Neurosci. Bull. February, 2023, 39(2):303–314
cn
https://doi.org/10.1007/s12264-022-00969-9
REVIEW
Mechanisms Underlying Brain Aging Under Normal
and Pathological Conditions
Menglong Jin1,2 · Shi‑Qing Cai1 
Received: 9 March 2022 / Accepted: 17 June 2022 / Published online: 27 November 2022
© The Author(s) 2022
Abstract  Aging is a major risk factor for many human
diseases, including cognitive impairment, which affects a
large population of the elderly. In the past few decades, our
understanding of the molecular and cellular mechanisms
underlying the changes associated with aging and age-
related diseases has expanded greatly, shedding light on the
potential role of these changes in cognitive impairment. In
this article, we review recent advances in understanding of
the mechanisms underlying brain aging under normal and
pathological conditions, compare their similarities and dif-
ferences, discuss the causative and adaptive mechanisms of
brain aging, and finally attempt to find some rules to guide
us on how to promote healthy aging and prevent age-related
diseases.
Keywords  Healthy aging · Pathological aging · Cognitive
impairment
Introduction
As we age, our bodies undergo many changes [1–3] that can
be physiological and pathological. Just like other organs,
the brain is susceptible to aging and it undergoes a series
of structural and functional changes during aging [2, 4]. In
the context of brain biology aging is a major risk factor for
* Shi‑Qing Cai
sqcai@ion.ac.cn
1
Institute of Neuroscience and State Key Laboratory
of Neuroscience, CAS Center for Excellence in Brain Science
and Intelligence Technology, Chinese Academy of Sciences,
Shanghai 200031, China
2
University of Chinese Academy of Sciences, Beijing 100049,
China
www.neurosci.
www.springer.com/12264
developing cognitive impairment like Alzheimer’s disease
(AD), the most common dementia that affects ~55 mil-
lion people worldwide and 15 million in China [5]. Thus,
the development of new drugs or treatments to prevent or
reverse cognitive impairment requires a comprehensive
understanding of the biological events associated with the
aging process in the brain.
In the past decades, our understanding of the molecu-
lar mechanism underlying the modulation of aging has
been greatly expanded. Most remarkably, several signaling
pathways have been identified as key aging modulators in
Caenorhabditis elegans (C. elegans), flies, and mammals,
suggesting that the biology of aging is conserved across
species and the rate of aging is plastic [6, 7]. Nine com-
mon age-related molecular and cellular alterations have been
proposed as hallmarks of aging [3]. Most of these hallmarks
occur in aging neurons, except for cellular senescence and
telomere attrition (both of which usually occur in prolifera-
tive peripheral tissues), which remain to be established [8].
A myriad of evidence has implied that these hallmarks also
occur in pathological aging brains at a more severe level
[9]. However, although brain atrophy and cognitive decline
appear both in normal and pathological aging brains, the
mechanisms underlying these phenomena are not exactly the
same. Cognitive decline in normal aging is attributed to the
disruption of circuits and synapses, without significant neu-
ron loss, and this is in contrast to AD and related dementias,
which are associated with extensive neuronal death [10, 11].
In this review, we mainly focus on several molecular and
cellular events (genomic instability, epigenetic alteration,
mitochondrial dysfunction, deregulated nutrient sensing,
altered cell proliferative capacity, altered intercellular com-
munication, and loss of proteostasis; Fig. 1) to review the
mechanisms of normal aging and how those processes inter-
face with pathological aging of the brain.
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Fig. 1  Molecular and cellular events occur in aging brains under nor-
mal and pathological conditions. Molecular and cellular alterations in
genomic stability, mitochondrial function, nutrient sensing, epigenetic
modification, cell proliferative capacity, intercellular communication,
and proteostasis can be similar or different in aging brains under nor-
mal and pathological conditions.
Genomic Instability
One common feature of aging is the accumulation of genetic
damage throughout life [12]. Genomic DNA is regularly
damaged by radiation, reactive oxygen species (ROS),
DNA replication errors, and other exogenous or endogenous
threats, and damaged DNAs are progressively accumulated
during the normal course of aging. Such accumulation is
more serious in aging neurons because excitatory synaptic
activity produces more ROS, causing more DNA damage.
Furthermore, neurons are post-mitotic cells and can not
repair double-strand breaks by the more accurate homolo-
gous recombination pathway. Indeed, analyses of tissue
samples from human and rodent brains have revealed that
the amount of damaged nuclear and mitochondrial DNA
increases and the capacity for DNA repair decreases during
aging [8]. In the cortex of the aging human brain, promoter
regions of a considerable proportion of genes are damaged,
resulting in reduction of expression of a subset of genes
associated with synaptic plasticity, mitochondrial function,
and neuronal survival [13]. Interestingly, a similar pattern
of DNA damage in vulnerable genes has also been found
in C. elegans, Drosophila, and mouse [14–17], suggesting
that selective DNA damage to gene promoter sequences is
a conserved mechanism underlying age-related cognitive
impairment.
Compared with the moderate DNA damage occurring
in normal aging brains, the damage to genomic DNA in
aging brains under pathological conditions is much more
severe. Studies have shown that in human brains with AD,
the genomic DNA is evidently disrupted, and the exten-
sive DNA damage may eventually lead to the death of a
large number of neurons [18]. Aggregated β-amyloid pep-
tide (Aβ), a major pathological hallmark of AD, worsens
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Neurosci. Bull. February, 2023, 39(2):303–314
the DNA damage by inducing aberrant synaptic activity,
which elicits more ROS [19]. Similarly, enhanced oxida-
tive DNA lesions and damage to mitochondrial DNA have
been reported in the neurons of amyotrophic lateral sclero-
sis (ALS) and Parkinson disease (PD) patients, respectively
[20–22].
Genomic instability is a key cause of age-related cogni-
tive impairment. Accumulating evidence has demonstrated
that impairment of DNA repair is sufficient to accelerate
aging phenotypes and induce neurodegeneration [23]. Cen-
tral dogma states that DNA transfers genetic information to
RNA and produces functional proteins. Thus, DNA dam-
age eventually affects the function of proteins, and therefore
accumulation of DNA damage is a likely major cause of
chronic systemic failures, which are further worsened under
pathological conditions. This inevitably confers insults on
the aging brain, consequently impairing cognitive function,
and may drive the onset or progression of neurodegenera-
tive diseases.
Mitochondrial Dysfunction
Mitochondrial impairment has been regarded as one of the
hallmarks of aging [3]. Neurons are more susceptible to
mitochondrial impairment as they need high energy to be
functional. In the aging brain, mitochondria exhibit a myriad
of structural and functional changes, including morphologi-
cal enlargement or fragmentation, membrane depolarization,
an impaired electron transport chain, and increased oxida-
tive damage to mitochondrial DNA (mtDNA) [3, 24]. The
molecular mechanism underlying age-related dysfunction of
mitochondria remains controversial. It has been suggested
that mitochondrial dysfunction is due to the gradual accumu-
lation of somatic mtDNA mutations. However, this hypoth-
esis has been challenged by the fact that a cell has multiple
mitochondrial genomes, which can tolerate the coexistence
of wild-type and some mutant genomes [25]. Clearly, dys-
function of the mitochondrion is at least partially attributable
to the age-related decline in the expression of mitochondrial
proteins [13]. A recent study provides evidence that epige-
netic changes contribute to mitochondrial dysfunction in the
aging brain. The age-related upregulation of bromodomain
adjacent to zinc finger domain 2B (BAZ2B) and euchro-
matic histone lysine methyltransferase 1 (EHMT1) underlie
the down-regulation of genes involving core metabolism
(mainly ribosome and oxidative phosphorylation), which
have been consistently reported in patients with AD and
mild cognitive impairment [26].
Pathological aging brains show more severe dysfunction
of mitochondria. Many lines of evidence have suggested
that mitochondrial dysfunction plays a central role in the
onset and development of neurodegenerative diseases. The
M. Jin, S.-Q. Cai: Mechanisms Underlying Brain Aging
age-related reductions in oxidative phosphorylation and
accumulation of mtDNA damage are aggravated in the
brains of AD patients [27–29]. Impaired mitochondrial
biogenesis and fission–fusion balance, as well as decreased
mitophagy, have also been reported in AD patients’ brains
[30, 31]. When it comes to the relationship between mito-
chondria and pathological brain aging, PD should not be
ignored [32, 33]. Although the exact cause of the disease
is not clear, aberrant mitochondrial clearance by autophagy
is a major factor in the death of dopaminergic neurons. The
protein kinase PTEN-induced putative kinase 1 (PINK1)
accumulates on the outer membrane of the mitochondria,
and then phosphorylates and activates the E3 ligase activity
of Parkin, which ubiquitinates outer mitochondrial mem-
brane proteins to trigger selective autophagy [34]. Healthy
neurons effectively remove damaged mitochondria through
mitochondrial phagocytosis; while in PD neurons, exces-
sive mitochondrial damage causes a failure in the clearance
of damaged mitochondria, resulting in extensive neuronal
death.
