Advances in Geroscience 1st Edition

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Felipe Sierra · Ronald Kohanski Editors

Advances in
Geroscience
Advances in Geroscience
&ELIPE 3IERRA s 2ONALD +OHANSKI
Editors

Advances in Geroscience
Editors
Felipe Sierra 2ONALD +OHANSKI
Division of Aging Biology Division of Aging Biology
.ATIONAL )NSTITUTES OF (EALTH.ATIONAL .ATIONAL )NSTITUTES OF (EALTH.ATIONAL
Institute of Aging Institute of Aging
"ETHESDA -$ "ETHESDA -$
USA USA

)3".      )3".      E"OOK

DOI 10.1007/978-3-319-23246-1

Library of Congress Control Number: 2015955267

3PRINGER #HAM (EIDELBERG .EW 9ORK $ORDRECHT ,ONDON

Ú 3PRINGER )NTERNATIONAL 0UBLISHING 
4HIS WORK IS SUBJECT TO COPYRIGHT !LL RIGHTS ARE RESERVED BY THE 0UBLISHER WHETHER THE WHOLE OR PART OF
THE MATERIAL IS CONCERNED SPECIlCALLY THE RIGHTS OF TRANSLATION REPRINTING REUSE OF ILLUSTRATIONS RECITATION
BROADCASTING REPRODUCTION ON MICROlLMS OR IN ANY OTHER PHYSICAL WAY AND TRANSMISSION OR INFORMATION
STORAGE AND RETRIEVAL ELECTRONIC ADAPTATION COMPUTER SOFTWARE OR BY SIMILAR OR DISSIMILAR METHODOLOGY
NOW KNOWN OR HEREAFTER DEVELOPED
4HE USE OF GENERAL DESCRIPTIVE NAMES REGISTERED NAMES TRADEMARKS SERVICE MARKS ETC IN THIS PUBLICATION
DOES NOT IMPLY EVEN IN THE ABSENCE OF A SPECIlC STATEMENT THAT SUCH NAMES ARE EXEMPT FROM THE RELEVANT
PROTECTIVE LAWS AND REGULATIONS AND THEREFORE FREE FOR GENERAL USE
4HE PUBLISHER THE AUTHORS AND THE EDITORS ARE SAFE TO ASSUME THAT THE ADVICE AND INFORMATION IN THIS BOOK
ARE BELIEVED TO BE TRUE AND ACCURATE AT THE DATE OF PUBLICATION .EITHER THE PUBLISHER NOR THE AUTHORS OR THE
EDITORS GIVE A WARRANTY EXPRESS OR IMPLIED WITH RESPECT TO THE MATERIAL CONTAINED HEREIN OR FOR ANY ERRORS
OR OMISSIONS THAT MAY HAVE BEEN MADE

Printed on acid-free paper

3PRINGER )NTERNATIONAL 0UBLISHING !' 3WITZERLAND IS PART OF 3PRINGER 3CIENCE "USINESS -EDIA
(WWWSPRINGERCOM
Foreword

)N AN INTRODUCTION TO A  SPECIAL ISSUE OF 3CIENCE ;= MY COLLEAGUES AND )

EMPHASIZED THAT h7E HAVE FOCUSED ON PHYSIOLOGICAL MECHANISMS UNDERLYING PRO-
CESSES OF AGING RATHER THAN ON THE LARGE ARRAY OF DEBILITATING AND COSTLY DISORDERS
THAT SO COMMONLY EMERGE DURING THE LATTER HALF OF THE LIFE SPANS OF HUMAN BEINGSv
4HAT WAS BEFORE THE DAYS OF 'EROSCIENCE HOWEVER
"UT WHAT EXACTLY is Geroscience?
)T IS A TERM COINED BY MY COLLEAGUE AND FRIEND 'ORDON ,ITHGOW A PROFESSOR AT THE
"UCK )NSTITUTE FOR 2ESEARCH ON !GING WHO TRUE TO HIS 3COTTISH HERITAGE IS THRIFTY
WITH THE USE OF ALL INSTRUMENTS OF COMMERCE INCLUDING TERMINOLOGY 'ORDON USED
THAT NOMENCLATURE TO SUMMARIZE A NEW INTERDISCIPLINARY RESEARCH ENTERPRISE AT THE
"UCK #ENTER ALTHOUGH IT NEEDS SOME GRAMMATICAL EDITING IT IS QUITE INFORMATIVE
h7E CONSIDER THAT THE RELATIONSHIP BETWEEN AGING AND AGE RELATED DISEASE IS AN
IMPORTANT PROBLEM THAT CAN BE TACKLED THROUGH AN INTERDISCIPLINARY APPROACHv
(HTTPWWWGEROSCIENCEONLINEORGINDEXPHP  4HIS VIEW EMPHASIZES THE CONCEPT
THAT IT IS NOT ONLY DIFlCULT TO DISASSOCIATE FUNDAMENTAL PROCESSES OF AGING FROM THE
NUMEROUS DISEASES OF AGING BUT THAT JOINT INVESTIGATIONS OF THESE TWO DOMAINS OF
SCHOLARSHIP ARE ESSENTIAL IF WE ARE TO UNRAVEL THE PATHOGENESIS OF ATHEROSCLEROSIS
MYOCARDIAL INFARCTIONS STROKES NON ISCHEMIC HEART FAILURE BENIGN AND MALIGNANT
NEOPLASMS DEMENTIAS OF THE !LZHEIMER TYPE FRONTAL TEMPORAL DEMENTIAS
0ARKINSONS DISEASE AND ,EWY BODY DEMENTIAS PERIPHERAL NEUROPATHIES CATARACTS
AND AGE RELATED MACULAR DEGENERATION PRESBYCUSIS CHRONIC OBSTRUCTIVE PULMONARY
DISEASE TYPE  DIABETES MELLITUS THE METABOLIC SYNDROME OSTEOPOROSIS OSTEOARTHRI-
TIS SARCOPENIA GLOMERULOSCLEROSIS ETC
4HE EDITORS OF THIS VOLUME &ELIPE 3IERRA AND 2ONALD +OHANSKI HAVE TAKEN
THIS CONCEPT TO AN EXCITING NEW LEVEL OF IMPLEMENTATION !S THE $IRECTOR OF THE
$IVISION OF !GING "IOLOGY OF THE .ATIONAL )NSTITUTE ON !GING &ELIPE APPROACHED
HIS COUNTERPARTS AT MORE THAN TWENTY SISTER .)( INSTITUTES WITH NARROW INTERESTS
IN SPECIlC DISEASES OF AGING WITH THE FOLLOWING PARAPHRASED SALES PITCH h,ETS
HAVE A DISCUSSION ABOUT HOW BASIC PROCESSES OF AGING ARE THE MAJOR RISK FACTOR FOR
YOUR DISEASE 8 "UT lRST ) WANT TO ASSURE YOU THAT ) DO NOT WANT YOUR MONEY FOR
MY OWN INSTITUTE
) WANT TO START A @'EROSCIENCE )NTEREST 'ROUP SO THAT WE CAN
WORK TOGETHER TO ACCELERATE PROGRESS TOWARDS THE ENHANCEMENT OF HEALTHY HUMAN

