The Effects of Sirtuin Activators on Cerebral White Matter, Redox Biomarkers, and Imaging Findings in Aging Brain

Abstract

Aging is usually accompanied by a cognitive decline in quantitative reasoning and perceptual speed, which is associated with decreased white matter volume and integrity in certain brain areas such as the prefrontal cortex. The decline in the antioxidant enzymes has been shown to be associated with the changes in structure and volume of white matter. This chapter focuses on the antioxidant biomarkers and their clinical significance in brain aging in relation to brain white matter.

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Healthy Ageing and Longevity
Series Editor: Suresh I. S. Rattan
15
UfukÇakatayEditor
Redox
Signaling and
Biomarkers in
Ageing

Healthy Ageing and Longevity
Volume 15
Series Editor
Suresh I. S. Rattan, Department of Molecular Biology and Genetics, Aarhus University,
Aarhus, Denmark
Editorial Board
Mario Barbagallo, Univeristy of Palermo, Palermo, Italy
Ufuk Çakatay, Istanbul University-Cerrahpasa, Istanbul, Turkey
Vadim E. Fraifeld, Ben-Gurion University of the Negev, Ber-Shiva, Israel
Tamàs Fülöp, Faculté de Médecine et des Sciences, Université de Sherbrooke,
Sherbrooke, QC, Canada
Jan Gruber, Yale-NUS, Singapore, Singapore
Kunlin Jin, Pharmacology and Neuroscience, University of North Texas Health Science Center,
Fort Worth, TX, USA
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Japan
Gurcharan Kaur, Department of Biotechnology, Guru Nanak Dev University,
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Eric Le Bourg, Recherches sur la Cognition Animale, Université Paul-Sabatier, Centre de, Toulouse Cedex 9,
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Ibaraki, Japan
Maciej Wnuk, Biotechnology, University of Rzeszow, Rzeszow, Poland

Rapidly changing demographics worldwide towards increased proportion of the
elderly in the population and increased life-expectancy have brought the issues,
such as “why we grow old”, “how we grow old”, “how long can we live”, “how to
maintain health”, “how to prevent and treat diseases in old age”, “what are the
future perspectives for healthy ageing and longevity” and so on, in the centre stage
of scientific, social, political, and economic arena. Although the descriptive aspects
of ageing are now well established at the level of species, populations, individuals,
and within an individual at the tissue, cell and molecular levels, the implications of
such detailed understanding with respect to the aim of achieving healthy ageing and
longevity are ever-changing and challenging issues. This continuing success of
gerontology, and especially of biogerontology, is attracting the attention of both the
well established academicians and the younger generation of students and
researchers in biology, medicine, bioinformatics, bioeconomy, sports science, and
nutritional sciences, along with sociologists, psychologists, politicians, public
health experts, and health-care industry including cosmeceutical-, food-, and
lifestyle-industry. Books in this series will cover the topics related to the issues of
healthy ageing and longevity. This series will provide not only the exhaustive
reviews of the established body of knowledge, but also will give a critical
evaluation of the ongoing research and development with respect to theoretical and
evidence-based practical and ethical aspects of interventions towards maintaining,
recovering and enhancing health and longevity.
More information about this series at https://link.springer.com/bookseries/13277

Chapter 14
The Effects of Sirtuin Activators
on Cerebral White Matter, Redox
Biomarkers, and Imaging Findings
in Aging Brain
A. Nedim Kahraman and Hale Z. Toklu
Abstract Aging is usually accompanied by a cognitive decline in quantitative
reasoning and perceptual speed, which is associated with decreased white matter
volume and integrity in certain brain areas such as the prefrontal cortex. The decline
in the antioxidant enzymes has been shown to be associated with the changes in struc-
ture and volume of white matter. This chapter focuses on the antioxidant biomarkers
and their clinical significance in brain aging in relation to brain white matter.
Keywords SIRT ·Brain imaging ·Redox ·Oxidative ·Brain white matter ·
Aging ·Antioxidant ·Oxidative stress
14.1 Cerebral White Matter and Aging
The white matter of the brain is primarily composed of myelinated axons and oligo-
dendrocytes. The white color originates from the fatty content and myelin, which
helps to speed the conduction of an electric impulse along an axon, allowing the
action potential to travel long distances faster. As we understand the pathophysiolog-
ical changes in neurodegenerative diseases, not only the structural changes but also
white matter plasticity has gained attention for its role in neuronal communication
(Sampaio-Baptista and Johansen-Berg 2017).
Aging usually accompanied by a cognitive decline in quantitative reasoning and
perceptual speed, which is associated with decreased white matter volume and
integrity in certain brain areas such as the prefrontal cortex. On the other hand,
verbal fluency and semantic memory are less affected (Caserta et al. 2009).
A. N. Kahraman (B
)
Department of Radiology, Health Sciences University Istanbul, Fatih Sultan Mehmet Training and
Research Hospital, Istanbul, Turkey
H. Z. Toklu (B
)
Department of Clinical Sciences, University of Central Florida College of Medicine, Orlando, FL
32827, USA
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
U. Çakatay (ed.), Redox Signaling and Biomarkers in Ageing, Healthy Ageing
and Longevity 15, https://doi.org/10.1007/978- 3-030- 84965-8_14
303