Mitochondria establish and maintain the aging rate of the
entire organism [24], but the effect of mitochondrial damage
on the aging phenotypes is not simply linear. Previously, it
was supposed that an energetic crisis in aging brains caused
by accumulating damaged mitochondria accelerates func-
tional deterioration and triggers neurodegenerative diseases.
However, recent genetic and pharmacological evidence has
discovered that, although severe mitochondrial dysfunc-
tion may cause cell death, mild respiratory defects extend
the lifespan. Down-regulating the function of the electron
transport chain in neurons has been reported to extend
the lifespan of C. elegans [24]. On the other hand, several
reports have demonstrated that caloric restriction, genetic/
pharmacological restoration of nicotinamide adenine dinu-
cleotide ­(NAD+), or manipulation of a glia-neuron signal
can increase mitochondrial function and activation of the
mitochondrial unfolded protein response (­ UPRmt) to miti-
gate many of the detrimental effects of aging and/or prolong
the healthspan [35–39]. Perhaps maintaining mitochondrial
function at the proper level, not too low or too high, is most
beneficial for promoting healthy aging.
Deregulated Nutrient Sensing
The function of the nutrient-sensing system changes with
age. Previous studies have shown that several nutrient-sens-
ing pathways play a role in regulating longevity and aging
[40]. As shown in Fig. 2, these pathways include insulin and
the insulin-like growth factor 1 (IGF-1) signaling (IIS) path-
way, the mammalian target of rapamycin (mTOR) pathway,
the adenosine 5′ monophosphate-activated protein kinase
(AMPK) pathway, and the sirtuin signaling pathway.
305
Fig. 2  Nutrient-sensing pathways and aging. Molecules proposed
to favor aging and prevent aging are shown in orange and green,
respectively. IR, insulin receptor; IGF-1, insulin-like growth factor 1;
IGF1R, IGF-1 receptor; IRS, IR substrates; PI3K, phosphoinositide
3-kinase; Akt, AKT serine/threonine kinase; FOXO, forkhead box
O; GSK3, glycogen synthase kinase-3; mTOR, mammalian target
of rapamycin; AMPK, adenosine 5′ monophosphate-activated pro-
tein kinase; ULK1, Unc-51 like autophagy activating kinase 1; Sirt1,
sirtuin 1; PGC1ɑ, PPARG coactivator 1 alpha; AMP, adenosine
monophosphate; ATP, adenosine triphosphate; N ­ AD+, nicotinamide
adenine dinucleotide; NADH, nicotinamide adenine dinucleotide
hydride.
The IIS pathway, which represents nutrient abundance
and anabolism, is the most conserved aging-modifying path-
way in the process of evolution, and its downstream targets,
forkhead box O (FOXO) family transcription factors, are
also highly conserved in regulating longevity across species:
inhibiting the activity of the IIS pathway extends the lifespan
of yeast, worms, flies, and mammals [40]. Brain IIS plays a
key role in sensing and regulating body metabolism, as well
as regulating synaptic plasticity, learning, and neural devel-
opment [41]. It is worth noting that, although the IIS path-
way plays a small role in glucose metabolism in the brain, it
is essential for maintaining a healthy brain metabolism [42].
The IIS pathway sends signals of the body’s energy status
to the brain and regulates eating behavior: excessive insulin
inhibits eating, while a decreased insulin level causes over-
eating through the IIS pathway in the hypothalamus [43, 44].
Interestingly, growth hormone and IGF-1 levels decrease
during normal aging, and this phenomenon has also been
reported in mouse models of premature aging [45]. One pos-
sible explanation for this is that cells compensate for aging
and age-related declines by downregulating the function of
IIS pathways. mTOR kinase, another highly-conserved fac-
tor for sensing and responding to nutrient signals (including
signals related to the availability of amino-acids), also plays
a key role in modulating aging, and administration of the
mTOR inhibitor rapamycin is considered to be one of the
most effective approaches to increasing the lifespan in mam-
mals [46, 47]. Of note, the activity of the mTOR signaling
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pathway also decreases during normal brain aging [48], but
in AD patients, the mTOR pathway is hyperactivated [49].
Some other pathways (like AMPK and sirtuins) sense nutri-
ent scarcity and catabolism, and they act in an opposite way
to modulate aging. Studies have shown that the responsive-
ness of AMPK signaling decreases with age and enhancing
AMPK activity delays aging [50]. In general, the available
evidence has demonstrated that anabolic signaling accel-
erates the rate of aging and reduced nutritional signaling
increases longevity [51].
In aging brains, reduced glucose metabolism is found in
many brain regions, particularly marked in the temporal and
parietal lobes, and the motor cortex [52]. This alteration is
much more profound in these regions of elderly patients with
dementia [53]. In patients with neurodegenerative diseases,
such as AD and PD, reduced brain glucose consumption and
energy production are associated with altered IIS, mTOR,
and AMPK signaling. Studies have shown that brain insulin
resistance accelerates aging, while maintaining brain insu-
lin sensitivity delays aging [54]. An abnormal distribution
and cellular localization of insulin receptors (IR and IGF1R)
have been reported in AD neurons, suggesting possible insu-
lin resistance in the AD brain [55]. The dysfunction of insu-
lin and IGF-1 signaling may also contribute to the progress
of AD, as insulin signaling plays a critical role in the clear-
ance of Aβ and inhibiting Tau aggregation [56]. Disrup-
tion of insulin receptor substrates 2 (IRS2) promotes Tau
phosphorylation by activating glycogen synthase kinase-3β
in the Irs2−/− mouse brain [57]. Interestingly, other lines of
evidence support the idea that inhibition of IIS alleviates
AD-related phenotypes [58]. Neuron-specific knockout of
IRS2 (but not IR or IGF1R) delays Aβ accumulation in a
mouse model of AD [59], suggesting that the role of IIS in
AD pathology is distinct in different cell types. Inconsistent
changes in the AMPK pathway have also been reported in
the AD brain. Generally, AMPK activity decreases in the
AD brain, but it is abnormally activated in neurons bearing
neurofibrillary pre-tangles and tangles; activated AMPK
accumulates near Aβ plaques and tau tangles instead of in
the nucleus, where AMPK usually functions [60]. Thus,
moderating the sensitivity of AMPK pathways rather than
simply inhibiting or activating them (which may cause
resistance) may be more effective for relieving AD symp-
toms [54].
The manipulation of nutritional signaling pathways may
provide effective approaches to alleviate brain aging and pre-
vent age-related neurodegenerative diseases. Dietary restric-
tion is probably the best known way to extend the lifes-
pan and the healthspan [61–63]. A reduced inflammatory
response and improved capacity of DNA repair are found
in dietary-restricted mice and rats, as a result of upregula-
tion of genes associated with inhibition of the inflamma-
tory response and DNA synthesis/repair [64–66]. In animal
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Neurosci. Bull. February, 2023, 39(2):303–314
models of AD and stroke, dietary restriction protects neu-
rons in the brain from degeneration [67]; however, no benefit
of dietary restriction on alleviation of the disease has been
reported in an animal model of ALS [68]. Recently, stud-
ies on intermittent fasting (IF) are gaining increasing inter-
est [69]. Studies suggest that IF has no positive short-term
effects on cognition in healthy subjects, but has benefits in
relieving the symptoms of epilepsy, AD, and multiple scle-
rosis [70]. Although the exact mechanism of IF in healthy
aging is still unclear, the process is thought to be associated
with the IIS pathway, the mTOR pathway, and the like [71].
Epigenetic Alteration
Epigenetics is the best choice for organisms to adapt to a
changeable environment: heritable changes in gene expres-
sion occur while the DNA sequence does not change. Epi-
genetic changes include alterations in DNA methylation
patterns, post-translational modification of histones, chro-
matin remodeling, and expression of non-coding RNAs [72].
