Fnagi 14 931536

REVIEW
published: 30 June 2022

doi: 10.3389/fnagi.2022.931536
Normal Aging Induces Changes in

the Brain and Neurodegeneration
Progress: Review of the Structural,
Biochemical, Metabolic, Cellular, and
Molecular Changes
Jiseon Lee and Hee-Jin Kim
Department of Neurology, Hanyang University Hospital, Seoul, South Korea
Aging is accompanied by many changes in brain and contributes to progressive

cognitive decline. In contrast to pathological changes in brain, normal aging brain
changes have relatively mild but important changes in structural, biochemical and
molecular level. Representatively, aging associated brain changes include atrophy
of tissues, alteration in neurotransmitters and damage accumulation in cellular
Edited by: environment. These effects have causative link with age associated changes which
Suzana Makpol, ultimately results in cognitive decline. Although several evidences were found in normal
Hospital Chancellor Tuanku Muhriz,
National University of Malaysia,
aging changes of brain, it is not clearly integrated. Figuring out aging related changes
Malaysia in brain is important as aging is the process that everyone goes through, and
Reviewed by: comprehensive understanding may help to progress further studies. This review clarifies
Ji-Young Park, normal aging brain changes in an asymptotic and comprehensive manner, from a gross
Korea University, South Korea
Jin-Woo Park, level to a microscopic and molecular level, and discusses potential approaches to seek
Korea University, South Korea the changes with cognitive decline.
*Correspondence:
Keywords: normal aging, neurodegeneration, microscopic changes, structural changes, cellular changes
Hee-Jin Kim
[email protected]
Specialty section: INTRODUCTION

This article was submitted to
Cellular and Molecular Mechanisms Due to improved economic status and public health care systems, global populations have
of Brain-aging, expanded, and life expectancy has increased. In Korea, the aging population is increasing very fast
a section of the journal (Baek et al., 2021). It has been reported that approximately 5% of the global elderly population is
Frontiers in Aging Neuroscience
affected by dementia. The number of patients with dementia has doubled or tripled within the last
Received: 29 April 2022 few decades (2020). Including dementia and neurodegenerative diseases are associated with brain
Accepted: 13 June 2022
aging. Brain aging is associated with anatomical and functional deterioration, which can result in
Published: 30 June 2022
neurodegenerative diseases.
Citation:
Lee J and Kim H-J (2022) Normal
Aging Induces Changes in the Brain Abbreviations: GM, gray matter; WM, white matter; AD, Alzheimer’s diseases; PHF, paired helical filament; CNS, central
nervous system; MCI, mild cognitive impairment; nAChR, nicotinic acetylcholine receptor; BBB, Brain-blood barrier; AP,
and Neurodegeneration Progress:
action potential; PET, positron emission tomography; NPC, neuro progenitor cell; ROS, reactive oxygen species; mtDNA,
Review of the Structural, Biochemical,
mitochondrial DNA; OXPHOS, oxidative phosphorylation; TCA cylce, tricarboxylic acid cycle; ETC, electron transport
Metabolic, Cellular, and Molecular complex; UPS, ubiquitin-proteasome system; LPO, lipid peroxidation; PD, Parkinson’s disease; PINK1,PTEN-induced novel
Changes. kinase 1; PSD, postsynaptic density; ER, Endoplasmic Reticulum; NMDAR, N-methyl-D-aspartate receptor; VDCC, voltage-
Front. Aging Neurosci. 14:931536. dependent Ca2+ channels; IP3 , inositol (1,4,5)-triphosphate; GPCR, G protein-coupled receptors; LTP, long term potentiation;
doi: 10.3389/fnagi.2022.931536 CICR, Ca2+ induced Ca2+ release; RyRs, ryanodine receptors; CBP, Ca2+ binding protein.
Frontiers in Aging Neuroscience | www.frontiersin.org 1 June 2022 | Volume 14 | Article 931536

Lee and Kim Brain Changes in Normal Aging
Neurons in the brain are post-mitotic cells that require features of tissue changes are partial loss of myelin, axons,
regulation systems that keep the levels of neuronal electrical oligodendroglial cells, and mild reactive astrocytic gliosis linked
activity consistently to maintain their neuronal network. to WM lesions (Schmidt et al., 2011). Furthermore, WM changes
However, dysfunction of energy metabolism could jeopardize this are related to arteriolosclerosis of small vessels, resulting in
system and lead to aging of the brain. incomplete ischemia and cell death and the emergence of
According to previous studies, brain aging shows several perivascular spaces that interfere with the glymphatic drainage
hallmarks in other tissues as follows (Mattson and Arumugam, of the brain’s waste products (Nedergaard and Goldman, 2020).
2018): (1) mitochondrial dysfunction; (2) intracellular During normal aging, the GM volume fraction has been reported
accumulation of oxidatively damaged proteins, nucleic acids, and to drop from 52.35% in those in their 40s to 50.49% in those
lipids; (3) dysregulated energy metabolism; (4) impaired cellular in their 80s (Taki et al., 2011). The WM has been reported
waste disposal mechanisms; (5) impaired adaptive stress response to decrease from 47.63% in those in their 40s to 40.29% in
signaling; (6) compromised DNA repair; (7) aberrant neuronal those in their 80s, whereas the ventricular volume fraction
network activity; (8) dysregulated neuronal Ca2+ handling; increases from 3.22 to 5.66% (Blinkouskaya and Weickenmeier,
(9) stem cell exhaustion; and (10) inflammation. Chronic 2021). In addition, ventricular enlargement is caused by an
positive energy balance accelerates brain aging and leads to increase in the space between folds and loss of gyrification
neurodegenerative diseases through mitochondrial dysfunction, (Blinkouskaya and Weickenmeier, 2021).
neurotoxic protein accumulation, and neuro-inflammation With respect to the sulci and gyrus of the cerebral cortex,
(Mattson and Arumugam, 2018). the grooves and folds or ridges, respectively, become wider
This review summarizes the structural, biochemical, and shallower with aging (Jin et al., 2018). Sulci modifications
metabolic, cellular, and molecular changes that occur with result from shrinkage in the gyri, both nearby and distally. They
normal brain aging (Table 1). In terms of structural changes, both may affect the global shape of the brain with many regional
gross and microscopic changes occur with aging. Biochemical outcomes (Jin et al., 2018). These integral forces are provoked
and metabolic changes can be categorized into different by the combined changes in the cortical GM and WM, along
neurotransmitter groups such as acetylcholine, monoamine, and with other subcortical structures. Sulci morphology differences
hormones. Cellular and molecular changes in the brain affect indicate that the sulci are wider (17.3%) in older people (Jin
the nucleus and mitochondria, oxidatively damage molecules, et al., 2018). In addition, the sulci depth has been reported to
lysosome and proteasome function, electrophysiological be shallower in older participants in the intraparietal sulcus.
regulation and neuronal calcium homeostasis. Moreover, sulci width is generally associated with local brain
volumetric differences (Jin et al., 2018).
A sufficient supply of blood and structural and functional
STRUCTURAL CHANGES blood vessels is important for normal brain function (Sweeney
et al., 2018). In the brain, cerebrovascular reactivity is crucially
Gross Changes important in maintaining cerebral autoregulation and cerebral
The brain undergoes various morphological changes with aging, blood flow over a large range of arterial pressures (Payne,
such as cerebral atrophy, gray and white matter changes (GM 2016). However, the aging process changes complex interactions
and WM, respectively), volume loss, ventricular enlargement, between the brain parenchyma and cerebrovascular system,
and sulci widening (Blinkouskaya and Weickenmeier, 2021). It and these changes have effects on health and functioning that
is widely known that the volume of the brain and its weight negatively impact cognition. Along with arterial inflammation,
decreases with age at a rate of around 5% per decade after 40 years arteriosclerosis is one of the earliest measurable changes in
of age (Peters, 2006). Furthermore, the rate of decline may vascular function (Anderson, 2006). Arterial stiffening occurs
acutely increases after 70 years old (Peters, 2006). For example, before many negative changes to the rest of the cerebrovascular
a large cross-sectional study of 2200 participants aged 34– system, brain, and cognition related to dementia, including
97 years suggests lobar volume loss during aging (DeCarli et al., Alzheimer’s disease (AD) in the elderly (Suri et al., 2020).
2005). The frontal lobe volume decrease about 12% across the Specifically, elastic fibers, collagen, and smooth muscle cells
cohort (DeCarli et al., 2005). The temporal lobe volume declined comprise the arterial wall, and these components deteriorate
about 9% (DeCarli et al., 2005). The occipital and parietal lobes over one’s life due to aging-associated mechanisms (Heinz, 2021).
shows no significant age-related volume change (DeCarli et al., Carotid artery dispensability and compliance start to decrease
2005). It is known that the volume loss is accompanied by around 30 years old (Heinz, 2021). However, elastin fibers
expansion of ventricular volume and other cerebrospinal fluid are not normally generated when they are impaired, whereas
spaces (Anderton, 2002). collagen, which increases the stiffness, is produced (Heinz, 2021).
In GM, cerebral atrophy occurs through morphological CBF pulsatility is directly related to carotid pulse pressure
alterations related to a decrease in the complexity of dendrite and predictive WM hyperintensities (Zimmerman et al., 2021).
arborization (Blinkouskaya and Weickenmeier, 2021). Dendritic Systolic blood pressure has been associated with GM volume loss
shortening, loss of dendritic shortening, and decreased dendritic in a cross-sectional study (Schaare et al., 2019), and can result in
spines trigger a progressive reduction in synaptic density and cerebrovascular injuries, accelerated atrophy, WM abnormalities,
synaptic transmission, with major consequences on cognitive and asymptomatic infarcts (Maillard et al., 2012). In addition,
decline (Dickstein et al., 2007). In contrast, in WM, the common cerebral vasculature is associated with cognitive function, as

