Aging. Oxidative Stress and Dietary Antioxidants

289 Pages·2014·17.06 MB·English

by  Victor Preedy (Eds.)

AGING: OXIDATIVE
STRESS AND
DIETARY
ANTIOXIDANTS
Edited by
V r. P
ictor reedy
King’s College London,
London, UK
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Contributors
Shadwan Alsafwah Division of Cardiovascular Diseases, Victor Farah Division of Cardiovascular Diseases, University
University of Tennessee Health Science Center, Memphis, of Tennessee Health Science Center, Memphis, TN, USA
TN, USA Antonio Garcia-Rios Lipids and Atherosclerosis Unit,
Fawaz Alzaid Diabetes and Nutritional Sciences Division, IMIBIC/Reina Sofia University Hospital/University of
School of Medicine, King’s College London, Franklin- Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion
Wilkins Building, London, UK (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain
B. Andallu Sri Sathya Sai Institute of Higher Learning, Anan- M. Garrido Department of Physiology (Neuroimmunophys-
tapur, A.P., India iology and Chrononutrition Research Group), Faculty of
Science, University of Extremadura, Badajoz, Spain
Raza Askari Division of Cardiovascular Diseases, University
of Tennessee Health Science Center, Memphis, TN, USA Jeffrey S. Greiwe Ausio Pharmaceuticals, LLC, Cincinnati,
Ohio, USA
Sylvette Ayala-Peña Department of Pharmacology and Toxi-
cology, University of Puerto Rico Medical Sciences Campus, Erika Hosoi Research Team for Promoting the Independence
San Juan, Puerto Rico of the Elderly, Tokyo Metropolitan Institute of Gerontology,
Tokyo, Japan
Mario Barbagallo Geriatric Unit, Department of Internal
Medicine DIBIMIS, University of Palermo, Italy Chao A. Hsiung Institute of Population Health Sciences,
National Health Research Institutes, Miaoli County, Taiwan
I.F.F. Benzie Department of Health Technology & Informat-
ics, The Hong Kong Polytechnic University, Hung Hom, Chih-Cheng Hsu Institute of Population Health Sciences,
Kowloon, Hong Kong National Health Research Institutes, Miaoli County, Taiwan
Syamal K. Bhattacharya Division of Cardiovascular Dis- Nikolay K. Isaev Lomonosov Moscow State University, A.N.
eases, University of Tennessee Health Science Center, Belozersky Institute of Physico-Chemical Biology, Moscow,
Memphis, TN, USA Russia
Brunna Cristina Bremer Boaventura Department of Nutri- Akihito Ishigami Molecular Regulation of Aging, Tokyo Met-
tion, Health Sciences Center, Federal University of Santa ropolitan Institute of Gerontology, Tokyo, Japan
Catarina, Campus Trindade, Florianópolis/SC, Brazil Hiroyasu Iso Public Health, Department of Social and Envi-
Corinne Caillaud Exercise Physiology and Nutrition, Faculty ronmental Medicine, Graduate School of Medicine, Osaka
of Health Sciences, University of Sydney, Lidcombe NSW, University, Suita, Osaka, Japan
Australia Richard L. Jackson Ausio Pharmaceuticals, LLC, Cincinnati,
Antonio Camargo Lipids and Atherosclerosis Unit, IMIBIC/ Ohio, USA
Reina Sofia University Hospital/University of Cordoba, and N.N. Kang Department of Nutritional Sciences, University of
CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Toronto, Toronto, Canada
Instituto de Salud Carlos III, Córdoba, Spain
Nadezhda A. Kapay Department of Brain Research, Research
José Eduardo de Aguilar-Nascimento Department of Center of Neurology, Russian Academy of Medical Sciences,
Surgery, Julio Muller University Hospital, Federal Univer- Pereulok Obukha 5, Moscow, Russia
sity of Mato Grosso, Cuiaba, Mato Grosso, Brazil
Jozef Kedziora Department of Biochemistry, Collegium
Javier Delgado-Lista Lipids and Atherosclerosis Unit, Medicum UMK in Bydgoszcz, Poland
IMIBIC/Reina Sofia University Hospital/University of Kornelia Kedziora-Kornatowska Department and Clinic of
Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion
Geriatrics, Collegium Medicum UMK in Bydgoszcz, Poland
(CIBEROBN), Instituto de Salud Carlos III, Córdoba,
Hirofumi Koyama Department of Advanced Aging Medi-
Spain
cine, Chiba University Graduate School of Medicine,
Patricia Faria Di Pietro Department of Nutrition, Health Sci- Inohana, Chuo-ku, Chiba, Japan
ences Center, Federal University of Santa Catarina, Campus
Xi-Zhang Lin Department of Internal Medicine, College of
Trindade, Florianópolis/SC, Brazil
Medicine, National Cheng Kung University, Tainan, Taiwan
Dwight A. Dishmon Division of Cardiovascular Diseases,
Xiaoyan Liu University of Texas Health Science Center at San
University of Tennessee Health Science Center, Memphis,
Antonio, Department of Cellular and Structural Biology, San
TN, USA
Antonio, TX, USA, and The Preclinical Medicine Institute of
Ligia J. Dominguez Geriatric Unit, Department of Internal Beijing, University of Chinese Medicine, Chao Yang District,