Generally, diversity of modification helps individuals adapt
to their environment; however, studies have shown that as
individuals age, heterogeneity of DNA modifications in the
brain decreases at both the individual and tissue levels, and
convergence of neighboring DNA modifications suggests
that there exist some rules of age-related alteration in DNA
modifications during brain aging [73]. Interestingly, changes
in the levels of DNA methylation at 353 CpG sites have been
proposed as an epigenetic clock (known as DNA methylation
age) to predict the biological age of human tissues including
the brain [74]. Generally, histone methylation levels in the
promoter regions of many synaptic function-related genes
increase, while histone acetylation levels decrease in aging
brains [75]. These epigenetic changes ultimately affect gene
expression, leading to cognitive decline during aging.
Epigenetic alterations have also been widely reported in
pathological brain aging [76], and these alterations may be
different from those that occur in normal aging. For exam-
ple, the methylation level in the promotor region of many
AD risk genes (such as APP, PS1, and BACE1) changes
significantly in AD patients’ brains compared with that
of age-matched normally aging brains [77]. However, the
global changes in DNA methylation under AD conditions is
controversial: a decreased DNA methylation level has been
found in the cell model of AD, but an increased DNA meth-
ylation level has been reported in a mouse model of AD [78].
Normal aging results in significant accumulation, while AD
entails a marked loss, of H4K16ac in the proximity of genes
associated with the aging process and AD, suggesting that
the marker H4K16ac plays a distinct role in normal aging
and age-associated neurodegeneration [79].
M. Jin, S.-Q. Cai: Mechanisms Underlying Brain Aging
On the other hand, some epigenetic changes could be a
continuous regulatory mechanism for normal and patho-
logical brain aging. Studies have reported an increase in the
levels of H3K9me2 and H3K9me3 in aging brains of aged
mice, mouse models of AD and Huntington’s disease (HD),
as well as AD and HD patients [80, 81]. Pharmacological
inhibition of the histone methyl transferases SUV39H1 and
EHMT1/EHMT2 decreases the levels of H3K9me3 in the
hippocampus and improves cognitive function in aged mice
and a mouse model of AD, respectively [82, 83]. Strikingly,
a recent study found that the expression levels of EHMT1
and an epigenetic reader BAZ2B increase with age, and are
positively correlated with the progress of AD in the pre-
frontal cortex of human brains. Ablation of Baz2b enhances
mitochondrial function in the brain and improves cognitive
function in aged mice by affecting the H3K9 methylation
level in the promotor regions of genes associated with core
metabolism [26].
MicroRNAs (miRNAs) provide another epigenetic mech-
anism for regulating brain aging. Although dysfunction of
miRNAs affects neuroinflammation, cognitive decline, and
other age-related deteriorations, currently little is known
about functional changes in brain miRNAs during aging
[84]. Microarray data indicate that some miRNAs, including
miR-139-5p, miR-342-3p, and miR-204, exhibit increased
expression levels in the hippocampus of aged mice, and
they may suppress the surface expression of neurotransmit-
ter receptors and contribute to age-related cognitive decline
[85, 86]. Recent evidence suggests that miRNAs can be
packed into exosomes, which can be transported cross tis-
sues and probably coordinate the ageing rate of different
organs. Astrocytic apolipoprotein E3 (APOE3) vesicles have
been reported to carry diverse regulatory miRNAs, which
specifically silence genes involved in neuronal cholesterol
biosynthesis, and ultimately promote histone acetylation and
activate gene expression in neurons. In contrast, APOE4, a
risk factor for AD, carries fewer miRNAs and thus down-
regulates the acetylation level of histone in the promoter
regions of synapse-related genes, ultimately leading to
repressed expression of these genes and a decline in cogni-
tive ability [87].
Overall, the potential reversibility of epigenetic altera-
tions provides exciting chances to alter the trajectory of brain
aging under both normal and pathological conditions. Stud-
ies have shown that some epigenetic factors regulate healthy
aging, such as BAZ2B and EHMT1, and they may be tar-
gets for slowing brain aging and treating age-related diseases
[26]. Expression of octamer-binding transcription factor 3/4,
SRY-Box transcription factor 2 (Sox2), Kruppel-like factor
4, and the proto-oncogene c-Myc (OSKM, also known as
Yamanaka factors) in cells reshapes epigenetic markers and
reprograms cells to a pluripotent state, as well as erasing
cellular markers of senescence [88–90]. Periodic expression
307
of OSKM for a short period of time improves the aging phe-
notypes of aged mice and prolongs the life span of progeroid
mice [90], and the effect on delaying aging increases with
the cumulative time of partial reprogramming in aged mice,
suggesting that epigenetic changes occur early during aging
and that earlier interventions may get better results [91].
Notably, despite controversy, reprogramming glial cells into
neurons is an exciting and challenging approach to treating
neurodegenerative diseases [92, 93]. However, more work
remains to be done to understand epigenetic regulation in
aging brains under both normal and pathological conditions.
Altered Cell Proliferative Capacity
In most organs, one of the most obvious age-related hall-
marks is the decline in the regenerative potential of tissues,
which is a result of telomere attrition, stem cell exhaustion,
and cellular senescence [94, 95]. Evidence shows that tel-
omere alteration affects the rate of aging. It has been dem-
onstrated that mice with shortened and lengthened telom-
eres show decreased and increased lifespan, respectively.
Pathological dysfunction of telomeres accelerates aging,
while experimental stimulation of telomerase delays aging
[96, 97]. However, neurons are permanently postmitotic and
neuronal telomeres do not shorten in aging brains. Interest-
ingly, changes in the telomere have shown an opposite role
in different studies of pathological brain aging. Telomere
lengths are shorter in AD patients, and telomerase-deficient
mice showed signs of neurodegeneration [98, 99]. However,
another study in the APP23 transgenic mouse have shown
that, although telomere shortening disrupts adult neurogen-
esis and the maintenance of neurons after mitosis, it reduces
the formation of amyloid plaques and alleviates the deficits
in learning and memory [100].
In the adult brain, neurogenesis only occurs in a few
regions, including the hippocampal dentate gyrus, sub-ven-
tricular zone (SVZ), and olfactory bulb [101, 102]. Age-
related changes in neurogenesis have been found in both
normal and pathological aging brains. During normal and
pathological aging, a decrease of neurogenesis in the hip-
pocampus, SVZ, and olfactory bulb may lead to cognitive
and olfactory deficits [103]. Neural stem cell transplanta-
tion has been considered as a potential treatment for some
age-related neurodegenerative diseases associated with neu-
ronal loss [104]. However, aberrant neurogenesis has been
reported in aging brains with neurodegenerative disorders,
including AD, PD, and HD [105]. For example, the human
HD brain exhibits greater neural progenitor cell (NPC)
proliferation that is proportional to the severity of the dis-
ease, and modifies the pathology of the disease [106]. Both
increased and decreased neurogenesis have been reported in
the brains of AD model mice and AD patients [105, 107].
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Some studies on postmortem brain tissue from AD patients
found a higher level of neurogenesis in the hippocampus
[108], while other studies found that neurogenic markers like
Musashi-1, Sox2, and doublecortin are downregulated in the
brains of AD patients [109, 110]. This discrepancy may be
explained by difference in the animal model used and the
stage of the disease. Overall, the capacity for neurogenesis
may change differently in normal and pathological brain
aging, despite the fact that their states are both abnormal
and may contribute to the cognitive impairments.
NPCs and proliferation-competent glial cells can undergo
senescence. Cells with features of senescence have been
found in aging brains under both normal and pathological
conditions [111]. Senescence alters cellular morphology and
proteostasis, decreases autophagy-lysosome function, and
enhances the secretory activity of cells, which leads to a
pro-inflammatory senescence-associated secretory pheno-
type [112]. Senescent cells accumulate during aging and
negatively influence a heathy lifespan. In AD model mice,
the telomeres in microglia shorten during continuous repli-
cation, leading to replicative senescence and contributing to
AD pathology [113]. Although neurons no longer undergo
mitosis, they show some features of senescence in aging
brains; the level of senescence-associated beta-galactosidase
activity increases in neurons in the CA3 region of aged rat
brains, and a DNA damage-induced senescence-like phe-
notype has also been reported in aging neurons [114, 115].
Removal of senescent cells in the brain by pharmacological
intervention, chimeric antigen receptor T cell therapy, or
genetic/antibody-mediated depletion alleviates the inflam-
mation and cognitive impairment in naturally aging mice,
and prevents tau-dependent pathology and cognitive decline
in mouse models of neurodegenerative diseases [116–119].
