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Molecular Biology of Aging
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IN MEMORIAM
P. Michael Conn, PhD
P. Michael Conn unexpectedly passed away

on Saturday, November 26, 2016 in
Lubbock, TX, United States. Dr. Conn
was a pioneer in the field and a role model
with great dedication to scientific discovery.
At Texas Tech University Health Sciences
Center (TTUHSC), Dr. Conn was an out-
standing and highly respected researcher,
educator, leader, director, consultant, and
manager of university programs. He elevated
the TTUHSC research mission by
supporting its scientists across disciplines,
departments, and schools.
He received his Bachelor of Science and a teaching certificate from the
University of Michigan (1971), a Master of Science from North Carolina
State University (1973), and a doctorate from Baylor College of Medicine
(1976). Dr. Conn received a postdoctoral fellowship to study the endocrine
research methods at the National Institutes of Health in Bethesda, MD
(1976–78). He then joined the faculty of the Department of Pharmacology
at Duke University Medical Center (1978) as an assistant professor and was
promoted to associate professor in 1982. In 1984, Dr. Conn went to the
University of Iowa College of Medicine, where he accepted a position as
professor and head of the Department of Pharmacology, a position he held
for 11 years.
Dr. Conn joined TTUHSC in December 2013 as the Senior Vice
President for Research. He was also Associate Provost and the Robert C.
Kimbrough Professor of Internal Medicine at TTUHSC, with joint
appointment in the Department of Cell Biology and Biochemistry. He
was previously the Director of Research Advocacy at TTUHSC. Before
coming to TTUHSC, Dr. Conn was a professor in the Departments of
Physiology and Pharmacology, Cell Biology and Development, and Obstet-
rics and Gynecology at the Oregon Health and Science University, and a
senior scientist at the Oregon National Primate Research Center. Dr. Conn
served for 12 years as a special assistant to the primate center director before
becoming Associate Director.
ix
x In Memoriam
For nearly 40 years, he was a leading scientist in elucidating the function

of the G protein-coupled receptor in the gonadotropin-releasing hormone
receptor system. Dr. Conn’s research led to a better understanding of
therapeutic targets to help patients with endocrine disease.
Dr. Conn was the first to report that membrane receptors, when they
bound to agonists, but not to antagonists. Dr. Conn’s research into
membrane receptors changed the way these proteins were viewed by the
scientific community.
Another line of research that Dr. Conn pursued was receptor–receptor
interactions. This research contributed to our understanding of the
function of membrane receptors, and it led to what was then called
microaggregation—the massing of receptor dimers, which Dr. Conn
distinguished from macroaggregation. Dr. Conn’s research into membrane
receptors and their interactions led to the development of oligomerization, a
chemical process that converts molecular aggregates into molecular com-
plexes. This process is important for our present understanding of how
receptors regulate and communicate information to other receptors.
Dr. Conn also contributed significantly to the scientific community’s under-
standing of the use of diacylglycerols, which are lipids. Working with
Jim Neidel, Dr. Conn revealed how these lipids are involved in hormonal
action.
Dr. Conn demonstrated that many receptor mutations result in the mis-
routing of molecules. With this information, Dr. Conn developed a treat-
ment strategy that restores mutant receptors to function. This strategy
appears useful in restoring a range of mutant receptors to normal function,
including receptors in cystic fibrosis, nephrogenic diabetes insipidus, hyper-
cholesterolemia, retinitis pigmentosa, and a range of digestive diseases.
Dr. Conn also created high-throughput screening, a drug-discovery process
widely used in the pharmaceutical industry, to automatically assay the bio-
chemical activity of drug-like compounds, from which chemical libraries are
formed. Dr. Conn’s research into high-throughput screenings has resulted in
the appreciation of pharmacoperone drugs as a new class of drugs to treat
abnormal receptors.
Dr. Conn authored or coauthored over 350 publications in receptor
research, and he wrote or was the editor of over 200 books, including text
books on neuroscience, molecular biology, and endocrinology. Dr. Conn
served as the editor of many professional journals and book series, including
Endocrinology, Journal of Clinical Endocrinology and Metabolism, Endocrine,
Methods, Progress in Molecular Biology and Translational Science, and
In Memoriam xi
Contemporary Endocrinology. Dr. Conn was also a member of numerous study

sections, and advisory committees and groups: 1986–87, Biochemical Endocri-
nology; 1991–95, Pharmacological Sciences; 1985–89, American Society for
Cell Biology, Council Member; 1992–97, The Endocrine Society, Council
Member; 1996, The Endocrine Society, President; 1997–2000, The
Hormone Foundation Board of Directors; 1998–2000, National Diabetes
Education Program Steering Committee; 1995–2002, Pituitary Tumor
Network Association Scientific Advisory Committee; and 2000–02, FASEB
Board of Directors.
Dr. Conn served on the National Board of Medical Examiners, including
2 years as the Chair of its Reproduction and Endocrinology Committee, and
he was on the Board of Scientific Councilors for the Intramural Program in
NICHD at the National Institutes of Health. Dr. Conn was a member of
Council for the American Society for Cell Biology and the Endocrine
Society, and he was a former president of the Endocrine Society, during
which time he founded the Hormone Foundation and worked with political
leaders throughout the United States to heighten the public’s awareness of
diabetes. Dr. Conn was an elected member of the Mexican Institute of
Medicine and a fellow of the American Association for the Advancement
of Science.
In recognition of Dr. Conn as an extraordinary scientist and educator, he
received many awards and honors. Dr. Conn’s students and fellows have
gone on to become leaders in industry and academia. Dr. Conn was given
a MERIT award from the National Institutes of Health; the J.J. Abel Award
of the American Society for Pharmacology and Experimental Therapeutics;
the Weitzman, Oppenheimer and Ingbar Awards of the Endocrine Society;
the National Science Medal of Mexico (the Miguel Aleman Prize); and the
Stevenson Award of Canada. He was also the recipient of the Medical
Research Foundation Oregon Award for Discovery, the Media Award of
the American College of Neuropsychopharmacology, and a distinguished
alumnus of Baylor College of Medicine. Dr. Conn’s honors included the
Dean’s Award from TTUHSC, bestowed upon him for outstanding work
as a scientist.
P. Michael Conn was our friend, teacher, and mentor, and we will miss
him dearly.
P. HEMACHANDRA REDDY, PHD
CONTRIBUTORS
F. Akhter
School of Pharmacy, Higuchi Bioscience Center, University of Kansas, Lawrence, KS,
United States
N. Basisty
University of Washington, Seattle, WA, United States
G.K. Bhatti
UGC Centre of Excellence in Nano Applications, Panjab University, Chandigarh, India
J.S. Bhatti
Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX,
United States; Department of Biotechnology, Sri Guru Gobind Singh College, Chandigarh,
India
D. Chen
United States
Y.-A. Chiao
J.W. Culberson
Texas Tech University Health Sciences Center, Lubbock, TX, United States
D.-F. Dai
C. Hayley
University of Kansas Alzheimer’s Disease Center, University of Kansas School of Medicine,
Landon Center on Aging, Kansas City, KS, United States
Y. Ji
R. Kandimalla
United States
S. Koppel
S. Kumar
United States
C.S. Kuruva
United States
xiii
xiv Contributors
M. Manczak
United States
D.J. Marcinek
G.M. Martin
S.S. Prabhakar
S. Pugazhenthi
University of Colorado, Aurora; Eastern Colorado Health Care System, Denver, CO,
United States
E.K. Quarles
P.S. Rabinovitch
A.P. Reddy
P.H. Reddy
Garrison Institute on Aging, Texas Tech University Health Sciences Center; Texas Tech
University Health Sciences Center, Lubbock, TX, United States
F. Smith
United States
H. Sobamowo
R.H. Swerdlow
M. Vijayan
United States
R. Wang
United States
I. Weidling
H.M. Wilkins
Contributors xv
J. Williams
United States
S.F. Yan
United States
S.S. Yan
United States
X. Yin
United States
PREFACE
The biology of aging is a topic that has long

interested me. When I was child, I witnessed
my grandfather dying at the relatively young
age of 55 years. And my father died at 61 years
of age. These losses have led me to try to
answer why some people die so early and
others live so long, 90 years and beyond.
What are factors that cause early death? Are
they genetic or environmental, or both? Is
lifestyle the main factor that may shorten a
life span?
In this modern era, with medical and
technological advancements and with
increased social media about health care, I am appreciative that longevity
is increasing, but not without costs. Dementia rates in persons older than
80 years are alarmingly increasing in many populations of the world. It is
important to better understand the biology behind aging and the aging brain.
And it is also important to identify biomarkers of aging in order to develop
effective therapeutic strategies.
There has been much research on aging and age-related diseases, and
important contributions to better understanding the molecular biology of
aging. This area is too broad to cover fully in this book or in a few books.
I have narrowed the scope of this book to four topics under the rubric of
molecular biology of aging: (1) molecular, cellular, and physiological bases
of metabolic syndromes, including diabetes, obesity, and Alzheimer’s dis-
ease; (2) the role of mitochondria in aging and Alzheimer’s disease;
(3) the role of microRNAs in aging and age-related human neurological
diseases; and (4) the aging kidney and its physiological and pathological
implications for diabetes.
Chapters 1, 2, and 8 primarily cover basic biology, and cellular and ther-
apeutic aspects of metabolic syndromes, including diabetes, obesity, and
Alzheimer’s disease. In the first chapter, John Culberson covers morbidity
in chronic diseases, with a focus on the role of aging and age-related chronic
diseases, such as sarcopenia. Sarcopenia is an age-related loss of skeletal mus-
cle mass, which is accelerated by chronic inflammation. Sarcopenia results in
xvii
xviii Preface
a cascade of cytokines, insulin resistance, hyperglycemia, and altered mito-

chondrial glucose signaling pathways. Dr. Culberson also covers neuro-
genesis and defective neuronal plasticity in the diabetic brain and
advanced glycation end-products generated by chronic hyperglycemia iden-
tified in postmortem brains of persons with Alzheimer’s disease.
In the second chapter, Jasvinder Singh Bhatti and colleagues discuss sev-
eral features of metabolic disorders, particularly the involvement of mito-
chondrial dysfunction and oxidative damage in aging and age-related
metabolic and neurodegenerative disorders. They focus on the structure,
function, and physiology of mitochondria in such disorders as diabetes, obe-
sity, cardiovascular diseases, and stroke. They also cover therapeutic strate-
gies for mitochondrial dysfunction and oxidative stress in different
age-related metabolic disorders, including such strategies as lifestyle inter-
vention, and pharmacological and mitochondria-targeted therapeutic
approaches.
Subbiah Pugazhenthi’s chapter focuses on cellular changes in obesity, dia-
betes, hypertension, and cardiovascular disease. He describes risk factors for
comorbidities, collectively referred to as the metabolic syndrome. This syn-
drome can play a critical role in driving neuroinflammation, an important
factor of Alzheimer’s disease pathogenesis. His research suggests a role for
microglia, the resident immune cells of the brain, in Alzheimer’s disease path-
ogenesis. Metabolic syndrome could reactivate microglia through the inter-
face of blood–brain barrier. As Dr. Pugazhenthi notes, an age-dependent
breakdown of the blood–brain barrier has been found in humans with
neurological diseases, including those with Alzheimer’s disease.
Chapters 6, 7, 9, and 11 focus on mitochondrial abnormalities and mito-
chondrial dysfunction, and protective effects of mitochondria-targeted anti-
oxidants. In Chapter 6, Arubala P. Reddy and P. Hemachandra Reddy
present a systematic review of mitochondria-targeted antioxidants and a
summary of antioxidants that researchers have used in studying mouse
models of Alzheimer’s disease, elderly populations, and clinical trials involv-
ing patients with Alzheimer’s disease. They also discuss recent progress in
the development and testing of mitochondria-targeted molecules, using
cell cultures and mouse models of Alzheimer’s disease. They cover
mitochondria-targeted molecules as potential therapeutic targets to delay
or prevent the progression of Alzheimer’s disease.
In Chapter 7, Peter Rabinovitch and colleagues discuss catalase mouse
models that they have developed in order to understand the role of catalase
in delaying aging. They describe three lines of mice—mice overexpressing
Preface xix
catalase targeted to mitochondria (mCAT), peroxisomes (pCAT), and the