v
vi &OREWORD

AGINGv 4HE RESPONSE WAS OVERWHELMINGLY ENTHUSIASTIC AND RESULTED IN A SERIES

OF PRODUCTIVE JOINT CONFERENCES INCLUDING A  3UMMIT MEETING AT THE .)(
;= 2EADERS ARE URGED TO LEARN MORE ABOUT THIS TRANS .)( INITIATIVE VIA &ELIPES
EXCELLENT VIDEO ON THE SUBJECT HTTPWWWNIANIHGOVABOUTLINKS
VIDEO DR FELIPE SIERRA DISCUSSES TRANS NIH GEROSCIENCE INTEREST GROUP AND MORE.
4HIS VOLUME DESPITE ITS  CHAPTERS AND ITS STELLAR LIST OF AUTHORS CAN BEST BE
VIEWED AS JUST A BEGINNING STEP FOR 'EROSCIENCE 'IVEN THE EXTENT OF RESEARCH FUND-
ING THAT IT RICHLY DESERVES n FAR MORE THAN THE CURRENT .)( PAY LINES n WE CAN ANTICI-
PATE MAJOR BASIC AND TRANSLATIONAL ADVANCES IN OUR HEALTHSPANS AT WHICH POINT WE
CAN GO TO THE &OOD AND $RUG !DMINISTRATION AND POINT OUT THAT THE SIDE EFFECT OF OUR
RESEARCH n INCREASED LONGEVITY n CAN REALLY BE A GOOD THING FOR HUMANITY !S THE LATE
#HARLIE #HAPLIN POINTED OUT hWE ARE ALL AMATEURS WE DONT LIVE LONG ENOUGH TO
BECOME ANYTHING ELSEv ;=

3EATTLE 7! 53! 'EORGE - -ARTIN -$

*UNE  

References

 -ARTIN '- ,A-ARCO + 3TRAUSS % , +ELNER +  2ESEARCH ON AGING THE END OF THE BEGIN-
NING 3CIENCE  n
 "URCH *" !UGUSTINE !$ &RIEDEN ,! (ADLEY % (OWCROFT 4+ *OHNSON 2 +HALSA 03 +OHANSKI
2! ,I 8, -ACCHIARINI & .IEDEREHE ' /H 93 0AWLYK !# 2ODRIGUEZ ( 2OWLAND *( 3HEN
', 3IERRA & 7ISE "#  !DVANCES IN GEROSCIENCE IMPACT ON HEALTHSPAN AND CHRONIC
DISEASE * 'ERONTOL ! "IOL 3CI -ED 3CI 3UPPL  3n3
Preface

'EROSCIENCE IS A NEW lELD THAT AIMS TO BRIDGE TWO COMMUNITIES BIOLOGISTS FOCUSED
ON UNDERSTANDING THE BASIC MECHANISMS THAT DRIVE AGING AND GERIATRICIANS ATTEMPT-
ING TO IMPROVE THE QUALITY OF LIFE OF ELDERLY PATIENTS 'EROSCIENCE HAS BEEN DElNED
7IKIPEDIA AS hAN INTERDISCIPLINARY lELD THAT AIMS TO UNDERSTAND THE RELATIONSHIP
BETWEEN AGING AND AGE RELATED DISEASESv "ECAUSE AGING IS THE MAJOR RISK FACTOR FOR
MOST CHRONIC DISEASES THE h'EROSCIENCE (YPOTHESISv POSITS THAT COMMON BIOLOGICAL
MECHANISMS OF AGING PLAY IMPORTANT ROLES IN THE SUSCEPTIBILITY OF AGED INDIVIDUALS
TO MULTIPLE CHRONIC DISEASES
4HE ROLE OF AGING AS A DRIVER OF CHRONIC DISEASES IS OFTEN DOWNPLAYED UNDER THE
ASSUMPTION THAT AGING IS A NON MODIlABLE RISK FACTOR 9ET WE KNOW THAT THE RATE OF
AGING HOWEVER THAT IS DElNED AS DECAY IN FUNCTION OR SUSCEPTIBILITY TO DISEASE IS
MODIlABLE BY SIMPLE CHANGES IN THE ENVIRONMENT A HEALTHY DIET MODERATE EXERCISE
AND OTHER ELEMENTS OF A GENERALLY HEALTHY LIFESTYLE WILL INCREASE A PERSONS CHANCES
OF LEADING A LONGER AND HEALTHIER LIFE )N FACT IT IS A DIETARY INTERVENTION DIET RESTRIC-
TION THAT PROVIDED THE lRST HANDLE TO BIOLOGISTS INTENT TO UNDERSTAND THE UNDERPIN-
NINGS OF THE AGING PROCESS 4HAT WORK COUPLED WITH GENETIC EXPERIMENTS IN
SHORT LIVED SIMPLE ORGANISMS RANGING FROM YEAST TO mIES AND WORMS ALLOWED SCIEN-
TISTS TO UNRAVEL SOME OF THE MAJOR MECHANISMS INVOLVED &URTHERMORE DRIVEN PRI-
MARILY BY THE )NTERVENTION 4ESTING 0ROGRAM CREATED AND SUPPORTED BY THE .ATIONAL
)NSTITUTE ON !GING THE lELD HAS MOVED RECENTLY TO DElNING PHARMACOLOGICAL INTER-
VENTIONS THAT EXPAND LIFESPAN IN RODENTS MAINLY MICE  )N ADDITION TO THESE IMPRES-
SIVE ADVANCES IN TERMS OF INCREASING LIFESPAN RECENTLY THERE HAS BEEN A SHIFT IN
FOCUS TOWARDS MEASURING HEALTHSPAN AS WELL AS LIFESPAN )NDEED WHILE SOME INTER-
VENTIONS SUCH AS RESVERATROL ONLY INCREASE HEALTH BUT NOT LIFESPAN IN MICE A HAND-
FUL OF OTHER INTERVENTIONS HAVE BEEN SHOWN TO INCREASE BOTH ALTHOUGH WITH THE STRONG
CAVEAT THAT NO MANIPULATION HAS ACHIEVED THAT GOAL WITHOUT HAVING SOME SECONDARY
negative effects.
4HE ENORMOUS AGING OF THE POPULATION WORLDWIDE WITH THE OLDEST OLD BEING THE
AGE SEGMENT WITH THE FASTEST GROWTH POSES AN URGENT DILEMMA IF AGING IS INDEED THE
LARGEST RISK FACTOR FOR MOST CHRONIC DISEASES THIS INCREASE IN THE PROPORTION OF ELDERLY
WILL NECESSARILY POSE AN INSURMOUNTABLE CHALLENGE TO THE WORLDS ECONOMIC AND