Altered Intercellular Communication
Maintaining connections with other cells is critical for
preserving the functions of neurons. With increasing age,
the communication between neuronal cells changes signifi-
cantly, causing decreased synaptic connections, increased
inflammation, and degenerated neurovascular units (NVUs)
[3, 8].
The fidelity of neural networks within and between
brain regions is disturbed with age. Functional imaging
studies have revealed a global loss of integrative func-
tion in aging human brains. Age-related dysfunction of
neural networks is not due to a loss of neurons (which is
minimal in normal aging brains), but to abnormal synaptic
connections that form the basis of neural circuits in the
hippocampus and prefrontal cortex [120]. The expression
levels of most synaptic function-related genes are down-
regulated [13] and the integrity of the white matter (which
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Neurosci. Bull. February, 2023, 39(2):303–314
is composed of bundles of axons) is compromised during
normal aging of the human brain [121]. Not surprisingly,
these alterations may render neurons more vulnerable to
degeneration under pathological conditions [122], rein-
forcing the importance of maintaining synaptic function
to achieve healthy aging of the brain. In support of this
notion, recent studies have demonstrated that improving
synaptic function by enhancing neurotransmitter levels
alleviates the age-related deterioration of cognitive func-
tion in old people and animal models [123, 124]. How-
ever, other lines of evidence have shown that inhibition of
neuronal excitability delays aging. Mutations that cause
defects in specific sensory neurons extends the lifespan
in C. elegans, and ablation of RE1 silencing transcription
factor causes abnormal neural excitation in the aged mouse
brain and accelerates aging through the IIS pathway [125,
126]. These findings suggest that higher neural activity is
not always better, and the changes of neural connections
may also be an adaptive mechanism in response to aging.
In addition to synaptic connections, factors such as neu-
rotrophic and inflammation factors from other cells influ-
ence neuronal survival. In neurodegenerative diseases,
synaptic inputs may be altered by inhibiting anterograde
axonal transport and/or axonal degeneration, resulting in
reduced release of transmitters and neurotrophic peptides
[127]. During aging, glial cells, particularly microglia, often
exhibit an activated state, causing long-term and chronic
inflammation in the nervous system [128], which may lead
to cognitive impairments as evidenced by the findings that
in both normal and pathological brain aging, inhibition of
the inflammatory responses has been reported to improve
learning and cognition [129, 130]. For example, activating
the cholinergic anti-inflammatory pathway, inhibiting the
activation of microglia, or restoring the metabolic levels of
myeloid cells in aging mice alleviates inflammation in the
nervous system and restores cognitive function [131–133].
NVUs also degenerate with age [134]. Changes of NVUs
in aging usually result in impaired integrity of the blood-
brain barrier (BBB) and infiltration of blood-derived pro-
teins, affecting the blood oxygen supply to nerve cells. The
degeneration of NVUs eventually impairs cognitive function
and increases the risk of stroke and cerebral small-vessel dis-
ease, among others [135, 136]. Interestingly, unique changes
in NVUs occur in some neurodegenerative diseases. For
example, Aβ42 has been reported to disturb the organization
of junctional complexes containing tight and adherent junc-
tions between endothelial cells, causing leakage of plasma
protein and more severe damage in brains with AD [137].
The deposition of α-synuclein and matrix metallopeptidase
3 damages the BBB and exacerbates inflammation in PD
patients’ brains [138–140]. Thus, it is reasonable to assume
that protecting the functions of NVUs is a promising strategy
for preventing some neurodegenerative diseases.
M. Jin, S.-Q. Cai: Mechanisms Underlying Brain Aging
Loss of Proteostasis
The proteostasis network regulates cellular protein homeo-
stasis and it consists of the protein biosynthetic machinery,
the molecular chaperone system, and protein clearance path-
ways including the proteasome and autophagy systems. The
loss of proteostasis, a failure of aging cells in responding
to proteotoxic challenges, has been considered a hallmark
of organismal aging [3]. A recent study has proposed that
age-related changes in translational efficiency initially drive
the deterioration of proteostasis [141]. Genetic and pharma-
cological strategies to improve proteostasis promote healthy
aging in animal models and delay the onset of age-related
pathologies associated with protein aggregation [142].
In aged brains, the functions of protein chaperones and
proteolytic systems decrease significantly [143]. Once the
capacity of these systems decreases below a threshold level,
some aggregation-prone proteins aggregate and exist in an
insoluble state. The threshold is lowered in some stress con-
ditions, such as the presence of disease-associated mutations
in genes encoding aggregation-prone proteins [142]. Indeed,
in age-related neurodegenerative diseases, loss of protein
homeostasis often shows more severe pathological features.
For example, aggregation of Aβ and hyperphosphorylation
of Tau are the most obvious pathological features of AD;
and a large amount of α-synuclein aggregates in dopamin-
ergic neurons in PD patients [144]. Stress response path-
ways shape the proteostasis network, affecting the process
of aging and the onset/progress of neurodegeneration. The
aggregation of unfolded proteins perturbs the homeostasis
in the endoplasmic reticulum (ER) and triggers ER stress-
induced activation of the unfolded protein response (UPR),
an initially adaptive mechanism that restores cellular proteo-
stasis [145, 146]. However, studies have demonstrated that
chronic activation of the UPR in the ER is associated with
Fig. 3  Similar and different
molecular and cellular changes
in aging brains under normal
and pathological conditions.
Changes occurring in normal
and pathological aging brains
are shown in green and in
orange, respectively. These
changes are only examples,
not the full range of changes
during normal and pathologi-
cal brain aging. IIS, the insulin
and IGF-1 signaling pathway;
mTOR, mammalian target of
rapamycin.
309
neuronal degeneration in post-mortem brain tissues from
patients with neurodegenerative diseases [145, 146]. Thus,
activation of the UPR in the ER has distinct and even oppo-
site effects on the progress of neurodegeneration, probably
depending on the stage of disease.
It is worth noting that the relation between cognitive
impairment and toxic protein aggregation remains controver-
sial. In about a quarter of patients diagnosed as having AD-
like diseases, the level of Aβ plaques and tau tangles does
not reach the diagnostic threshold of AD [147, 148]. Many
old people who exhibit extensive Aβ plaque accumulation
only have minimal neuronal loss and a marginal decline in
cognitive function [149, 150]. These suggest that there may
be neuroprotective mechanisms that we have not yet found
that influence the role of proteostasis during brain aging.
Conclusions and Perspective
Brain aging is a major risk factor for many neurodegenera-
tive diseases, but the mechanisms underlying the transi-
tion from normal aging to neurodegenerative disorders are
complex and remain to be fully elucidated. The hallmarks
of brain aging have been associated with the pathogenesis
of neurodegenerative diseases, which are quite common
among older populations, leading to the hypothesis that neu-
rodegeneration is accelerated brain ageing [151]. Indeed,
as shown in Fig. 3, some hallmarks of brain aging occur
in both normal and pathological brain aging, but they are
more exacerbated in a pathological state. These are genomic
instability, deregulated nutrient sensing, loss of proteosta-
sis, and mitochondrial dysfunction. However, some unique
molecular and cellular processes occur in normal aging or
neurodegenerative diseases. For instance, some changes in
intercellular communication (such as NUV damage caused
13

310
Fig. 4  Functional interconnections between the molecular and cel-
lular events occurring in aging brains under normal and pathologi-
cal conditions. The seven molecular and cellular events occurring in
aging brains can be divided into three categories. Genome instabil-
ity, loss of proteostasis, and altered cell proliferative capacity are sup-
posed to be causative mechanisms; deregulated nutrient sensing and
altered intercellular communication are mostly adaptive mechanisms;
while mitochondrial dysfunction and epigenetic alteration could be
both causative and adaptive for brain aging and neurodegeneration.
by Aβ in AD [137]) and epigenetic modifications (such as
methylation level in the promotor region of many AD risk
genes [77]) specifically occur in aging brains under patho-
logical conditions. Strikingly, other molecular and cellular
changes (such as alteration in telomeres and stem cells) in
the brain are distinct between normal aging and neurode-
generation, showing an antagonistic mechanism. It is worth
noting that the opposite changes that occur in neurodegen-
erative diseases ultimately exacerbate the pathological phe-
notype rather than alleviate the aging phenotype.
Brain aging is a key regulator of longevity and functional
deterioration. Molecular and cellular alterations associated
with the aging process in the brain could be adaptive fac-
tors for maintaining neural function or causative factors for
deteriorating systemic functions [3]. Generally speaking, as
shown in Fig. 4, genome instability, loss of proteostasis, and
altered cell proliferative capacity are causative mechanisms
for cognitive impairment [23, 95, 142]; while deregulated
nutrient sensing and altered intercellular communication are
mainly considered to be adaptive mechanisms for brain aging
because down-regulation of nutrient sensing and neuronal
excitability have been reported to extend lifespan [45, 125].