TABLE 1 | Summary of the aging process in the brain.
Gross changes Microscopic changes
Structural Aging
• Volume loss • Lipofuscin accumulation
• Neurodegeneration in the GM, Demyelination in the WM, • Neurofibrillary tangles, amyloid plaque formation
Ventricular enlargement
• Sulci widening • Dendritic tree decrease, axon number decreases,
demyelination
• Cerebrovascular diseases
Acetylcholine Monoamine Neurosteroid
Biochemical and Metabolic Aging

• Dysfunction in the cholinergic system: • Disturbed dopaminergic pathway • Decreased testosterone disturbs BBB, and invoke
memory decline inflammation activity
• Nicotinic binding ability lost • Disturbed serotonergic pathway • Decreased androgen and estrogen reduce receptor
expression and synapse density.
• Nicotinic acetylcholine receptors • Decreased receptors and binding ability
decrease
Changes in the nucleus Mitochondrial dysfunction Accumulation of

oxidatively damaged molecules
Cellular and Molecular aging

• Alteration in gene expression • mtDNA damage • ETC damage
• Decrease in synaptic function • Disturbed ATP production • Lipid, protein DNA/RNA damage
• Increase in stress responses • Apoptosis induced • Disturb cellular metabolic pathway or homeostasis
• Telomere shortening
Impaired lysosome and Electrophysiological Changes Dysregulation of neuronal calcium homeostasis

proteosome function in the Brain by Aging
• Autophagy and UPS reduction • AP threshold changes: changes in voltage-gated • Plasma membrane proteins:
• Increase cellular wastes Na+ channel activation prperties and subtypes - Decreased NMDAR function
expression pattern. - Post-translational alterations in receptors
• AP amplitude decrease. - Increased VDCC number
• AP axonal conduction rate decrease • Changes in Ca2+ influx and disturb cellular
Ca2+ homeostasis
- Cellular organelles
- Mitochondria
: Depolarization disturbs electrochemical gradients
- ER
: Ca2+ regulating receptors changes.
: Changes in calcium-binding protein
: Decreased expression and disturbs Ca2+ buffering
GM, gray matter; WM, white matter; BBB, brain blood barrier; mtDNA, mitochondrial DNA; ETC, electron transport complex; UPS, ubiquitin proteasome system; AP,
action potential; NMDAR, N-methyl-D-aspartate receptor; VDCC, voltage-dependent calcium channel; ER, endoplasmic reticulum; ATP, adenosine triphosphate.
metabolic demand decreases with increasing age and functional (Klaips et al., 2018). Normally, lipofuscin is located in the
adult neurogenesis. Specifically, large-vessel factors, such as lysosome, as macroautophagy triggers lysosomes to uptake
atherosclerosis, increase the risk of AD and may play a role in these aggregates (Moreno-Garcia et al., 2018). However, when
vertebral vessel amyloid deposition (Peters, 2006). macroautophagy pathways are blocked for reasons such as
aging, lipofuscin can accumulate in the cytosol (Moreno-
Microscopic Changes Garcia et al., 2018). In normal aged mammalian brains,
Microscopically, lipofuscins, neurofibrillary tangles, and senile lipofuscins correlate with a specific senescence pattern that
plaques form and increase with age (Moreno-Garcia et al., alters the neuronal cytoskeleton and cellular trafficking (Moreno-
2018). Lipofuscin accumulates in some neurons. Lipofuscin Garcia et al., 2018). The normal brain aging process involves
contains peroxidased proteins and lipids and may express intraneuronal deposits of lipofuscin and neuromelanin pigment
the frequent failure of cells to clear these products of (Moreno-Garcia et al., 2018). In contrast, in neurodegenerative
peroxidation-induced cell damage (Anderton, 2002). With aging, disorders, lipofuscin accumulation increases with age and
cellular proteostasis declines and disturbs the degradation of pathological processes such as neuronal loss or cellular
misfolded proteins that are prone to aggregating into aggrosomes alterations related to oxidative stress, proteasome, lysosomal,