nucleus (nCAT) that they have developed to investigate the role of hydro-
gen peroxide in aging. They review features of all three mouse models,
noting that the mCAT mice have the longest and healthiest life span.
Dr. Rabinovitch’s group extensively studied mCAT mice and reviewed
well in their chapter.
In Chapter 9, Russell Swerdlow and colleagues describe mitochondrial
and bioenergetic functional changes in aging and Alzheimer’s disease. They
link mitochondrial and bioenergetic impairments to the aging brain, and
they discuss a new avenue that involves transferring mitochondria from
patients with Alzheimer’s disease to cell lines depleted of endogenous mito-
chondrial DNA, in order to develop cytoplasmic hybrid cell lines of mice
that exhibit specific biochemical, molecular, and histologic features of
Alzheimer’s disease. They also discuss their proposed mitochondrial cascade
hypothesis that places mitochondrial dysfunction at the apex of the pathol-
ogy pyramid for Alzheimer’s disease.
In Chapter 11, Shirley ShiDu Yan and colleagues provide a review of
major recent findings on mitochondrial abnormalities and synaptic dysfunc-
tion relevant to aging, neurodegeneration, and cognitive decline in persons
with Alzheimer’s disease and diabetes. Dr. Yan argues that elucidation of the
role of mitochondrial perturbation can inform the development of specific
small molecules capable of targeting aberrant mitochondrial function as a
therapeutic delivery system for combating aging-related dementia and neu-
rodegenerative diseases.
Chapters 3–5 focus on the role of microRNAs in aging and age-related
diseases. In Chapter 3, Murali Vijayan and colleagues focused on ischemic
stroke in aging and Alzheimer’s disease, explaining that stroke and vascular
dementia increase with an increase in a number of modifiable factors. They
suggest that most strokes can be prevented or controlled through pharma-
cological and surgical interventions, and lifestyle changes. They also identify
cellular changes that are implicated in ischemic stroke, including inflamma-
tory responses, microRNA alterations, and marked changes in brain pro-
teins. They review the latest developments of research that identifies
protein biomarkers in peripheral and central nervous system tissues from
aged persons.
In Chapter 4, Subodh Kumar and colleagues review research on the bio-
genesis of microRNAs and the role of miRNAs, particularly circulatory
mRNAs, in detecting aging and neurodegenerative diseases, particularly
Alzheimer’s, Parkinson’s, and Huntington’s diseases. They hypothesize that,
xx Preface
at a pathological level, changes in cellular homeostasis lead to the modulation

of molecular function in cells, resulting in the deregulation of miRNA
expression. They suggest that identification of these changes may open a
new avenue for developing biomarkers capable of detecting aging and cel-
lular senescence.
In Chapter 5, P. Hemachandra Reddy and colleagues discuss several
aspects of aging, including oxidative damage, mitochondrial dysfunction,
telomere shortening, and inflammation, all of which leads to cellular senes-
cence. Reddy and colleagues hypothesize that cellular senescence may
induce age-related human diseases, including Alzheimer’s, Parkinson’s,
multiple sclerosis, amyotrophic lateral sclerosis, cardiovascular, cancer,
and skin diseases. They also discuss microRNAs in aging persons and persons
with Alzheimer’s disease, as possible blood-based peripheral biomarkers of
Alzheimer’s disease.
In Chapter 10, Hezekiah Sobamowo and Sharma Prabhakar cover the
physiology and pathology of the aging kidney, noting that aging is linked
to a progressive decline in renal function along with concurrent morpho-
logical changes in kidney, ultimately leading to glomerulosclerosis. They
also discuss cellular changes in the aging kidney.
I sincerely thank all the contributors for their outstanding chapters. I also
thank Magesh Mahalingham, Helene Kabes, and Alex White at Elsevier, for
their support and help in assembling this volume. I also recognize and thank
P. Michael Conn, PhD, posthumously for introducing me to the first
volume in the series Molecular Biology of Aging in the Progress in Molecular
Biology and Translational Science.
P. HEMACHANDRA REDDY, PHD
CHAPTER ONE
Clinical Aspects of Glucose

Metabolism and Chronic Disease
J.W. Culberson1
1
Corresponding author: e-mail address: john.culberson@ttuhsc.edu
Contents
1. Introduction 2
2. Diabetes Mellitus 2
3. Cardiovascular Disease 3
4. Chronic Kidney Disease 3
5. Sarcopenia 3
6. The Frailty Syndrome 4
7. Dementia 5
8. Exercise and Brain Metabolism 6
9. Pharmacological Treatments for Dementia 7
10. Reducing Chronic Disease Burden 8
References 8
Abstract
The burden of chronic disease is an emerging world health problem. Advances made
in the treatment of individual disease states often fail to consider multimorbidity
patterns in clinical research models. Adjusting for age as a confounder ignores its
contribution as a powerful risk factor for most chronic diseases. Sarcopenia is an
age-related loss of skeletal muscle mass, which is accelerated by chronic inflammation
and its resulting cascade of cytokines. Skeletal muscle loss results in insulin resistance,
hyperglycemia, and altered mitochondrial glucose signaling pathways. Vascular
disease in the brain may alter blood–brain barrier function, allowing transport of
substances into the brain which adversely affect the “astrocyte-centric” subunit.
Neurogenesis that provides neuronal plasticity is impaired in the diabetic brain, while
insulin resistance markers such as insulin-like growth factor (IGF-1) and insulin
receptor substrate (IRS-1) are associated with poor cognitive performance. Advanced
glycation end products generated by chronic hyperglycemia are found in
postmortem AD brain. Intranasal insulin administration, a preferential route for CNS
delivery, improved cognitive function in healthy adults, without affecting circulating
levels of insulin or glucose. Exercise has demonstrated a neuroprotective effect
through induction of antioxidative enzymes, neurotrophic, and vascular endothelial
#
Progress in Molecular Biology and Translational Science, Volume 146 2017 Elsevier Inc. 1
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/bs.pmbts.2016.12.011
2 J.W. Culberson
growth factors. Sarcopenia appears to be a dynamic process and is potentially revers-

ible with attention to nutrition and cardiovascular fitness. Early detection and inter-
vention may slow the progression of multimortality disease states and should be a
focus of worldwide health systems.
1. INTRODUCTION
The burden of chronic disease is an emerging world health problem.
Improved sanitation and medical care is dramatically decreasing the mortal-
ity of communicable disease, and life expectancy has increased sharply in
many developing countries.1 Advancing agricultural infrastructure, technol-
ogy, and cultural shifts are resulting in behavioral and lifestyle changes across
a large portion of the world population. Many of these changes significantly
increase the risk of chronic disease, including diabetes mellitus, cardiovascu-
lar disease (CVD), chronic renal disease, and dementia.2 The aging popula-
tion demographic and a gradual shift toward multimorbidity patterns are
challenging all healthcare systems. In recognition of the increasing
importance of chronic diseases, the 2008 World Health Assembly endorsed
a Global Non-Communicable Disease (NCD) Action Plan for NCD
prevention and control.3 While more highly developed health care systems
have made great advances toward treating individual disease states,
multimorbidity management systems, and prevention programs have not
been a priority.
2. DIABETES MELLITUS
The number of people with diabetes mellitus worldwide has more
than doubled over the past 3 decades and is projected to affect 7.7% of
the total adult population of the world by 2030.4,5 The most common form
of diabetes, Type 2 Diabetes (T2DM), is characterized by insulin resistance
(IR) and is considered a metabolic disorder closely tied to overweight
(BMI > 25%) or obesity (BMI > 30%).6 The prevalence of overweight or
obesity in the world’s population is predicted to rise from 33% in 2005 to
58% in 2030.2 Ongoing research has demonstrated that the diabetes epi-
demic is the result of a complex interaction between genetic and epigenetic
predispositions and societal factors that, in combination, determine
behavioral and environmental risks.7
Clinical Aspects of Glucose Metabolism 3
3. CARDIOVASCULAR DISEASE
CVD remains the most significant global health burden, and its
prevalence in developing countries is expected to increase significantly
due, in part, to the impending worldwide epidemic of DMT2.8 While
the risk of CVD is known to increase with obesity, recent work has found
that metabolic status is more important than measures of adipose tissue quan-
tity in estimating cardiac risk in individuals with T2DM.9 Additionally,
excessive dietary salt and caloric intake are linked not only to increased risk
due to elevated blood pressure, but also to insulin resistance and impaired
glucose metabolism. Insulin resistance, in turn, affects not only skeletal mus-
cle but also the cardiovascular system, where it increases the risk of both
CVD and chronic kidney disease (CKD).10
4. CHRONIC KIDNEY DISEASE

CKD is another common comorbidity in patients with T2DM. The
presence and severity of T2DM, and associated cardiovascular complica-
tions, markedly influence the progression of CKD.3 CKD is more common
in certain patient populations including the elderly, obese, and certain ethnic
groups. Similar to CVD, the association between obesity and CKD may
have a metabolic component, and a favorable type of body fat, with low
insulin resistance and low subclinical inflammation has been identified.11
Both CKD and T2DM are increasing in prevalence in low to middle income
countries. The increasing prevalence of younger individuals with T2DM,
along with improvements in cardiovascular survival, may contribute to
increase the prevalence and burden of CKD.12 CKD is a key determinant
of the poor health outcomes of diabetes and CVD.3 Progression to end-stage
renal disease (ESRD) is accompanied by increasing IR and loss of lean mus-
cle mass.10 Furthermore, aging populations will exert pressure to increase
the absolute number of people with ESRD who are dependent on renal
replacement therapy (RRT). As developing nations realize economic pros-
perity, access to RRT will further increase the total economic burden of
CKD.13
5. SARCOPENIA
A primary mechanism for the increased morbidity and mortality
associated with CKD involves a loss of muscle mass, strength, and function
4 J.W. Culberson
known as sarcopenia. The reported prevalence of sarcopenia in persons over

60 years-of-age varies from 8% to 40% depending on diagnostic criteria and
method of assessment. Muscle mass is reported to decline in disease-free
individuals at an annual rate of approximately 1.5%–3% per year after age
60 and becomes more rapid after age 75.14 Complex signaling pathways
have been identified, which may regulate sarcopenia and its relationship
with T2DM, CVD, and advanced CKD.15 T2DM will accelerate the
reduction of muscle mass and strength because of hyperglycemia, diabetic
complications, and insulin resistance.14 Insulin resistance in skeletal muscle
is particularly important because skeletal muscle mass is responsible for more
than 75% of all insulin mediated the glucose disposal.15 Accumulating
evidence indicates that inflammatory cytokines such as interleukin 6 (IL6)
and tumor necrosis factor (TNF) contribute to the link between elevated
levels of inflammation and oxidative stress common in T2DM, CVD,
and CKD, and the development of skeletal muscle insulin resistance, and
ultimately, sarcopenia.16 Other studies have provided evidence that varia-
tion in apoptosis and transcription regulation-related genes related to inflam-
mation and muscle maintenance appears to be associated with frailty.17
Other chronic inflammatory diseases may contribute to the overall sys-
temic burden of inflammatory factors. Osteoarthritis is a very common
chronic joint disease most commonly affecting overweight older adults
and associated with increased peripheral inflammatory markers.18 Periodon-
titis, a common chronic oral infection, has long been associated with CVD
and T2DM, and more recently, with an increased risk of Alzheimer’s
disease.19,20
6. THE FRAILTY SYNDROME