Mitochondrial dysfunction and epigenetic changes could be
both causative and adaptive mechanisms for brain aging [24,
25, 72]. For example, mild downregulation of mitochondrial
function promotes longevity, while severe impairment of
mitochondria leads to neuronal death and neurodegenera-
tion. Yet, the causative and adaptive mechanisms are not
absolutely inconvertible; the adaptive molecular and cellular
changes in the aging brain may also contribute to the decline
of some subsets of behaviors. Future comprehensive studies
13
Neurosci. Bull. February, 2023, 39(2):303–314
on single-cell transcriptomics [152] of normal, protected,
and pathological aging human brains may help to further
clarify the causative and adaptive age-related molecular and
cellular events in a cell type-specific pattern.
It is worth noting that the hallmarks of brain aging are
interrelated and interdependent, and none of them occur in
isolation. For example, age-related accumulation of DNA
damage and epigenetic aberrations alters gene expression,
resulting in dysfunction of mitochondria, deregulation of
nutrient sensing, and loss of proteostasis; all of which in
turn lead to more severe cytotoxicity and genomic insta-
bility, finally causing pathological changes in intercellular
communication and transforming physiological changes
into pathological changes in the whole brain. Accumulating
evidence has demonstrated that caloric restriction protects
aging brains from deterioration by stimulating mitochondrial
biogenesis and neural signaling pathways in neurons [8],
supporting a link between nutrient sensing and mitochon-
drial function in modulating aging of the brain.
Given that normal and pathological brain aging are
closely linked, approaches that promote healthy aging are
worth trying to treat aging-related diseases. Recent stud-
ies have demonstrated that exposure of an aged animal to
young blood improves the aging phenotypes, and plasma
replacement has also been reported to be beneficial for treat-
ing AD [153–155]. A combination of removal of senescent
cells with transient somatic reprogramming synergistically
extends lifespan and improves health [156]. On the other
hand, brain aging is a complex and integral process, there-
fore future development of therapeutic approaches for treat-
ing neurodegenerative diseases needs a greater understand-
ing of not only the distinct molecular changes occurring in
pathological aging brains, but also the biological context
of normal aging of the brain. Many mouse models of AD
develop disease symptoms too early, which may not be suit-
able for the search for the true pathogenesis of the disease
[157, 158]. Researchers must take these questions into
account when using these model mice.
Acknowledgements  This review was supported by grants from
the National Key R&D Program of China (2018YFC2000400),
the National Natural Science Foundation of China (31925022 and
91949206), the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB32020100), the Shanghai Municipal Sci-
ence and Technology Major Project (2018SHZDZX05), and the Inno-
vative Research Team of High-level Local Universities in Shanghai
(SHSMU-ZDCX20212501).
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the article’s Creative Commons licence and your intended use is not 18. Adamec E, Vonsattel JP, Nixon RA. DNA strand breaks in Alz-
permitted by statutory regulation or exceeds the permitted use, you will heimer’s disease. Brain Res 1999, 849: 67–77.
need to obtain permission directly from the copyright holder. To view a 19. Merlo D, Cuchillo-Ibañez I, Parlato R, Rammes G. DNA damage,
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. neurodegeneration, and synaptic plasticity. Neural Plast 2016,
2016: 1206840.
20. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK,
Perry RH, et al. High levels of mitochondrial DNA deletions
References in substantia nigra neurons in aging and Parkinson disease. Nat
Genet 2006, 38: 515–517.
21. Fitzmaurice PS, Shaw IC, Kleiner HE, Miller RT, Monks TJ,
1. de Almeida A, Ribeiro TP, de Medeiros IA. Aging: Molecular
Lau SS, et al. Evidence for DNA damage in amyotrophic lateral
Pathways and Implications on the Cardiovascular System. Oxid
sclerosis. Muscle Nerve 1996, 19: 797–798.
Med Cell Longev 2017, 2017: 7941563. https://​doi.​org/​10.​1155/​
22. Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall
2017/​79415​63.
NW, Khrapko K. Mitochondrial DNA deletions are abundant
2. Eikelboom WS, Bertens D, Kessels RPC. Cognitive rehabilita-
and cause functional impairment in aged human substantia nigra
tion in normal aging and individuals with subjective cognitive
neurons. Nat Genet 2006, 38: 518–520.
decline. Cognitive Rehabilitation and Neuroimaging. Cham:
23. Madabhushi R, Pan L, Tsai LH. DNA damage and its links to
Springer International Publishing, 2020: 37–67.
neurodegeneration. Neuron 2014, 83: 266–282.
3. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G.
24. Durieux J, Wolff S, Dillin A. The cell-non-autonomous nature
The hallmarks of aging. Cell 2013, 153: 1194–1217.
of electron transport chain-mediated longevity. Cell 2011, 144:
4. Nouchi R, Taki Y, Takeuchi H, Sekiguchi A, Hashizume
79–91.
H, Nozawa T. Four weeks of combination exercise training
25. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative
improved executive functions, episodic memory, and process-
stress in neurodegenerative diseases. Nature 2006, 443: 787–795.
ing speed in healthy elderly people: Evidence from a randomized
26. Yuan J, Chang SY, Yin SG, Liu ZY, Cheng X, Liu XJ, et al. Two
controlled trial. Age (Dordr) 2014, 36: 787–799.
conserved epigenetic regulators prevent healthy ageing. Nature
5. Jia L, Du Y, Chu L, Zhang Z, Li F, Lyu D, et al. Prevalence, risk
2020, 579: 118–122.
factors, and management of dementia and mild cognitive impair-
27. Bonda DJ, Wang X, Lee HG, Smith MA, Perry G, Zhu X. Neu-
ment in adults aged 60 years or older in China: A cross-sectional
ronal failure in Alzheimer’s disease: A view through the oxida-
study. Lancet Public Health 2020, 5: e661–e671.
tive stress looking-glass. Neurosci Bull 2014, 30: 243–252.
6. Kenyon CJ. The genetics of ageing. Nature 2010, 464: 504–512.
28. Chen Z, Zhong C. Oxidative stress in Alzheimer’s disease. Neu-
7. Gems D, Partridge L. Genetics of longevity in model organ-
rosci Bull 2014, 30: 271–281.
isms: Debates and paradigm shifts. Annu Rev Physiol 2013, 75:
29. Wang W, Zhao F, Ma X, Perry G, Zhu X. Mitochondria dysfunc-
621–644.
tion in the pathogenesis of Alzheimer’s disease: Recent advances.
8. Mattson MP, Arumugam TV. Hallmarks of brain aging: Adaptive
Mol Neurodegeneration 2020, 15: 30.
and pathological modification by metabolic states. Cell Metab
30. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, et al.
2018, 27: 1176–1199.
Impaired balance of mitochondrial fission and fusion in Alzhei-
9. Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL,
mer’s disease. J Neurosci 2009, 29: 9090–9103.
et al. Ageing as a risk factor for neurodegenerative disease. Nat
31. Cai Q, Tammineni P. Alterations in mitochondrial quality control
Rev Neurol 2019, 15: 565–581.
in Alzheimer’s disease. Front Cell Neurosci 2016, 10: 24.
10. Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WGM, Lou W,
32. Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neu-
et al. Selective changes in thin spine density and morphology in
rons are differentially susceptible to degeneration in Parkinson’s
monkey prefrontal cortex correlate with aging-related cognitive
disease. Nature 1988, 334: 345–348.
impairment. J Neurosci 2010, 30: 7507–7515.
33. Galvan A, Wichmann T. Pathophysiology of Parkinsonism. Clin
11. Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat
Neurophysiol 2008, 119: 1459–1474.
Rev Neurosci 2006, 7: 30–40.
34. Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mito-
12. Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov
chondrial fidelity in Parkinson’s disease. Neuron 2015, 85:
A, Budovsky A, Yanai H, et al. The role of DNA damage and
257–273.
repair in aging through the prism of Koch-like criteria. Ageing
35. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L,
Res Rev 2013, 12: 661–684.
et al. Calorie restriction promotes mitochondrial biogenesis by
13. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, et al. Gene regula-
inducing the expression of eNOS. Science 2005, 310: 314–317.
tion and DNA damage in the ageing human brain. Nature 2004,
36. Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova
429: 883–891.
