy go us mu ta ti on Im pa ir ed mo to r co or di n at io n; pa ra ly si s an d tr em or ; l os s of ri ght in g re fl ex 56 In cr ea se d E R st re ss, p ro te in ag gr eg at io n an d ne ur od eg en er at io n in th e mo to n eu ro ns o f sp in al c or d 56 Ig f-1 Co nd it io na l Ig f-1 KO in liv er Im pa ir ed sp at ia l me mo ry le ar ni ng 58 In cr ea se d nu m be r of GF A P po si ti ve c el ls in D G 58 In su lin -li ke gr ow th fa ct or I d ef ic ie nc y Ig f1 r As tr oc yt e-sp ec if ic K O o f Ig f1 r Im pa ir ed wo rk in g me mo ry 59 Im pa ir ed mi to ch on dr i al fu nc ti on ; de fi ci en t i n gl uc os e an d am yl oi d-be ta up ta ke in as tr oc yt es 59 IG F-1 re si st an ce
Ge n e o r pr o te in Ge n et ic ma n ip u la ti o n Be h av io ra l ab no rm al it ie s Br ai n si ze Ne ur o n phe n o ty p es As tr o cy te phe n o ty p es Mi cr o gl ia p h en o ty p es Ol ig o de n d ro cy te phe n o ty p es Hu m an sy n dr o m e( s) Fo xo 1/ 3/ 4 KO Ax on al de ge n er at io n 60 Ex te ns iv e as tr oc yt es ac ti vat io n in th e br ai n an d sp in al c or d 60 Ex te ns iv e m ic ro gl ia l ac ti vat io n in th e br ai n an d sp in al c or d 60 Al ve ol ar rha bd om yo sa rc om a Ne ur on -sp ec if ic K O o f Fo xo 1 /3 /4 Au dit or y st ar tl e re fl ex es, th e vo lu nta ry wh ee l-run ni ng ac ti vi ty , im pa ir ed lo co m ot io n an d m ot or co or di n at io n; in cr ea se d le g cl as pi ng be ha vi or 60 As tr oc yt es ac ti vat io n in th e ce re be llu m 60 Mi cr og lia l a ct iv at io n in th e ce re be llu m 60 Ab br ev ia ti on s: K O , k no ck ou t; D A , d op am in e; SN , su bst an ti a ni gr a; G A B A , g am m a-am in ob ut yr ic a ci d; P Cs , P ur ki nj e ce lls ; A T , A ta xi a-te la ng ie cta si a; G FA P, gl ia l f ib ri lla ry a ci di c pr ot ei n; CA , co rn u am m on is ; R O S, r ea ct iv e ox yg en s pe ci es ; CO FS , ce re br o-oc ul o-fa ci o-sk el et al ; X P, x er od er m a p ig m en to su m ; Ib a-1, io ni ze d c al ciu m -bi nd in g ad ap te r m ole cu le 1 ; C S, Co ck ay ne s yn dr om e; X P CS , xe ro de rm a pi gm en to su m c om bi n ed w it h Co ck ay n e sy ndr om e; T T D , tr ic ho th io dy st ro ph y; D G , de nt at e gy ru s; D K C, d ys ke ra to si s co ng en it a; pT au , ph os ph or yl at ed T au ; S TR , st ri at um ; A PP , a m yl oi d pr ec ur so r pr ot ei n; ER , e nd op la sm ic r et ic ul um .
2 Conflicts of interests The authors have no conflicts of interest to declare. Acknowledgements This work was supported by a China Scholarship Council (CSC) and Graduate School of Medical Science (GSMS) joint fellowship to Yang Heng. Susanne M Kooistra is funded by the Netherlands Organisation for Scientific Research (NWO, VENI, #016.161.072) and the MS Research Foundation.
References 1 Vanhooren, V. & Libert, C. The mouse as a model organism in aging research: usefulness, pitfalls and possibilities. Ageing Res Rev 12, 8-21 (2013). 2 Harkema, L. et al. Pathology of mouse models of accelerated aging. Veterinary Pathology 53, 366-389 (2016). 3 Yeoman, M. et al. Insights into CNS ageing from animal models of senescence. Nat Rev Neurosci 13, 435-445 (2012). 4 de Magalhaes, J. P. et al. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25, 875-881 (2009).
5 Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Molecular Cell 49, 359-367 (2013).
6 Spiers, H. et al. Age-associated changes in DNA methylation across multiple tissues in an inbred mouse model. Mech Ageing Dev 154, 20-23 (2016).
7 Zahn, J. M. et al. AGEMAP: a gene expression database for aging in mice. PLOS Genetics 3, e201 (2007). 8 Loerch, P. M. et al. Evolution of the aging brain transcriptome and synaptic regulation. PLOS ONE 3, e3329 (2008). 9 Bishop, N. A. et al. Neural mechanisms of ageing and cognitive decline. Nature 464, 529-535, (2010). 10 Lopez-Otin, C. et al. The hallmarks of aging. Cell 153, 1194-1217 (2013). 11 Chow, H. M. & Herrup, K. Genomic integrity and the ageing brain. Nat Rev Neurosci 16, 672-684 (2015).