and mitochondrial dysfunction, which will be described below old age (Huebner and Strittmatter, 2009). However, it is delayed
(Moreno-Garcia et al., 2018). and proceeds at a slower rate in the elderly than in younger
In the process of aging, toxic proteins, such as amyloid- people. The materials move along the axon by slow transport,
beta (Aβ) protein in AD and tau in frontotemporal dementia, and the speed of this transport decreases with aging. The
are potential contributory factors in cognitive decline (Nikhra, decreased rate of transport is believed to explain the process
2017). Normally, amyloid plaques and neurofibrillary tangles are of degeneration of axons (Huebner and Strittmatter, 2009).
considered hallmarks of AD. However, it is observed during Furthermore, the myelin sheaths of nerve fibers and synapses are
normal aging (Guillozet et al., 2003). Aβ is a protein deposited also affected by aging. The myelin sheath plays a crucial role in
in the brain in some individuals with aging (Guillozet et al., the rapid propagation of action potentials by providing insulation
2003). In addition, Aβ is higher in some normal individuals to axons (Suminaite et al., 2019). However, they are altered
with mild cognitive impairment (MCI) than in normal older by demyelination, remyelination, and myelin decomposition.
adults (Guillozet et al., 2003). When neuropsychologically Through these changes, myelin sheaths lose conduction velocity,
normal, healthy older adults have significant neuropathology and the degrees are slowed with aging (Peters, 2007). In addition,
at autopsy, and amyloid is common because of the form of the number of synapses is reduced, with the rate ranging from
amyloid deposition (Rodrigue et al., 2009). The number of 15 to 50% depending on the species and the region of the
tangles located in the cell body of affected neurons is low nervous system (Peters, 2006). This alteration is associated
and restricted to the hippocampus, amygdala, and entorhinal with the regression of the postsynaptic structure and loss of
cortex in normal aging (Hof et al., 1996). However, when presynaptic structures. Although the number of synapses may
minimal neurofibrillary tangles are present, they are located decrease, the structure of synapses does not change with old age
in the transentorhinal region of individuals without dementia (Pannese, 2011).
(Braak et al., 2006). When neurofibrillary changes increase
in the brain, the entorhinal cortex is also affected, and
cognitive impairment, related to the hippocampus, is triggered BIOCHEMICAL AND METABOLIC
with further progress (Braak et al., 2006). Paired helical CHANGES
filaments (PHF) and occasional straight filaments comprise
neurofibrillary tangles, and it has been shown that patients Acetylcholine
with AD have neurons severely affected by PHF, as the Aging is accompanied by several biological changes in the
normal cytoskeleton of microtubules and neurofilaments totally brain. The manner in which neurons transmit information
disappear (Bamburg and Bloom, 2009). Therefore, it is believed through nerve impulses is called the action potential. When
that a shortage of functional cytoskeleton probably triggers an action potential is transmitted to the presynaptic terminal
neuronal loss (Anderton, 2002). The contrast between normal of the synapse, it may trigger the release of neurotransmitters.
and pathological aging is the presence and distribution of These neurotransmitters are released by synaptic cleavage and
neurofibrillary tangles (Bamburg and Bloom, 2009). The number bind to synaptic receptors. This process affects other neurons
of tangles in each affected tissue is lower in normal aging than in in an exciting or inhibitory manner, causing other neurons
pathological cases and is limited to the olfactory nucleus, para- to induce action potentials (Lodish et al., 2000). It revealed
hippocampal gyrus, amygdala, and entorhinal cortex (Bamburg that various neurotransmitters and receptors change in several
and Bloom, 2009). In contrast, in pathological aging, the regions of the brain during the aging process. Specifically,
neurodegenerative way, in other words, neurofibrillary tangles major neurotransmitter systems can be classified as cholinergic
are often found with amyloid plaque in patients with AD systems, monoamine systems (catecholamine: norepinephrine
(Nikhra, 2017). and dopamine, and indole amine: serotonin), and others such as
Other microscopic changes include morphological alterations amino acids, nitro oxide, and hormones (Nikhra, 2017).
in neurons. It has been revealed that neuronal loss during Acetylcholine activates skeletal muscles in the somatic nervous
normal aging occurs slightly (no more than 10%) (Morrison system and may affect internal organs in the autonomic
and Baxter, 2012). However, morphological changes in neurons, systems (Sam and Bordoni, 2022). In particular, cholinergic
especially dendrites and axons, are involved in cognitive decline pathways control cognitive processes and behaviors such as
and behavioral changes (Dickstein et al., 2013). With increasing wakefulness, mood, learning motor function, motivation, short-
age, the dendritic tree underwent regression. Dendritic shafts term memory, and a minor part of reward responses (Nikhra,
decrease in number, become shorter and less branched, and 2017). According to the cholinergic hypothesis, dysfunction of
have fewer spines (Dickstein et al., 2013). Moreover, not every the cholinergic system plays a role in the memory decline often
spine is affected to the same extent, and in the specific observed in aging and dementia (Araujo et al., 2005). With
area of the cortex, thin spines are lost (Dickstein et al., normal aging, the nicotinic binding ability is lost. In particular,
2013). These spines have high motility and plasticity and are cholinergic neurons and certain nicotinic acetylcholine receptor
believed to be related to learning (Dickstein et al., 2013). (nAChRs) subtypes are specifically reduced or eliminated during
Axons may have glycogen inclusion, degenerated mitochondria, normal aging (Rogers et al., 1998). It has been revealed
and accumulations of filaments (Wang et al., 2021). These that high-affinity nicotine-binding sites in the entorhinal
modifications may lead to degeneration. Regeneration of axons cortex and presubiculum are largely lost in those over
follows degeneration, and these axons enable regeneration in 40 years (Utkin, 2019). Moreover, considering that nAchRs

trigger the reactivation of neurogenesis by endogenous neural swing, increase in rigidity, and cognitive flexibility changes
stem/progenitor cells, it is easy to believe that reduction (Nikhra, 2017).
in nAchRs may affect neurogenesis (Utkin, 2019). In fact, The serotonergic pathway is associated with cognitive
it has been identified that a decreased cholinergic input processes and behaviors such as wakefulness, body temperature
disturbs proliferation, short-term survival, and differentiation regulation, emotion, and mood, including aggression, feeding
into mature neurons, whereas it promotes apoptosis in and energy homeostasis, and sensory perception (Nikhra, 2017).
the hippocampus in mice (Seib and Martin-Villalba, 2015). It affects appetite, sleep, memory, learning, temperature, mood
Cognitive deficits associated with aging and AD are also behavior, muscle contraction, and function of the cardiovascular
associated with cholinergic deficits. Therefore, the maintenance and endocrine system (Nikhra, 2017). The number of serotonin
of nicotinic receptors may be important for neuronal survival receptors and transporters decreases with increasing age.
(Rehman and Masson, 2001). According to PET studies, the number of S1 receptors in
the caudate nucleus, putamen, and frontal cerebral cortex
decreases. In the same context, the binding capacity for serotonin
Monoamine: Catecholamine transporters in the thalamus and midbrain is also diminished
(Norepinephrine, Dopamine), Indole (Kumar and Mann, 2014).
Amine (Serotonin)
Norepinephrine and dopamine are the most important
neurotransmitters that are associated with aging (Nikhra, 2017). NEUROSTEROIDS
They play important roles in the regulation of synaptic plasticity
and neurogenesis in the adult brain (Nikhra, 2017). Serotonin The brain is a steroidogenic organ that retains steroidogenic
and brain-derived neurotrophic factor levels decrease with aging enzymes and produces neurosteroids (Zwain and Yen, 1999).
(Nikhra, 2017). Furthermore, monoamine oxidase increases Neurosteroids are steroids produced from various regions of
with age and results in the generation of excess free radicals that the brain, mainly in the hippocampus, and they are the
exceed the inherent antioxidant process (Nikhra, 2017). endogenous regulator of neuronal excitability (Reddy, 2010).
Norepinephrine or epinephrine functions in the central The precursors of neurosteroids are the circulating steroid
nervous system to regulate sleep patterns and alertness. These hormones (Reddy, 2010). Neurosteroids belonging to the sex
charges regulate adrenal glands and fight-or-flight responses hormones may have neuroprotective effects against brain aging
(Bennun, 2014). Norepinephrine is associated with cognitive features, especially Aβ- or tau-related toxicity and oxidative
processes and behaviors such as anxiety, arousal, circadian stress (Grimm et al., 2016). For example, with the neurosteroid
rhythm, cognitive control, and working memory (Nikhra, estrogen receptors widely distributed in the brain, estrogen plays
2017). They also regulate feeding and energy homeostasis, a role as a neuroprotective antioxidant against several toxins,
medullary control of respiration, negative emotional memory, which in turn encourage the production of free radical (Norbury
nociception and play a minor role in the reward related system et al., 2003). The brain consumes a high rate of oxygen and
(Nikhra, 2017). consists of the neuronal membrane with a high concentration of
Dopaminergic pathways are related to cognitive processes polyunsaturated fatty acids, factors that leads to the risks of lipid
and behaviors such as wakefulness, aversion, cognitive control, peroxidation (Norbury et al., 2003). Therefore, the antioxidant
working memory (along with norepinephrine), emotion and activity of the brain is required for its homeostasis (Norbury
mood, motivation, motor function, positive reinforcement, et al., 2003). Estrogen may play important role in the regulation
reward, sexual arousal, and the refractory period (Schultz, 2007). of mitochondrial function both directly and indirectly, yet this
In age-related changes in the dopaminergic system in the brain, process has not been identified clearly (Zarate et al., 2017).
dopamine synthesis, binding ability, and its receptors decrease. Their effects are important to the central nervous system (CNS)
According to positron emission tomography (PET) of the normal which demands high energy (Zarate et al., 2017). Along with
aged brain, dopamine synthesis is significantly reduced in the the metabolism regulation, estrogen also affects mitochondria in
striatum and parastriatal region with aging (Harada et al., neuronal tissues during biogenesis, apoptosis, and morphology
2002). In addition, D1, D2, and D3 dopamine receptors also (Zarate et al., 2017). Further, estrogen protects mitochondria
decreased. Dopamine levels decrease by 10% per decade from from oxidative damage, which may cause mitochondrial DNA
early adulthood, and in accordance with this change, cognitive mutations (Zarate et al., 2017).
and motor performance decline (Rieckmann et al., 2011). That In the senescence process, the decline of neurosteroids,
is, with increasing age, the levels of dopamine decline, and especially that of testosterone in men and estrogen in women
synapses/receptors and binding ability are also reduced in the after menopause, may impair neuronal function and cause
dopaminergic pathway between the frontal cortex and striatum significant age-associated neurodegenerative diseases (Zarate
(Ota et al., 2006). Moreover, dopamine levels are associated et al., 2017). Testosterone regulates brain functions including
with various brain regions, such as the anterior cingulate dendritic spine morphology, neurogenesis, and learning and
cortex, frontal cortex, lateral temporal cortex, hippocampus, memory (Parks, 2020). When testosterone level declines in the
medial temporal cortex, amygdala, medial thalamus, and lateral serum and brain, the blood–brain barrier (BBB) integrity and the
thalamus (Kaasinen et al., 2000). These deficiencies cause age- expression of tight junction proteins are disrupted, which may
related neurological symptoms such as a decrease in arm in turn induce an inflammation activity (Parks, 2020). Androgen,