Medicine DIBIMIS, University of Palermo, Italy Beijing, China
ix
x CONTRIBUTORS
Jose Lopez-Miranda Lipids and Atherosclerosis Unit, A.B. Rodríguez Department of Physiology (Neuroimmuno-
IMIBIC/Reina Sofia University Hospital/University of physiology and Chrononutrition Research Group), Faculty
Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion of Science, University of Extremadura, Badajoz, Spain
(CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain Sergio A. Rosales-Corral Centro de Investigacion Biomedica
Konstantin G. Lyamzaev Lomonosov Moscow State Univer- de Occidente, Instituto Mexicano Del Seguro Social, Guada-
sity, A.N. Belozersky Institute of Physico-Chemical Biology, lajara, Jalisco, Mexico, and University of Texas Health
Moscow, Russia Science Center at San Antonio, Department of Cellular and
Structural Biology, San Antonio, TX, USA
Lucien C. Manchester University of Texas Health Science
Center at San Antonio, Department of Cellular and Struc- Joanna Rybka Department of Biochemistry, Collegium
tural Biology, San Antonio, TX, USA Medicum UMK in Bydgoszcz, Poland, and Life4Science
Foundation, Bydgoszcz, Poland
Koutatsu Maruyama Department of Basic Medical Research
and Education, Ehime University Graduate School of Medi- Kyoko Saito Research Team for Promoting the Independence
cine, Shitsukawa, Toon, Ehime, Japan of the Elderly, Tokyo Metropolitan Institute of Gerontology,
Tokyo, Japan
M.S. Mekha Sri Sathya Sai Institute of Higher Learning,
Anantapur, A.P., India Dipayan Sarkar Department of Plant Sciences, Loftsgard
Hall, NDSU, Fargo, ND, USA
Maria Grazia Modena University of Modena and Reggio
Rahul Saxena Department of Biochemistry, School of Medical
Emilia, Italy
Sciences & Research, Sharda University, Greater Noida (UP),
Suhaila Mohamed Institute of BioScience, Universiti Putra
India
Malaysia, Serdang, Selangor, Malaysia
Irina N. Scharonova Department of Brain Research, Research
Daichi Morikawa Department of Advanced Aging Medi-
Center of Neurology, Russian Academy of Medical Sciences,
cine, Chiba University Graduate School of Medicine, Chuo-
Pereulok Obukha 5, Moscow, Russia
ku, Chiba, Japan, and Department of Orthopaedics, Juntendo
Richard J. Schwen Ausio Pharmaceuticals, LLC, Cincinnati,
University Graduate School of Medicine, Bunkyo-ku, Tokyo,
Ohio, USA
Japan
Kalidas Shetty Department of Plant Sciences, Loftsgard Hall,
Hidetoshi Nojiri Department of Orthopaedics, Juntendo
NDSU, Fargo, ND, USA
University Graduate School of Medicine, Bunkyo-ku, Tokyo,
Shuichi Shibuya Department of Advanced Aging Medicine,
Japan
Chiba University Graduate School of Medicine, Chuo-ku,
Vinood B. Patel Department of Biomedical Science, Faculty of
Chiba, Japan
Science & Technology, University of Westminster, London, UK
Takahiko Shimizu Department of Advanced Aging Medi-
Francisco Perez-Jimenez Lipids and Atherosclerosis Unit,
cine, Chiba University Graduate School of Medicine,
IMIBIC/Reina Sofia University Hospital/University of
Inohana, Chuo-ku, Chiba, Japan
Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion
R.I. Shobha Sri Sathya Sai Institute of Higher Learning,
(CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain
Anantapur, A.P., India
Pablo Pérez-Martinez Lipids and Atherosclerosis Unit,
David Simar Inflammation and Infection Research, School of
IMIBIC/Reina Sofia University Hospital/University of
Medical Sciences, Faculty of Medicine, University of New
Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion
South Wales, Sydney NSW, Australia
(CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain
P.M. Siu Department of Health Technology & Informatics,
Olga V. Popova Department of Brain Research, Research
The Hong Kong Polytechnic University, Hung Hom,
Center of Neurology, Russian Academy of Medical Sciences,
Kowloon, Hong Kong
Pereulok Obukha 5, Moscow, Russia
Vladimir G. Skrebitsky Department of Brain Research,
Ananda S. Prasad Department of Oncology, Wayne State
Research Center of Neurology, Russian Academy of Medical
University School of Medicine and Barbara Ann Karmanos
Sciences, Pereulok Obukha 5, Moscow, Russia
Cancer Institute, Detroit, MI, USA
Vladimir P. Skulachev Lomonosov Moscow State Univer-
Victor R. Preedy Diabetes and Nutritional Sciences Division, sity, A.N. Belozersky Institute of Physico-Chemical Biology,
School of Medicine, King’s College London, Franklin- Moscow, Russia
Wilkins Building, London, UK
John M. Starr Centre for Cognitive Ageing and Cognitive
C.U. Rajeshwari Sri Sathya Sai Institute of Higher Learning, Epidemiology, Edinburgh, United Kingdom
Anantapur, A.P., India
Robert J. Starr School of Medicine and Dentistry, Polwarth
A.V. Rao Department of Nutritional Sciences, University of Building, Foresterhill, Aberdeen, United Kingdom