vii
viii Preface

HEALTH CARE SYSTEMS &ORTUNATELY AT THE SAME TIME THAT THIS DEMOGRAPHIC CHANGE IS
REACHING A CRITICAL STAGE OUR UNDERSTANDING OF AGING BIOLOGY IS ALLOWING SCIENTISTS TO
CONSIDER THE POSSIBILITY OF INTERVENING TO DELAY AGING AND HOPEFULLY WITH IT ALL
MAJOR CHRONIC DISEASES 4HIS IMPROVED KNOWLEDGE HAS ALLOWED THE ORGANIZATION OF
CONCEPTS INTO SIX TO EIGHT HALLMARKS OR PILLARS BELIEVED TO BE THE MAIN DRIVERS OF THE
PROCESS 7HILE SOME DETAILS STILL NEED FURTHER CLARIlCATION THERE IS BROAD AGREEMENT
WITHIN THE RESEARCH COMMUNITY ABOUT THESE MAJOR DRIVERS AND DIFFERENCES ONLY
REmECT DIFFERENT BIASES AND GRANULARITY
4HESE ADVANCES AND THE EMERGING OPPORTUNITY TO MODIFY THE PROCESS OF AGING BY
PHARMACOLOGICAL MEANS SPAWNED THE APPEARANCE OF THE NEW lELD OF 'EROSCIENCE
4HE INITIAL CONCEPT CAME FROM A GROUP AT THE "UCK )NSTITUTE FOR 2ESEARCH ON !GING
WHICH UNDER THE LEADERSHIP OF $R 'ORDON ,ITHGOW PUT FORWARD A SUCCESSFUL PRO-
POSAL TO THE #OMMON &UND OF THE .ATIONAL )NSTITUTE OF (EALTH 4HIS PROJECT
)NTERDISCIPLINARY 2ESEARCH #ONSORTIUM ON 'EROSCIENCE WAS FUNDED FOR  YEARS
BETWEEN  AND  3UBSEQUENT TO THAT EFFORT THE EDITORS OF THIS BOOK STARTED A
TRANS .)( EFFORT FOLLOWING THE SAME LINE OF THINKING AND RESULTING IN THE FORMATION
OF THE TRANS .)( 'ERO3CIENCE )NTEREST 'ROUP '3)'  4HE EFFORT ATTRACTED THE ATTEN-
TION OF OVER  DIFFERENT INSTITUTES WITHIN THE .)( AS WELL AS WIDE SUPPORT FROM BOTH
THE SCIENTIlC COMMUNITY AND IMPORTANTLY NON FEDERAL ADVOCACY AND SUPPORT
GROUPS 7ITH THE IMPRIMATUR OF SO MANY .)( INSTITUTES THE SUBSEQUENT GROWTH OF
THE lELD WAS IMPRESSIVE AND CULMINATED IN THE ORGANIZATION OF A LARGE 3UMMIT
!DVANCES IN 'EROSCIENCE )MPACT ON (EALTHSPAN AND #HRONIC $ISEASE HELD IN THE
.)( #AMPUS ON /CTOBER.OVEMBER  )N TURN THAT EFFORT RESULTED IN THE PUBLI-
CATION OF A 7HITE 0APER IN .OVEMBER  IN THE *OURNAL Cell.
&OR WHOM IS THE BOOK WRITTEN 'EROSCIENCE IS AN INTERDISCIPLINARY lELD ATTEMPT-
ING TO ADDRESS THE MECHANISMS BY WHICH AGING BIOLOGY IS THE MAIN RISK FACTOR FOR
CHRONIC DISEASES !S SUCH THIS BOOK EXAMINES THOSE MECHANISMS AND IT PROVIDES AN
EMERGING OVERVIEW OF THE NEW DISCIPLINE OF 'EROSCIENCE %ACH CHAPTER AIMS AT CON-
NECTING THE CLINICAL MANIFESTATION OF SPECIlC AGE RELATED CHRONIC DISEASES WITH THE
MAJOR PILLARS OF AGING BIOLOGY 4HESE PILLARS ARE SUSPECTED OR IN SOME CASES KNOWN
TO PLAY A ROLE IN THE ETIOLOGY OF THESE DISEASES NOT JUST SINGLY BUT IN MULTIPLE DIS-
EASES BECAUSE AGING IS THE MAJOR RISK FACTOR FOR THEIR APPEARANCE !S SUCH EACH
CHAPTER COMBINES FEATURES OF CLINICAL SCIENCE AND BASIC BIOLOGY AND IT IS HOPED THAT
THIS APPROACH WILL BE INFORMATIVE AND ENLIGHTENING TO BOTH THESE COMMUNITIES PHY-
SICIANS WILL HOPEFULLY LEARN ABOUT THE BASIC UNDERPINNINGS OF AGING THAT MIGHT AFFECT
THE OUTCOME OF CHRONIC DISEASES ANDOR TREATMENTS WHILE BASIC SCIENTISTS MIGHT
PROlT FROM LEARNING ABOUT CLINICAL ASPECTS OF THEIR DISEASE OF INTEREST IN THE CONTEXT
OF AGING !LTOGETHER THE EDITORS AND AUTHORS ANTICIPATE THAT THIS BOOK WILL RAISE FUR-
THER AWARENESS OF THE MOLECULAR MECHANISMS WHICH MIGHT BECOME TARGETS FOR FUR-
THER INVESTIGATION AND ULTIMATELY NEW TARGETS TO COMBAT MULTIPLE COMORBIDITIES AT
once.
4HIS BOOK EXAMINES THE BIOLOGICAL MECHANISMS AND CLINICAL CONSEQUENCES OF
AGING BY PROVIDING SPECIlC COVERAGE ON A WIDE RANGE OF CHRONIC DISEASES FROM
ARTHRITIS AND CANCER TO DEMENTIA AND STROKE AMONG OTHERS 4HIS BOOK BEGINS WITH AN
INTRODUCTION OF THE GENERAL PRINCIPLES INCLUDING BOTH A DESCRIPTION OF CURRENT
Preface IX