Sarcopenia is a significant risk factor for frailty, a common syndrome in
older adults that carries an increased risk of poor health outcomes including
falls, incident disability, hospitalization, and mortality due to decreased phys-
iological reserves.14 Frailty has been associated with a measurable loss of
reserve in the respiratory, cardiovascular, renal, hematopoietic, and clotting
systems.21 Nutritional status can also be a mediating factor. Decline in
skeletal muscle mass results in decreased basal metabolic rate and subsequent
appetite and nutritional deficits.22 Studies have found that variation in
apoptosis and transcription regulation-related genes related to inflammation
and muscle maintenance appears to be associated with frailty.17 Recently,
the concept of sarcopenic obesity (SO) has described a syndrome present
in a group of older adults in whom obesity is accompanied by sarcopenia and

insulin resistance. The prevalence of SO in the United States was estimated
to be 80% of women and 42% of men at age 70 years. These individuals
demonstrate two to three times the normal risk of developing disability asso-
ciated with reduced activities of daily living.23 Sarcopenia and fluctuations in
systemic blood sugar levels have been associated with impaired grip strength,
exhaustion, slow gait speed, weight loss, and reduction in activities.21 At the
cellular level, mitochondria contribute to the dynamics of cellular metabo-
lism, the production of reactive oxygen species, and apoptotic pathways.
Consequently, mitochondrial genetic variation may be related to vulnerabil-
ity to disease and contribute to altered susceptibility to the frailty syndrome
in older adults.24
The presence of frailty also increases the risk of dementia. Clinical studies
of older persons without dementia at baseline have found that greater muscle
strength was associated with a decreased risk of developing AD.25 These
findings have motivated work to determine whether the frailty syndrome
should be expanded to include aspects of cognition and affect.26
7. DEMENTIA
Dementia rates are growing at an alarming proportion in all regions
of the world and are related to population aging. The Global Burden of
Disease 2010 study identified dementia as the third leading cause of
“years lived with disability” at the global level. In 2010, there were an esti-
mated 35.6 million people with Alzheimer’s disease and other dementias
worldwide. This number will increase with an aging population, and will
reach 66 million by the year 2030, and 115 million by 2050.27 The main
increase will take place in low and middle income countries, where more
than 70% of the people with dementia will live by 2050.28 Loss of lean mus-
cle mass has been found to accelerate the progression of Alzheimer’s disease
(AD) and is associated with brain atrophy and lower cognitive performance.
This may be a direct or indirect consequence of the pathophysiology of AD,
or a shared mechanism.29
Most dementia in older individuals is due to a combination of
Alzheimer’s disease, neurodegeneration, and vascular pathology.30 Prospec-
tive evaluation using MRI found that 44% of the incident dementia cases in
older individuals had vascular disease, either as the sole cause or a contrib-
utory factor, usually with Alzheimer’s disease.31 Vascular disease in the brain
may alter the blood–brain barrier (BBB) function allowing transport of
6 J.W. Culberson
substances into the brain and adversely affect the perivascular clearance of
amyloid from brain to periphery.32 Additionally, ischemic injury within
the “astrocyte-centric” subunit may result in an inflammatory response
and increased intracellular phosphorylation of tau protein and resulting
neurodegeneration.33
Chronic inflammation is a characteristic of metabolic disorders, frailty,
and AD. A metaanalysis of 40 studies found that AD is accompanied by
higher peripheral concentrations of a number of inflammatory markers,
including IL6 and TNF.34 Damage to the BBB can lead to infiltration of
immune cells into the brain, potentially contributing to central inflamma-
tion. Inflammatory mediators have adverse effects on beta amyloid and
glucose metabolism. Impaired metabolism of brain glucose and lower hip-
pocampal volume, hallmarks of AD, are strongly associated with peripheral
insulin resistance.35
Neuroimaging has supported the hypothesis that T2DM is associated
with accelerated cognitive decline and dementia. The structural basis for
these cognitive deficits includes both vascular lesions and global cerebral
atrophy.36 Vascular complications associated with chronic T2DM have been
shown to cause BBB breakdown that proceeds and drives the pathological
changes within the white matter progressing to symptomatic AD.37
Impaired brain insulin signaling contributes to Alzheimer’s disease
pathogenesis as first proposed by Hoyer.38 Increased levels of the insulin
resistance markers, insulin growth factor (IGF-1), and insulin receptor
substrate (IRS-1) are associated with poor performance on tests of working
an episodic memory.39 Increased amounts of advanced glycation end prod-
ucts generated by chronic hyperglycemia are found in postmortem AD
brain. Adult neurogenesis that provides neuronal plasticity is also impaired
in the diabetic brain.40
8. EXERCISE AND BRAIN METABOLISM

Exercise is one of the most effective strategies to promote brain plas-
ticity, increase cognition, and reduce risk of cognitive decline in later life.41
There is evidence that an evolutionary requirement for exercise promotes
beneficial adaptive responses that may inhibit, or even reverse, the effects
of a sedentary, overindulgent lifestyle.42 The beneficial effects resulting from
increased physical activity occur at different levels of cellular organization,
with mitochondria being preferential target organelles. Mitochondrial adap-
tations to exercise include an improvement of redox modulation
bioenergetics, decreased apoptotic signaling, activation of mitochondrial

biogenesis, and modulation of autophagy.43
Moderate and high intensity exercise have demonstrated a neuro-
protective effect through the induction of antioxidative enzymes, neuro-
trophic factors, IGF-1, and vascular endothelial growth factor. Expression
of these cellular products has been shown to reduce AB amyloid plaques
and tau phosphorylation in cognitive regions, improve cerebral blood flow,
and stimulate formation of synaptic connections.44
Diffusion-tensor magnetic resonance imaging has shown that greater
cardiorespiratory fitness is positively associated with more brain volume
and greater neuronal white matter integrity.45 Exercise involving power
and balance improves several aspects of cognitive function, including atten-
tional capacity, processing speed, executive function, episodic memory, and
procedural memory.46
Skeletal muscle activation by exercise appears to play a role in the
cognitive effects of aerobic activity through transcriptional factors regulating
muscle fiber contraction and metabolic genes.47 Findings suggest that brain
plasticity is maintained throughout lifespan and that it can be enhanced by
exercise and other interventions that activate AMP-activated protein kinase
(AMPK). AMPK acts as a mediator for metabolic hormones and cytokines
such as leptin, adiponectin, and ghrelin, which regulate glucose homeostasis,
appetite, and exercise physiology.48 Regular exercise promotes an energy
demanding, stress response efficiency, which involves a host of evolved
neuroendocrine responses.47 The brain plays fundamental roles in regulating
peripheral glucose metabolism by pathways and signaling mechanisms that
remain incompletely understood.49 Overall, physical activity produces
numerous changes in the brain and the periphery that converge to promote
stress robustness.42 Although challenging the brain and body intermittently
through physical exercise is beneficial, a society-wide effort will be required
to implement brain and body health programs in the educational and
healthcare systems, communities, and work places.47
9. PHARMACOLOGICAL TREATMENTS FOR DEMENTIA

Shared mechanisms and associations between T2DM, CVD, CKD,
and AD provide an opportunity to prevent, and significantly reduce, chronic
disease burden. Unfortunately, few clinical trials have demonstrated efficacy
of lowering blood pressure, cholesterol, or treating diabetes to reduce the
risk of dementia.32 A search for interventions to prevent, treat, reduce
8 J.W. Culberson
the progression, or cure AD continues. To date, most proposed treatments

for AD have disappointingly failed in clinical trials.50 Restoring insulin
signaling might be beneficial to AD patients. Intranasal insulin administra-
tion, a preferential route for CNS delivery, improved memory in healthy
adults, without affecting circulating levels of insulin or glucose. Intranasal
insulin also received enhanced verbal memory in memory-impaired subjects
and improved cognitive performance in early AD patients.51 Insulin was
found to protect neurons against AD causing neurotoxins in cellular and
animal models of AD.52 Brain insulin resistance may have a role in prenatal
development as well. It is conceivable that brain insulin resistance is a cause
rather than a consequence of obesity and T2DM, and perhaps even a
precursor to AD.35
10. REDUCING CHRONIC DISEASE BURDEN

Aging is typically considered an important confounder in clinical
research. Adjusting for age ignores the contribution of age as the most pow-
erful risk factor for many chronic diseases, and the clinical fact that chrono-
logical age is a poor approximation of physiological aging. The phenotypes
of aging and frailty may both result from a core set of mechanisms that con-
tribute to a multimorbidity that is modifiable with appropriate interventions.
This leads to the possibility that chronic diseases in older age and frailty both
originate from accelerated aging and may precipitate or exacerbate one
another.53 The ability to identify and modify the course of most chronic
medical conditions is well established. The U.S. Preventive Services Task
Force (USPSTF), World Health Organization (WHO), and other medical
specialty organizations have issued evidence-based guidelines for the pri-
mary, secondary, and tertiary prevention of T2DM, CVD, CKD, and
dementia.54–57 Sarcopenia may be an intermediate step in the development
of frailty in people with chronic illness, including AD.21 It appears to be a
dynamic process and potentially reversible. Therefore, early detection and
interventions which specifically target the molecular mechanisms
of sarcopenia should be a focus of worldwide health systems.14
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CHAPTER TWO
Therapeutic Strategies for

Mitochondrial Dysfunction and
Oxidative Stress in Age-Related
Metabolic Disorders
J.S. Bhatti*,†,1, S. Kumar*, M. Vijayan*, G.K. Bhatti{, P.H. Reddy*,§
*Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, United States
†
Department of Biotechnology, Sri Guru Gobind Singh College, Chandigarh, India
{
UGC Centre of Excellence in Nano Applications, Panjab University, Chandigarh, India
§
1
Corresponding author: e-mail address: jasvinder.bhatti@ttuhsc.edu
Contents
1. Introduction 14
2. Global Prevalence of Metabolic Disorders 16
3. Structure and Functions of Mitochondria 19
3.1 Mitochondrial Dynamics 20
3.2 Mitochondrial Biogenesis 21
4. Mitochondrial Dysfunction in Age-Related Metabolic Disorders 23
4.1 Type 2 Diabetes Mellitus 26
4.2 Obesity 27
4.3 Cardiovascular Diseases 28
4.4 Stroke 29
5. Strategies Directed to Target Mitochondrial Dysfunction 29
5.1 Lifestyle Interventions 30
5.2 Pharmacological Interventions 31
6. Concluding Remarks 33
Acknowledgments 34
References 34
Abstract
Mitochondria are complex, intercellular organelles present in the cells and are involved in
multiple roles including ATP formation, free radicals generation and scavenging, calcium
homeostasis, cellular differentiation, and cell death. Many studies depicted the involve-
ment of mitochondrial dysfunction and oxidative damage in aging and pathogenesis of
age-related metabolic disorders and neurodegenerative diseases. Remarkable advance-
ments have been made in understanding the structure, function, and physiology of
mitochondria in metabolic disorders such as diabetes, obesity, cardiovascular diseases,
Progress in Molecular Biology and Translational Science, Volume 146 # 2017 Elsevier Inc. 13
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/bs.pmbts.2016.12.012
14 J.S. Bhatti et al.
and stroke. Further, much progress has been done in the improvement of therapeutic
strategies, including lifestyle interventions, pharmacological, and mitochondria-targeted
therapeutic approaches. These strategies were mainly focused to reduce the mitochon-
drial dysfunction caused by oxidative stress and to retain the mitochondrial health in
various diseases. In this chapter, we have highlighted the involvement of mitochondrial
dysfunction in the pathophysiology of various disorders and recent progress in the
development of mitochondria-targeted molecules as therapeutic measures for meta-
bolic disorders.
ABBREVIATIONS
ATP adenosine triphosphate
CAT catalase
ERR estrogen-related receptors
ETC electron transport chain
GPx glutathione peroxidase
GSH glutathione
MetS metabolic syndrome
MitoQ mitochondria-targeted quinone
MtDNA mitochondrial DNA
NAC N-acetylcysteine
OXPHOS oxidative phosphorylation
PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha
RNS reactive nitrogen species
ROS reactive oxygen species
SOD superoxide dismutase
T2DM type 2 diabetes mellitus
TCA tricarboxylic acid
TNF-α tumor necrosis factor-α
1. INTRODUCTION
Aging is basically a degenerative process associated with impaired
metabolism and cell damage that leads to decline in all physiological func-
tions. There are several underlying rationales behind the “Free Radical
Theory” of aging proposed in 1956 by Harman but the exact reason of aging
is still poorly understood. However, the fundamental role of mitochondria
in aging has been established several decades ago.1,2 Mitochondria are
self-autonomous intracellular organelles responsible for producing energy
in the form of adenosine triphosphate (ATP) by metabolizing nutrients
via oxidative phosphorylation (OXPHOS) in concurrence with the
Mitochondria-Targeted Therapeutic Strategies in Age-Related Metabolic Disorders 15
oxidation of metabolites by Krebs’s cycle and β-oxidation of fatty acids.