Toronto, Toronto, Canada
Elena V. Stelmashook Department of Brain Research,
L.G. Rao Department of Medicine, St Michael’s Hospital and Research Center of Neurology, Russian Academy of Medical
University of Toronto, Toronto, Canada Sciences, Pereulok Obukha 5, Moscow, Russia
Russel J. Reiter University of Texas Health Science Center at Dun-Xian Tan University of Texas Health Science Center at
San Antonio, Department of Cellular and Structural Biology, San Antonio, Department of Cellular and Structural Biology,
San Antonio, TX, USA San Antonio, TX, USA
CONTRIBUTORS xi
M.P. Terrón Department of Physiology (Neuroimmuno- Karl T. Weber Division of Cardiovascular Diseases, Univer-
physiology and Chrononutrition Research Group), sity of Tennessee Health Science Center, Memphis, TN, USA
Faculty of Science, University of Extremadura, Badajoz, I-Chien Wu Institute of Population Health Sciences, National
Spain
Health Research Institutes, Miaoli County, Taiwan
Carlos A. Torres-Ramos Department of Physiology, Univer- Tetsuji Yokoyama Department of Human Resources Devel-
sity of Puerto Rico Medical Sciences Campus, San Juan, opment, National Institute of Public Health, Saitama, Japan
Puerto Rico
Elena M. Yubero-Serrano Lipids and Atherosclerosis Unit,
Floor van Heesch Division of Pharmacology, Utrecht Insti- IMIBIC/Reina Sofia University Hospital/University of
tute for Pharmaceutical Sciences (UIPS), Faculty of Science, Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion
Utrecht University, Utrecht, The Netherlands (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain
S. Wachtel-Galor Department of Health Technology & Infor- Dmitry B. Zorov Lomonosov Moscow State University, A.N.
matics, The Hong Kong Polytechnic University, Hung Hom, Belozersky Institute of Physico-Chemical Biology, Moscow,
Kowloon, Hong Kong Russia
Preface
In the past few decades there have been major In the present volume, Aging: Oxidative Stress and
advances in our understanding of the etiology of disease Dietary Antioxidants, holistic information is imparted
and its causative mechanisms. Increasingly it is becom- within the structured format of two main sections:
ing evident that free radicals are contributory agents:
1. Oxidative Stress and Aging
either to initiate or propagate the pathology or add to
2. Antioxidants and Aging
an overall imbalance. Furthermore, reduced dietary
antioxidants can also lead to specific diseases and pre- The first section on Oxidative Stress and Aging cov-
clinical organ dysfunction. On the other hand, there is ers the basic biology of oxidative stress, from molecular
abundant evidence that dietary and other naturally biology to physiological pathology. Topics include mark-
occurring antioxidants can be used to prevent, amelio- ers of frailty, skin aging, cardiovascular disease, the liver,
rate or impede such diseases. The science of oxidative arthritis and diabetes. The second section, Antioxidants
stress and free radical biology is rapidly advancing and and Aging, covers cellular and molecular processes of
new approaches include the examination of polymor- vegetarian diets, enteral nutrition, natural antioxidants
phism and molecular biology. The more traditional sci- in foods and the diet, herbs and spices, coenzyme Q10,
ences associated with organ functionality continue to be vitamins C and D, S-equol, zinc, magnesium, trypto-
explored but their practical or translational applications phan, melatonin-enriched foods and lycopene. There is
are now more sophisticated. also material on the aging processes, age-related patholo-
However, most textbooks on dietary antioxidants do gies and organ systems, including menopause, physical
not have material on the fundamental biology of free performance, skin, bone and osteoporosis, the brain and
radicals, especially their molecular and cellular effects neurodegeneration, the cardiovascular system, diabetes,
on pathology. They may also fail to include material muscle, arthritis, inflammation, mitochondria and leuko-
on the nutrients and foods which contain antioxidative cytes. The aforementioned provide a detailed framework
activity. In contrast, most books on free radicals and for understanding the relationships between aging, oxi-
organs disease have little or no text on the usage of natu- dative stress and dietary components. However, more sci-
ral antioxidants. entifically vigorous trials and investigations are needed
The series Oxidative Stress and Dietary Antioxi- to determine the comprehensive properties of many of
dants aims to address the aforementioned deficiencies in these antioxidants, food items or extracts, as well as any
the knowledge base by combining in a single volume the adverse properties they may have.