304 A. N. Kahraman and H. Z. Toklu
White matter is vulnerable to decreased blood flow. Hypoperfusion of the white
matter due to cerebrovascular aging and small vessel disease is associated with
cognitive and sensorimotor decline (Joutel and Chabriat 2017; Yang et al. 2017).
The decreased production of myelin is another factor for age-related changes
of the white matter. Degeneration of oligodendrocytes, decreased lactate trans-
port for energy, and decreased levels of fatty acids contribute to the impairment
in myelin synthesis. As a result, the conduction of nerve impulses is altered (Liu
et al. 2017). In addition to oligodendrocytes, the changes in neuroglia cells such as
microglia and astrocytes also influence white matter integrity via increased blood–
brain barrier permeability, secretion of proinflammatory cytokines, and increased
oxidative stress (Liu et al. 2017). Given the fact that aging is also associated
with decreased antioxidant levels, the oxidation–reduction balance is challenged
to maintain homeostasis.
Besides senescence, several diseases may lead to early aging of the brain struc-
tures. Traumatic brain injury, stroke (both ischemic and hemorrhagic), Parkinson’s
disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), schizophrenia,
infectious diseases lead to such changes in white matter due to enhanced early
aging (Griesbach et al. 2018; Joutel and Chabriat 2017; Liu et al. 2017; Marin and
Carmichael 2019; Peters and Karlsgodt 2015; Yang et al. 2017).
14.2 Cerebral White Matter Changes and Findings
in Diagnostic Imaging
Aging is associated with cognitive decline. Aging-induced cognitive changes were
demonstrated with studies using positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI), which showed a reduction in the lateralization
of brain activity (Guo et al. 2017). The functional changes are often accompanied by
structural changes in the brain, which can be seen by imaging techniques- primarily
MRI. The T1WI- and T2WI imaging consistently identified the burden of aging and
dementia-related decline of structural brain health. Small vessel changes, micro-
hemorrhage, impaired white matter integrity, and atrophy are the most common
changes observed in the MRI. Each of these subtle changes can coexist and interact,
producing both independent and additive impacts on brain health (Guo et al. 2017).
There are controversial reports on the atrophy of whether white matter or gray matter
changes are more significant. Nevertheless, the frontal lobe and temporal areas have
more prominent changes in comparison to the others (Caserta et al. 2009). Medial
temporal lobe atrophy (MTA) is a hallmark change for AD. The shrinking of cortical
areas and enlargement of the ventricles are particularly predictive for the progression
of dementia. The extend of atrophy, lacunar infarcts, and white matter hyperintensity
can be correlated; and the vascular and white matter changes in mid-adulthood can
lead to a more severe degeneration of the white matter as the age advances (Gunning-
Dixon et al. 2009; Guo et al. 2017). A large-scale investigation demonstrated vascular

14 The Effects of Sirtuin Activators on Cerebral White Matter… 305
changes leading to AD are the very first structural brain changes detected in MRI
follow-ups (De Reuck et al. 2015).
MR diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) allow
quantification of microscopic water movement. In areas with little or no physical
boundaries, such as CSF in the ventricles, water freely diffuses, and therefore it is
isotropic. By contrast, the path of a water molecule in white matter is constrained
by physical boundaries, such as the myelin sheath, causing the movement to be
greater along the axon than across it and typically measured as fractional anisotropy
(FA). DTI is therefore sensitive in detecting tightly packed nerve fibers in a locally
parallel orientation, characterizing white matter tracts in the brain (Caserta et al.
2009; Sullivan and Pfefferbaum 2007).
T1WI, T2WI, and T2-FLAIR are all suitable for the basal ganglia and surrounding
areas, and global atrophy, while T1WI or T2WI is most suitable for malacia, trauma,
neoplasm, and malformations. In addition, T2*-weighted gradient recalled echo
sequence (T2*GRE) is optimal for detecting microbleeds and calcium deposition,
although it is not reliable to score other MRI-based Brain Atrophy and Lesion Index
(BALI) categories due to a patchy low signal intensity associated with normal depo-
sition of paramagnets or flow artifacts (Guo et al. 2017). T2-FLAIR is more sensitive
in detecting white matter lesions in the subcortical area. On the other hand, the dilated
perivascular spaces located in multiple sites are not seen on T2FLAIR (Guo et al.
2017) We also observed white matter changes (seen as hyperintensity in Fig. 14.1)
in our patients with dementia (Fig. 14.1).
Fig. 14.1 The areas with cerebral white matter lesions show up as areas of increased brightness
(leukoaraiosis) due to hyperintensity, when visualized by T2-FLAIR magnetic resonance imaging
(MRI)