a metabolite of testosterone, also carries neuroprotective isoforms (Fraser et al., 2005). Other categories of age-reduced
function (Parks, 2020). Its depletion, which comes with that genes are vesicle-mediated protein transport and mitochondrial
of testosterone, may stretch into the decline of CA1 spine function (Fraser et al., 2005). In addition, genes related to
synapse density (Zarate et al., 2017). Again when age, the local stress responses, such as antioxidant defense, DNA repair,
synthesis of estrogen is declined due to the reduced expression and immune function, represent the largest category and have
of aromatase, the enzyme that synthesizes estrogen utilizing been found in several different cortical areas of the aging
androgen (Li et al., 2014). Additionally, the expression of estrogen human brain (Fraser et al., 2005). Gene expression alterations
receptors in the brain drops during aging, successively causing affect the susceptibility of the aging brain to neurodegenerative
detrimental impacts on memory and learning by retarding the disorders (Yankner et al., 2008). For instance, a microarray
signaling pathways in the brain areas where estrogen receptors study of AD indicated that a substantial number of expressions
are mediated, that is hippocampus and prefrontal cortex (Zarate are related to pathological markers and cognitive test scores
et al., 2017). The reduction of synapse number and spine density (Blalock et al., 2004). Specifically, it is upregulated in signaling
in the CA1 area of the hippocampus is observed in multiple and tumor suppressor genes and downregulated in protein
animal models, especially those with rats, when their ovarian folding, metabolism, and energy-related genes (Blalock et al.,
hormones decreased either naturally or artificially (Zarate et al., 2004). Therefore, neurodegeneration and cognitive decline
2017). Estrogen’s effects on the hippocampus are also shown to be may be involved in specific alterations in gene expression
less responsive for older models than younger ones, for there is a (Yankner et al., 2008).
significant gap in the number of estrogen receptors between the One of the primary hallmarks is telomere shortening (Lopez-
two groups (Adams et al., 2001). Otin et al., 2013). According to the telomere theory of aging and
Sex hormones, or neurosteroids, interact with the insulin cellular senescence, cells have a definite number of divisions and
receptor, which regulates glucose and carbohydrate metabolism define when replication is suitable (Olovnikov, 1996). Telomeres,
(Baquer et al., 2009). Glucose being the main energy source of the which have a role in the biological clock, have thousands of
brain, approximately 20% of the total metabolized glucose in the tandem DNA repeats, TTAGGG at the end of each linear
body at a rest state is consumed by it (Mergenthaler et al., 2013). chromosome (Zia et al., 2021). Telomeres are important because
Therefore, disturbed glucose metabolism can lead to various they are engaged in genome maintenance and promote stability
brain malfunction (Mergenthaler et al., 2013). Considering that through replication procedures, preventing chromosomal fusion
peptides and steroid hormones control the influx of glucose in and unnecessary recombination (Muraki et al., 2012). Telomerase
cells, the decrease in neurosteroids during aging may pervert is a ribonucleoprotein enzyme consisting of two essential
glucose homeostasis of the brain (Baquer et al., 2009). subunits: telomerase reverse transcriptase protein (TERT) and
telomerase RNA (TER) (Nandakumar and Cech, 2013). It
reverses telomere shortening like stem cells (Nandakumar and
CELLULAR AND MOLECULAR AGING IN Cech, 2013). Telomere shortening and its role in the healthy aging
THE BRAIN (Figure 1) process of the brain and neuronal senescence at the cellular level
have not been explained (Takubo et al., 2010).
Changes in the Nucleus Age-related alterations in neurons are not fully understood
Associated with aging, a number of microarray studies have (Zia et al., 2021). As neurons are post-mitotic, cell division,
been implemented to identify genome-wide changes in gene the main factor for telomere shortening, has been regarded as
expression, particularly in the brain (Yankner et al., 2008). absent in neurons when they reach terminal replication (Zia
Specific biological pathways change due to the aging process, et al., 2021). However, this view has been opposed by the
as opposed to the genome-wide dysregulation of transcription investigation of DNA content variants, describing cell cycle
(Yankner et al., 2008). In addition, the expressed genes triggered activity in approximately 10–20% of post-mitotic neurons in the
by the induction of stress are related to aging (Yankner et al., cortex of healthy aging brains and AD (Mosch et al., 2007).
2008). In a study that conducted transcriptional profiling of Telomerase activity restores various features of aging in somatic
the aging human frontal cortex in 30 individuals from 26 to cells, such as senescence. However, in some somatic tissues,
106 years of age, approximately 4% of the genes expressed in including the central nervous system, the telomerase enzyme has
the brain were found to be age-regulated (Lu et al., 2004). downregulated transcript levels and activity, which are related
Specifically, age-associated changes in gene expression become to protein levels (Wright et al., 1996). In particular, telomerase
obvious in middle age and are most clear after 70 years of age function in post-mitotic cells, such as neurons, is not related to
(Yankner et al., 2008). Synaptic function-related genes, which telomere elongation but is involved in cell survival-promoting
mediate memory and learning, were significantly downregulated function (Zia et al., 2021). Furthermore, hippocampal TERT
(Yankner et al., 2008). These genes include glutamate receptor plays a role in modulating mood behaviors by controlling the
subunits, synaptic and vesicle proteins, and members of major proliferation of neural progenitor cells (NPCs) and is needed
signal transduction systems that mediate long-term potentiation for spatial memory formation (Rolyan et al., 2011). In this
(LTP) (Yankner et al., 2008). For example, synaptic calcium respect, hippocampal-dependent learning and memory functions
signaling systems are probably affected by decreased expression and neurogenesis in the hippocampus are downregulated in
of calmodulins 1 and 3, several Ca2+ /calmodulin-dependent telomerase-knock mice (Rolyan et al., 2011). In addition, when
protein kinases (CAM kinases), and multiple protein kinase C human NPCs are cultured, it is shown that NPCs have a restricted