THINKING IN AGING BIOLOGY AND A DESCRIPTION OF THE 'EROSCIENCE (YPOTHESIS WITH

SOME BACKGROUND ON THE CRITICAL ROLE THAT EPIDEMIOLOGY HAS PLAYED IN DElNING OUR
BASIC UNDERSTANDING OF AGE RELATED CHRONIC DISEASES %ACH OF THE FOLLOWING  CHAP-
TERS FOCUSES ON ONE PARTICULAR DISEASE OR GROUP OF RELATED DISEASES WITH AN EMPHASIS
ON HOW AGING IS A RISK FACTOR 4HIS BOOK lNISHES WITH A GLOBAL DISCUSSION OF PAIN IN
THE ELDERLY AND A COMMENTARY ON THE IMPORTANT TOPIC OF TRANSLATION INTO THE CLINIC
AND THE NECESSITY OF CROSS FERTILIZATION BETWEEN CLINICIANS AND BASIC SCIENTISTS
5NFORTUNATELY NOT ALL DISEASES AFmICTING THE ELDERLY HAVE BEEN COVERED AND THIS
OMISSION IS SIMPLY THE RESULT OF SPACE LIMITATIONS )T IS HOPED THAT THIS BOOK WILL
ENTICE EXPERTS IN THOSE AREAS TO THINK MORE DEEPLY ABOUT THE BASIS ON WHICH AGING AS
A RISK FACTOR FOR THEIR SPECIALTY DISEASE AND PERHAPS PUBLISH THEIR THOUGHTS ON THIS
SUBJECT
#ONTRIBUTORS TO THIS VOLUME REPRESENT A LARGE RANGE OF DISCIPLINES !N EFFORT WAS
MADE WHENEVER POSSIBLE AND APPROPRIATE TO ENGAGE IN EACH CHAPTER BOTH BASIC
SCIENTISTS AND CLINICIANS THE EDITORS ARE ENORMOUSLY THANKFUL TO ALL AUTHORS FOR THE
EFFORT AND SENSE OF SHARED RESPONSIBILITY )MPORTANTLY THE EDITORS THANK ALL MEMBERS
OF THE '3)' EXECUTIVE COMMITTEE FOR THEIR SUPPORT DURING THE PREPARATION OF THIS
BOOK AND THE HELP PROVIDED ON THE SELECTION OF AUTHORS 3IMILARLY '3)' MEMBERS
ARE TO BE COMMENDED FOR THE ADDITIONAL EDITORIAL WORK TO COMPLETE THIS VOLUME
4HE EDITORS BELIEVE THAT THIS BOOK PRESENTS VITAL INFORMATION AND IDEAS THAT CAN
HELP READERS BETTER UNDERSTAND HOW AGING IS A CRITICAL n BUT MALLEABLE n RISK FACTOR IN
CHRONIC DISEASES OF THE ELDERLY 4HE POTENTIAL TO ALTER THE RATE OF AGING IS AT THE HEART
OF 'EROSCIENCE AND ACHIEVING THAT GOAL SHOULD IMPROVE LIFESPAN AND HEALTHSPAN IN
THE HUMAN POPULATION

"ETHESDA -$ 53! &ELIPE 3IERRA

2ONALD ! +OHANSKI
Contents

The Geroscience Hypothesis: Is It Possible to Change the Rate

of Aging? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Steven N. Austad
Etiological Role of Aging in Chronic Diseases: From Epidemiological
Evidence to the New Geroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Linda P. Fried and Luigi Ferrucci
The Impact of Aging on Cancer Progression and Treatment . . . . . . . . . . . . 53
3HENGHUI (E AND .ORMAN % 3HARPLESS
The Impact of Cancer Treatments on Aging . . . . . . . . . . . . . . . . . . . . . . . . . 85
#HANGHAN ,EE AND 6ALTER ,ONGO
Cardiovascular Disease and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
9ING !NN #HIAO %DWARD ,AKATTA :OLTAN 5NGVARI $AO &U $AI
AND 0ETER 2ABINOVITCH
The Impact of Aging on Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
&ARIDA 3OHRABJI
The Role of Aging in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 197
'EOFFREY ! +ERCHNER AND 4ONY 7YSS #ORAY
Parkinson’s Disease and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
*ULIE + !NDERSEN AND 3HANKAR #HINTA
Aging and the Bone-Muscle Interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
3IMON -ELOV AND #LIFFORD * 2OSEN
Osteoporosis and Mechanisms of Skeletal Aging . . . . . . . . . . . . . . . . . . . . . 277
*ULIE 'LOWACKI AND 4AMARA 6OKES
Osteoarthritis in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
2ICHARD & ,OESER AND -ARTIN ,OTZ

XI
XII Contents

Diabetes and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

.ICOLAS -USI AND !NDRZEJ "ARTKE
Renal Aging and Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
*OHN 0 (IGGINS AND 3TUART + +IM
Asthma and Aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
.ICOLA ! (ANANIA AND 0AULA "USSE
Aging in COPD and Idiopathic Pulmonary Fibrosis . . . . . . . . . . . . . . . . . . 429
#ECILIA ' 3ANCHEZ
Age-Related Macular Degeneration and Vision Impairment . . . . . . . . . . . 471
#HARLES 7RIGHT AND *AYAKRISHNA !MBATI
HIV and Aging: Parallels and Synergistic Mechanisms Leading
to Premature Disease and Functional Decline . . . . . . . . . . . . . . . . . . . . . . . 509
!NNA (EARPS +ATHERINE 3CHAFER +EVIN (IGH AND !LAN ,ANDAY
Pain in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
2OGER " &ILLINGIM $ENNIS # 4URK AND 2OBERT 0 9EZIERSKI
The Way Forward: Translation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
*AMES , +IRKLAND AND 4AMAR 4CHKONIA
Contributors