306 A. N. Kahraman and H. Z. Toklu
14.3 Cerebral White Matter Changes and Redox
Biomarkers in Brain Tissue
Aging is associated with a systemic decline in activities, which result in physi-
ological changes in structure and function. Oxidative stress is one of the impor-
tant factors, which affect aging and cognitive function. Genetic polymorphisms that
encode antioxidant enzymes are one of the key determinants of healthy aging of the
brain (Salminen and Paul 2014).
The brain is particularly vulnerable to oxidative stress because brain cells require
a substantial amount of oxygen. The adult brain consumes 20% of the oxygen in the
body. While 95% of the oxygen is used for ATP synthesis, approximately 5% forms
free oxygen radicals (also known as reactive oxygen species (ROS)) (see Fig. 14.2).
The endogenous antioxidant system consists of several enzymes, which serve as free
radical scavengers. These enzymes include glutathione peroxidase (GPx), superoxide
dismutase (SOD), catalase (CAT), and sirtuins (SIRTs) (Toklu and Ginory 2018). A
homeostatic imbalance of ROS and redox biomarkers is associated with long-term
potentiation and cognitive function.
The metalloproteins, i.e., GPx, SOD, CAT are the first line of antioxidant defense
against ROS (Salminen and Paul 2014). Besides ROS, accumulation of iron, polyun-
saturated lipids because of lipid peroxidation, oxidized proteins in large quantities
are the challenges for the antioxidant system. The failure in detoxification results in
injury in the macromolecules such as DNA and RNA.
Fig. 14.2 Reactive oxygen species (ROS) have uncoupled electrons, therefore they can bind
to macromolecules (DNA, RNA) and/ or cause oxidative damage in protein or lipid structures
within the cell. Superoxide (•O2
‾) can form a complex with nitric oxide (NO) to form perox-
ynitrite (ONOO‾), or it can be subtracted to superoxide dismutase (SOD) to form hydrogen
peroxide (H2O2), which may be involved in Fenton reaction with iron and generate hydroxyl radical
(•OH‾). Both ONOO‾and •OH‾are highly reactive and cytotoxic as they cause DNA damage.
However, the endogenous antioxidant system has a number of defensive enzymes such as glutathione
peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) to neutralize/scavenge these above
mentioned reactive metabolites. Abbreviations: COX: cyclooxygenase; GPx: glutathione peroxi-
dase; L-arg: L-arginine; MPO: myeloperoxidase; NOS: nitric oxide synthase; SOD: superoxide
dismutase; XO: Xanthine oxidase