They are also accountable for many other metabolic processes such as energy
metabolism, generation of free radicals and calcium homeostasis, and cell
survival and death.3,4 Currently, impaired mitochondrial functions such as
diminished oxidative capacity and antioxidant defense by enhanced produc-
tion of free radicals reduced OXPHOS and ATP production is substantially
linked with biological aging and many other metabolic diseases. There is a
decline in mitochondrial biogenesis in aging due to alterations in mitochon-
drial fission and fusion and the inhibition of mitophagy, a process which
eliminates dysfunctional mitochondria.5 Previous studies demonstrated that
aging is one of the major risk factors associated with life-threatening condi-
tions, including cancer, diabetes, obesity, cardiovascular, and neurodegen-
erative diseases.6
The reactive oxygen species (ROS) are a family of free radicals includes
superoxide anions, hydroxyl, peroxyl radicals, and other nonradicals capable
of generating free radicals.7,8 Although the intracellular generation of ROS
per se is an inevitable process, but cells possess numerous defense systems to
counter it. The overproduction of ROS subsequently leads to exponentially
increased oxidative damage inflicted on lipids, DNA, and proteins.4,9 Oxi-
dative stress is an imbalance between the generation of ROS and the antiox-
idant defense system, wherein the damaging effects of ROS are more
powerful compared to the compensatory effect of antioxidants in the
cells.10,11 It is evident from the previous studies that oxidative stress is in asso-
ciated with various pathophysiological conditions involving aging, cancer
and age-related metabolic disorders, and neurodegenerative diseases.12–22
The escalating prevalence of age-related metabolic disorders posed major
public health problems in the modern society, associated with enormous
personal, social, and economic burden across the world.23–28 Earlier studies
demonstrated the interaction of genetic variants and environmental factors
contributing the present alarming situation of age-related metabolic disor-
ders.29–32 However, oxidative stress and mitochondrial dysfunction are
implicated in a number of aging pathologies such as cancer, diabetes, obesity,
and neurodegenerative diseases.9,18,19,22,33–46 This chapter highlights the
escalating situation of metabolic syndrome (MetS), possible mechanisms
linking mitochondrial dysfunction with aging pathologies and promising
therapeutic strategies for prevention and treatment of age-related metabolic
disorders. We specifically focused on diabetes, obesity, stroke, and heart dis-
eases which are intimately related to mitochondrial dysfunction induced by
16 J.S. Bhatti et al.
overproduction of ROS in the cell. Then, pharmacologic strategies trans-

lated from the bench to bedside will be provided to target mitochondrial
dysfunction for the prevention of risk associated with age-related metabolic
diseases.
2. GLOBAL PREVALENCE OF METABOLIC DISORDERS

MetS represents a constellation of several risk factors such as central
obesity, elevated blood pressure, abnormal levels of triglycerides and
high-density lipoproteins-cholesterol (HDL-C), and impaired glucose tol-
erance. Previous studies demonstrated the high prevalence of MetS world-
wide which leads to the development of type 2 diabetes and cardiovascular
diseases (CVD).47–49 In the past decades, many definitions of MetS have
been recommended by various international organizations (Table 1) includ-
ing the World Health Organization (WHO), the European Group for the
Study of Insulin Resistance (EGIR), the National Cholesterol Education
Program-Third Adult Treatment Panel (NCEP-ATPIII), the American
Association of Clinical Endocrinology (AACE), and the International Dia-
betes Federation (IDF); however, the most widely accepted and clinically
used criteria of MetS are those acclaimed by WHO (1998), modified
NCEP-ATPIII (2005), and IDF (2005). As shown in Table 1, each organi-
zation has established their own criteria for defining MetS, having thresholds
for each component of MetS. Furthermore, in 2009, a joint interim state-
ment for the new definition of MetS was published by the International Dia-
betes Federation Task Force on Epidemiology and Prevention; National
Heart, Lung, and Blood Institute; American Heart Association; World Heart
Federation; International Atherosclerosis Society; and International Associ-
ation for the Study of Obesity.50 This joint definition stated that obesity and
IR are not prerequisites for MetS but that three of the five components
would suffice for a diagnosis of MetS, with the thresholds for measuring
waist circumference (WC) requiring ethnic and nation specificity.50,51
Indeed, the varying diagnostic criteria of MetS impede the actual estimates
of MetS worldwide, as well as within specific countries, genders, and
ethnicities.
Despite ambiguity in the precise definition of MetS, several studies have
reported worldwide prevalence of MetS varying between 10% and 84%
depending on the ethnicity, age, gender, and race of the population, whereas
IDF estimates that one-quarter of the world’s population with MetS.49
Recent studies have shown that approximately one-fifth of the adult US
Table 1 Various Definitions Proposed for the Clinical Diagnosis of Metabolic Syndrome
Modified
NCEP-ATPIII Harmonizing
Parameters WHO (1998)52 EGIR (1999)53 ATPIII (2001)54 AACE (2003)55 (2005)56 IDF (2005)57 Criteria (2009)50
Insulin GT, IFG, T2DM, Plasma insulin None, but any IGT or IFG plus None None None
resistance or lowered insulin >75th percentile three of the any of the
Sensitivity plus any plus any two of the following five following based
two of the following features on the clinical
following judgment
Abdominal Men: waist-to-hip WC 94 cm in WC 102 cm in BMI 25 kg/m2 Increased WC Increased WC Increased WC
obesity ratio >0.90; men or 80 cm in men or 88 cm (ethnic-specific) (population (population- and
women: waist-to- women in women plus any two of the specific) plus any country-specific
hip ratio >0.85 following two of the definitions)
and/or following
BMI > 30 kg/m
Lipids TGs 150 mg/dL TGs 150 mg/dL TGs TGs TGs 150 mg/dL TGs TGs
abnormality and/or HDL-C and/or HDL-C 150 mg/dL 150 mg/dL and HDL-C 150 mg/dL or 150 mg/dL or
<35 mg/dL in men <39 mg/dL in HDL-C HDL-C <40 mg/dL in HDL-C HDL-C
or <39 mg/dL in men or women <40 mg/dL in <40 mg/dL in men or 40 mg/dL in 40 mg/dL in
women men or men or <50 mg/dL in males; males; 50 mg/dL
<50 mg/dL in <50 mg/dL in women 50 mg/dL in in females (or
women women females (or drug drug treatment
treatment for for elevated
elevated triglycerides or
triglycerides or reduced
reduced HDL-C)
HDL-C)
Continued
Table 1 Various Definitions Proposed for the Clinical Diagnosis of Metabolic Syndrome—cont’d
Modified
NCEP-ATPIII Harmonizing
Parameters WHO (1998)52 EGIR (1999)53 ATPIII (2001)54 AACE (2003)55 (2005)56 IDF (2005)57 Criteria (2009)50
Hypertension 140/90 mm Hg 140/90 mm Hg 130/85 mm Hg 130/85 mm Hg 130/85 mm Hg 130/85 mm Hg 130/85 mm Hg
or on treatment or on treatment or on treatment or on treatment
for hypertension for hypertension for hypertension for hypertension
Fasting IGT, IFG, or IGT or IFG (but >110 mg/dL IGT or IFG (but >110 mg/dL 100 mg/dL 100 mg/dL or
glucose levels T2DM not diabetes) (includes not diabetes) (includes diabetes) (includes drug treatment
diabetes) diabetes) for elevated
glucose
Other Microalbuminuria: Other features of
urinary excretion insulin resistance
rate of
>20 mg/min or
albumin: creatinine
ratio of >30 mg/g
Mitochondria-Targeted Therapeutic Strategies in Age-Related Metabolic Disorders 19
population is suffering from MetS.58 A number of previous studies estimated

an increase in the prevalence of MetS (20%–25%) in Asian Indians.32,59–63
Also, a consistent increase in the prevalence of the MetS associated with
abdominal adiposity leads to higher risk of morbidity and mortality in East
and Southeast Asian populations.61 These studies demonstrated potential
culprits involved in the development of MetS including rapid urbanization,
higher economic growth, increasing age, sedentary lifestyle, bad dietary
habits, and Westernization.64,65 It has been established that subjects with
MetS have a five times more risk of developing type 2 diabetes mellitus
(T2DM) and three times more risk of developing CVD.32,66 Recent
advances in pharmacological treatment, lifestyle interventions, and disease
awareness have slightly limited the progression of MetS all over the world.
Furthermore, increasing trends of some components of MetS including
hyperglycemia and abdominal obesity still increased risk of MetS.58 Previous
studies implicated the association of oxidative stress with the epidemics of
MetS.22,67
3. STRUCTURE AND FUNCTIONS OF MITOCHONDRIA