FIGURE 1 | Cellular organism and molecular changes due to aging. In the process of normal aging, various alterations occur in the cellular organelles in a
degenerative way. mtDNA, mitochondrial DNA; ETC, electron transport complex; NMDAR, N-methyl-D-aspartate receptor; VDCC, voltage-dependent calcium
channel; ER, endoplasmic reticulum.
amount of cell divisions and undergo senescence (Wright et al., mutations affect mitochondrial morphology. mtDNA integrity
2006). Telomere erosion occurs in the aging brain in a cell cycle- is maintained by mitochondrial dynamics, fusion, and fission
independent and dependent way (Zia et al., 2021). In addition, (Ureshino et al., 2014). The mtDNA heteroplasmy, a mixture of
one controversial study reported that leukocyte telomere length mutated and normal mtDNA, is formed during mitochondrial
is associated with structural changes to the brain and impaired dynamics and is controlled by proteins such as mitofusins
cognitive capacity during aging (Zia et al., 2021). (Mfs1 and Mfs2), mitochondrial dynamin-like GTPase (Opa1:
fusion), and dynamin-related protein 1 (Drp1: fission) (Ureshino
Mitochondrial Dysfunction et al., 2014). Prevalent fission triggers respiratory impairment
Mitochondria are intracellular organelles known for producing and an increase in ROS levels, whereas excess fusion can
cellular energy substances (ATP, adenosine triphosphate) hinder mitochondrial autophagy induced by large and defective
and managing cell functions by controlling secondary mitochondria (Ureshino et al., 2014).
messengers in cell signaling mechanisms (Calcium ion, From the perspective of ATP production, since neuronal
Ca2+ ) and reactive oxygen species (ROS) (Misrani et al., 2021). cells are highly energy-consuming, mitochondrial dysfunction
Mitochondria drive the derivation and storage of energy using is considered a serious factor in neuronal disease (Cunnane
the respiratory chain via oxidative phosphorylation. A single et al., 2020). In terms of brain energy metabolism, ATP is
neuron contains hundreds or thousands of mitochondria the main source of the cellular system (Cunnane et al., 2020).
(Rango and Bresolin, 2018). However, abnormal ROS and Specifically, ATP is consumed by the cell membrane pumps
calcium ion levels induce mitochondrial damage, which triggers Na+ /K+ -ATPase and Ca2+ ATPase, which regulate ion gradients
mitochondrial dysfunction. Specifically, mitochondrial damage during neuronal signaling (Cunnane et al., 2020). ATP is also
disturbs mitochondrial DNA (mtDNA) maintenance and ATP used in the arrangement of neuronal cell organelles (Cunnane
production and promotes apoptosis (Ureshino et al., 2014). et al., 2020). When axons transport mitochondria, RNA, proteins,
The aging process is accompanied by mitochondrial vesicles, and other cargo to the presynaptic terminal, the process
alterations, and key reported features are somatic point is controlled by calcium, motor protein, and microtubules, ATP is
mutations and large deletions in mitochondrial mtDNA required (Cunnane et al., 2020). Additionally, neuronal networks
(Cunnane et al., 2020). These mtDNA mutations alter the related to fast-spiking interneurons demand high metabolic
transcription of electron transfer complex proteins, which are energy, and this process is supported by mitochondrial oxidative
used in the mitochondrial respiratory system. This alteration has phosphorylation (OXPHOS) (Cunnane et al., 2020). However, at
been shown to be accountable for mitochondrial dysfunction, the cellular level, mitochondrial dysfunction, specifically mutated
especially in interfering with ATP production and increasing mtDNA, occurs, leading to a decrease in ATP production
ROS generation (Ureshino et al., 2014). Moreover, mtDNA generated by OXPHOS, beta-oxidation, and the Tricarboxylic

acid cycle(TCA) cycle (Rango and Bresolin, 2018). In particular, However, most cellular ROS (90%) are generated through
AD has features of mitochondrial dysfunction with a lower mitochondrial ATP production by OXPHOS (Warraich et al.,
uptake of glucose and a decrease in the TCA cycle (Rango and 2020). While the mitochondrial electron transfer chain system
Bresolin, 2018). Many PET studies have shown that MCI is (ETC) operates during OXPHOS and produces ATP, complexes
related to a 10–12% deficit in glucose uptake (Rango and Bresolin, I and III of the ETC mainly generate ROS (Warraich et al., 2020).
2018). Furthermore, this deficit becomes more widespread If this damage is not compensated by the antioxidant process,
with the advent of AD and worsens during its progression elevated generation of ROS triggers neuronal damage (Bhatia
(Rango and Bresolin, 2018). and Sharma, 2021). Antioxidant systems protect against ROS and
Furthermore, mitochondrial dysfunction induces apoptosis consist of antioxidant enzymes such as glutathione peroxidase
and programmed cell death (Bhatia and Sharma, 2021). (GPX), non-enzymatic antioxidant factors, superoxide dismutase
Mitochondria play a role in the intrinsic apoptotic pathway (SOD), and catalase (Bhatia and Sharma, 2021). During
(Bhatia and Sharma, 2021). The intrinsic apoptotic pathway is aging, it has been reported that antioxidant capacity decreases
the prevalent mechanism of neuronal death. This mechanism (Bhatia and Sharma, 2021).
involves increased production of ROS, cytochrome c release, Molecules damaged by oxidative stress are present in lipids,
which mediates the TCA cycle in mitochondria, ATP depletion, proteins, DNA, and RNA. Lipid peroxidation (LPO) is triggered
and caspase 9 and 3 activation (Erekat, 2018). Probable triggers by lipids that are attacked by ROS through a free-radical chain
of apoptosis include the interaction with α-synuclein (Erekat, mechanism to generate LPO products (Bhatia and Sharma,
2018). α-Synuclein is abundant in the central nervous system 2021). In particular, 4-hydroxy-2,3-non-enal (HNE), a common
and is a major factor in Lewy bodies, a pathological indicator of cytotoxic product of LPO, damages neurons and functions of
PD (Erekat, 2018). Aggregation of α-synuclein in dopaminergic membrane proteins, such as the neuronal glucose transporter
neurons decreases the activity of mitochondrial complex I GLUT (Bhatia and Sharma, 2021).
and increases ROS (Erekat, 2018). ROS and the release of In terms of damaged proteins, those vulnerable to oxidative
cytochrome c into the cytosol evoke mitochondria-mediated stress can be classified into several groups: metabolic pathways
apoptosis as mitochondrial dysfunction occurs (Erekat, 2018). responsible for glycolysis and metabolism, energy metabolism,
Another factor that causes apoptosis is dopamine metabolism mitochondrial proteins, cytoskeleton, chaperones, and members
(Erekat, 2018). Dopamine blocks mitochondrial complex I, which of the ubiquitin-proteasome system (UPS) (Martinez et al.,
leads to mitochondrial dysfunction, and produces anti- and 2010). Protein oxidative damage may result in abnormalities
pro-apoptotic factors (Erekat, 2018). Dopamine metabolism is in the nervous system, such as abnormal glycolysis and energy
also accompanied by the generation of ROS and dysfunction metabolism, abnormal protein folding and oxidative stress
of the mitochondrial complex I (Erekat, 2018). Damage to responses, abnormalities in the cytoskeleton, and damaged
the activity of mitochondrial complex I has been suggested to protein degradation (Martinez et al., 2010). For example, a
increase the vulnerability of dopaminergic neurons to neuronal number of proteins are sensitive to oxidative stress, such as the
disorders by downgrading the threshold for activation of the chaperone and ubiquitin-proteasome systems, and this damage
intrinsic apoptotic pathway (Erekat, 2018). Although it is not results in abnormal neuronal function in AD (Martinez et al.,
clear whether apoptosis induces neurodegeneration in AD, it is 2010). Therefore, it is appropriate to think that some of the
certain that several molecules of this pathway are triggered in metabolic disturbances monitored at the advent of degenerative
the AD brain (Bhatia and Sharma, 2021). For instance, caspase processes are engaged with oxidative damage of selected proteins
3, an executive caspase that regulates apoptosis, is cleaved and other than neuron loss (Martinez et al., 2010).
activated in AD and is linked to tau cleavage and neurofibrillary In the case of mtDNA damaged by oxidative stress, as
tangle (NFTs) formation (Bhatia and Sharma, 2021). mentioned above, most ROS are generated from mitochondria,
and impaired mtDNA is the common oxidative damaged
molecule (Nissanka and Moraes, 2018). Whether mitochondrial
Accumulation of Oxidatively Damaged ROS affects mtDNA mutations has not been confirmed, but
Molecules mtDNA changes are more likely to increase ROS beyond normal
Cellular ROS are generally produced by both exogenous and concentrations, causing neuronal damage (Nissanka and Moraes,
endogenous sources. Exogenous sources of ROS production are 2018). According to the mitochondrial theory of aging proposed
ultraviolet (UV) radiation, ionizing radiation, and drugs that by Harman in the 1970s, somatic mtDNA mutations injure
mediate their mechanism through ROS production (Martinez OXPHOS complexes, resulting in ROS production (complex I
et al., 2010). Additionally, environmental toxins and chemicals and III) (Pinto and Moraes, 2015). Subsequently, these ROS
are responsible for ROS, which are metabolism by-products impair proteins, lipids, and DNA, including mtDNA, and again,
(Martinez et al., 2010). In the case of endogenous sources, these impaired molecules produce new ROS and damage normal
mitochondrial and non-mitochondrial ROS-generating enzyme molecules. Through this process, a vicious cycle is formed
produces ROS (Martinez et al., 2010). Non-mitochondrial ROS (Pinto and Moraes, 2015).
enzymes include nicotinamide adenine dinucleotide (NADH) From the perspective of cellular DNA, oxidative stress can
phosphate oxidase (Nox), xanthine oxidase, cytochrome P450 induce DNA double-strand breaks, DNA/protein or DNA/DNA
from the endoplasmic reticulum, and flavin oxidases from cross-linking, and base modification (Bhatia and Sharma,
peroxisomes (Martinez et al., 2010). 2021). DNA bases are sensitive to oxidative damage such as