14 The Effects of Sirtuin Activators on Cerebral White Matter… 307
Postmortem studies demonstrated a significant decrease in antioxidant enzymes in
the hippocampus, frontal cortex, and substantia nigra of aging brains (Venkateshappa
et al. 2012).
14.4 Catalase, Glutathione Peroxidase, and Superoxide
Dismutase Levels and Brain White Matter Changes
The changes in white matter integrity and antioxidant enzyme levels are crucial for the
onset of AD as shown in cadavers (Venkateshappa et al. 2012). Besides the evidence
from the brain tissue, lower serum SOD, and GPx levels were shown in the blood
of patients with mild cognitive impairment (Kumar et al. 2019). Polymorphisms in
CAT and SOD2 genes suggested being the risk factors for enhanced oxidative damage
of the white matter and thus cognition among older individuals with these genetic
variants (Salminen et al. 2017). Besides aging, CAT, GPx1, and SOD1 and SOD2
levels were significantly lower in oligodendrocytes in the white matter of the brains
of the patients with major depression (Szebeni et al. 2014). Decreased white matter
integrity was associated with depleted levels of hippocampal glutathione suggesting
that this particular disruption may be linked to oxidative stress at the early stages
of mood disorders (Hermens et al. 2018) and psychosis (Monin et al. 2015). The
disruption in myelin production and white matter maturation in the prefrontal cortex
might be the underlying mechanism for advancement to schizophrenia. A randomized
controlled study with N-acetyl cysteine seems to be a safe and effective agent to
protect white matter integrity in early psychosis (Klauser et al. 2018). Decreased
white matter intensities accompanied with decreased antioxidant levels were also
observed in migraine patients (Aytac et al. 2014).
14.5 Sirtuins
Sirtuins are transcription-silencing histone deacetylase enzymes, which have a
diverse role in cellular function. They modulate physiological and pathological
processes such as metabolism, longevity, senescence, cell survival, proliferation,
apoptosis, DNA repair, and aging.
SIRTs also have an important role in the pathogenesis of brain injuries such
as traumatic brain injuries (closed head trauma, ischemia, stroke), neurodegenera-
tive disorders (Parkinson’s, Alzheimer’s, Huntington’s, Amyotrophic Lateral Scle-
rosis (ALS)), psychiatric disorders (depression, anxiety, sleep disorders) and aging
(Morris 2013; Satoh et al. 2017). The process of normal brain aging is associated
with a decrease in white matter volume, neurogenesis, neurotransmitter produc-
tion, synaptic neurotransmission, and myelination. Sirtuins regulate neurogenesis

308 A. N. Kahraman and H. Z. Toklu
and synaptic plasticity. Sirtuin activation was shown to slow down the cognitive
decline associated with aging (Toklu and Ginory 2018).
There are seven subtypes of sirtuin enzymes. The brain neurons express all
subtypes. SIRT1, SIR5, SIRT6, SIRT7 are expressed in astrocytes, while SIRT2
is detected in myelin-producing cells, i.e., oligodendrocytes. The localization of
sirtuins in the brain is summarized in Table 14.1.
Sirtuins (primarily SIRT1) have been shown to contribute to glial progenitor prolif-
eration and regeneration in white matter after neonatal brain injury (Jablonska et al.
2016) and SIRT3 expression in the periventricular white matter was upregulated in
hypoxia (Li et al. 2018).
The study cohort comparing SIRT1, 3, and 5 immunoblots and immunohistochem-
istry in the entorhinal cortex, hippocampus, and white matter of 45 cases demon-
strated that: (1) the neuronal subcellular redistribution of SIRT1 is parallel to the
decline in its expression, suggesting a loss of neuroprotection which is dependent
Table 14.1 The distribution of subtypes of sirtuins (SIRT) in the brain. Adapted from the work by
Toklu and Ginory (2018) with permission from Springer Nature
Enzyme subtype Intracellular
location
Cell type Region in brain
SIRT1 Nucleus, cytoplasm Neurons and
astrocytes
Brain stem, cortex,
cerebellum, hypothalamus,
hippocampus, olfactory bulb,
striatum
SIRT2 Cytoplasm Neurons and
oligodendrocytes
Brain stem, cortex,
cerebellum, hypothalamus,
hippocampus, olfactory bulb,
striatum
SIRT3 Mitochondria Neurons Brain stem, cortex,
cerebellum, hypothalamus,
hippocampus, olfactory bulb,
striatum
SIRT4 Mitochondria Neurons and
astrocytes
Brain stem, cortex,
cerebellum, hypothalamus,
hippocampus, olfactory bulb,
preoptic area, striatum
SIRT5 Mitochondria Neurons and
astrocytes
Brain stem, cortex,
cerebellum, hypothalamus,
hippocampus, olfactory bulb,
preoptic area, striatum
SIRT6 Nucleus Neurons and
astrocytes
Amygdala, brain stem,
cortex, cerebellum,
hypothalamus, hippocampus,
olfactory bulb, striatum
SIRT7 Nucleus Neurons and
astrocytes
Amygdala, cortex,
hippocampus, striatum,
thalamus