Mitochondria are complex ubiquitous intracellular, rod-shaped
organelles ranging from 0.5 to 1.0 μm in diameter, which present in most
of the eukaryotic cells. These organelles use carbohydrates, fats, and proteins
as fuel and produce energy in the form of ATP and that is why they are called
as the “powerhouse of the cell.” Mitochondria also perform many other key
functions including cell signaling, cell differentiation, and senescence and
also regulate cell growth. Each mitochondrion is composed of double
membrane with intermembrane space between outer and inner mitochon-
drial membranes. Outer mitochondrial membrane is smooth and having
a number of integral proteins called phorins making it relatively more
permeable to nutrients and other molecules. In contrast, the inner mem-
brane is complex, strictly permeable and having many folded structures
called cristae and contains enzymes of OXPHOS. This membrane surrounds
the mitochondrial matrix, wherein the electrons produced by tricarboxylic
acid (TCA) cycle are taken in by electron transport chain (ETC) for
the production of ATP. Each mitochondrion contains between 800 and
1000 copies of self-replicating, mitochondrial DNA (mtDNA), which are
maternally inherited and packaged in high-ordered nucleoprotein struc-
tures called nucleoids.68 Although nucleoids are distributed throughout
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A Carbonaria italiana, dirigida pelo mystico republicano Mazzini,
alargando os seus ramos por toda a Europa, para fundar a republica
universal e redemptora, infiltrara-se entre nós tambem com a sua
alta-venda ou choça-mãe d’onde dependiam as vendas ou choças
filiaes e as barracas. Em Coimbra havia a choça de Kossuth, o
hungaro. (M. Carvalho, Hist. contemp.) N’esta maçonaria novissima
alistavam-se os moços, e d’ahi saía a direcção politica, republicana
e democratica.
N’este estado veiu a Regeneração encontrar os elementos
desordenados e fracos dos revolucionarios portuguezes; e os laivos
de socialismo que n’elles havia fizeram com que ella em grande
parte absorvesse a cauda moça do partido setembrista, já tambem
eivada de doutrinas ou sentimentos cosmopolitas e philantropicos.
Das vendas carbonarias passou então o foco da agitação
revolucionaria para as sociedades operarias. Fundou-se em Lisboa
o Centro-promotor. «As idéas societarias que desde 48 tinham ido
calando no coração dos desvalidos da fortuna» inspiravam ao
mesmo tempo os typographos que se faziam litteratos-politicos
(Vieira-da-Silva, Albuquerque, etc.), os engenheiros mais ou menos
socialistas (Rolla, Latino, Brandão), e os antigos setembristas que
viam a urgencia de infiltrar idéas e sangue novo no partido. Ao
theatro romantico de Mendes-Leal, heroes panta-façudos, homens-
de-ferro com uma linguagem de medos, substituiu-se um outro
genero: eram os homens ou as mulheres de marmore, dramas
satanicos mostrando ao povo a corrupção dos ricos; eram as peças
operarias, inspiradas pelas obras de Sand e Eugenio-Sue, em que o
homem de trabalho apparecia heroe, luctando com energia e talento
contra os crimes e preconceitos de uma sociedade madrasta.
Desgarrados, sem cohesão nem consistencia todos estes
elementos revolucionarios, a Regeneração tendia a inclinar todos os
dias mais no sentido revolucionario, á imagem do que succedia por
toda a Europa latina.
Rodrigo, que a principio se apoiara no grupo setembrista da
Revolução, foi pouco a pouco bolinando tanto no sentido opposto,
que a presidencia official do partido passou de Saldanha para
Terceira (no gabinete de 59). Já em 54 D. João de Azevedo escrevia
de Lisboa a José Passos: «Conte que antes de pouco tempo muitas
notabilidades do partido cabralista hão-de obter graças e mercês,
porque a estrategia de Rodrigo está hoje posta n’isso.» (Carta, na
corr. autogr. dos Passos) Assim tinha de ser. Que era a
Regeneração, senão o utilitarismo cabralista sem doutrina? Que fôra
o cabralismo, senão uma regeneração sem dinheiro nem
scepticismo, só com doutrina e violencias? 48 levantara uma
labareda, mas o incendio apagou-se rapido. A Polonia, a Italia, a
Hungria ficaram quaes se achavam antes; a França restaurou o
papa em Roma, e tolerou em Milão o austriaco. Depois dos dias de
junho em que o socialismo de Paris foi esmagado, viera Napoleão III
pôr um freio ás temeridades revolucionarias.
O romantismo politico, a que nós estudámos as duas faces
successivas (1826-1838, Palmella, Herculano), finara-se de todo
com uma revolução em que já entravam elementos de diversa
origem.
O que caracterisa esse periodo é a grandeza generosa das
aspirações, combinada com a indeterminação das idéas, um
vago idealismo ou antes sentimentalismo que envolve e
abraça, sem dar por isso, as maiores contradicções praticas
e se lança no caminho das mais perigosas aventuras com um
sorriso de confiança ingenua e quasi infantil. Este
phenomeno de uma revolução sem pensamento explica-se
pelas condições particulares do meio em que se
desenvolveu.
Era em primeiro lugar um individualismo sentimental, ao
mesmo tempo cheio de reivindicações e de effusões e que
pretendia corrigir o egoismo das reclamações do direito
individual com os preceitos moraes e poeticos da
fraternidade.—Em segundo lugar, a attitude
determinadamente hostil das monarchias constitucionaes
dominadas pela alta burguezia ávida e agiota, tornava-lhes
imminente a queda sem que se podesse dizer que essa
queda implicava uma verdadeira revolução porque as classes
contra ellas insurgidas não tinham principalmente em vista
destruir, no seu principio, o regimen existente, mas pelo
contrario, entrar n’elle, apossar-se d’elle, alargando-o (pelo
suffragio) até ás proporções da nova democracia.—Em
terceiro lugar, finalmente a attitude das classes operarias
vinha lançar no meio d’esta confusão intellectual e politica
mais um elemento de perturbação, e o mais formidavel de
todos. O Socialismo, tão mal comprehendido pelos seus
adversarios, como mal definido pelos seus partidarios, foi
transformado n’um monstro, o famoso espectro vermelho; e o
terror abria caminho a uma reacção tão geral e irresistivel
que arrastou comsigo não só o Socialismo, não só a
Republica, mas ainda o proprio regimen liberal e todas as
garantias legaes tão custosamente conquistadas.
O drama romantico veiu a dar por toda a parte n’uma
conclusão tragica. A Hungria foi esmagada, esmagadas a
Italia, a Rumania, a Polonia. Na Alemanha, na Austria, o
cezarismo dissolve os parlamentos nacionaes, rasga as
constituições que o susto lhe fizera jurar no primeiro
momento de surpreza e estabelece solidamente e por muitos
annos o regimen militar. Em França, d’onde partira o impulso
revolucionario, o Socialismo, tornado a execração de todos
os partidos, cae exangue nas barricadas de junho, e o
movimento reaccionario, uma vez lançado, não pára sem ter
destruido a republica, as garantias liberaes constitucionaes,
humilhado a democracia, e sobre todas estas ruinas
estabelecido o imperio conservador, ao mesmo tempo rural,
militar, bancario e clerical.
Taes foram os resultados da evolução romantica. Mas a
geração que a preparou e a consummou não podia prever
taes resultados. A sua confiança era tão longa, como vastas
as suas aspirações: e se aquella era infundada, estas eram
generosas e alevantadas. Talvez nunca a historia registrasse
uma tão completa catastrophe, saída d’um tal concurso de
bellos sentimentos, de elevados intuitos, de personalidades
brilhantes e heroicas. Os promotores e fautores d’aquelle
movimento, os Lamartine, Ledru Rollin, Arago, Luis Blanc,
Proudhon, Raspail, Mazzini, Garibaldi, Manin, Gagern,
Rosetti, Bem, Kossuth, e todos os que indirectamente o
prepararam, oradores, pensadores, poetas, Lammenais,
Michelet, Quinet, Hugo, Sand, Sue, Leroux, Mickiewicz,
Gioberti, Manzoni, Cantu, Mamiani, Feuerbach, Heine,
formam uma pleiade incomparavel pelo talento e pelo
caracter; e não admira que, apezar do vago e do incoherente
das suas doutrinas, dominassem tão completamente o
espirito da geração que atraz d’elles se lançou fanatisada no
caminho de inevitavel desastre. (A. de Quental, Lopez de
Mendonça, no Operario.)
Em Portugal, varias causas concorriam para que a revolução de
48 não chegasse a nascer. Era o cançasso dos partidos, era a
miseria da nação, era a influencia de Rodrigo, epilogo sceptico da
historia liberal. Era tambem a circumstancia de que dos dois motivos
do 48 europeu, o democratico já entre nós fôra ensaiado e ficara
desacreditado em 36; e o socialista não tinha classes operarias
fabrís bastante numerosas para o fazerem vingar. Em vez de uma
revolução, tivemos uma Regeneração a que os revolucionarios
como José-Estevão, Lopes-de-Mendonça etc., adheriram, conforme
sabemos. Mas quando todos esses viram o partido novo tornar-se
cada dia mais velho; quando assistiram ao accordo de
Regeneradores e Historicos a favor das irmans-da-Caridade, que
era a questão ardente, separaram-se, para fundar o Futuro, jornal,
partido das aspirações vagas de um romantismo serodio cujo chefe
era José-Estevão. A ausencia de numerosas classes operarias
principalmente impedira antes a revolução, e impedia agora o nova
partido de ganhar estabilidade. E como não chegou a haver lucta,
não houve motivo para repressões: e como uma das causas da paz
era a fraqueza, manteve-se a liberdade por não haver interesses
nem motivos fortes em conflicto.
Opportunamente morreu o tribuno (nov. 4 de 62) que durante a
vida não cessara de praticar nobres actos inopportunos. Como typo
e symbolo de uma geração que nunca chegou a ter voz, passou
para o tumulo deixando os companheiros dispersos, entregues á
desillusão, absorvidos pelos seus trabalhos profissionaes. Ao Futuro
succedeu ainda a Politica-liberal; á Patriotica, o club do Pateo-do-
Salema, d’onde saíu ainda a força bastante para em janeiro de 68
derrubar os conservadores do governo.
Veiu logo a revolução de Hespanha complicar a situação com
esperanças republicanas e intrigas ibericas; veiu depois a guerra do
Paraguay seccar a fonte dos ingressos de dinheiro do Brazil: tudo
isto declarou em crise o resto das antigas esperanças.
Debandaram todos, cada qual para seu lado. Os excentricos
ficaram esperando pela republica doirada; os praticos, ou se
alliaram aos conservadores, ou se congregaram em reformismo
opportunista. E as velhas idéas societarias? Tambem a iniciação do
fomento influiu sobre ellas; mas a dureza do regime capitalista da
burguezia, em vez de lhes fazer como a politica realista fazia aos
romanticos: em vez de as reduzir a um pó de chimeras, obrigou-as a
declararem-se em partido dos pobres contra os ricos, n’uma guerra
de classes, anachronica de certo, mas ameaçadora. A Hespanha
teve Carthagena, a França teve ainda a Communa de 71: nós
tivemos umas gréves apenas, por não possuirmos sufficiente
industria fabril.
Tal foi o caracter que o Socialismo tomou, sob o influxo do
Utilitarismo, sem que se veja ainda que outro e melhor o espera.
Dissipadas as chimeras, conquistadas as garantias individuaes,
conferida ao povo uma soberania negada ao throno: crê alguem que
tudo está feito? Espera alguem que esse povo, soberano e mendigo
ao mesmo tempo, não reclamará uma revisão da legislação
economica? Perigosa teima será negal-o, porque as revoluções
inevitaveis, se se não consummarem de cima para baixo, dar-se-
hão ao inverso, de baixo para cima—como a labareda que sóbe
crepitante!
4.—D. PEDRO V
Esquecemos, n’estes successivos relances, o throno. E entretanto