hydroxylation, nitration, and protein carbonylation (Bhatia and instance, changes in PTEN-induced novel kinase 1(PINK1)
Sharma, 2021). Similarly, RNA is commonly single-stranded and parkin, which are related to mitophagy, correspond to 5%
and is a target of oxidative damage/modification, similar to of PD (Ureshino et al., 2014). Normally, when mitochondria
DNA. Generally, oxidative damage to DNA/RNA is increased are impaired, PINK1 aggregates in the outer membrane of
in AD (Bhatia and Sharma, 2021). Specifically, 8-hydroxy-2- mitochondria, parkin is recruited, and mitochondria start to
deoxyguanosine and 8-hydroxyguanosine levels, which indicate degrade (Ureshino et al., 2014). However, if the PINK1-parkin
DNA and RNA oxidation, are elevated, and these markers are pathway is dysfunctional due to aging, the homeostatic process
localized in Aβ plaques and NFTs (Bhatia and Sharma, 2021). In conducted by the mitochondria is disturbed (Quinn et al., 2020).
addition, the levels of oxidized rRNA or mRNA are also increased The other perspective of protein degradation is the
in AD (Ding et al., 2005; Bhatia and Sharma, 2021). proteasome (Tai and Schuman, 2008). Proteins that are fated for
degradation are tagged with ubiquitin by UPS (Tai and Schuman,
2008). The UPS targets intracellular, soluble, and transmembrane
Impaired Lysosome and Proteasome proteins that are extracted from the membrane into the cytosol
Function (Tai and Schuman, 2008). The UPS plays a significant role in
The features of neuronal cells are retained in cellular machinery the regulation of memory and neurotransmitter release (Tai and
for protein synthesis and degradation (Tai and Schuman, Schuman, 2008). The balance between protein synthesis and
2008). In contrast to other cells, neuronal cells have a degradation is responsible for long-term plasticity and memory
unique morphology, which is a specific area of presynaptic (Tai and Schuman, 2008). In addition, synaptic transmission at
neurotransmitter release, postsynaptic receptor activation, and the pre- and postsynaptic terminals is controlled by UPS (Tai
plasticity of synapses related to alterations in the synaptic and Schuman, 2008). For example, in hippocampal neurons at
proteome (Tai and Schuman, 2008). Since molecular machinery presynapse, the frequency of miniature excitatory postsynaptic
proteins play a role in mediating signal transduction, protein currents increases when the proteasome is inhibited (Yao et al.,
synthesis and degradation are important for maintaining the 2007). In animal models, transgenic animals lacking SCRAPPER
plasticity and memory of neuronal cells (Tai and Schuman, showed a large increase in excitatory postsynaptic currents (Yao
2008). In eukaryotic cells, there are two major degradation et al., 2007). Considering that SCRAPPER is an E3 enzyme
systems that provide cell recycling of cellular components, located in the presynaptic membrane and regulates vesicle
ranging from soluble proteins to intracellular organelles: release, the UPS at the presynaptic membrane plays an important
autophagy, which plays a role in the degradation of long- role in controlling the size of the vesicle pool and vesicle release
lived, insoluble or accumulated proteins and cellular organelles, (Yao et al., 2007). Furthermore, the UPS is responsible for the
and UPS, which usually degrades the most soluble, short- abundance of proteins that regulate postsynaptic responses,
lived protein. Although they have different mechanisms of including ionotropic glutamate receptors and proteins related
action, both play important roles in regulating cell homeostasis to postsynaptic density (PSD) (Tai and Schuman, 2008).
(Kocaturk and Gozuacik, 2018). Chronic inhibition of action potentials, such as tetrodotoxin,
Cells can digest cytosolic components via autophagy or of inhibitory neurotransmission, bicuculline, changes PSD
lysosomal degradation (Ureshino et al., 2014). In addition to proteins (Ehlers, 2003; Tai and Schuman, 2008). Interestingly,
clearing the cytosol for macromolecules and impaired organelles, these changes are blocked by proteasome inhibitors, which
the autophagy process provides cells with amino acids and indicates the significance of proteolysis in restructuring the
energy by recycling, which is energy efficient (Ureshino et al., synapse corresponding to changes in neural activity (Tai and
2014). Since autophagy plays an important role in the production Schuman, 2008). In the process of aging, cellular proteostasis
of long-lived proteins and the elimination of damaged organelles declines, misfolds, and damaged proteins aggregate (Saez and
and cellular debris, it is considered a part of the antiaging process Vilchez, 2014). These failures in proteostasis are involved in the
(Bergamini, 2006). However, lipofuscins, which are aggregates stabilization of correctly folded proteins and protein clearance
of insoluble particles formed during the aging process in post- systems (Saez and Vilchez, 2014).
mitotic cells, accumulate in autophagosomes and hinder the
autophagic system, which is a critical protective mechanism in the
cell (Ureshino et al., 2014). Impairment of the autophagic system, Electrophysiological Changes in the
which is induced by aging, causes excessive ROS production from Brain by Aging
the mitochondrial respiratory system, interrupts recycling, and Electrolytes, located in extracellular and intracellular fluid, form
increases oxidative stress (Ureshino et al., 2014). For example, electrical currents in the body (Terry, 1994). These ions exercise
mitophagy reduction (mitochondrial autophagy) is related to a crucial role in maintaining homeostasis (Terry, 1994). Along
aging-induced diseases such as Parkinson’s disease (PD) (Foltynie with Ca2+ , the movement of ions through ionic channels engages
et al., 2002). Mitophagy reduction disturbs the removal of Lewy in the action potential (AP), the process which is essential for
bodies and the aggregation of filamentous intracytoplasmic neuronal signals (Strickland et al., 2019). In neurons, ions move
inclusions, which could trigger brain disorders, such as AD or rapidly through a whole course of depolarization, repolarization,
PD (Ureshino et al., 2014). Another neurodegenerative disease and signal propagation, producing AP (Levitan et al., 2002).
related to autophagy reduction involves genetic alterations and Such ionic channel actions are categorized by which ions
protein expression modification (Ureshino et al., 2014). For participate and how the ion channel gating permeation works