14 The Effects of Sirtuin Activators on Cerebral White Matter… 309
to the neuronal population; (2) in contrast to SIRT1 and 3, expression of SIRT5
increases during the progression of AD; (3) which might be related to its appearance
in activated microglial cells (Lutz et al. 2014).
Sirtuin-mediated neuroprotection involves several mechanisms such as regulation
of DNA repair enzymes, protein kinases, transcription factors, and co-activators
(Zhang et al. 2011).
14.6 The Effects of SIRT Activators and Senolytics
on White Matter Changes and Redox Biomarkers
Cellular senescence is a phenomenon characterized by the cessation of cell division.
In the past, it was thought to be an irreversible cell-cycle arrest mechanism that acts
to protect against cancer, but recent discoveries have extended to a role in complex
biological processes such as development, tissue repair, aging, and age-related disor-
ders. In humans, senescent cells accumulate in adipose tissue in diabetes and obesity,
in the hippocampus and frontal cortex in AD, the substantia nigra in PD, bone and
marrow in age-related osteoporosis, lungs in idiopathic pulmonary fibrosis, liver in
cirrhosis, retina in macular degeneration, plaques in psoriasis, kidneys in diabetic
kidney disease, endothelium in pre-eclampsia, and the heart and major arteries in
cardiovascular disease, amongst many other conditions (Kirkland and Tchkonia
2020).
The groundbreaking research on senescent cells and their clearance delaying
aging-associated disorders was published less than a decade ago (Baker et al. 2011).
Since then, drugs acting on senescent cells are being investigated as senotherapeu-
tics (Kim and Kim 2019; Kirkland and Tchkonia 2020; Wissler Gerdes et al. 2020).
Earlier studies focused on the enzymes and signaling pathways such as SIRT, Protein
Kinase C (PKC), Protein Kinase A (PKA), Calcium/calmodulin-dependent Protein
Kinase (CaMK), Tyrosine Kinase, which are accepted as the key molecules asso-
ciated with memory and brain senescence (Govoni et al. 2010). Hence, the target
of true senolytics is senescent cells, not a single receptor, enzyme, or biochemical
pathway (Kirkland and Tchkonia 2020).
One of the most recent findings in the field is that oxylipin may be a biomarker for
tracking the activity of the senescent drugs. Oxylipin is a lipid metabolite, exclusively
intracellular in normal conditions, but is released when senescent cells are forced
to die. This signaling metabolite is detectible in blood and urine. With a growing
list of senolytic drugs in development, detecting this metabolite could verify the
performance of senolytic drugs (Wiley et al. 2021).
A publication in 2019 showed that the senolytic combination of dasatinib
and quercetin selectively cleared senescent cells from the plaque environment,
reduced neuroinflammation, lessened Aβload, and ameliorated cognitive deficits in

310 A. N. Kahraman and H. Z. Toklu
Alzheimer’s disease in a mice model (Zhang et al. 2019b). Thus, the first human clin-
ical trial (NCT04063124) with senolytic drug treatment with this combination (dasa-
tinib +quercetin) is ongoing for Alzheimer’s disease. On the other hand, the prelim-
inary results for its efficacy on idiopathic pulmonary fibrosis and diabetic kidney
disease are published and looks promising (Hickson et al. 2019; Justice et al. 2019).
Recently, fisetin, a flavonoid polyphenol became another candidate as senothera-
peutic after showed to extend lifespan (Yousefzadeh et al. 2018). The mechanism
of action for fisetin is suggested to be via SIRT1 activation. Prior to fisetin, other
SIRT activators also gained attention for their antiaging/senolytic effects. Caloric
restriction, rapamycin, melatonin, tempol, vitamin E, and polyphenols, i.e., resvera-
trol, curcumin, quercetin, and fisetin are some of the most widely studied activators
of the sirtuin system, which are further being investigated for their role in modu-
lating cellular senescence (Table 14.2). While SIRT1 activation is associated with
senescence and longevity, SIRT1 deficiency results in elevated mTOR (mammalian
target of rapamycin) signaling. mTOR is a key kinase enzyme in modulating energy
metabolism, nutrient sensing, aging, and longevity. Excessive mTORactivity is inhib-
ited by caloric restriction and several agents like rapamycin. Both activate SIRT 1
and increase life span (Ehninger et al. 2014).
•Caloric restriction
Caloric restriction refers to a dietary regimen that reduces daily calorie intake
without incurring malnutrition, i.e. ≥10% in humans, ≥20% in animals (Bales
and Kraus 2013). Caloric restriction and rapamycin have been shown to increase
longevity in mice via SIRT1 activation (Libert and Guarente 2013; Nikolai et al.
2015). Caloric restriction also improves antioxidant status by enhancing SOD,
CAT, GPx activities, and increasing GSH concentration in the cerebral cortex
and hippocampus (Alugoju et al. 2018; Santin et al. 2011). Caloric restriction
preserves white matter integrity, brain energy production, and long-term memory
in aging mice and ischemic injury models (Guo et al. 2015; Zhang et al. 2019a).
•Curcumin
Curcumin is the major constituent of turmeric (Curcuma longa) root. It has antiox-
idant, anti-inflammatory, and anticancer activities (Aggarwal et al. 2007; Jurenka
2009). Curcumin also upregulated SIRT1 expression in the brain following stroke
(Miao et al. 2016). In a mice model of hypoxic-ischemic brain injury, immediate
post-treatment with curcumin was significantly neuroprotective, reducing gray
and white matter tissue loss (Rocha-Ferreira et al. 2019).
The protective effect of curcumin against white matter injury is associated
with the protection of oligodendrocytes, inhibition of microglial activation, and
suppression of iNOS and NADPH oxidase activation (He et al. 2010). Long-term
curcumin supplementation improved white matter integrity in limbic, cerebellar,
and brain stem regions in aging primates (Koo et al. 2018). Not only the white
matter in brain, but also the white matter of the spinal cord was preserved with
nano-formulated curcumin supplementation after spinal cord injury (Krupa et al.
2019).