B, Deutsch WA, et al. Calorie restriction increases muscle mito-
14. Lopes AFC, Bozek K, Herholz M, Trifunovic A, Rieckher M,
chondrial biogenesis in healthy humans. PLoS Med 2007, 4: e76.
Schumacher BAC. elegans model for neurodegeneration in Coc-
37. Lanza IR, Zabielski P, Klaus KA, Morse DM, Heppelmann CJ,
kayne syndrome. Nucleic Acids Res 2020, 48: 10973–10985.
Bergen HR III, et al. Chronic caloric restriction preserves mito-
15. Shaposhnikov M, Proshkina E, Shilova L, Zhavoronkov A,
chondrial function in senescence without increasing mitochon-
Moskalev A. Lifespan and stress resistance in Drosophila with
drial biogenesis. Cell Metab 2012, 16: 777–788.
overexpressed DNA repair genes. Sci Rep 2015, 5: 15299.
38. Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D,
16. Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann
Cantó C, et al. The N ­ AD+/sirtuin pathway modulates longevity
J, Park SK, et al. SIRT1 redistribution on chromatin promotes
through activation of mitochondrial UPR and FOXO signaling.
genomic stability but alters gene expression during aging. Cell
Cell 2013, 154: 430–441.
2008, 135: 907–918.
39. Yin JA, Gao G, Liu XJ, Hao ZQ, Li K, Kang XL, et al. Genetic
17. Schumacher B, Pothof J, Vijg J, Hoeijmakers JHJ. The central
variation in glia–neuron signalling modulates ageing rate. Nature
role of DNA damage in the ageing process. Nature 2021, 592:
2017, 551: 198–203.
695–703.

13

312
40. Fontana L, Partridge L, Longo VD. Extending healthy life span—
from yeast to humans. Science 2010, 328: 321–326.
41. Akintola AA, van Heemst D. Insulin, aging, and the brain: Mech-
anisms and implications. Front Endocrinol (Lausanne) 2015, 6:
13.
42. Heni M, Kullmann S, Preissl H, Fritsche A, Häring HU. Impaired
insulin action in the human brain: Causes and metabolic conse-
quences. Nat Rev Endocrinol 2015, 11: 701–711.
43. Schwartz MW, Sipols AJ, Marks JL, Sanacora G, White JD,
Scheurink A, et al. Inhibition of hypothalamic neuropep-
tide Y gene expression by insulin. Endocrinology 1992, 130:
3608–3616.
44. Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban
PC, et al. Role of brain insulin receptor in control of body weight
and reproduction. Science 2000, 289: 2122–2125.
45. Schumacher B, van der Pluijm I, Moorhouse MJ, Kosteas T,
Robinson AR, Suh Y, et al. Delayed and accelerated aging
share common longevity assurance mechanisms. PLoS Genet
2008, 4: e1000161.
46. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flur-
key K, et al. Rapamycin fed late in life extends lifespan in
genetically heterogeneous mice. Nature 2009, 460: 392–395.
47. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topi-
sirovic I, et al. mTOR as a central regulator of lifespan and
aging. F1000Res 2019, 8: F1000FacultyRev–F1000Faculty998.
48. Romine J, Gao X, Xu XM, So KF, Chen J. The proliferation
of amplifying neural progenitor cells is impaired in the aging
brain and restored by the mTOR pathway activation. Neurobiol
Aging 2015, 36: 1716–1726.
49. Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ. Levels of
mTOR and its downstream targets 4E-BP1, eEF2, and eEF2
kinase in relationships with tau in Alzheimer’s disease brain.
FEBS J 2005, 272: 4211–4220.
50. Salminen A, Kaarniranta K. AMP-activated protein kinase
(AMPK) controls the aging process via an integrated signal-
ing network. Ageing Res Rev 2012, 11: 230–241.
51. Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The criti-
cal role of metabolic pathways in aging. Diabetes 2012, 61:
1315–1322.
52. Goyal MS, Vlassenko AG, Blazey TM, Su Y, Couture LE,
Durbin TJ, et al. Loss of brain aerobic glycolysis in normal
human aging. Cell Metab 2017, 26: 353-360.e3.
53. Kato T, Inui Y, Nakamura A, Ito K. Brain fluorodeoxyglucose
(FDG) PET in dementia. Ageing Res Rev 2016, 30: 73–84.
54. Masternak MM, Panici JA, Bonkowski MS, Hughes LF, Bartke
A. Insulin sensitivity as a key mediator of growth hormone
actions on longevity. J Gerontol A Biol Sci Med Sci 2009,
64A: 516–521.
55. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid
R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and
IRS-1/2 in Alzheimer’s disease indicate possible resistance
to IGF-1 and insulin signalling. Neurobiol Aging 2010, 31:
224–243.
56. Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alz-
heimer’s disease. Trends Neurosci 2003, 26: 404–406.
57. Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL,
et al. Insulin receptor substrate-2 deficiency impairs brain
growth and promotes tau phosphorylation. J Neurosci 2003, 23:
7084–7092.
58. Candeias E, Duarte AI, Carvalho C, Correia SC, Cardoso S, San-
tos RX, et al. The impairment of insulin signaling in Alzheimer’s
disease. IUBMB Life 2012, 64: 951–957.
59. Freude S, Hettich MM, Schumann C, Stöhr O, Koch L, Köhler
C, et al. Neuronal IGF-1 resistance reduces Abeta accumulation
and protects against premature death in a model of Alzheimer’s
disease. FASEB J 2009, 23: 3315–3324.
13
Neurosci. Bull. February, 2023, 39(2):303–314
60. Vingtdeux V, Davies P, Dickson DW, Marambaud P. AMPK is
abnormally activated in tangle- and pre-tangle-bearing neurons
in Alzheimer’s disease and other tauopathies. Acta Neuropathol
2011, 121: 337–349.
61. Caprara G. Diet and longevity: The effects of traditional eating
habits on human lifespan extension. Mediterr J Nutr Metab 2018,
11: 261–294.
62. McCay C, Crowell MF. Prolonging the life span. Science
Monthly 1934, 39: 405–414.
63. Hansen M, Kennedy BK. Does longer lifespan mean longer
healthspan? Trends Cell Biol 2016, 26: 565–568.
64. Vermeij WP, Dollé MET, Reiling E, Jaarsma D, Payan-Gomez C,
Bombardieri CR, et al. Restricted diet delays accelerated ageing
and genomic stress in DNA-repair-deficient mice. Nature 2016,
537: 427–431.
65. Green CL, Lamming DW, Fontana L. Molecular mechanisms
of dietary restriction promoting health and longevity. Nat Rev
Mol Cell Biol 2022, 23: 56–73.
66. Morgan TE, Wong AM, Finch CE. Anti-inflammatory mecha-
nisms of dietary restriction in slowing aging processes. Inter-
discip Top Gerontol 2007, 35: 83–97.
67. Prolla TA, Mattson MP. Molecular mechanisms of brain aging
and neurodegenerative disorders: Lessons from dietary restric-
tion. Trends Neurosci 2001, 24: S21–S31.
68. Pedersen WA, Mattson MP. No benefit of dietary restriction on
disease onset or progression in amyotrophic lateral sclerosis
Cu/Zn-superoxide dismutase mutant mice. Brain Res 1999,
833: 117–120.
69. Varady K. Intermittent fasting is Gaining interest fast. Nat Rev
Mol Cell Biol 2021, 22: 587.
70. Gudden J, Arias Vasquez A, Bloemendaal M. The effects of
intermittent fasting on brain and cognitive function. Nutrients
2021, 13: 3166.
71. Longo VD, di Tano M, Mattson MP, Guidi N. Intermittent and
periodic fasting, longevity and disease. Nat Aging 2021, 1:
47–59.
72. Bollati V, Baccarelli A. Environmental epigenetics. Heredity
2010, 105: 105–112.
73. Oh G, Ebrahimi S, Wang SC, Cortese R, Kaminsky ZA, Gottes-
man II, et al. Epigenetic assimilation in the aging human brain.
Genome Biol 2016, 17: 76.
74. Horvath S. DNA methylation age of human tissues and cell
types. Genome Biol 2013, 14: R115.
75. Maity S, Farrell K, Navabpour S, Narayanan SN, Jarome TJ.
Epigenetic mechanisms in memory and cognitive decline asso-
ciated with aging and Alzheimer’s disease. Int J Mol Sci 2021,
22: 12280.
76. Tecalco-Cruz AC, Ramírez-Jarquín JO, Alvarez-Sánchez ME,
Zepeda-Cervantes J. Epigenetic basis of Alzheimer disease.