Jayakrishna Ambati $EPARTMENT OF /PHTHALMOLOGY AND 6ISUAL 3CIENCES

5NIVERSITY OF +ENTUCKY ,EXINGTON +9 53!
Julie K. Andersen, Ph.D. "UCK )NSTITUTE FOR 2ESEARCH ON !GING .OVATO #!
USA
Steven N. Austad, Ph.D. $EPARTMENT OF "IOLOGY 5NIVERSITY OF !LABAMA
AT "IRMINGHAM "IRMINGHAM 5+
Andrzej Bartke, Ph.D. $EPARTMENT OF -EDICINE 3OUTHERN )LLINOIS 5NIVERSITY
3CHOOL OF -EDICINE 3PRINGlELD ), 53!
Paula Busse, M.D. $EPARTMENT OF -EDICINE )CAHN 3CHOOL OF -EDICINE
-OUNT 3INAI .9 53!
Ying Ann Chiao, Ph.D. $EPARTMENT OF 0ATHOLOGY 5NIVERSITY OF 7ASHINGTON
3EATTLE 7! 53!
Shankar Chinta, Ph.D. "UCK )NSTITUTE FOR 2ESEARCH ON !GING .OVATO #! 53!
Dao-Fu Dai, M.D., Ph.D. $EPARTMENT OF 0ATHOLOGY 5NIVERSITY OF 7ASHINGTON
3EATTLE 7! 53!
Luigi Ferrucci )NTRAMURAL 2ESEARCH 0ROGRAM .ATIONAL )NSTITUTE ON !GING
"ETHESDA -$ 53!
Roger B. Fillingim, Ph.D. 0AIN 2ESEARCH AND )NTERVENTION #ENTER OF %XCELLENCE
5NIVERSITY OF &LORIDA 'AINESVILLE &, 53!
Linda P. Fried -AILMAN 3CHOOL OF 0UBLIC (EALTH #OLUMBIA 5NIVERSITY -EDICAL
#ENTER .EW 9ORK .9 53!
Julie Glowacki, Ph.D. $EPARTMENT OF /RTHOPEDIC 3URGERY "RIGHAM AND
7OMENS (OSPITAL "OSTON -! 53!
Nicola A. Hanania, M.D., M.S. $EPARTMENT OF -EDICINE "AYLOR #OLLEGE
OF -EDICINE (OUSTON 48 53!

XIII
XIV Contributors

Shenghui He, Ph.D. $EPARTMENT OF 'ENETICS 4HE ,INEBERGER #OMPREHENSIVE

#ANCER #ENTER 5NIVERSITY OF .ORTH #AROLINA 3CHOOL -EDICINE #" 
#HAPEL (ILL .# 53!
Anna Hearps, Ph.D. #ENTRE FOR "IOMEDICAL 2ESEARCH "URNET )NSTITUTE
-ELBOURNE 6)# !USTRALIA
John P. Higgins, M.D. $EPARTMENT 0ATHOLOGY 3TANFORD 5NIVERSITY -EDICAL
#ENTER 3TANFORD #! 53!
Kevin High, M.D. $EPARTMENT OF )NTERNAL -EDICINE 3ECTION ON )NFECTIOUS
$ISEASES 7AKE &OREST 3CHOOL OF -EDICINE 7INSTON 3ALEM .# 53!
Geoffrey A. Kerchner $EPARTMENT OF .EUROLOGY AND .EUROLOGICAL 3CIENCES
3TANFORD 5NIVERSITY 3CHOOL OF -EDICINE 3TANFORD #! 53!
Stuart K. Kim, Ph.D. $EPARTMENT $EVELOPMENTAL "IOLOGY AND 'ENETICS
3TANFORD 5NIVERSITY -EDICAL #ENTER 3TANFORD #! 53!
James L. Kirkland, M.D., Ph.D. !GING 2ESEARCH 2OBERT AND !RLENE +OGOD
#ENTER ON !GING -AYO #LINIC 2OCHESTER -. 53!
Edward Lakatta, M.D. ,ABORATORY OF #ARDIOVASCULAR 3CIENCE "IOMEDICAL
2ESEARCH #ENTER .ATIONAL )NSTITUTE OF !GING "ALTIMORE 53!
Alan Landay, Ph.D. $EPARTMENT OF )MMUNOLOGY-ICROBIOLOGY 2USH 5NIVERSITY
-EDICAL #ENTER #HICAGO ), 53!
Changhan Lee, Ph.D. $AVIS 3CHOOL OF 'ERONTOLOGY 5NIVERSITY OF 3OUTHERN
#ALIFORNIA ,OS !NGELES #! 53!
Richard F. Loeser, M.D. $IVISION OF 2HEUMATOLOGY !LLERGY AND )MMUNOLOGY
4HURSTON !RTHRITIS 2ESEARCH #ENTER 5NIVERSITY OF .ORTH #AROLINA 3CHOOL OF
-EDICINE #HAPEL (ILL .# 53!
Valter Longo, Ph.D. $AVIS 3CHOOL OF 'ERONTOLOGY 5NIVERSITY OF 3OUTHERN
#ALIFORNIA ,OS !NGELES #! 53!
)&/- &)2# )NSTITUTE OF -OLECULAR /NCOLOGY -ILAN )TALY
Martin Lotz, M.D. $EPARTMENT OF -OLECULAR AND %XPERIMENTAL -EDICINE
4HE 3CRIPPS 2ESEARCH )NSTITUTE ,A *OLLA #! 53!
Simon Melov, Ph.D. "UCK )NSTITUTE FOR 2ESEARCH ON !GING .OVATO #! 53!
Nicolas Musi, M.D. $EPARTMENT OF -EDICINE 3AM AND !NN "ARSHOP )NSTITUTE
FOR ,ONGEVITY AND !GING 3TUDIES 3AN !NTONIO 'ERIATRIC 2ESEARCH
%DUCATION AND #LINICAL #ENTER 5NIVERSITY OF 4EXAS (EALTH 3CIENCE #ENTER
3AN !NTONIO 48 53!
Peter Rabinovitch, M.D., Ph.D. $EPARTMENT OF 0ATHOLOGY 5NIVERSITY
OF 7ASHINGTON 3EATTLE 7! 53!
Contributors XV