14 The Effects of Sirtuin Activators on Cerebral White Matter… 311
Table 14.2 Sirtuin (SIRT) activators and their sources
Drug Chemical structure and name Source (natural/
chemical)
Caloric
restriction
– Intermittent fasting,
Fasting diet
Curcumin
(1E,6E)-1,7-bis (4-hydroxy- 3-methoxyphenyl) -
1,6- heptadiene-3,5-dione
Turm eri c
Fisetin
7,3ʹ,4ʹ-flavon-3-ol
Strawberry, apple,
persimmon, grape,
onion, kale, kiwi,
cucumber
Melatonin
N-acetyl-5-methoxy tryptamine
Eggs, fish, walnuts,
peanuts, grains (rice,
barley, wheat, oat),
sunflower seeds,
pistachios, fruits and
vegetables (cherries,
strawberries, grapes,
pomegranate, tomatoes,
mushrooms, olives,
broccoli, cucumber)
Quercetin
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H
chromen-4-one
Grapes, raspberry,
nectarine,
broccoli, red onion,
black tea, red wine
(continued)
•Fisetin
Fisetin is a plant polyphenol found in many fruits and vegetables, such as straw-
berries, apples, persimmons, onions, and cucumbers. As a polyphenol, fisetin is
an antioxidant and immunomodulator which can counteract via AMPK/SIRT1,

312 A. N. Kahraman and H. Z. Toklu
Table 14.2 (continued)
Drug Chemical structure and name Source (natural/
chemical)
Resveratrol
trans-3,5,4ʹ-Trihydroxyslbene
Grapes, wine, grape
juice, peanuts, cocoa,
blueberries, bilberries,
and cranberries
Rapamycin
(Sirolimus)
(1R,15R,16E,18R,19R,21R,23S,24Z,26E,28E,30S,
35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-
hydroxy-3-methoxycyclohexyl]propan-2-yl]-
19,30-dimethoxy-15,17,21,23,29,35-
hexamethyl-11,36-dioxa-4-azatricyclo
[30.3.1.04,9] hexatriaconta-16,24,26,28-
tetraene-2,3,10,14,20-pentone
A natural antifungal,
macrolide antibiotic
produced by
Streptomyces
hygroscopicus
Tempol
4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxy
l
Synthetic
(continued)
Nfr2, and PPAR pathways (Iside et al. 2020). Yet no study evaluated the effect of
fisetin on cerebral white matter.

14 The Effects of Sirtuin Activators on Cerebral White Matter… 313
Table 14.2 (continued)
Drug Chemical structure and name Source (natural/
chemical)
Vit amin E
α-tocopherol
Plant source (Wheat
germ oil, Hazelnut oil,
Canola/rapeseed oil,
Sunflower oil, Almond
oil, Safflower oil,
Grapeseed oil,
Sunflower seed kernels,
Almonds, Almond
butter, Wheat germ,
Canola oil, Palm oil,
Peanut oil, Margarine,
Hazelnuts, Corn oil,
Olive oil, Soybean oil,
Pine nuts, Peanut
butter, Peanuts)
Animal source (Fish,
Chicken, Pork)
•Melatonin
Melatonin is a hormone primarily secreted by the pineal gland. Its primary func-
tion is to regulate the circadian clock. Melatonin is also a powerful antioxi-
dant whose role goes beyond free radical scavenging. Mostly due to antioxidant
activity, neuroprotective effects of melatonin in many central nervous system
(CNS) disease conditions such as amyotrophic lateral sclerosis, PD, AD, ischemic
injury, neuropsychiatric disorders, subarachnoid hemorrhage and head injury are
well documented (Kaur and Ling 2008;Er¸sahin et al. 2009; Ersahin et al. 2009).
Melatonin has been shown to promote myelination in white matter (Villapol et al.
2011). The moderate-to-severe calcification of the pineal gland and white matter
hyperintensity was independently associated with elderly individuals (Del Brutto
et al. 2020).
•Quercetin
Quercetin is a polyphenolic compound that has antioxidant, anti-inflammatory,
immuno-protective, and anti-carcinogenic effects (Andres et al. 2018). Quercetin
increased hippocampal SIRT1 levels and improved cognitive function in aged
rats (Sarubbo et al. 2018). Other studies showed that quercetin‘s effect to improve
cognitive function was due to the preservation of white matter against hypoxic-
ischemic damage (Huang et al. 2012; Takizawa et al. 2003). Furthermore,
quercetin improved the age-associated decline in the activities of endogenous
antioxidant enzymes such as SOD, CAT, GPx and reduced glutathione content and
attenuated elevated levels of protein carbonyl content (PCC), lipid peroxidation,
lipofuscin, ROS, and nitric oxide in rat brains (Alugoju et al. 2018).