12 Maynard, S. et al. DNA Damage, DNA Repair, Aging, and Neurodegeneration. Cold Spring Harb
Perspect Med 5 (2015).
13 Specks, J. et al. Modeling the study of DNA damage responses in mice. Methods Mol Biol 1267, 413-437 (2015).
14 Friedberg, E. C. & Meira, L. B. Database of mouse strains carrying targeted mutations in genes affecting biological responses to DNA damage Version 7. DNA Repair 5, 189-209 (2006).
15 Shiloh, Y. & Lederman, H. M. Ataxia-telangiectasia (A-T): An emerging dimension of premature ageing. Ageing Res Rev 33, 76-88 (2017).
16 Stern, N. et al. Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice. J Biol Chem 277, 602-608 (2002).
17 Kamsler, A. et al. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice. Cancer Res 61, 1849-1854 (2001).
18 Chiesa, N. et al. Atm-deficient mice Purkinje cells show age-dependent defects in calcium spike bursts and calcium currents. Neuroscience 96, 575-583 (2000).
19 Eilam, R. et al. Late degeneration of nigro-striatal neurons in ATM-/- mice. Neuroscience 121, 83-98, (2003).
20 Raz-Prag, D. et al. A role for vascular deficiency in retinal pathology in a mouse model of ataxia-telangiectasia. Am J Pathol 179, 1533-1541(2011).
21 Baker, D. J. et al. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol 15, 96-102 (2013). 22 Yang, Z. et al. Age-related decline in BubR1 impairs adult hippocampal neurogenesis. Aging Cell 16, 598-601 (2017). 23 Choi, C. I. et al. The progeroid gene BubR1 regulates axon myelination and motor function. Aging 8, 2667-2688 (2016). 24 Hartman, T. K. et al. Mutant mice with small amounts of BubR1 display accelerated age-related gliosis. Neurobiol Aging 28, 921-927 (2007). 25 Liu, L. et al. Insufficient DNA methylation affects healthy aging and promotes age-related health problems. Clin Epigenetics 2, 349-360 (2011). 26 Feng, J. et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13, 423-430 (2010). 27 McKinnon, P. J. Maintaining genome stability in the nervous system. Nat Neurosci 16, 1523-1529 (2013). 28 Borgesius, N. Z. et al. Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair. J Neurosci 31, 12543-12553 (2011). 29 de Waard, M. C. et al. Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice. Acta Neuropathol 120, 461-475 (2010).
2
30 Vegh, M. J. et al. Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging. J Proteome Res 11, 1855-1867 (2012).
31 Raj, D. D. et al. Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol
Aging 35, 2147-2160 (2014).
32 Holtman, I. R. et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun 3, 31 (2015). 33 Karikkineth, A. C. et al. Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev 33, 3-17 (2017). 34 La Fata, G. et al. Vitamin E supplementation reduces cellular loss in the brain of a premature aging mouse model. J Prev Alzheimers Dis 4, 226-235 (2017). 35 Barnhoorn, S. et al. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. PLOS Genetics 10, e1004686 (2014). 36 Jaarsma, D. et al. Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology. PLOS Genetics 7, e1002405 (2011). 37 Satoh, A. et al. The brain, sirtuins, and ageing. Nat Rev Neurosci 18, 362-374 (2017). 38 Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218-221 (2012). 39 Kaluski, S. et al. Neuroprotective functions for the histone deacetylase SIRT6. Cell Rep 18, 3052-3062 (2017).
40 Sykora, P. et al. DNA polymerase beta deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res 43, 943-959 (2015). 41 Blasco, M. A. Telomere length, stem cells and aging. Nat Chem Biol 3, 640-649 (2007). 42 Khan, A. M. et al. Telomere dysfunction reduces microglial numbers without fully inducing an aging phenotype. Neurobiol Aging 36, 2164-2175 (2015). 43 Rolyan, H. et al. Telomere shortening reduces Alzheimer's disease amyloid pathology in mice. Brain 134, 2044-2056 (2011). 44 Raj, D. D. et al. Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening. Aging Cell 14, 1003-1013 (2015). 45 Linkus, B. et al. Telomere shortening leads to earlier age of onset in ALS mice. Aging 8, 382-393 (2016). 46 Scheffold, A. et al. Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model. Acta Neuropathol Commun 4, 87 (2016). 47 Strong, M. A. et al. Phenotypes in mTERT(+)/(-) and mTERT(-)/(-) mice are due to short telomeres, not telomere-independent functions of telomerase reverse transcriptase. Mol Cell Biol 31, 2369-2379 (2011). 48 Zhou, Q. G. et al. Reactivation of Tert in the medial prefrontal cortex and hippocampus rescues aggression and depression of Tert(-/-) mice. Transl Psychiatry 6, e836 (2016). 49 Zhou, Q. G. et al. Hippocampal TERT regulates spatial memory formation through modulation of neural development. Stem Cell Rep 9, 543-556 (2017). 50 Hekimi, S. et al. Taking a "good" look at free radicals in the aging process. Trends Cell Biol 21, 569-576 (2011). 51 Iommarini, L. et al. Mitochondrial diseases part II: Mouse models of OXPHOS deficiencies caused by defects in regulatory factors and other components required for mitochondrial function.