science of oxidative stress and the putative therapeutic The series is designed for dietitians and nutrition-
usage of natural antioxidants in the diet, its food matrix ists, and food scientists, as well as health care workers
or plants. This is done in relation to a single organ, dis- and research scientists. Contributions are from leading
ease or pathology. These include cancer, addictions, national and international experts including those from
immunology, HIV, aging, cognition, endocrinology, world-renowned institutions.
pregnancy and fetal growth, obesity, exercise, liver, kid-
ney, lungs, reproductive organs, gastrointestinal tract, Professor Victor R. Preedy,
oral health, muscle, bone, heart, kidney and the CNS. King’s College London
xiii
C H A P T E R
1
Oxidative Stress and Frailty: A Closer Look at
the Origin of a Human Aging Phenotype
I-Chien Wu, Chao A. Hsiung, Chih-Cheng Hsu
Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan
Xi-Zhang Lin
Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
List of Abbreviations
INTRODUCTION
ATM ataxia-telangiectasia mutated
ATR ataxia telangiectasia and Rad3-related Oxidative stress, defined as a disturbance in the
BER base excision repair
prooxidant-antioxidant balance leading to oxidative
BubR1 mitotic checkpoint serine/threonine-protein kinase BUB1 beta
damage,1 has a key role in aging. More importantly, an
CDC25 cell-division cycle 25
CHK1 checkpoint kinase 1 increasing amount of evidence suggests that oxidative
CHK2 checkpoint kinase 2 stress acts causally in the pathogenesis of numerous
CREBH cyclic AMP response element binding protein hepatocyte age-dependent and age-related chronic diseases. Over
CuZnSOD copper/zinc superoxide dismutase (SOD1)
the past few decades, frailty has been increasingly
DDR DNA-damage response
recognized as a major health problem for older adults.
DHEA dehydroepiandrosterone
DHEAS dehydroepiandrosterone sulfate As a distinct pathologic state, frailty contributes to
eNOS endothelial nitric oxide synthase numerous poor health outcomes independently of dis-
ER endoplasmic reticulum eases and disability, and it is characterized by clinical
IκB inhibitor of kappa B
presentations which are well defined and easily iden-
IKK1 inhibitor of nuclear factor kappa-B kinase subunit alpha
tifiable. Because of years of research, we have a b etter
IKK2 inhibitor of nuclear factor kappa-B kinase subunit beta
IL-2 interleukin-2 understanding of the system-level pathogenesis of
IL-6 interleukin-6 frailty. It is becoming clear that frailty may have its ori-
IL-8 interleukin-8 gin in the fundamental aging process. Oxidative stress
IRS-1 insulin receptor substrate-1
could play a crucial role in the cellular-level pathogen-
JNK kinases c-jun N-terminal kinases
esis of frailty. In this chapter, the relationship between
MDA malondialdehyde
MnSOD Mn-superoxide dismutase (SOD2) oxidative stress and frailty is delineated. To address
MPT mitochondrial permeability transition this issue comprehensively, we attempt to integrate
mtDNA mitochondrialDNA the results from human studies and model organism
MTH1 mutT human homolog 1
experiments. After a brief overview of oxidative stress
NADPH reduced form of nicotinamide adenine dinucleotide phosphate
in aging, the better known system-level abnormalities
NER nucleotide excision repair
NF-κB nuclear factor-κB associated with the frailty syndrome are introduced.
nNOS neuronal nitric oxide synthase We then discuss whether and how oxidative stress
NUDT5 Nudix (nucleoside diphosphate linked moiety X)-type motif 5 at cellular levels causes frailty. Finally, we present a
8-OHdG 8-hydroxy-2’-deoxyguanosine
model of frailty pathogenesis incorporating the cur-
ROS reactive oxygen species
rent understanding of frailty at the levels of molecules,
TNF-α tumor necrosis factor-α
WRN Werner protein cells, organs, and systems.