Clifford J. Rosen, M.D. $EPARTMENT OF -EDICINE -USCULOSKELETAL #ENTER

#ENTER FOR #LINICAL  4RANSLATIONAL 2ESEARCH -AINE -EDICAL #ENTER 2ESEARCH
)NSTITUTE 3CARBOROUGH -% 53!
Cecilia G. Sanchez, Ph.D. 3ECTION OF 0ULMONARY $ISEASES #RITICAL #ARE
AND %NVIRONMENTAL -EDICINE 4ULANE 5NIVERSITY -EDICAL 3CHOOL
.EW /RLEANS ,! 53!
Katherine Schafer, M.D. $EPARTMENT OF )NTERNAL -EDICINE 3ECTION ON )NFECTIOUS
$ISEASES 7AKE &OREST 3CHOOL OF -EDICINE 7INSTON 3ALEM .# 53!
Norman E. Sharpless, M.D. $EPARTMENT OF 'ENETICS 4HE ,INEBERGER
#OMPREHENSIVE #ANCER #ENTER 5NIVERSITY OF .ORTH #AROLINA 3CHOOL -EDICINE
#HAPEL (ILL .# 53!
Farida Sohrabji, Ph.D. 4EXAS !- (EALTH 3CIENCE #ENTER "RYAN 48 53!
Tamar Tchkonia, Ph.D. $EPARTMENT OF -EDICINE 2OBERT AND !RLENE +OGOD
#ENTER ON !GING -AYO #LINIC 2OCHESTER -. 53!
Dennis C. Turk, Ph.D. $EPARTMENT OF !NESTHESIOLOGY AND 0AIN -EDICINE
5NIVERSITY OF 7ASHINGTON 3EATTLE 7! 53!
Zoltan Ungvari, M.D., Ph.D. $EPARTMENT OF 'ERIATRIC -EDICINE 2EYNOLDS
/KLAHOMA #ENTER ON !GING 5NIVERSITY OF /KLAHOMA (EALTH 3CIENCE #ENTER
/KLAHOMA #ITY /+ 53!
Tamara Vokes, M.D. $EPARTMENT OF -EDICINE 3ECTION OF %NDOCRINOLOGY
5NIVERSITY OF #HICAGO #HICAGO ), 53!
Charles Wright $EPARTMENT OF /PHTHALMOLOGY AND 6ISUAL 3CIENCES
5NIVERSITY OF +ENTUCKY ,EXINGTON +9 53!
Tony Wyss-Coray $EPARTMENT OF .EUROLOGY AND .EUROLOGICAL 3CIENCES
3TANFORD 5NIVERSITY 3CHOOL OF -EDICINE 3TANFORD #! 53!
#ENTER FOR 4ISSUE 2EGENERATION 2EPAIR AND 2ESTORATION 6ETERANS !FFAIRS 0ALO
!LTO (EALTH #ARE 3YSTEM 0ALO !LTO #! 53!
Robert P. Yezierski, Ph.D. 0AIN 2ESEARCH AND )NTERVENTION #ENTER OF %XCELLENCE
5NIVERSITY OF &LORIDA 'AINESVILLE &, 53!
Abbreviations

!!6 !DENO ASSOCIATED VIRUS

Aβ Amyloid beta
!#%I !NGIOTENSIN CONVERTING ENZYME INHIBITOR
ACL Anterior cruciate ligament
!#/3 !STHMA #/0$ OVERLAP SYNDROME
!#4 !STHMA CONTROL TEST
!$ !LZHEIMERS DISEASE
!$## !NTIBODY DEPENDENT CELLULAR CYTOTOXICITY
ADE Adverse drug events
!& !TRIAL lBRILLATION
AGE Advanced glycation end product
!(2 !IRWAY HYPERRESPONSIVENESS
!)$3 !CQUIRED IMMUNODElCIENCY SYNDROME
!+4 0ROTEIN KINASE "
!-$ !GE RELATED MACULAR DEGENERATION
!-0+ !DENINE MONOPHOSPHATE ACTIVATED PROTEIN KINASE
ANI Asymptomatic neurocognitive impairment
APP Amyloid precursor protein
!2" !NGIOTENSIN  RECEPTOR BLOCKER
!24 !NTI RETROVIRAL THERAPY
!40 !DENOSINE  TRIPHOSPHATE
"!,& "RONCHOALVEOLAR LAVAGE mUID
BBB Blood brain barrier
"$.& "RAIN DERIVED NEUROTROPHIC FACTOR
"%2 "ASE EXCISION REPAIR
"-$ "ONE MINERAL DENSITY
"-) "ODY MASS INDEX
"-0 "ONE MORPHOGENETIC PROTEIN
"-3#" -3# "ONE MARROW DERIVED STEM CELL
"-5 "ASIC MULTICELLULAR UNIT
"REG 2EGULATORY " CELLS

XVII
XVIII Abbreviations

"646 "ONE VOLUME FRACTION

CAC Coronary artery calcium
#"4 #OGNITIVE BEHAVIOR THERAPY
##) #HRONIC CONSTRICTION INJURY
CD Cluster of differentiation
CDC Center for Disease Control and Prevention
#$+ #YCLIN DEPENDENT KINASE
#%% #ONJUGATED EQUINE ESTROGENS
#&! #OMPLETE &REUNDS ADJUVANT
CFB Complement factor B
#'20 #ALCITONIN GENE RELATED PEPTIDE
#(& #ONGESTIVE HEART FAILURE
#,"0 #HRONIC LOW BACK PAIN
#- #ONDITIONED MEDIUM
#-6 #YTOMEGALOVIRUS
CNS Central nervous system
#.6 #HOROIDAL NEOVASCULARIZATION
#/,$ #HRONIC OBSTRUCTIVE LUNG DISEASE
#/-0 #ARTILAGE OLIGOMERIC PROTEIN
#/-4 #ATECHOL / METHYL TRANSFERASE
#/0$ #HRONIC OBSTRUCTIVE PULMONARY DISEASE
#/8 #YCLOOXYGENASE 
#0- #ONDITIONED PAIN MODULATION
#2 #ALORIC RESTRICTION
#20 # REACTIVE PROTEIN
#3% #IGARETTE SMOKE EXTRACT
#4 #OMPUTED TOMOGRAPHY
#4'& #ONNECTIVE TISSUE GROWTH FACTOR
#6$ #ARDIOVASCULAR DISEASE
DA Dopamine
DAergic Dopaminergic
DBP Diastolic blood pressure
DBS Deep brain stimulation
DC Dendritic cell
DDI Drug-drug interactions
DG Dentate gyrus
$(%! $EHYDROEPIANDROSTERONE
$," $EMENTIA WITH ,EWY BODIES
$,#/ #ARBON MONOXIDE DIFFUSING CAPACITY
$-- $ESTABILIZED MEDIAL MENISCUS
DPP Diabetes prevention program
$2 $IETARY RESTRICTION
$2' $ORSAL ROOT GANGLIA
$3" $OUBLE STRAND BREAK
$32 $IFFERENTIAL STRESS RESISTANCE
Abbreviations XIX

DS2.! $OUBLE STRANDED 2.!