World J Biol Chem 2020, 11: 62–75.
77. Chouliaras L, Rutten BPF, Kenis G, Peerbooms O, Visser PJ,
Verhey F, et al. Epigenetic regulation in the pathophysiology
of Alzheimer’s disease. Prog Neurobiol 2010, 90: 498–510.
78. Sanchez-Mut JV, Gräff J. Epigenetic alterations in Alzheimer’s
disease. Front Behav Neurosci 2015, 9: 347.
79. Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer
F, et al. Dysregulation of the epigenetic landscape of normal
aging in Alzheimer’s disease. Nat Neurosci 2018, 21: 497–505.
80. Ryu H, Lee J, Hagerty SW, Soh BY, McAlpin SE, Cormier
KA, et al. ESET/SETDB1 gene expression and histone H3 (K9)
trimethylation in Huntington’s disease. Proc Natl Acad Sci U
S A 2006, 103: 19176–19181.
81. Walker MP, LaFerla FM, Oddo SS, Brewer GJ. Reversible epi-
genetic histone modifications and Bdnf expression in neurons
with aging and from a mouse model of Alzheimer’s disease.
AGE 2013, 35: 519–531.
M. Jin, S.-Q. Cai: Mechanisms Underlying Brain Aging
82. Snigdha S, Prieto GA, Petrosyan A, Loertscher BM, Dieskau
AP, Overman LE, et al. H3K9me3 inhibition improves mem-
ory, promotes spine formation, and increases BDNF levels in
the aged hippocampus. J Neurosci 2016, 36: 3611–3622.
83. Zheng Y, Liu A, Wang ZJ, Cao Q, Wang W, Lin L, et al. Inhibi-
tion of EHMT1/2 rescues synaptic and cognitive functions for
Alzheimer’s disease. Brain 2019, 142: 787–807.
84. Danka Mohammed CP, Park JS, Nam HG, Kim K. microRNAs
in brain aging. Mech Ageing Dev 2017, 168: 3–9.
85. Cosín-Tomás M, Alvarez-López MJ, Sanchez-Roige S, Lalanza
JF, Bayod S, Sanfeliu C, et al. Epigenetic alterations in hip-
pocampus of SAMP8 senescent mice and modulation by vol-
untary physical exercise. Front Aging Neurosci 2014, 6: 51.
86. Mohammed CPD, Rhee H, Phee BK, Kim K, Kim HJ, Lee H, et
al. miR-204 downregulates EphB2 in aging mouse hippocampal
neurons. Aging Cell 2016, 15: 380–388.
87. Li X, Zhang J, Li D, He C, He K, Xue T, et al. Astrocytic ApoE
reprograms neuronal cholesterol metabolism and histone-acety-
lation-mediated memory. Neuron 2021, 109: 957-970.e8.
88. Takahashi K, Yamanaka S. Induction of pluripotent stem cells
from mouse embryonic and adult fibroblast cultures by defined
factors. Cell 2006, 126: 663–676.
89. Buganim Y, Faddah DA, Jaenisch R. Mechanisms and models of
somatic cell reprogramming. Nat Rev Genet 2013, 14: 427–439.
90. Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A,
Hatanaka F, Hishida T, et al. In vivo amelioration of age-associ-
ated hallmarks by partial reprogramming. Cell 2016, 167: 1719-
1733.e12.
91. Browder KC, Reddy P, Yamamoto M, Haghani A, Guillen IG,
Sahu S, et al. In vivo partial reprogramming alters age-associ-
ated molecular changes during physiological aging in mice. Nat
Aging 2022, 2: 243–253.
92. Wang F, Cheng L, Zhang X. Reprogramming glial cells into
functional neurons for neuro-regeneration: Challenges and prom-
ise. Neurosci Bull 2021, 37: 1625–1636.
93. Jiang Y, Wang Y, Huang Z. Targeting PTB as a one-step proce-
dure for in situ astrocyte-to-dopamine neuron reprogramming in
Parkinson’s disease. Neurosci Bull 2021, 37: 430–432.
94. Sousounis K, Baddour JA, Tsonis PA. Aging and regeneration in
vertebrates. Curr Top Dev Biol 2014, 108: 217–246.
95. Rando TA, Jones DL. Regeneration, rejuvenation, and replace-
ment: Turning back the clock on tissue aging. Cold Spring Harb
Perspect Biol 2021, 13: a040907.
96. Calado RT, Dumitriu B. Telomere dynamics in mice and humans.
Semin Hematol 2013, 50: 165–174.
97. Liu J, Wang L, Wang Z, Liu JP. Roles of telomere biology in cell
senescence, replicative and chronological ageing. Cells 2019, 8:
54.
98. Hochstrasser T, Marksteiner J, Humpel C. Telomere length is
age-dependent and reduced in monocytes of Alzheimer patients.
Exp Gerontol 2012, 47: 160–163.
99. Whittemore K, Derevyanko A, Martinez P, Serrano R, Pumarola
M, Bosch F, et al. Telomerase gene therapy ameliorates the
effects of neurodegeneration associated to short telomeres in
mice. Aging 2019, 11: 2916–2948.
100. Rolyan H, Scheffold A, Heinrich A, Begus-Nahrmann Y, Lang-
kopf BH, Hölter SM, et al. Telomere shortening reduces Alz-
heimer’s disease amyloid pathology in mice. Brain 2011, 134:
2044–2056.
101. Altman J, Das GD. Autoradiographic and histological evidence
of postnatal hippocampal neurogenesis in rats. J Comp Neurol
1965, 124: 319–335.
102. Altman J, Das GD. Autoradiographic and histological studies
of postnatal neurogenesis. I. A longitudinal investigation of the
kinetics, migration and transformation of cells incorporating triti-
ated thymidine in neonate rats, with special reference to postnatal
313
neurogenesis in some brain regions. J Comp Neurol 1966, 126:
337–389.
103. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag
H. When neurogenesis encounters aging and disease. Trends
Neurosci 2010, 33: 569–579.
104. Lunn JS, Sakowski SA, Hur J, Feldman EL. Stem cell technology
for neurodegenerative diseases. Ann Neurol 2011, 70: 353–361.
105. Liszewska E, Jaworski J. Neural stem cell dysfunction in human
brain disorders. Results Probl Cell Differ 2018, 66: 283–305.
106. Curtis MA, Penney EB, Pearson AG, van Roon-Mom WMC,
Butterworth NJ, Dragunow M, et al. Increased cell proliferation
and neurogenesis in the adult human Huntington’s disease brain.
Proc Natl Acad Sci U S A 2003, 100: 9023–9027.
107. Liu H, Song N. Molecular mechanism of adult neurogenesis and
its association with human brain diseases. J Cent Nerv Syst Dis
2016, 8: 5–11.
108. Ghosal K, Stathopoulos A, Pimplikar SW. APP intracellular
domain impairs adult neurogenesis in transgenic mice by induc-
ing neuroinflammation. PLoS One 2010, 5: e11866.
109. Crews L, Adame A, Patrick C, Delaney A, Pham E, Rockenstein
E, et al. Increased BMP6 levels in the brains of Alzheimer’s
disease patients and APP transgenic mice are accompanied by
impaired neurogenesis. J Neurosci 2010, 30: 12252–12262.
110. Perry EK, Johnson M, Ekonomou A, Perry RH, Ballard C,
Attems J. Neurogenic abnormalities in Alzheimer’s disease dif-
fer between stages of neurogenesis and are partly related to cho-
linergic pathology. Neurobiol Dis 2012, 47: 155–162.
111. Sikora E, Bielak-Zmijewska A, Dudkowska M, Krzystyniak A,
Mosieniak G, Wesierska M, et al. Cellular senescence in brain
aging. Front Aging Neurosci 2021, 13: 646924.
112. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O,
Bishop C, et al. Cellular senescence: Defining a path forward.
Cell 2019, 179: 813–827.
113. Hu Y, Fryatt GL, Ghorbani M, Obst J, Menassa DA, Martin-
Estebane M, et al. Replicative senescence dictates the emergence
of disease-associated microglia and contributes to Aβ pathology.
Cell Rep 2021, 35: 109228.
114. Geng YQ, Guan JT, Xu XH, Fu YC. Senescence-associated beta-
galactosidase activity expression in aging hippocampal neurons.
Biochem Biophys Res Commun 2010, 396: 866–869.
115. Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, et
al. Postmitotic neurons develop a p21-dependent senescence-like
phenotype driven by a DNA damage response. Aging Cell 2012,
11: 996–1004.
116. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM,
Baker DJ. Clearance of senescent glial cells prevents tau-depend-
ent pathology and cognitive decline. Nature 2018, 562: 578–582.
117. Jin WN, Shi K, He W, Sun JH, van Kaer L, Shi FD, et al. Neu-
roblast senescence in the aged brain augments natural killer cell
cytotoxicity leading to impaired neurogenesis and cognition. Nat
Neurosci 2021, 24: 61–73.
118. Jin JL, Liou AK, Shi Y, Yin KL, Chen L, Li LL, et al. CART
treatment improves memory and synaptic structure in APP/PS1
mice. Sci Rep 2015, 5: 10224.
119. Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo
D, et al. Senolytic CAR T cells reverse senescence-associated
pathologies. Nature 2020, 583: 127–132.
120. Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing
and cognitive decline. Nature 2010, 464: 529–535.
121. Cox SR, Ritchie SJ, Tucker-Drob EM, Liewald DC, Hagenaars
SP, Davies G, et al. Ageing and brain white matter structure in
3, 513 UK Biobank participants. Nat Commun 2016, 7: 13629.
122. Bennett IJ, Madden DJ. Disconnected aging: Cerebral white mat-
ter integrity and age-related differences in cognition. Neurosci-
ence 2014, 276: 187–205.
13

314
123. Chowdhury R, Guitart-Masip M, Lambert C, Dayan P, Huys Q,
Düzel E, et al. Dopamine restores reward prediction errors in old
age. Nat Neurosci 2013, 16: 648–653.
124. Yin JA, Liu XJ, Yuan J, Jiang J, Cai SQ. Longevity manipula-
tions differentially affect serotonin/dopamine level and behav-
ioral deterioration in aging Caenorhabditis elegans. J Neurosci
2014, 34: 3947–3958.
125. Zullo JM, Drake D, Aron L, O’Hern P, Dhamne SC, Davidsohn
N, et al. Regulation of lifespan by neural excitation and REST.
Nature 2019, 574: 359–364.
126. Apfeld J, Kenyon C. Regulation of lifespan by sensory perception
in Caenorhabditis elegans. Nature 1999, 402: 804–809.
127. Garden GA, la Spada AR. Intercellular (mis)communication in
neurodegenerative disease. Neuron 2012, 73: 886–901.
128. Norden DM, Godbout JP. Review: Microglia of the aged brain:
Primed to be activated and resistant to regulation. Neuropathol
Appl Neurobiol 2013, 39: 19–34.
129. Ownby RL. Neuroinflammation and cognitive aging. Curr Psy-
chiatry Rep 2010, 12: 39–45.
130. Colonna M, Butovsky O. Microglia function in the central nerv-
ous system during health and neurodegeneration. Annu Rev
Immunol 2017, 35: 441–468.
131. Minhas PS, Latif-Hernandez A, McReynolds MR, Durairaj AS,
Wang Q, Rubin A, et al. Restoring metabolism of myeloid cells
reverses cognitive decline in ageing. Nature 2021, 590: 122–128.
132. Jang S, Dilger RN, Johnson RW. Luteolin inhibits microglia and
alters hippocampal-dependent spatial working memory in aged
mice. J Nutr 2010, 140: 1892–1898.
133. Benfante R, Lascio SD, Cardani S, Fornasari D. Acetylcholinest-
erase inhibitors targeting the cholinergic anti-inflammatory path-
way: A new therapeutic perspective in aging-related disorders.
Aging Clin Exp Res 2021, 33: 823–834.
134. Li Y, Xie L, Huang T, Zhang Y, Zhou J, Qi B, et al. Aging
neurovascular unit and potential role of DNA damage and repair
in combating vascular and neurodegenerative disorders. Front
Neurosci 2019, 13: 778.
135. Yousufuddin M, Young N. Aging and ischemic stroke. Aging
2019, 11: 2542–2544.
136. De Silva TM, Faraci FM. Contributions of aging to cerebral small
vessel disease. Annu Rev Physiol 2020, 82: 275–295.
137. Carrano A, Hoozemans JJM, van der Vies SM, Rozemuller AJM,
van Horssen J, de Vries HE. Amyloid Beta induces oxidative
stress-mediated blood-brain barrier changes in capillary amyloid
angiopathy. Antioxid Redox Signal 2011, 15: 1167–1178.
138. Chung YC, Kim YS, Bok E, Yune TY, Maeng S, Jin BK. MMP-3
contributes to nigrostriatal dopaminergic neuronal loss, BBB
damage, and neuroinflammation in an MPTP mouse model of
Parkinson’s disease. Mediators Inflamm 2013, 2013: 370526.
139. Jangula A, Murphy EJ. Lipopolysaccharide-induced blood brain
barrier permeability is enhanced by alpha-synuclein expression.
Neurosci Lett 2013, 551: 23–27.
140. Dohgu S, Takata F, Matsumoto J, Kimura I, Yamauchi A,
Kataoka Y. Monomeric α-synuclein induces blood-brain barrier
dysfunction through activated brain pericytes releasing inflam-
matory mediators in vitro. Microvasc Res 2019, 124: 61–66.
13
Neurosci. Bull. February, 2023, 39(2):303–314
141. Stein KC, Morales-Polanco F, van der Lienden J, Rainbolt TK,
Frydman J. Ageing exacerbates ribosome pausing to disrupt
cotranslational proteostasis. Nature 2022, 601: 637–642.
142. Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its
decline in ageing. Nat Rev Mol Cell Biol 2019, 20: 421–435.
143. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE. Bio-
logical and chemical approaches to diseases of proteostasis defi-
ciency. Annu Rev Biochem 2009, 78: 959–991.
144. Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias
R, Bezard E, et al. Initial clinical manifestations of Parkinson’s
disease: Features and pathophysiological mechanisms. Lancet
Neurol 2009, 8: 1128–1139.
145. Stranahan AM, Mattson MP. Recruiting adaptive cellular stress
responses for successful brain ageing. Nat Rev Neurosci 2012,
13: 209–216.
146. Hetz C, Saxena S. ER stress and the unfolded protein response
in neurodegeneration. Nat Rev Neurol 2017, 13: 477–491.
147. Mattson MP. Late-onset dementia: A mosaic of prototypical
pathologies modifiable by diet and lifestyle. NPJ Aging Mech
Dis 2015, 1: 15003.
148. Geddes JW, Tekirian TL, Soultanian NS, Ashford JW, Davis DG,
Markesbery WR. Comparison of neuropathologic criteria for the
diagnosis of Alzheimer’s disease. Neurobiol Aging 1997, 18:
S99–S105.
149. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal
NT, Shah RC, et al. Neuropathology of older persons without
cognitive impairment from two community-based studies. Neu-
rology 2006, 66: 1837–1844.
150. Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo
H, et al. Apolipoprotein E-dependent accumulation of Alzheimer
disease-related lesions begins in middle age. Ann Neurol 2009,
65: 650–657.
151. Wyss-Coray T. Ageing, neurodegeneration and brain rejuvena-
tion. Nature 2016, 539: 180–186.
152. Ximerakis M, Lipnick SL, Innes BT, Simmons SK, Adiconis X,
Dionne D, et al. Single-cell transcriptomic profiling of the aging
mouse brain. Nat Neurosci 2019, 22: 1696–1708.
153. Ding XL, Lei P. Plasma replacement therapy for Alzheimer’s
disease. Neurosci Bull 2020, 36: 89–90.
154. Sha SJ, Deutsch GK, Tian L, Richardson K, Coburn M, Gaudioso
JL, et al. Safety, tolerability, and feasibility of young plasma infu-
sion in the plasma for alzheimer symptom amelioration study: A
randomized clinical trial. JAMA Neurol 2019, 76: 35–40.
155. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher
KI, Luo J, et al. Young blood reverses age-related impairments
in cognitive function and synaptic plasticity in mice. Nat Med
2014, 20: 659–663.
156. Kaur P, Otgonbaatar A, Ramamoorthy A, Chua EHZ, Harmston
N, Gruber J, et al. Combining stem cell rejuvenation and senes-
cence targeting to synergistically extend lifespan. bioRxiv 2022,
DOI:https://​doi.​org/​10.​1101/​2022.​04.​21.​488994.
157. King A. The search for better animal models of Alzheimer’s dis-
ease. Nature 2018, 559: S13–S15.
158. Hall AM, Roberson ED. Mouse models of Alzheimer’s disease.
Brain Res Bull 2012, 88: 3–12.