3
Aging
http://dx.doi.org/10.1016/B978-0-12-405933-7.00001-9 © 2014 Elsevier Inc. All rights reserved.
4 1. OXIDATIVE STRESS AND FRAILTY
FRAILTY
OXIDATIVE STRESS AND AGING
Definition
Aging represents ‘progressive deterioration d uring
the adult period of life that underlies an increasing As an extreme phenotype of human aging, frailty is a
vulnerability to challenges and a decreasing ability of state of increased vulnerability with a decreased ability to
an organism to survive’.2 The deterioration is due to maintain homeostasis.11 Although it can be compounded
progressive accumulation of unrepaired damage and by disease or disability, this vulnerability is primarily
has the following core features: intrinsicality, univer- age related and is caused by a reduced reserve capac-
sality, progressiveness and irreversibility, and it is ity of interconnected physiologic systems that adapt
genetically programmed.2 The literature suggests that to stressors, leading to a breakdown of homeostasis.11
oxidative stress is the major cause of somatic damage.2 Despite the lack of a clear consensus, there are several
Denham Harman proposed the free-radical theory of operational definitions of frailty in the literature; these
aging in 1956, which states that aging results from ran- definitions are based on different theories on the under-
dom deleterious damage to tissue by free radicals. His lying causes of frailty. Comprehensive reviews of the
theory is among the most acknowledged theories of definition of frailty are beyond the scope of this a rticle
aging.3 Since then, an increasing amount of evidence and can be found elsewhere.11 Two commonly used defi-
has indicated that oxidative stress increases with age nitions are discussed.
and contributes to numerous age-related pathologic According to the operational definition of frailty phe-
processes.4 notype proposed by Fried et al, a person is considered
The laboratory model organism experiments pro- frail if three or more of the following five criteria are
vide direct evidence that supports the importance of present: unintentional weight loss, muscle weakness,
oxidative stress in aging. Numerous mutations that slow walking speed, low physical activity, and exhaus-
extend the lifespan of yeast, worms, flies, and mice tion (Table 1.1).12 Older adults with one or two of the
have elevated antioxidant defenses and reduced oxi- criteria are considered prefrail, whereas those without
dative stress. In yeast, major mutations that extend any criteria are considered robust.12 Being the commonly
replicative and/or chronologic lifespans involve cited operational definition in frailty research, the frailty
Ras-AC-PKA or Tor-Sch9 signaling.5 Lifespan exten- phenotype is based on the assumption that frailty arises
sion associated with altered activities in these path-
ways has been shown to require the antioxidant enzyme
superoxide dismutase (Mn-SOD), which scavenges TABLE 1.1 Frailty Phenotype According to Fried et al12 a
superoxide free radicals.5 In Caenorhabditis elegans,
Frailty
lifespan extension can be achieved by reducing the
Criteria Characteristic Measure
activities of insulin/IGF-like signaling pathways
(e.g. age-1 and daf-2 mutants), thereby activating the 1 Weight loss >10 lbs lost unintentionally in prior
Forkhead FoxO transcription factor daf-16.6 Active (unintentional) year (reported)
DAF-16 promotes the transcription of major anti- Shrinking
oxidant genes, including genes encoding catalases,
Sarcopenia
MnSOD, and CuZnSOD. These antioxidants are nec-
essary for lifespan extension in these mutant worms.6 2 Muscle weakness Grip strength below cutoff value,12
adjusted for gender and body mass
As in yeast and worms, insulin/IGF1 signaling path-
index
ways affect longevity in mice. Acting downstream
of IGF receptors, p66Shc enhances production of 3 Exhaustion Answering ‘moderate or most of the
time’ to ‘I feel that everything I do
mitochondrial reactive oxygen species (ROS) by cat- Poor endurance
is an effort’ or ‘I cannot get going’.
alyzing redox reactions, which yield hydrogen per-
oxide.7 Deleting p66Shc in mice results in decreased 4 Slow walking Walking speed below cutoff value,12
speed based on time to walk 15 feet,
oxidative stress, which correlates with an increased
adjusting for gender and standing
lifespan.7 height.
Results of human studies are congruent with the find-
5 Low physical Kilocalories expended per week
ings of model organism experiments. An a ge-related
activity below cutoff value (383 kcal/wk in
increase in oxidative damage to macromolecules men; 270 kcal/wk in women)12
has been observed in humans.8 DNA variants in the
aAn individual is considered frail if three or more of the five criteria are present. People
genes that modulate oxidative stress were linked to
with one or two of the criteria are considered prefrail, whereas those without any criteria
longevity.9,10 are considered robust.