314 A. N. Kahraman and H. Z. Toklu
•Rapamycin (Sirolimus)
Rapamycin, also called sirolimus is an immunosuppressant drug used for
preventing the rejection of organ transplants. It is the first pharmacological agent
shown to extend lifespan in mammalian species (Carter et al. 2016; Ehninger
et al. 2014). As mentioned earlier, caloric restriction has been shown to augment
longevity via the activation of SIRT pathway (Zhang et al. 2011), and SIRT1 defi-
ciency results in elevated mammalian mTOR signaling, which has a key role in
longevity and energy metabolism (Ghosh et al. 2010). Furthermore, mTOR over-
activity has pathological effects on white matter, which can be modified pharma-
cologically by mTOR inhibitor rapamycin or its derivative everolimus (Lin et al.
2020; Peters et al. 2019; Tillema et al. 2012; Wong 2019; Toklu et al. 2016).
Rapamycin was also shown to enhance the differentiation of oligodendrocytes,
thus contributes to myelination (Nicaise et al. 2019).
•Resveratrol
Resveratrol is a plant polyphenol with potential therapeutic effects in cancers,
cardiovascular, and neurological diseases (Lopez et al. 2015; Toklu et al. 2010). It
is a promising agent for brain aging, neurotrauma, epilepsy, Alzheimer’s disease,
and other neurodegenerative diseases, because of the ability to improve cognitive
function and neuronal plasticity (Dias et al. 2016; Lange and Li 2018; Poulose et al.
2015; Sarubbo et al. 2017; Toklu et al. 2010). As a SIRT1 activator and mTOR
inhibitor, resveratrol mimics the favorable effects of caloric restriction (Carafa
et al. 2016; Dolinsky and Dyck 2011; Ghosh et al. 2010; Villalba and Alcain
2012) but was not proven to prolong life span as caloric restriction does. On
the other hand, evidence suggests that resveratrol delays the onset of age-related
diseases (McCubrey et al. 2017).
Preservation of brain white matter, improved cerebral microvascular circulation,
improved mitochondrial function, neurogenesis, neuroprotection, and neuronal
survival are achieved with resveratrol treatment in experimental studies. Resver-
atrol treatment also decreased macular degeneration, retinal aging, and aging-
induced hearing loss in rats (Karalis et al. 2011; McCubrey et al. 2017; Revuelta
et al. 2016).
•Tempol
Tempol is a membrane-permeable free radical scavenger. The protective effect of
tempol against neuronal injury and aging is widely being investigated (Dornas
et al. 2015; Hamel 2015;Tokluetal.2017; Wilcox 2010). Tempol has SOD-
mimetic effects (Dornas et al. 2015) and was shown to improve cognitive function
via white matter protection (Liu et al. 2013).
•Vitamin E
Vitamin E includes a group of lipid-soluble tocopherols and tocotrienols. α-
tocopherol is the most plentiful and bioavailable form of vitamin E for humans (La
Fata et al. 2014). It is a well-known antioxidant. A recent study has demonstrated
that long-term deficiency of vitamin E remarkably decreased the expression of
silent mating type information regulation (SIRT)-2 mRNA compared to short-
term deficiency (Fukui et al. 2014). Vitamin E is widely studied for its effect on