(Sather et al., 1994). The voltage-gated ion (Na+ , K+ , Cl− , and Moreover, intracellular organelles, such as mitochondria or
Ca2+ ) channels and ligand-gated ion channels are two examples Endoplasmic Reticulum (ER), and Ca2+ -binding proteins (CBP)
(Strickland et al., 2019). When depolarization is activated, ions also manage homeostatic mechanisms (Chandran et al., 2019).
cross the membrane through the channels that match their Intracellular organelles store Ca2+ , and CBP functions as a
electrochemical gradients (Strickland et al., 2019). Ion channels buffering agent that reduces the peak intracellular calcium ion
in membranes trigger nerve impulses and synaptic transmission concentration (Chandran et al., 2019).
(Strickland et al., 2019). N-methyl-D-aspartate receptors (NMDARs), which are
The intrinsic electrophysiological properties change with ionotropic non-selective cationic glutamate receptors, play a
age (Rizzo et al., 2014). Normally, AP has three main major role in the rapid control of synaptic plasticity (Kumar
stages: depolarization, repolarization, and hyperpolarization et al., 2009). NMDARs are composed of ubiquitously expressed
(Grider et al., 2019). Depolarization occurs when the influx essential subunits (NR1) and modulatory subunits (NR2A-
of Na+ exceeds the AP threshold and the voltage-gated NR2D) (Cull-Candy and Leszkiewicz, 2004). NMDAR activation
Na+ channels are open (Grider et al., 2019). Repolarization requires glutamate (binding of ligand), membrane depolarization
happens with the closing of Na+ channels and the opening of (to eliminate the Mg2+ that blocks the channel), and binding
K+ channels (Grider et al., 2019). Hyperpolarization is when of glycine, which is a co-agonist (Kumar et al., 2009). Although
excessive K+ is accumulated and moves outside the cell through NMDARs are non-selective, they are the most permeable to
the opened K+ channels (Grider et al., 2019). Nonetheless, Ca2+ ion (Xin et al., 2005). NMDAR functions within the brain
recent studies show that the AP threshold of the hippocampal region decline with aging, including learning and memory
CA1 pyramidal cell is higher for aged rats (Matthews et al., (Gribkova and Gillette, 2021). There are several reasons why a
2009). Similarly, even though it has not been fully proven, this decrease in NMDAR function due to aging may occur (Kumar
age-based variation in the AP threshold may also be applied et al., 2009). One of the mechanisms is a decrease in the level
to humans, affecting the voltage-gated Na+ channel activation of NMDAR protein expression, especially its subunits, in the
properties and channel subtype expression patterns (Randall hippocampus with aging (Zhao et al., 2009). The decrease
et al., 2012). This variation in the AP threshold may disturb the primarily occurs in the CA1 region (Kumar et al., 2009).
excitability of neurons and repress neuronal activities by lowering Specifically, the expression of NR1 and NR2 (NR2A, NR2B)
the transmissive function of neurons (Rizzo et al., 2014). Such subunit proteins and their mRNA levels have been found to
impairment in the brain might have a correlation with cognitive decrease in the aged hippocampus (Kumar et al., 2009). The
decline during senescence (Rizzo et al., 2014). alteration in the expression of specific NR2 subunits may severely
Action potential amplitude takes up a critical role in evoking affect NMDAR function in relation to the regulation of the
Ca2+ currents and regulating the neurotransmitter release average channel open time and conductance of NMDARs.
through axon terminals (Rizzo et al., 2014). Some studies show Modified NR2 subunits induce changes in the time course
AP amplitude decreases in primates while they age (Rizzo and magnitude of Ca2+ signaling, resulting in reduced Ca2+
et al., 2014). This phenomenon can be explained by either a influx (Cull-Candy et al., 2001). Therefore, a shift in NR2A and
reduction of Na+ channels or an increase in K+ channels (Rizzo NR2B expression triggers developmental changes in cognition
et al., 2014). Age-based changes in AP amplitude could be a and synaptic function (Kumar et al., 2009). Moreover, the
result of the altered expression of voltage-gated Na+ channel NMDAR binding affinity of glutamate decreases during aging
subunits, reduced expression of Na+ , or altered expression of and is related to memory decline (Magnusson, 2012). There are
K+ channel which involves the K+ currents (Rizzo et al., 2014). several changes in the binding affinity of NMDAR, including
Additionally, several studies reveal that AP axonal conduction glycine or other antagonist (Kumar et al., 2009). Additionally,
velocity decreases alongside the aging process (Aston-Jones et al., post-translational modifications of receptors are related to
1985). The cause of such a decrease might be demyelination, the NMDAR functions (Kumar et al., 2009). For example, the
process that induces an ion leakage and reduces the efficiency of phosphorylation state of NMDAR, which is triggered by several
transduction (Coggan et al., 2010). kinases such as tyrosine kinase, protein kinase C, and protein
kinase A, increases NMDAR-mediated current (Kumar et al.,
2009). In contrast, protein phosphatases such as calcineurin
Dysregulation of Neuronal Calcium act vice versa (Shi et al., 2000). Aging is associated with a
Homeostasis disturbance of kinase/phosphatase activity, which is inclined to
Calcium (Ca2+ ) is a secondary messenger in the cell signaling phosphatase activity, which decreases NMDAR function (Kumar
mechanism (Gleichmann and Mattson, 2011). The optimal et al., 2009). Therefore, NMDAR function is disturbed by aging
concentration of Ca2+ remained constant in the cell and due to altered phosphorylation (Kumar et al., 2009). In terms
extracellular space at the expense of energy (Gleichmann of VDCC, VDCCs are ion channels in the plasma membrane
and Mattson, 2011). Through this process, cells promote and open during membrane depolarization (Tanaka and Ando,
Ca2+ -induced signaling pathways and inhibit Ca2+ driven 2001). VDCC enables cellular Ca2+ influx from the extracellular
excitotoxicity (Chandran et al., 2019). Ca2+ is mainly regulated space. VDCC is classified into L-, P/ Q-, and N type channels
by Ca2+ influx through ligand-gated glutamate receptors, such (Tanaka and Ando, 2001). Interestingly, during aging, L-channels
as N-methyl-D-aspartate receptors (NMDARs) and various increase in the hippocampus, which inhibits the blockade of
voltage-dependent Ca2+ channels (VDCCs) (Kumar et al., 2009). L-type VDCCs (Foster, 2007). Increased L-channels lead to an