1. OXIDATIVE STRESS AND AGING
FRAILTy 5
from unique pathologic processes that are independent medicine. In contrast to the younger population, the
of diseases and disability. Previous research has shown older population is characterized by a greater variation
that the frailty phenotype is able to predict adverse in health status, outcomes, or response to therapy, which
health outcomes independently of disease and disability, cannot be explained by age and disease alone.16 As a
and frail older adults are at greater risk compared with measure of biologic age, frailty permits superior risk
prefrail adults.12 M oreover, there are clues that specific prediction in older adults compared with chronologic
pathophysiologic processes lead to the development of age and diseases. Regardless of the o perational defi-
frailty in the absence of disease.13 nitions used, it has been repeatedly demonstrated
Unlike the Fried definition, Rockwood et al hypoth- that, compared with age and chronic diseases, frailty
esized that frailty arises from the accumulation of stratification is more strongly associated with an older
potentially unrelated diseases, subclinical dysfunctions, adult’s risk of poor outcomes, including infections,
and disability, and represents an intermediary mecha- disabilities, institutionalization, and death.12,15
nism linking these conditions to poor health outcomes.14
The concept of frailty being a distinct pathologic state,
Organ and System Abnormalities Associated
separate from diseases and disability, is less emphasized.
with Frailty
Frailty is defined by a frailty index, which is created
by counting the number of health deficits in an older As described, frailty is caused by abnormal inter-
adult. The health deficits can be any clinical symptom, connected physiologic systems, which are essential for
sign, disease, disability, laboratory, imaging, or other maintaining homeostasis. The key physiologic systems
examination abnormality.14 Using this definition, frailty currently known to be involved in frailty pathogenesis
is associated with poor health outcomes in different include the musculoskeletal system (skeletal muscle),
populations.15 metabolism (adiposity, insulin activity), immune system
(inflammation), endocrine system (insulin-like growth
factor-1, dehydroepiandrosterone sulfate, and testoster-
Clinical Significance
one), and autonomic nervous system (Fig. 1.1).11
The prevalence of frailty is high. It is estimated that a
minimum of 10–25% of people aged 65 years and older Sarcopenia
(and 30–45% of those aged 85 years and older) are frail.12 Body composition changes with age. An age-related
Frailty is the core issue in healthy aging and geriatric loss of skeletal muscle mass is termed sarcopenia.17
FIGURE 1.1 Organ and system
(cid:43)(cid:82)(cid:80)(cid:72)(cid:82)(cid:86)(cid:87)(cid:68)(cid:86)(cid:76)(cid:86)(cid:3) abnormalities associated with frailty.
(cid:41)(cid:85)(cid:68)(cid:76)(cid:79)(cid:87)(cid:92)(cid:3)(cid:51)(cid:75)(cid:72)(cid:81)(cid:82)(cid:87)(cid:92)(cid:83)(cid:72)
(cid:37)(cid:85)(cid:72)(cid:68)(cid:78)(cid:71)(cid:82)(cid:90)(cid:81) As a human aging phenotype, frailty
is characterized by an increased like-
lihood of homeostasis breakdown.
(cid:44)(cid:81)(cid:86)(cid:88)(cid:79)(cid:76)(cid:81)(cid:3)(cid:85)(cid:72)(cid:86)(cid:76)(cid:86)(cid:87)(cid:68)(cid:81)(cid:70)(cid:72) (cid:36)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:3)(cid:43)(cid:72)(cid:68)(cid:79)(cid:87)(cid:75)(cid:3) Frailty, either alone or in the presence
(cid:50)(cid:88)(cid:87)(cid:70)(cid:82)(cid:80)(cid:72)(cid:86) of diseases, predicts future adverse
health outcomes in older adults. Previ-
(cid:135)(cid:41)(cid:68)(cid:79)(cid:79)(cid:86)(cid:18)(cid:44)(cid:81)(cid:77)(cid:88)(cid:85)(cid:76)(cid:72)(cid:86)
ous research has suggested that several
(cid:44)(cid:81)(cid:73)(cid:79)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)
(cid:48)(cid:48)(cid:88)(cid:86)(cid:70)(cid:79)(cid:79)(cid:72)(cid:3) organ/system abnormalities are respon-
(cid:41)(cid:68)(cid:87)(cid:76)(cid:74)(cid:88)(cid:72)