$33 $IFFERENTIAL STRESS SENSITIZATION
DXA Dual energy X-ray absorptiometry
E2 Estradiol
%A!A 2ATIO OF EARLY TO LATE DIASTOLIC MITRAL ANNULAR VELOCITY
%"6 %PSTEIN "ARR VIRUS
%#- %XTRACELLULAR MATRIX
%& %JECTION FRACTION
%& %NHANCE&ITNESS
%-4 %PITHELIAL MESENCHYMAL TRANSITION
%0# %NDOTHELIAL PROGENITOR CELL
E14, %XPRESSION QUANTITATIVE TRAIT LOCI
%2 %NDOPLASMIC RETICULUM
%2+ %XTRACELLULAR REGULATED KINASE
%4# %LECTRON TRANSPORT CHAIN
%7!3 %PIGENOME WIDE ASSOCIATION STUDY
FDA Food and Drug Administration
FFA Free fatty acid
&'& &IBROBLAST GROWTH FACTOR
&'&2 &IBROBLAST GROWTH FACTOR RECEPTOR 
&)2+/ &AT TISSUE SPECIlC INSULIN RECEPTOR KNOCKOUT
&/8/ &ORKHEAD BOX PROTEIN /
&20 &RAILTY RELATED PHENOTYPE
&3 &RACTIONAL SHORTENING
&4)2- &OURIER TRANSFORMED INFRARED MICROEPECTROSCOPY
'! 'EOGRAPHIC ATROPHY
'!$ 'LUTAMIC ACID DECARBOXYLASE
'!,4 'UT ASSOCIATED LYMPHOID TISSUE
'$&  'ROWTH AND DIFFERENTIATION FACTOR 
'$.& 'LIAL DERIVED NEUROTROPHIC FACTOR
'%2$ 'ASTROESOPHAGEAL REmUX DISEASE
'&!0 'LIAL lBRILLARY ACIDIC PROTEIN
'&0 'REEN mUORESCENT PROTEIN
'( 'ROWTH HORMONE
'(2 'ROWTH HORMONE RECEPTOR
GTT Glucose tolerance test
'7!3 'ENOME WIDE ASSOCIATION STUDY
'ZM" 'RANZYME "
(!$ ()6 ASSOCIATED DEMENTIA
(!.! ()6 ASSOCIATED NON !)$3
(!.$ ()6 ASSOCIATED NEUROCOGNITIVE DISORDER
(!4 (ISTONE ACETYL TRANSFERASE
(#6 (EPATITIS # VIRUS
($!# (ISTONE DEACETYLASE
(%26 (UMAN ENDOGENOUS RETROVIRUSES
XX Abbreviations

(&$ (IGH FAT DIET

()6 (UMAN IMMUNODElCIENCY VIRUS
(,! (UMAN LEUKOCYTE ANTIGEN
(0! (YPOTHALAMO PITUITARY AXIS
(0# (EMATOPOIETIC PROGENITOR CELL
(0,# (IGH PRESSURE LIQUID CHROMATOGRAPHY
(06 (UMAN PAPILLOMAVIRUS
(2 (EART RATE
(3# (EMATOPOIETIC STEM CELLS
HS#20 (IGH SENSITIVITY # REACTIVE PROTEIN
(30 (EAT SHOCK PROTEIN
(36 (ERPES SIMPLEX VIRUS
(4 (ORMONE THERAPY
)#( )NTRACEREBRAL HEMORRHAGE
)#3 )NHALED CORTICOSTEROIDS
I-FABP Intestinal fatty acid binding protein
IFN Interferon
)'& )NSULIN LIKE GROWTH FACTOR
IGFBP IGF binding protein
IGT Insulin glucose tolerance test
), )NTERLEUKIN
).$ )NVESTIGATIONAL NEW DRUG
I./3 )NDUCIBLE NITRIC OXIDE SYNTHASE
)/- )NSTITUTE OF -EDICINE
)0& )DIOPATHIC PULMONARY lBROSIS
iPS/iPSC Induced pluripotent stem cell
)2 )ONIZING RADIATION
)2!0 ),  RECEPTOR ANTAGONIST PROTEIN
)23 )NSULIN RECEPTOR SUBSTRATE 
)3( )SOLATED SYSTOLIC HYPERTENSION
)4- )NTIMA MEDIA THICKNESS
ITP Interventions Testing Program
+-4 ,YSINE METHYL TRANSFERASE
,"0 ,OW BACK PAIN
LBP LPS binding protein
,$, ,OW DENSITY LIPOPROTEIN
L-DOPA Levo-DOPA
LNC2.! ,ONG NON CODING 2.!
,/! ,ATE ONSET ASTHMA
,03 ,IPOPOLYSACCHARIDE
,3! ,ONG STANDING ASTHMA
,3$ ,YSINE SPECIlC DEMETHYLASE
,6 ,EFT VENTRICLE
,6( ,EFT VENTRICULAR HYPERTROPHY
-!# -EMBRANE ATTACK COMPLEX
Abbreviations XXI

-!/ " -ONOAMINE OXIDASE "

-!0 -EAN ARTERIAL PRESSURE
-#!O -IDDLE CEREBRAL ARTERY OCCLUSION
-#!4 -ITOCHONDRIAL DIRECTED CATALASE
-$ -YELOID DIFFERENTIATION FACTOR 
-$0 -ITOCHONDRIAL DERIVED PEPTIDES
MI2.!MI2 -ICRO2.!
--0 -ATRIX METALLOPROTEINASE
--3% -INI MENTAL STATUS EXAM
-.$ -ILD NEUROCOGNITIVE DISORDER
M040 -ITOCHONDRIAL PERMEABILITY TRANSITION PORE
-2) -AGNETIC RESONANCE IMAGING
-23 -AGNETIC RESONANCE SPECTROSCOPY
-3# -ARROW STROMAL CELL
-3# -ESENCHYMAL STEM CELL
MT$.! -ITOCHONDRIAL $.!
M4/2 -ECHANISTIC TARGET OF RAPAMYCIN
M4/2# M4/2 COMPLEX 
MT2/3 -ITOCHONDRIAL 2/3
.!$ .ICOTINAMIDE ADENINE DINUCLEOTIDE
.!$# .ON !)$3 DElNING CANCERS
NC2.! .ON CODING 2.!
.%2 .UCLEOTIDE EXCISION REPAIR
.%4 .EUTROPHIL EXTRACELLULAR TRAP
.(%* .ON HOMOLOGOUS END JOINING
NIA National Institute on Aging
.)( .ATIONAL )NSTITUTES OF (EALTH
.+ CELL .ATURAL KILLER CELL
.,20 .UCLEOTIDE BINDING DOMAIN AND LEUCINE RICH REPEAT PYRIN DOMAIN
containing 3
.-$! . METHYL $ ASPARTATE
./ .ITRIC OXIDE
./8 .!00 ( OXIDASE
NPC Neural precursor/progenitor cell
.RF .UCLEAR FACTOR ERYTHROID DERIVED 
.24) .UCLEOST IDE REVERSE TRANSCRIPTASE INHIBITOR
.3!)$ .ONSTEROIDAL ANTI INmAMMATORY DRUG
NV!-$ .EOVASCULAR !-$
/! /STEOARTHRITIS
OPG Osteoprotegerin
/2 /DDS RATIO
/2& /PEN READING FRAME
0!-0 0ATHOGEN ASSOCIATED MOLECULAR PATTERN
0!7( 0EOPLE AGING WITH ()6
0"-# 0ERIPHERAL BLOOD MONONUCLEAR CELL
XXII Abbreviations