increase in after-hyperpolarization (AFP) in accordance with levels in accordance with increasing age, finally provoking
an increase in Ca2+ influx (Foster, 2007). Considering that neurodegeneration (Kostyuk and Verkhratsky, 1994).
long-term potentiation (LTP) occurs from depolarization and
LTP requires blocking specific Ca2+ sources, an aging-related
increase in the L-channel impairs the LTP threshold and LTP CONCLUSION
is inhibited (Foster, 2007). Ca2+ channels suggest a point of
crosstalk between age-related Ca2+ regulatory disorders and Aging is a risk factor for a number of neurodegenerative diseases.
signaling in neurodegenerative diseases (Foster, 2007). There are mechanisms in the normal brain aging process that
Intracellular Ca2+ reserves include cellular organelles and can converge to neuronal disorders. Under conditions of normal
CBP (Kumar et al., 2009). Cellular organelles, mitochondria, brain aging, the changes were reviewed in terms of structural,
ER, and lysosomes have Ca2+ buffering systems, which release biochemical, metabolic, cellular, and molecular mechanisms.
and sequester Ca2+ (Kumar et al., 2009). In the case of Both gross and microscopic structural changes have been
mitochondria, mitochondrial Ca2+ induce the TCA cycle to reported. Gross changes include multiple morphological
generate energy by neutralizing the polarized negative membrane changes, including cerebral atrophy, sulci widening, and
potential, which is produced from ATP production in the cerebrovascular changes. In contrast, microscopically, lipofuscins
mitochondrial matrix (Chandran et al., 2019). However, aged are accumulated, occupying a large space of cytoplasm
mitochondria have structural changes in the mitochondrial DNA where glycoproteins, lipoproteins, and neurotransmitters
and mitochondrial membrane, which results in a net reduction in are synthesized. However, from another perspective, lipofuscin
the Ca2+ buffering capacity (Kumar et al., 2009). Decreased Ca2+ has a positive role in energy production when synergized
uptake capacity directly contributes to decreased electrochemical with myoglobin and respiratory enzymes. Other microscopic
gradients across the mitochondrial membrane (Xiong et al., changes are associated with amyloid-beta and neurofibrillary
2004). This mitochondrial depolarization may increase the tangles, which are regarded as neurotoxic proteins. These
threshold level of Ca2+ required to initiate mitochondrial uptake changes starve the neurons and have the potential to
(Xiong et al., 2004). Consequently, this triggers an age-dependent cause cognition loss. In addition, morphological changes in
delay in Ca2+ sequestration or the recovery of intracellular neuronal cells can be considered aging-related degeneration.
Ca2+ (Xiong et al., 2004). However, from the perspective of Overall, structural changes initiate the destruction of the
ER, ER regulates Ca2+ in two pathways: the inositol (1,4,5)- surrounding neuropil, leading to cognitive damage in dementia.
triphosphate (IP3 ) pathway activated by G protein-coupled Histopathologic changes appear, especially in the limbic system
receptors (GPCRs) and Ca2+ induced Ca2+ release (CICR) and most of the CNS.
(Thillaiappan et al., 2019). In short, the GPCR and CICR Regarding the biochemical and metabolic changes involved in
pathways regulate Ca2+ through IP3 R and ryanodine receptors aging, several types of neurotransmission molecules are involved,
(RyRs), respectively (Kumar et al., 2009). However, with aging, such as acetylcholine, monoamine, and neurosteroid. They affect
the effect of Ca2+ dysregulation due to activation of these the intracellular condition by diminishing related enzymes,
receptors is cell-specific and depends on other Ca2+ cellular receptors, and protein functions and triggering an imbalance
regulating mechanism (Kumar et al., 2009). For example, CICR of neurotransmitters. This disrupted balance influences various
is reduced during aging in peripheral synapses because of regions of the brain, such as the hypothalamus, pituitary gland,
decreased expression of RyRs, and the reduction in Ca2+ and pineal gland, and cascades of dysfunction occur.
amplification in basal forebrain neurons is compensated by Lastly, cellular and molecular changes with aging largely occur
mitochondrial buffering (Kumar et al., 2009). Furthermore, in the nucleus, mitochondria, oxidatively managed molecules,
recent studies have proposed the possibility of lysosomes lysosomes, proteasomes, electrophysiological regulation and
acting as Ca2+ storage organelles (McGuinness et al., 2007). Ca2+ homeostasis. During normal brain aging, DNA expression
Although altered lysosomal control of Ca2+ is due to aging changes, and telomere length are shortened in the nucleus
remains unclear, it has been revealed that the aging brain (Figure 1). Conversely, mitochondrial dysfunction is largely
shows increased lysosomal markers and decreased lysosomal caused by mtDNA, ROS, and calcium alterations. These changes
function (Lynch and Bi, 2003). CBP, such as parvalbumin, have been attributed to abnormal mtDNA integrity, ATP
calbindin-D28K, calretinin, calmodulin, and hippocalcin, which production, and apoptosis. Oxidatively damaged molecules
handle the intracellular Ca2+ level by rapid Ca2+ buffering have been reported to be promoted mainly by the respiration
in cytosol, is regarded to be neuroprotective (Gattoni and of mitochondria. This alteration affects the mitochondrial
Bernocchi, 2019). Generally, with aging, changes include a respiratory system itself, especially in complexes I and III. In
decrease in the expression of CBP, which is related to the addition, these damaged molecules, such as lipids, proteins,
loss of function, and these changes are cell and region specific and DNA/RNA, along with successive damage, form a vicious
(Kumar et al., 2009). A decrease in Ca2+ buffering or delayed cycle that triggers neurodegenerative disorders. As neurons have
elimination could cause larger or prolonged Ca2+ responses, exotic morphology and function compared with other cells,
which are common in aged neurons (Kumar et al., 2009). Slight efficient utilization of energy systems is essential. Lysosomal
alterations in the concentration of Ca2+ are fatal for neurons autophagy and ubiquitin-proteasome functions are important for
(Kostyuk and Verkhratsky, 1994). However, Ca2+ homeostasis in the reutilization of useful molecules and the removal of cellular
neurons is disturbed by changes in physiological and molecular waste. However, during the aging process, the functions of the

clearance system decrease, and abnormal proteins accumulate. generate age-induced neuronal disorders is expected. As
This disturbance contributes to age-related neurodegenerative everyone ages, it is important to comprehend and limit risk
disorders such as AD and PD. Electrophysiological regulation factors to promote healthy brains and quality of life. The
is controlled by the homeostasis of electrolytes. During mechanism of normal aging-induced neuronal disorders should
senescence, however, the regulation is disturbed by the be considered in the future.
alteration of channel expression and the modification of the
conductive rate of currents. In respect of Ca2+ homeostasis,
Ca2+ alteration is fatal to neurons, and its regulation is AUTHOR CONTRIBUTIONS
tightly regulated through NMDAR, VDCC, mitochondria,
ER, and Ca2+ related proteins. However, due to aging, H-JK: study concept and design and critical revision of the
homeostasis is attributed to alterations in ion exchange systems, manuscript. H-JK and JL: acquisition, analysis, and interpretation
a decline in metabolic events, and Ca2+ related proteins of data and drafting of the manuscript. Both authors contributed
such as receptors. They are also associated with abnormal to the article and approved the submitted version.
neuronal functions.
Therefore, normal brain aging entails neurodegenerative
changes in the brain. It is worth concentrating on how and why ACKNOWLEDGMENTS
normal aging processes are correlated with neurodegenerative
disorders. Through this analysis, a profound understanding We would like to thank Editage (www.editage.co.kr) for English
of aging in the normal brain and the related factors that language editing.
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published: 30 June 2022

Normal Aging Induces Changes in

Aging is accompanied by many changes in brain and contributes to progressive

Specialty section: INTRODUCTION

Frontiers in Aging Neuroscience | www.frontiersin.org 1 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 2 June 2022 | Volume 14 | Article 931536

TABLE 1 | Summary of the aging process in the brain.

Gross changes Microscopic changes

Acetylcholine Monoamine Neurosteroid

Biochemical and Metabolic Aging

Changes in the nucleus Mitochondrial dysfunction Accumulation of

Cellular and Molecular aging

Impaired lysosome and Electrophysiological Changes Dysregulation of neuronal calcium homeostasis

Frontiers in Aging Neuroscience | www.frontiersin.org 3 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 4 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 5 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 6 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 7 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 8 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 9 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 10 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 11 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 12 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 13 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 14 June 2022 | Volume 14 | Article 931536

Frontiers in Aging Neuroscience | www.frontiersin.org 15 June 2022 | Volume 14 | Article 931536

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