(cid:90)(cid:72)(cid:68)(cid:78)(cid:81)(cid:72)(cid:86)(cid:86) (cid:135)(cid:36)(cid:70)(cid:88)(cid:87)(cid:72)(cid:3)(cid:76)(cid:79)(cid:79)(cid:81)(cid:72)(cid:86)(cid:86)(cid:72)(cid:86) sible for homeostasis breakdown at an
advanced age, and frailty may represent
(cid:54)(cid:68)(cid:85)(cid:70)(cid:82)(cid:83)(cid:72)(cid:81)(cid:76)(cid:68) (cid:135)(cid:43)(cid:82)(cid:86)(cid:83)(cid:76)(cid:87)(cid:68)(cid:79)(cid:76)(cid:93)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81) the clinical manifestations of the patho-
genic processes. The key pathogenic
(cid:57)(cid:76)(cid:70)(cid:76)(cid:82)(cid:88)(cid:86)(cid:3)(cid:70)(cid:92)(cid:70)(cid:79)(cid:72)
processes are (i) insulin resistance; (ii)
(cid:135)(cid:39)(cid:76)(cid:86)(cid:68)(cid:69)(cid:76)(cid:79)(cid:76)(cid:87)(cid:92)
(cid:36)(cid:71)(cid:76)(cid:83)(cid:82)(cid:86)(cid:76)(cid:87)(cid:92) (cid:54)(cid:54)(cid:79)(cid:79)(cid:82)(cid:82)(cid:90)(cid:90)(cid:72)(cid:72)(cid:71)(cid:71)(cid:3) inflammation; (iii) sarcopenia; (iv) adi-
(cid:58)(cid:58)(cid:72)(cid:72)(cid:76)(cid:76)(cid:74)(cid:74)(cid:75)(cid:75)(cid:87)(cid:87)(cid:3) (cid:90)(cid:68)(cid:79)(cid:78)(cid:76)(cid:81)(cid:74)(cid:3) posity; (v) age-related hormone decline;
(cid:79)(cid:82)(cid:86)(cid:86) (cid:86)(cid:83)(cid:72)(cid:72)(cid:71) (cid:135)(cid:39)(cid:72)(cid:83)(cid:72)(cid:81)(cid:71)(cid:72)(cid:81)(cid:70)(cid:92) and (vi) nervous system dysfunction.11
(cid:36)(cid:74)(cid:72)(cid:16)(cid:85)(cid:72)(cid:79)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3) These processes are interrelated, and a
(cid:75)(cid:82)(cid:85)(cid:80)(cid:82)(cid:81)(cid:72)(cid:3)(cid:71)(cid:72)(cid:70)(cid:79)(cid:76)(cid:81)(cid:72) (cid:135)(cid:44)(cid:81)(cid:86)(cid:87)(cid:76)(cid:87)(cid:88)(cid:87)(cid:76)(cid:82)(cid:81)(cid:68)(cid:79)(cid:76)(cid:93)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81) vicious cycle typically develops. Sub-
(cid:51)(cid:75)(cid:92)(cid:86)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)
(cid:68)(cid:70)(cid:87)(cid:76)(cid:89)(cid:76)(cid:87)(cid:92)(cid:3) clinical diseases may have a role in
(cid:49)(cid:72)(cid:85)(cid:89)(cid:82)(cid:88)(cid:86)(cid:3)(cid:86)(cid:92)(cid:86)(cid:87)(cid:72)(cid:80)(cid:86)(cid:3)(cid:3) (cid:71)(cid:71)(cid:72)(cid:72)(cid:70)(cid:70)(cid:79)(cid:79)(cid:76)(cid:76)(cid:81)(cid:81)(cid:72)(cid:72) (cid:135)(cid:39)(cid:72)(cid:68)(cid:87)(cid:75) frailty development.16
(cid:71)(cid:92)(cid:86)(cid:73)(cid:88)(cid:81)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)
(cid:38)(cid:75)(cid:85)(cid:82)(cid:81)(cid:76)(cid:70)(cid:3)(cid:71)(cid:76)(cid:86)(cid:72)(cid:68)(cid:86)(cid:72)(cid:86)(cid:3)(cid:11)(cid:72)(cid:17)(cid:74)(cid:17)(cid:3)(cid:70)(cid:68)(cid:85)(cid:71)(cid:76)(cid:82)(cid:89)(cid:68)(cid:86)(cid:70)(cid:88)(cid:79)(cid:68)(cid:85)(cid:15)(cid:3)(cid:80)(cid:72)(cid:87)(cid:68)(cid:69)(cid:82)(cid:79)(cid:76)(cid:70)(cid:15)(cid:3)(cid:81)(cid:72)(cid:88)(cid:85)(cid:82)(cid:71)(cid:72)(cid:74)(cid:72)(cid:81)(cid:72)(cid:85)(cid:68)(cid:87)(cid:76)(cid:89)(cid:72)(cid:3)(cid:71)(cid:76)(cid:86)(cid:72)(cid:68)(cid:86)(cid:72)(cid:86)(cid:15)(cid:3)(cid:70)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:12)
1. OXIDATIVE STRESS AND AGING
6 1. OXIDATIVE STRESS AND FRAILTY
Sarcopenia is common among older people, with preva- maintaining body composition.28 Low levels of serum
lence ranging from 9% to 18% over the age of 65 years.17 testosterone have been shown to have an independent
Skeletal muscle contractions provide the power neces- relationship with frailty.29 Insulin-like growth factor-1
sary for human mobility. In addition, skeletal muscles (IGF-1) is primarily produced by the liver; production
account for a large portion of human body mass and is regulated by growth hormone secreted from the pitu-
are essential for metabolism.17 Thus, the loss of skeletal itary gland. The amount of growth hormone secreted
muscle mass with age could have significant effects on from the pituitary gland declines gradually with age.