em Portugal nunca deixou de haver monarcha. Depois de D. Maria
ii, matrona antiga coroada, veiu o rei-artista, cezar sem amor á
guerra; depois D. Pedro v; por fim o rei actual. O seu finado irmão
era um romantico posthumo. Contava dezoito annos quando subiu
ao throno (n. 16 de set. de 37; r. 55) e com um temperamento
observador, grave, desde creança o foram impressionando os
episodios deploraveis da historia d’esse tempo. Tem o leitor
presente a memoria de D. Duarte, o infeliz rei, tão sabio, tão bom,
tão cheio de terrores e de escrupulos? Foi como elle D. Pedro v
«esse pobre rapaz» que o destino condemnara a ser principe. Já
não estava nos usos consultar bruxas e adivinhos, mas o rei tinha
em si o feitio de espirito que pede milagres. Considerava-se
predestinado, ao inverso de D. Sebastião, para um fim breve e
funebre; via-se coberto de terra, mettido n’uma cova, imagem viva
da morte, fatalidade ambulante movido por uma sina triste. Era uma
saudade, a sua alma; e o coração, batendo, parecia-lhe um dobre
de finados! Saudade de uma honra esquecida, dobres pela morte de
um povo desditoso? Symbolo de uma nação cadaver, considerava-
se, elle rei, minado por todas as pestes. Roía o um remorso
inconsciente que o fazia apparecer bisonho e triste, com um sorriso
doentio na face, a mudez nos labios, no olhar o quer que é de
somnambulo. Interpretando os acasos com o seu fado, explicando
tudo pela sua sina, achava em si a causa de muitas desgraças.
Quando o patriarcha voltava de o baptisar, partiram-se-lhe as rodas
da carruagem e caíu ... Aos dez annos, já o principe tinha pesadelos
que o faziam scismar: uma grande aguia negra tomava-o nas
garras, levantava-o ao ar, deixando-o caír e despedaçar-se ... A
aguia tornava a subir levando para os ares o mano Luiz ... Tinha
então dez annos e contava os terrores ao seu mestre. (Bastos,
Mem. bio. de D. Pedro V) Depois chegou a crer que matava o que
tocasse. O general Loureiro morrera de apoplexia? porque elle o
affligira com certos ditos. D. Carlos de Mascarenhas morrera?
porque elle o obrigara a um passeio excessivo. E o Curso-superior,
o filho do seu amor ás lettras, era baptisado com o cadaver de D.
José d’Almada, com a loucura de Lopez de Mendonça! (Andrade
Ferreira, Vida, etc.) Tragica figura de um rei que se acredita a má
sina do seu povo! Não seria ella o summario de uma historia
miseravel, o symbolo de uma nação pobre, o espectro de um povo
caduco? Não viria como resultado de trinta annos de miseria,
lentamente cristolisados n’um cerebro impressionavel, definir com o
seu genio a epocha?
Se ás superstições funebres se póde achar esta razão de
psychologia historica, não é mistér appellar para tão longe quando
se observa o outro lado do seu caracter. Com olhos de pessimista, e
esses eram os bons olhos para vêr Portugal, tinha em tanta conta os
que o rodeavam, cria tanto n’elles, que mandou pôr á porta do seu
palacio uma caixa-verde, cuja chave guardava, para que o seu povo
podesse falar-lhe com franqueza, queixar-se, accusar os crimes dos
governantes. Singular modo de conceber o seu papel de rei de uma
nação livre, parlamentar! Os ministros que não escarneciam d’elle,
principiavam a temel-o; outros a odial-o. O povo começava a amar a
bondade e a justiça de um rei tão triste. Já corria de bocca em
bocca a lenda do novo monarcha: um infeliz! E o amor não era feito
de esperanças, mas de presentimentos funebres e de uma
consciencia certa da fatalidade commum do povo e do rei. «Se elle
podesse!» Mas entre elle e o povo simples havia de permeio os
politicos.—«Como o rei é justo, bom e nobre! Nem quer que lhe
beijem a mão, nem que dobrem o joelho, nem quer matar um só
criminoso, o santo! Se não fossem os politicos!» E esta corrente de
intimidade entre o povo e o rei cresceu a ponto de se chegarem a
formular votos pelo absolutismo. (Th. Braga, Hist. do rom.) A alma
espontanea dos povos latinos, idealistas, sem os calculos, as
reservas, os planos de outras raças, só acclama os factos simples: é
inaccessivel ás fórmulas. Quem no meio-dia quizer ser grande, seja
forte, seja rei: Pombal, D. Miguel, Saldanha ainda, ou seja um bom
pae, um bom protector do povo!
Como o seria porém D. Pedro v, se se acreditava marcado por
uma estrella funesta; se, fumando como um estudante o seu cigarro,
ouvia a licção do seu mestre Herculano, licção em que ás fórmulas
liberaes-romanticas se juntava o ensino de uma reprovação
universal—dos politicos, um bando; do povo, um desgraçado? As
fórmulas sabias murchariam a flor da ambição, se ella viesse a
desabrochar, porque as jeremiadas do propheta enraizavam na
alma do rei o seu pessimismo. Como que abdicava, instruindo-se; e,
em vez de se entregar ao officio proprio do seu posto, velava as
noites a estudar, os dias passava-os aferindo a realidade por uma
historia vista com oculos de metaphisicas nebulosas, de idealismos
mysticos. Parecia um monge somnambulo; mas a mocidade, a
virtude estampada no seu rosto, ganhavam um encanto de
melancholia com essa perda das noites veladas. O dia, a luz do sol,
a realidade, os homens, tudo então se lhe affigurava um sonho:
pesadelo triste, a sua má sina! Quando não era funebre, era ironico,
epigrammatico: o seu reino parecia-lhe o peior da Europa. Lera o
livro de About La Grèce contemporaine, e annotando-o, poz no
titulo: La Grèce—et Portugal.
Ora Portugal já por fórma alguma era como a Grecia
contemporanea. Fôra-o sem duvida, mas desde que o espirito
pratico vencera em 51, conquistando a si o primeiro dos palikaras
portuguezes, Saldanha, todas as ambições nacionaes estavam
tornados para uma Beocia antiga, farta de cearas. O genio do rei
não chegava a conceber um ideal tão mesquinho, e só via o
passado, com os olhos cégos para o futuro iniciado. Elle era o fim
de uma historia, o epilogo summario de um tomo, inserido por erro
depois das primeiras paginas do livro seguinte. Por isso lhe
chamámos posthumo. Considerava-se a si um nuncio da morte e via
moribundo o seu povo. Estimaria que o caminho de ferro se fizesse
com inglezes «para metter sangue novo nas veias d’esta raça
atrophiada». Como se sabe, os operarios cruzam com as
camponezas e o caminho de ferro ia atravessar o reino em dois
sentidos. Singulares, dramaticas deviam ter sido as conversas entre
o mystico principe e o Salamanca, o aventureiro audaz das
novissimas emprezas que se propuzera regenerar Portugal. O
embaixador que as ouviu, apresentando ao rei antigo o moderno
barão da industria e do banco, dizia que para descrever bem a
acena «seria necessario la pluma de un Cervantes.» Salamanca,
soccarron, affectando gravidade na sua face castelhana, como um
Gil-Blaz, ouvia D. Pedro que queria lucir-se. O picaro confessava a
sua ignorancia: nem era philosopho, nem sabio! um homem-de-
negocios, senhor! E D. Pedro V contava-lhe a nossa pobreza, a
incapacidade de sustentarmos caminhos de ferro, filiando estas
opiniões tristes no quadro lugubre da decadencia das raças latinas.
Saindo, o emprezario sagaz, que estudando um doente vira um
homem, disse para o embaixador companheiro: «Deus nos livre de
que este rei tivesse os meios e o valor das suas convicções.»
De casa do filho, foram ambos a casa do pae. Que mudança!
Tambem Salamanca era artista, tambem apaixonado pelo bric-à-
brac, derradeira poesia dos scepticos; tambem sybarita, viveur
aristocratico, distincto, palaciano. «Parecian hechos el uno para el
otro». Viram os museus, commentaram as faianças, os charões, as
porcellanas, os quadros, rindos como gréculos. O pensamento de
ambos, inconscientemente, nadava na expressão classica do papa
da Renascença: Quod commoda da Deus nobis hœc otia, Christi!
«Quedaran encantados.» E para rematar a amisade, o rei D.
Fernando fazia indirectamente a apologia dos povos latinos,
confessando o seu desamor pelos inglezes que maltratava. (V.
Desp. de Pastor Dias, 10 dez. 59 ap. Rios, Mision) Triste engano do
acaso, que invertera o lugar proprio das pessoas. O pae devia ser o
rei; o filho o principe que, sem os cuidados do throno, acaso teria
tido, no Portugal novissimo, o papel de D. Henrique no de Aviz—o
papel de um iniciador na sciencia!
Quem se não lembra de ter visto o rei, attento como um discipulo,
a ouvir nas salas do seu Curso as lições dos professores, com o
aspecto grave, a mão cofiando o pequeno bigode, denunciando a
actividade do seu cerebro? Porque lhe não concedia a sorte viver a
vida para onde o seu genio o chamava? Porque a sua sina era
perdida e uma estrella má o condemnava a elle a reinar, e ao reino a
padecer as consequencias de um destino cruel. A bofetada que a
França nos deu, vindo buscar armada ao Tejo o negreiro apresado
em Africa, arroxeou-lhe a face, e o rei chorou afflicto. Veiu uma
epidemia de cholera em 56; outra de febre-amarella em 57; veiu a
irritação cruel das irmans-da-Caridade. As desgraças, os embaraços
teciam a rede de malhas cerradas em que se lhe afogava a
existencia; sem lhe occultar, mostrando-lhe sempre, fatidica, a
estrella má do seu destino.
Quando um sceptico tem superstições—contradicção só aparente,
e de resto vulgar, do espirito humano—não reage, obedece; não
resiste, cae. Quando ellas atacam um mystico, fortalecem-no com
uma coragem transcendente. D’ahi veem os monges heroicos,
stylitas e outros. A alma de um santo que havia em D. Pedro V,
retemperada pelo estoicismo aprendido nas licções de sua nobre
mãe, mostrou-se quando Lisboa dizimada o via passar nas ruas,
visitando os enfermos, caminhando para os fócos do contagio, como
um Isaac para o sacrificio biblico. O amor do povo tornou-se então
uma paixão; e corriam as anedoctas com que a imaginação popular
cristallisa os heroes. Mandara a um medico medroso descalçar a
luva para tomar o pulso ao enfermo. E se Portugal já tivera em D.
Sebastião um rei Arthur, não é verdade que se formava uma lenda,
diversa sem ser menos bella: a lenda da santa rainha de Hungria,
ou do rei santo de França? Nas pestes milanezas, o Borromeu
ganhou a canonisação; nas de Lisboa, D. Pedro V foi canonisado
pelo povo. E quando, quatro annos depois, morreu, na aureola da
caridade o povo engastou palmas de martyrio.
Nas angustias d’esses dias afflictivos, o moço, infeliz rei achar-se
hia bem, sem o crer, sem o pensar, sem o sentir. Assim a cevadilha
só floresce nos terrenos da malaria. Assim os maus só crescem no
seio da pravidade. Tambem os temperamentos funebres, com o
espirito feito de presagios, se prazem no seio das desgraças. Ellas
vêem como confirmação dos presagios. E nada aflige mais o
homem do que a duvida, quando o que o rodeia não obedece ao
que pensa, ou ao que sente. Como não viria a peste, se a estrella
do rei era mortal? Cumpria-se o fado da sua existencia. Os
presagios não mentiam; o seu coração falava verdade. E esta
affirmação externa do seu sentimento intimo, afogava-o mais, cada
vez mais, nas suas superstições funestas, no seu pessimismo
ingenito.
Em taes momentos, os temperamentos como o de D. Pedro V
raras vezes caem: quasi involuntariamente requintam. Formula-se
então em doutrina o que era apprehensão. O acaso, segredo ou
mysterio do Universo, torna-se Providencia; e, quando se é christão,
por via de regra, entra-se nos moldes conhecidos, que tantos
mysticos formularam, desde Alexandria até Manreza. A religião arde
como chamma a que se dá, em novo combustivel, a somma de
apprehensões coordenadas. Era D. Pedro V christão? ou apenas
deista á moda romantica, isto é, reconhecendo no christianismo a
mais pura fórma de deismo até hoje concebida? Não sei. As licções
de Herculano, os livros modernos da sua leitura deviam ter abalado
a sua orthodoxia; mas os espiritos romanticos, na inconsistencia das
doutrinas, na poesia dos sentimentos, conservavam sempre aberta
a porta para o arrependimento. E tantos foram os que, penitentes,
se curvaram beijando a terra: tantos, tão dignos, tão nobres,
obedecendo tão espontanea e sinceramente, que hesitamos em
dizer se o rei teria ou não sido um d’esses.
A occasião levava a um tal fim a vida moral de D. Pedro v,
quando o casamento (18 de maio de 58) trouxe para o seu lado uma
rainha piedosa, candida, pura, como anjo que vinha, entoando os
canticos da Egreja, acompanhal-o a bem morrer, ou mostrar-lhe,
apparição fugitiva, vaporosa Beatriz de religioso encanto, o paraiso
que o esperava depois da selva escura da existencia terrestre.
Tinha vinte e um annos Dona Estephania, (n. 15 julho 37) quando
casou com o rei que contava edade egual. Eram duas creanças?
Não; apesar dos annos. Porque a elle a imaginação tinha-lhe feito
viver já uma longa existencia de pensamentos, presagios e
angustias; e a rainha desde creança vasara toda a sua bondade
angelica nos moldes da devoção catholica. Apesar dos annos, pois,
eram ambos, em moços, como se já fossem velhos; e a edade
juntava ao encanto d’esse par tão nobre, tão cheio de sympathia.
Ella tinha retratada a candura da sua alma na suave expressão de
um rosto meigo; e o rei, no aspecto carregado, mostrava a força do
seu caracter, a tristeza do seu espirito. Um presentimento tragico
assaltava quem os via passar nas ruas da cidade: nenhum dos dois
parecia bem d’este mundo—elle uma victima expiatoria, ella um anjo
custodio!
A devoção da rainha e a superstição do rei davam de si uma
authoridade espontanea á primeira no espirito do segundo. Era
então o tempo em que a questão das irmans-da-Caridade,
complicada com a politica, se tornara um espinho irritante; e a
rainha devota e o rei funebre começavam a ser accusados de
clericaes e ultramontanos. Com effeito, nenhum dos dois fôra feito
para o throno. Tinham demasiada virtude, ambos, para reinar em
qualquer dos nações latinas, sobretudo em Portugal. A sua
sinceridade não era comprehendida, e arriscava-os a soffrer as
consequencias de uma politica desalmada.
D. Estephania morreu a tempo (julho de 59), antes que se
desmanchasse ás mãos duras de quem não tinha coração para a
amar, a cristallisação poetica formada no espirito do povo sensivel
com a sua formosura angelica, com a sua devoção ingenua, com a
sua caridade fervente. Morreu, e ainda bem! É como quando no
meio da charneca desolada e secca, fatigado, o viandante depara
com um puro arroyo cristallino, e bebe: assim nos acontece a nós
deparando com um typo de candura e poesia na vasta charneca de
urzes d’esta historia. Que importa morrer? Mais vale que o arroyo
logo se perca, sorvído por alguma fenda ... Se corresse e seguisse
atravez do chão empoeirado, não é verdade que as suas aguas se
haviam de sujar, misturando-se com as gredas do solo e as folhas
podres das urzes?
Mas o pobre rei, mais a sua sina fatal, quando se viu só, depois
dos breves mezes de casado, mais se enraizou ainda nos seus
presagios. Era a morte, elle que matava tudo o que tocava. Via-se já
nos ares arrebatado pelo aguia negra dos seus pesadelos. Sentia
sobre si o peso de muitas vidas ceifadas; e, chorando, lamentava o
seu triste isolamento. Não estaria cumprido ainda o seu fado? Que
novas desgraças havia de causar? Quando lhe seria dado terminar
o seu desterro d’este mundo, para ir n’um céu, visto em sonhos,
sentar-se ao lado do anjo que para lá fugira? Como uma pomba
branca voando breve no horisonte da sua vida, tocando-lhe com a
aza a face a dispertal-o dos seus sonhos tristes, assim passara a
idolatrada rainha, assim fugira, assim desapparecera no seu vôo. De
longe, accenava-lhe agora. Era a Beatriz dos seus pensamentos
mysticos: não uma Laura de amores humanos.
Assim um novo motivo de tristeza se juntava aos anteriores;
assim tudo ganhava um caracter fatidico para o espirito do rei. A
fatalidade estava n’elle, e não nas cousas. Quando um relampago
azulado illumina a noite, tudo nos apparece azul. Caía triste o
outomno de 61: havia dois annos que D. Estephania morrera,
quando o rei e os principes foram a Villa Viçosa caçar, e voltaram de
lá envenenados pelos miasmas de um charco dos jardins. Eloquente
symbolo, porque os miasmas do charco portuguez eram o veneno
que o rei tragara no berço e lhe fizera da vida uma enfermidade
chronica.
As mortes galoparam rapidas como na ballada de Burger. Caíu
primeiro o joven infante D. Fernando, e o rei tinha a certeza de
morrer tambem. Já no leito ardia com febre delirante. Em frente do
palacio, fundeada no rio, a corveta Estephania de espaço a espaço
soltava um tiro—como o bater do relogio lugubre da morte. E esses
tiros ouvia-os o rei, chamavam-no, excitavam-no, davam-lhe os
desejos de acabar por uma vez com a vida miseravel, para ir
abraçar no céu a Beatriz do seu delirio. Se a voz dos anjos podesse
ser o troar dos canhões, não era ella que o chamava? Talvez;
porque os tiros chegavam á camara do rei, já brandos, como um
ecco, um murmurio, e vinham do navio que tivera o nome d’ella—
Estephania! Seguidos, constantes, infalliveis como um destino,
repetiam-se; e o delirio do rei, interpretava-os: eram vozes! A sua
vista conturbada já perdera a noção da realidade; e vivo ainda, já se
julgava transportado ás regiões sonhadas n’uma longa existencia de
vinte annos ...
Dizem que na agonia murmurava os threnos de Dante:
Per me si vá nella citá dolente ...