Mitochondrion 22, 96-118 (2015). 52 Jones, J. M. et al. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425, 721-727 (2003). 53 Rubinsztein, D. C. et al. Autophagy and aging. Cell 146, 682-695 (2011). 54 Stoffel, W. et al. SMPD3 deficiency perturbs neuronal proteostasis and causes progressive cognitive impairment. Cell Death Dis 9, 507 (2018). 55 Hetz, C. & Mollereau, B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15, 233-249 (2014). 56 Jin, H. et al. Late-onset of spinal neurodegeneration in knock-in mice expressing a mutant BiP. PLOS ONE 9, e112837 (2014).
57 Broughton, S. & Partridge, L. Insulin/IGF-like signalling, the central nervous system and aging.
58 Svensson, J. et al. Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice. J Endocrinol 189, 617-627 (2006).
59 Logan, S. et al. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-beta uptake in astrocytes. Mol Metab 9, 141-155 (2018). 60 Tia, N. et al. Role of Forkhead Box O (FOXO) transcription factor in aging and diseases. Gene 648,
97-105 (2018).
61 Hwang, I. et al. FOXO protects against age-progressive axonal degeneration. Aging Cell e12701 (2018).
62 Takeda, T. et al. Senescence-accelerated mouse (SAM): a novel murine model of accelerated senescence. J Am Geriatr Soc 39, 911-919 (1991).
63 Akiguchi, I. et al. SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions. Neuropathology 37, 293-305 (2017). 64 Virgili, J. et al. Characterization of a 3xTg-AD mouse model of Alzheimer's disease with the
senescence accelerated mouse prone 8 (SAMP8) background. Synapse 72, e22025 (2018). 65 Cosin-Tomas, M. et al. Epigenetic alterations in hippocampus of SAMP8 senescent mice and
modulation by voluntary physical exercise. Front Aging Neurosci 6, 51 (2014).
66 Wang, C. M. et al. Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8. Biogerontology 11, 87-102 (2010). 67 Pal, S. & Tyler, J. K. Epigenetics and aging. Sci Adv 2, e1600584 (2016). 68 Jesko, H. et al. Sirtuins and their roles in brain aging and neurodegenerative disorders. Neurochem Res 42, 876-890 (2017). 69 Karagiannis, T. C. & Ververis, K. Potential of chromatin modifying compounds for the treatment of Alzheimer's disease. Pathobiol Aging Age Relat Dis 2, doi: 10.3402 (2012). 70 Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232-236 (2011). 71 Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 8, 422 (2017).
72 Spittau, B. Aging microglia-phenotypes, functions and implications for age-related neurodegenerative diseases. Front Aging Neurosci 9, 194 (2017). 73 Rawji, K. S. et al. Immunosenescence of microglia and macrophages: impact on the ageing central nervous system. Brain 139, 653-661 (2016). 74 Fontana, L. et al. Extending healthy life span--from yeast to humans. Science 328, 321-326 (2010). 75 Vidal, R. L. et al. Targeting autophagy in neurodegenerative diseases. Trends Pharmacol Sci 35, 583-591 (2014).
76 Bartke, A. Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146, 3718-3723 (2005).
77 Mitchell, S. J. et al. Animal models of aging research: implications for human aging and age-related diseases. Annu Rev Anim Biosci 3, 283-303 (2015).
78 Kirkland, J. L. Translating the Science of Aging into Therapeutic Interventions. Cold Spring Harb
Perspect Med 6, a025908 (2016).
79 Shineman, D. W. et al. Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies. Alzheimers Res Ther 3, 28 (2011). 80 Mattison, J. A. & Vaughan, K. L. An overview of nonhuman primates in aging research. Exp Gerontol 94, 41-45 (2017). 81 Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159-171 (1996). 82 Eilam, R. et al. Selective loss of dopaminergic nigro-striatal neurons in brains of Atm-deficient mice. PNAS USA 95, 12653-12656 (1998). 83 Meshulam, L. et al. The role of the neuro-astro-vascular unit in the etiology of ataxia telangiectasia. Front Pharmacol 3, 157 (2012).
84 Liu, N. et al. ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes. Lab Invest 85, 1471-1480 (2005). 85 Nevedomskaya, E. et al. Metabolic profiling of accelerated aging ERCC1 d/- mice. J Proteome Res 9, 3680-3687 (2010). 86 Sun, X. Z. et al. A genetic mouse model carrying the nonfunctional xeroderma pigmentosum group G gene. Congenit Anom (Kyoto) 43, 133-139 (2003). 87 van der Horst, G. T. et al. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell 89, 425-435 (1997).