14 The Effects of Sirtuin Activators on Cerebral White Matter… 315
brain aging and cognitive function (La Fata et al. 2014; Tucker 2016). Frontal
lobes exhibited an age-related decline in retinol, total tocopherol, total xantho-
phyll, and total carotenoid (Craft et al. 2004). Lower carotenoid and vitamin E
levels were associated with cerebral deep white matter lesions in aging subjects
(Ohshima et al. 2013; Schmidt et al. 1996). Alpha-tocopherol was significantly
and inversely related to the presence of beginning confluent and confluent white
matter changes after adjustment for the between-group differences in age, arterial
hypertension, cardiac disease, and cholesterol (Schmidt et al. 1996). The studies
suggest that older adults consuming more polyunsaturated fatty acids and vitamin
E rich foods had better white matter integrity and that maintaining white matter
microstructural integrity might be a mechanism for the beneficial role of diet on
cognition (Gopalan et al. 2014;Guetal.2016; Prinelli et al. 2019).
14.7 Clinical Trials with Senolytics/SIRT Activators
At present, there are only a few human clinical trials ongoing with SIRT activators/
senolytics. Three of them involve caloric restriction, diet, and aging (NCT01256840,
NCT00996229, NCT01219244). Senolytic combination dasatinib and quercetin clin-
ical trials are also ongoing for investigation of their effects in AD (NCT04063124,
NCT04685590). See Table 14.3 for the list of other clinical trials.
14.8 Conclusion
Antioxidants and SIRT activators may have beneficial effects in preventing cerebral
white matter changes and thus improve neurocognitive function. However, random-
ized controlled clinical trials are needed to demonstrate the mechanism of action
further.

316 A. N. Kahraman and H. Z. Toklu
Table 14.3 Human Clinical Trials with SIRT activators, which evaluate brain structure or cognitive
function
Drug Study ID (NCT no) and Title
Caloric restriction/ diet •NCT01256840 (Long-term Caloric Restriction and Cellular Aging
Markers (CRONA))
•NCT00996229 (Effects of Dietary Interventions on the Aging Brain)
•NCT01219244 (Effects of Dietary Interventions on the Brain in Mild
Cognitive Impairment (MCI))
Dasatinib +Quercetin •NCT04063124 (Senolytic Therapy to Modulate Progression of
Alzheimer’s Disease (SToMP-AD))
•NCT04685590 Senolytic Therapy to Modulate the Progression of
Alzheimer’s Disease (SToMP-AD) Study (SToMP-AD)
Fisetin •NCT03675724 (Alleviation by Fisetin of Frailty, Inflammation, and
Related Measures in Older Adults (AFFIRM-LITE))
Resveratrol •NCT01504854 (Resveratrol for Alzheimer’s Disease)
•NCT00678431(Randomized Trial of a Nutritional Supplement in
Alzheimer’s Disease)
•NCT01354977 Effect of Resveratrol on Age-related Insulin
Resistance and Inflammation in Humans)
•NCT02502253 (BDPP Treatment for Mild Cognitive Impairment
(MCI) and Prediabetes or Type 2 Diabetes Mellitus (T2DM))
Melatonin •NCT03954899 (Disease Modifying Potential of 5 mg of Melatonin
on Cognition and Brain Health in Aging)
•NCT02395783 Therapeutic Effects of Maternal Melatonin
Administration on Brain Injury and White Matter Disease
(PREMELIP)
•NCT04400266 (Buspirone and Melatonin for Depression Following
Traumatic Brain Injury)
•NCT04522960 (Melatonin in Alzheimer’s disease: Effect on Disease
Progression and Epileptiform Activity (MADE))
•NCT03590197 (Effect of Melatonin on Seizure Outcome, Neuronal
Damage and Quality of Life in Patients With Generalized Epilepsy)
•NCT00940589 (Efficacy of Circadin® 2 mg in Patients With Mild to
Moderate Alzheimer Disease Treated With AChE Inhibitor)
•NCT04421339 (Melatonin for Huntington’s Disease (HD) Gene
Carriers With HD Related Sleep Disturbance—a Pilot Study)
Rapamycin •NCT04629495 (Rapamycin—Effects on Alzheimer’s and Cognitive
Health (REACH))
Vit amin E •NCT00040378 (Prevention of Alzheimer’s Disease by Vitamin E
and Selenium (PREADVISE))
•NCT00753532(Neuroprotective and Cardioprotective Effects Of
Palm Vitamin E Tocotrienols)
•NCT02263924 (Stroke and Tocotrienol: Unique Role in
Neuroprotection (SATURN))

14 The Effects of Sirtuin Activators on Cerebral White Matter… 317
Acknowledgements The authors are thankful to Olivia Beriau Vallandingham and Zeynep Tutku
Toklu for proofreading and linguistic edits.
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