Per me si vá n’ell’ eterno dolore ...
No largo do palacio o povo espesso, na sua afflicção, dividia-se

entre as lagrimas e as coleras. Era um espectaculo antigo, como
quando outr’ora, nos seus pequenos reinos, os reis eram paes,
protectores, quasi idolos. A um povo desgraçado, a desgraça do rei
apparecia como symbolo dos proprios infortunios; e a crueldade de
uma estrella funesta tinha o condão de ferir ainda a alma de uma
gente já descrente e scepticamente regenerada; tinha uma virtude
que decerto não teria tido o talento, a audacia, a ambição de um rei
heroe. A morte no paço era symbolica, e a turba obedecia
inconscientemente a um d’esses movimentos de psychologia
collectiva, tão mysteriosos ainda. A morte no paço era o symbolo da
morte no reino, e por isso, repetimos, na sua afflicção, o povo
dividia-se entre as lagrimas e a colera. Os olhos choravam a sorte
do rei, a sorte de todos! e o sangue pulava nas veias contra os réus
do assassinato—do rei? da nação? Envenenadores, salteadores,
burlões, homicidas!
Quando finalmente se soube que D. Pedro v tinha expirado (11 de
novembro de 1861), o clamor das coleras reunidas soltou-se,
extravagante, absurdo, cruel, mas inconscientemente justo, como é
sempre o povo em massa. O symbolo do Juizo-de-Deus, grosseira
expressão de um mysterio de electricidade popular, via-se no calor
com que pelas ruas, n’essas noites attribuladas, a turba corria
proclamando a sentença final de uma historia miseravel. Partiam ás
pedradas as vidraças dos palacios dos grandes, pediam as vidas
dos ministros, tombavam da sua carruagem e deixavam por morto
na estrada o typo dos amoucos do palacio. Todos eram réus.
Tinham envenenado o rei! Tinham envenenado tudo! Tinham
roubado, tinham vendido, tinham retalhado o povo, o reino, a
fazenda, e a nossa miseria era a consequencia dos seus crimes.
Agora este queria para si a corôa, aquelle queria vender-nos a
Castella: queriam todos a desgraça do povo. Havia ahi partidos?
Não; esse clamor provocado pela morte do rei martyr era uma
condemnação total, universal, espontanea! Era um ultimo adeus ao
ultimo dos reis amados, um dissolver da monarchia, em lagrimas
tristes, soluçadas!
Objectarão os homens seccos que umas companhias de tropa
bastaram para emmudecer as vozes desvairadas da turba. É
verdade. Nem de outro modo podia ser. As revoluções não saem
dos tumulos. As covas provocam lagrimas e arrancar de cabellos.
Mas o que á historia importa agora, não é a força d’essas turbas
afflictas, pois sabemos todos por que vias a nação chegara a sentir
cravada em si a estrella fatidica do rei; pois sabemos todos que
pessimismo intimo, que desesperança absoluta, que vaga tristeza,
que anemia organica, a historia de meio seculo nos trouxera. Não é
pois uma força que todos sabemos extincta, é o caracter do
protesto, é a natureza dos clamores condemnando a côrte e o
governo na sua totalidade, os partidos, os estadistas e a historia: é
esse caracter singular que tem para nós uma gravidade reveladora
...
As companhias de tropa acalmaram a turba; e quando se fez o
enterro, só já se ouvia o sussurro languido dos soluços. Cem mil
pessoas estavam nas ruas. Tambem o azul do céu de Lisboa
entristecera, tambem se cobrira de dó n’esse dia nublado e triste;
tambem chorava lagrimas, ennegrecendo com chuva o basalto das
calçadas. «Deus mandou a chuva, para até as pedras vestir de
luto!» diziam mulheres carpindo. E todos ouviam os soluços
murmurar, como se ouve o bater das azas quando passa nos ares
um bando. Eram esperanças, aladas, brancas, fugindo tambem,
voando!
NOTAS DE RODAPÉ:
[41] V. Hist. de Port. (3.ª ed.) ii, pag. 42-5.

IV
CONCLUSÕES
1.—AS QUESTÕES CONSTITUCIONAES
Com o finado rei desappareceram as irmans-da-Caridade. O