physical functions and health in old age. Sarcopenia has In parallel, levels of circulating IGF-1 decrease with
been demonstrated to lead to frailty.18 Frailty can worsen aging.30 The primary function of IGF-1 is to promote
the severity of sarcopenia through certain mechanisms growth and development, including muscle protein
(e.g. adiposity with lipid infiltration of muscle tissue), synthesis. As a crucial regulator of muscle mass, IGF-1
and a vicious cycle typically develops.19 levels are associated with muscle strength and mobil-
ity.31 Dehydroepiandrosterone (DHEA) and its sulfate
Adiposity
form (DHEAS) are secreted from the adrenal gland.
Unlike skeletal muscle mass, fat increases with age.20 Adrenocortical cells that produce hormones decrease
In addition, aging is accompanied by fat redistribution, in activity in aging.32 DHEAS is converted to andro-
with accumulation inside and around skeletal muscles.19 genic and estrogenic steroid in peripheral tissues, and
Older adults with a high body mass index (BMI) are represents another hormone that has significant trophic
more likely to be frail compared to those with a normal effects on skeletal muscles.32 Low circulating DHEAS
BMI.21 Abdominal obesity with an elevated waist cir- levels have been shown to be independently linked to
cumference also increases the risk of frailty in humans.21 frailty.33
Adipose tissue, particularly visceral adipose tissue, is
Autonomic Nervous System Dysfunction
not only an organ specializing in the storage and mobili-
zation of lipids, but is also a remarkable endocrine organ The autonomic nervous system controls vital organ
that regulates the entire body’s energy metabolism by functions and has a crucial role in maintaining homeo-
secreting numerous molecules.22 Increasing abdominal stasis. However, the functions of the autonomic nervous
fat is known to lead to insulin resistance.22 Insulin resis- system change with age.34 Although the sympathetic
tance and related metabolic disorders have been shown nervous system activities of the heart, skeletal muscles,
to be major risk factors of frailty, possibly by altering the and gut increase with age, epinephrine secretion from
muscle metabolism.13 the adrenal medulla and cardiac vagal tone are m arkedly
reduced with age.34 Low heart-rate variability, a mani-
Inflammation
festation of autonomic nervous system dysfunction, is
Inflammation is crucial in the pathogenesis of frailty. associated with frailty.35
Inflammatory cytokines, including interleukin-6 (IL-6),
increase with age, and related pathways are strongly
implicated in aging.23 In prospective cohort studies, OXIDATIVE STRESS AND FRAILTY
older adults with higher baseline levels of inflam-
matory cytokines were more vulnerable to the future Frailty is a state of homeostasis breakdown in
occurrences of frailty.13 Activation of inflammation can advanced age caused by sarcopenia, adiposity, insulin
directly contribute to muscle-mass loss and muscle resistance, inflammation, age-related hormone decline,
dysfunction,24 resulting in a frailty phenotype with a and nervous system dysfunction. What remains unclear
slow gait speed and low muscle strength.25 Specifically, is how these abnormalities in multiple systems occur. It
TNF-α is recognized to be involved in inflammation- is apparent that age is the greatest risk factor for frailty.
related and age-related impairments in muscle mass Because oxidative stress increases with age, oxidative
and function.26 In addition, inflammation can cause stress may be involved in frailty. A growing number of
frailty by triggering global metabolic derangements, studies have suggested that cellular oxidative stress may
including increased adiposity, insulin resistance, and cause multiple organ/system pathologies that lead to
endothelial dysfunction.13 frailty and may trigger the vicious cycle leading toward
failure of the homeostasis mechanism.
Age-Related Hormone Decline
Endocrine system activity is known to change
Oxidative Stress Is Associated with Frailty and
markedly with age. Because of decreased releases of
Frailty Components
gonadotropin and decreased secretions at the gonadal
level, a gradual decline in serum testosterone levels The association between oxidative stress and frailty
occurs during aging.27 Testosterone plays a key role in has been consistently observed in studies of older
1. OXIDATIVE STRESS AND AGING