successor expulsou-as, liberalmente, sempre em nome da
liberdade! e seccas as lagrimas, esquecido o passado, rasgados os
crepes, tambem o throno se entregou nos braços da Regeneração.
Na côrte onde reinara o mysticismo devoto, reinava agora
catholicamente ao lado do monarcha, por esposa, a filha do rei
excommungado da Italia: sempre fieis á religião! N’um systema de
fórmulas, mais do que nunca vasias da realidade, liberalismo,
catholicismo, que são? Hypocrisias inconscientes de quem não tem
na alma a força, nem na mente a capacidade de conceber e
defender idéas. Velhos bordões rhetoricos, politicos, ou como
escoras de madeira carunchosa, pintada para illudir, aguentando o
edificio desconjuntado.
Em 68, como já vimos, houve a sombra de uma revolução contra
a sombra de uma tyrannia. Embuçada logo ao nascer pelo duque
d’Avila, veiu com o tempo achar no bispo de Vizeu o seu definidor.
Singular povo! singular revolução! Já se pensou bem no valor
psychologico d’esse movimento? Que reclamava, que promettia,
que applaudia? Negação tudo.
Nem uma só palavra affirmativa. «Moralidade, economias!» Esse
programma patenteava o vasio, porque nenhum partido jámais
prégou a corrupção nem o desperdicio. Mas praticavam-nos ambos,
os regeneradores? Era pois uma questão de homens, nada mais.
Não paremos, comtudo, aqui. O pessimismo constitucional do
caracter portuguez via tambem no Bispo outra cousa: um bota-
abaixo! Os derrocadores foram os unicos homens acclamados pelo
povo, desde que em 1820 se declarou a crise: por esta razão
simples de o povo ter a consciencia da podridão universal. Além
d’estas negações que havia? No Porto, uns mercieiros lesados pelo
imposto do consumo, que se cotisaram para fazer arruaças; em
Lisboa uns conspiradores platonicos que, apesar de já terem
distribuido entre si os cargos da republica, se declararam satisfeitos
com a quéda da Regeneração. O duque d’Avila preenchia bem o
lugar de porta-voz da revolução! N’esta éra nova iniciada, o duque
tornou-se a bomba-de-choque para amortecer a violencia das
transições.
Veio a revolução de Hespanha complicar as cousas de um modo
subito; veiu a guerra brazileira, baixando o cambio, seccar o rio de
dinheiro que annualmente vasava no Thesouro para o alimentar a
elle e nos sustentar a nós. Aggravaram-se as cousas, cresceram os
perigos: a nação pedia um demolidor! Bota-abaixo! Mas como
ninguem sabia que pôr em lugar do existente, o sentimento
acclamador do Bispo era uma gritaria van de gente possidonea, e
consolava os conservadores vingados. Demolir é facil, mais duro o
construir. Derrubar paredes arruinadas, qualquer hombro o póde;
mas levantar novos muros com os materiaes velhos, ninguem. E
que nova materia-prima existia? Nenhuma. Homens? Zero. Idéas?
Menos. O fundo do sacco das fórmulas liberaes era pó. Nós
tinhamos já vasado tudo; e depois de tudo isso já Rodrigo,
mostrando o avesso com uma careta, como um arlequim n’um
tablado de feira, viera dizer, «meus senhores, peça nova!»
Agora os discipulos, seguindo o mestre, voltavam. Pois que
querem? Falta ainda alguma cousa á Liberdade? Pois ha, devéras,
omissão? Querem reformados os Pares? Porque não? Suffragio
universal? Tambem. E viu-se os conservadores fazerem o que a
revolução não fizera; viu-se alargar o direito de suffragio, sem que
longas, prévias campanhas o exigissem. E ninguem o exigia, porque
já passara o tempo em que se esperava nas alterações de fórmulas.
E fizeram-no os conservadores, porque tinham visto em França
Napoleão dar-se bem com isso; e sabiam que quantos mais
camponios votassem, maior seria o poder formal—e positivo, pois
fórmulas, apparencias são tudo—de cada um dos barões ruraes, de
cada um dos senhores da finança que nas cidades compram a
dinheiro os votos da plebe. Desde que no espirito d’essas plebes a
loucura setembrista se acabara, que perigo havia em lhes dar a
soberania? Nenhum, de facto; só a vantagem de bater o inimigo
reformista com as suas armas, e consagrar mais uma conquista da
liberdade.
Este facto curioso mostra ao critico uma das feições da apathica
physionomia nacional. O leitor sabe que 33 não saíu do sangue da
nação, como um 89. Foi uma conquista á mão-armada, que
substituiu a classe governativa do reino. No decurso da historia que
narrámos, o facto da separação do governo e do povo cresceu com
o descredito do primeiro e com a miseria do segundo, até que
Rodrigo veiu confessar que «comprando-se feitos deputados e
casas» era tudo uma comedia; até que o povo, percebendo-o, poz
de banda o bacamarte de guerrilheiro, deitando-se á enxada e
esperando em casa o politico, para lhe pedir estradas, isenções de
recruta, e uns cobres pelo dia perdido com a Urna. Consummado
este accordo tacito, houve logo paz e liberdade. Os politicos
bulharam de palavras: já não havia guerrilhas; e o povo deixou fazer
leis sobre leis em Lisboa, sem dar por isso. Cada qual vive como
gosta, e Portugal é verdadeiramente agora aquelle torrão de
assucar de que falava o corregedor de Vizeu. Falstaff e Prudhomme
fazem bem as suas digestões, e consideram este canto occidental
do mundo o modêlo das nações livres.
E é, com effeito, é. Como não haveria liberdade, se não ha
opiniões divergentes? Viu-se já tamanha paz? tão grande accordo?
Nem póde deixar de haver paz, concordia, liberdade, entre todos os
portuguezes, desde que todos elles, como uma boa população de
provincianos, chegando ao cumulo da sabedoria salomonica—
Vanitas vanitatum! descobriram que no mundo ha só dois homens,
Quixote e Sancho, e que só o segundo é credor de applauso.
Opiniões, partidos, paixões, esperanças? Fumo, meus amigos.
Nobreza, justiça, virtude, heroismo? Poesia! Espantado com a
nossa liberdade, dizia-me alguem uma vez, perante a sala das
côrtes: «Veinte padres, amigo mio! veinte curas ... y todos liberales!»
Com effeito, n’este «jardim da Europa á beira-mar plantado», até o
clero, combatente em França, na Belgica, na Allemanha, é liberal.
«Todos liberales!» Alguns extasiam-se com isto; outros, sem
patriotismo nenhum, acham que esta liberdade prova um
entorpecimento deploravel da intelligencia e do caracter. São modos
de vêr differentes.
O leitor já sabe que as populações, indifferentes, alheias ao
governo do paiz, só reclamam que elle lhes dê obras-publicas e lhes
torne o mais doce possivel o recrutamento. Enriquecendo, pouco se
lhes dá o resto. Nas aldeias são politicos os empregados, nas
cidades os bachareis: por toda a parte os que vivem ou aspiram a
viver do Thesouro. Os trabalhadores, os rendeiros, os pequenos
proprietarios «não querem saber d’isso» e no fundo,
instinctivamente, desprezam o politico pela razão simples de o
verem depender d’elle para os votos. Desprezam, mas não lhes
passa pela cabeça o supprimil-o. Para que? Isso não rende; e
entretanto arderia a ceara. Até ahi chega o instincto, e instrucção
não têem nenhuma.
Mas não é raro, antes commum, e n’um sentido até normal,
verem-se populações, embora soberanas de direito, viverem
passivamente sob o governo de minorias, ou aristocraticas ou
burguezas, a que a riqueza ou a illustração dão a força. Commum é
tambem que n’essas classes directoras exista a consciencia do
facto, e por systema ou interesse se procure manter esse estado
social: foi o pensamento do doutrinarismo em França, na Hespanha,
e foi até entre nós a idéa dos cabralistas. Mas desde que a
democracia vaga e sentimental de 48 destruiu similhante plano,
condemnando o machiavelismo liberal dos seus authores, o facto,
embora contestado, manteve-se por outras fórmas em toda a parte
onde essas classes directoras tinham, com a consciencia da sua
força, a illustração bastante para governar. D’ahi saíu o cezarismo
francez. Ora o triste em Portugal, e acaso o primeiro motivo da
physionomia singular da nação, é a ignorancia, ou, peior ainda, a
sciencia desordenada nas classes medias. Todos sabem de que
genero é a educação secundaria; todos sabem o que é a instrucção
superior, em tudo o que não diz respeito ás profissões technicas
(medicina, engenharia, etc.) cuja importancia é para o nosso caso
subalterna. Com tal ensino se cria em Coimbra um viveiro de
estadistas que annualmente cáem sobre Lisboa pedindo fama e
empregos. O proprietario é em geral illetrado, o capitalista é
brazileiro. A fortuna dos ricos, a sorte dos pobres, vão pois guiados
por uma cousa peior ainda do que a ignorancia—a sciencia falsa,
pedante sempre.
Que alguem se atreva a dizer a sombra de uma verdade e será
condemnado. Que alguem se lembre de bolir n’um qualquer dos
idolos do tempo, e será apedrejado—liberalmente! Por isso a
liberdade que provém da apathia parece ao critico o symptoma do
contrario da vida: da verdadeira liberdade forte, independente, na
concorrencia de opiniões conscientes e sábias. Por isso nós
apresentamos caracteres singulares. Leiam-se os jornaes, ouçam-
se os discursos. Ninguem fala mais de papo, desculpem a
expressão. De quê? De tudo. Os Pico-de-Mirandola, senhores de si,
anafados, satisfeitos, sempre na rua, sempre verbosos, com as
cabecinhas álerta, a resposta prompta, a fórmula breve, um andar
miudinho de pedante, um livrinho azul debaixo do braço se não são
janotas, nos miolos a consciencia do seu saber, da verdade
definitiva da «sciencia moderna», uma grande prosapia ingenua,
uma grande segurança e entono: os Pico-de-Mirandola, que sejam
conservadores ou demagogos, deputados da direita ou rabiscadores
de jornaes esquerdos, têem uma physionomia commum. A patria
são elles; a sciencia sabem-na toda, a moderna. Sómente uns
acham que é moderna a que já governa, outros fossil a de hoje: só
verdadeira a de ámanhan, quando elles derem a lei!
Pêccos fructos de uma arvore contaminada, se dão um passo
cáem. Um dos phenomenos curiosos em Portugal é o devorar dos
homens pelo governo. Hoje sobem, ámanhan somem-se, corridos,
desprezados. Porque? porque a arvore, secca, apenas tem vida
para reconhecer o seu definhar, para desprezar os que no seu
pedantismo ingenuo, mais ainda do que na sua corrupção,
successivamente se lhe seguram aos ramos. Outro phenomeno é a
facilidade com que a opinião muda n’essas classes directoras da
sociedade portugueza. Como um catavento, sobre um pião giratorio,
batido, movido pela brisa leve, assim anda o juizo dos homens
graves. Se lhes falta o alicerce do saber, e mais ainda o alicerce
social de raizes lançadas pelo meio das classes vivas da sociedade!
Se são um rifacimento, uma superfetação politica em um povo que

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Molecular Biology of Aging

P.Hemachandra Reddy (Eds.)

Biology physiology and molecular biology of weeds 1st

Molecular Basis of Nutrition and Aging: A Volume in the

Systems Biology Methods in Molecular Biology 2745

Diagnostic Molecular Biology Chang-Hui Shen

Fundamentals of Molecular Structural Biology 1st

International Review of Cell and Molecular Biology 1st

Molecular and Cellular Biology of Viruses 1st Edition

Molecular Biology Structure and Dynamics of Genomes and

First edition 2017

Copyright © 2017 Elsevier Inc. All rights reserved.

For information on all Academic Press publications

Publisher: Zoe Kruze

P. Michael Conn unexpectedly passed away

For nearly 40 years, he was a leading scientist in elucidating the function

Contemporary Endocrinology. Dr. Conn was also a member of numerous study

The biology of aging is a topic that has long

a cascade of cytokines, insulin resistance, hyperglycemia, and altered mito-

catalase targeted to mitochondria (mCAT), peroxisomes (pCAT), and the

at a pathological level, changes in cellular homeostasis lead to the modulation

Clinical Aspects of Glucose

growth factors. Sarcopenia appears to be a dynamic process and is potentially revers-

4. CHRONIC KIDNEY DISEASE

known as sarcopenia. The reported prevalence of sarcopenia in persons over

6. THE FRAILTY SYNDROME

in a group of older adults in whom obesity is accompanied by sarcopenia and

8. EXERCISE AND BRAIN METABOLISM

bioenergetics, decreased apoptotic signaling, activation of mitochondrial

9. PHARMACOLOGICAL TREATMENTS FOR DEMENTIA

the progression, or cure AD continues. To date, most proposed treatments

10. REDUCING CHRONIC DISEASE BURDEN

3. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney

Therapeutic Strategies for

oxidation of metabolites by Krebs’s cycle and β-oxidation of fatty acids.

overproduction of ROS in the cell. Then, pharmacologic strategies trans-

2. GLOBAL PREVALENCE OF METABOLIC DISORDERS

population is suffering from MetS.58 A number of previous studies estimated

3. STRUCTURE AND FUNCTIONS OF MITOCHONDRIA

Esquecemos, n’estes successivos relances, o throno. E entretanto

Per me si vá nella citá dolente ...

No largo do palacio o povo espesso, na sua afflicção, dividia-se

[41] V. Hist. de Port. (3.ª ed.) ii, pag. 42-5.

Com o finado rei desappareceram as irmans-da-Caridade. O

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