0$ 0ARKINSONS DISEASE
0$ 0ROGRAMMED CELL DEATH PROTEIN 
0$'& 0LATELET DERIVED GROWTH FACTOR
0%$& 0IGMENTED EPITHELIUM DERIVED FACTOR
0%4 0OSITRON EMISSION TOMOGRAPHY
PGC-1α 00!2 GAMMA COACTIVATOR  ALPHA
PGE2 Prostaglandin E2
0(" 0ROHIBITIN 
0) 0ROTEASE INHIBITOR
0)+ 0HOSPHATIDYL INOSITOL  KINASE
0+! 0ROTEIN KINASE !
0+# 0ROTEIN KINASE #
0-. 0OLYMORPHONUCLEAR CELL
Polg DNA polymerase gamma
00!2γ 0EROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA
P1#4 0ERIPHERAL QUANTITATIVE COMPUTED TOMOGRAPHY
022 0ATTERN RECOGNITION RECEPTOR
PSNL Partial sciatic nerve ligation
0364 0AROXYSMAL SUPRAVENTRICULAR TACHYCARDIA
04%. 0HOSPHATASE AND TENSIN HOMOLOG
04( 0ARATHYROID HORMONE
2!!3 2ENIN ANGIOTENSIN ALDOSTERONE SYSTEM
2!'% 2ECEPTOR FOR ADVANCED GLYCATION END PRODUCT
2!.+, 2ECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA " LIGAND
2!0 2ETINAL ANGIOMATOUS PROLIFERATION
2!3 2ENIN ANGIOTENSIN SYSTEM
2" 2ETINOBLASTOMA
2#4 2ANDOMIZED CONTROL TRIAL
2) 2ECOMBINANT INBRED
2.3 2EACTIVE NITROGEN SPECIES
2/3 2EACTIVE OXYGEN SPECIES
20% 2ETINAL PIGMENTED EPITHELIUM
236 2ESPIRATORY SYNCYTIAL VIRUS
24 2EVERSE TRANSCRIPTASE
24, 2ECOMBINANT 4 CELL RECEPTOR LIGAND
3!"! 3HORT ACTING B ADRENERGIC  RECEPTOR AGONIST
SA-βGal Senescence-associated beta galactosidase
3!(& 3ENESCENCE ASSOCIATED HETEROCHROMATIC FOCI
3!- 3ENESCENCE ACCELERATED MOUSE
3!30 3ENESCENCE ASSOCIATED SECRETORY PHENOTYPE
SBP Systolic blood pressure
sCD Soluble cluster of differentiation
3$ /#4 3PECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY
3%2- 3ELECTED ESTROGEN RECEPTOR MODULATOR
3': 3UBGRANULAR ZONE
Abbreviations XXIII

3(2 3PONTANEOUSLY HYPERTENSIVE RAT

3)24 3IRTUIN
3)6 3IMIAN IMMUNODElCIENCY VIRUS
SNAE Serious non-AIDS events
3.0 3INGLE NUCLEOTIDE POLYMORPHISM
SNpc Substantia nigra pars compacta
3.3 3YMPATHETIC NERVOUS SYSTEM
3/$ 3UPEROXIDE DISMUTASE
30& 3PECIlC PATHOGEN FREE
304 3KIN PRICK TESTING
32- 3ELECTED REACTION MONITORING
STAT Signal transducer and activator of transcription
36: 3UBVENTRICULAR ZONE
T Testosterone
4$- 4YPE  DIABETES MELLITUS
TB Tuberculosis
4# 4AI #HI
4#2 4 CELL RECEPTOR
4%24 4ELOMERASE REVERSE TRANSCRIPTASE
TGFβ 4RANSFORMING GROWTH FACTOR BETA
4)! 4RANSIENT ISCHEMIC ATTACK
4)-0 4ISSUE INHIBITOR OF MATRIX METALLOPROTEINASE
4,2 4OLL LIKE RECEPTOR
TNFα 4UMOR NECROSIS FACTOR ALPHA
4.&2 4UMOR NECROSIS FACTOR RECEPTOR 
tPA Tissue plasminogen activator
4REG 2EGULATORY 4 CELLS
43! 4RICHOSTATIN !
502 5NFOLDED PROTEIN RESPONSE
503 5BIQUITIN PROTEASOME SYSTEM
UPS Unfolded protein stress
6% 6ENTRICULAR ECTOPY
6%'& 6ASCULAR ENDOTHELIAL GROWTH FACTOR
6%'&2 6%'& RECEPTOR
6&! 6ERTEBRAL FRACTURE ASSESSMENT
7() 7OMENS (EALTH )NITIATIVE
72. 7ERNERS
The Geroscience Hypothesis: Is It Possible
to Change the Rate of Aging?

Steven N. Austad

Contents
1 Introduction 1
2 Aging and Its Relation to Disease 3
3 Experimental Organisms in Aging Research 4
3.1 Uses and Caveats in the Use of Model Organisms 4
3.2 Worms (Caenorhabditis elegans) 6
3.3 Fruit Flies (Drosophila melanogaster) 8
3.4 Laboratory Mice (Mus musculus) 8
3.5 Other Species 10
4 Is It Really Possible to Change the Rate of Aging? 11
4.1 Dietary Restriction: The First Experimental Paradigm 12
4.2 Genetic Approaches to Retarding Aging 18
4.3 Pharmacological Approaches to Retarding Aging 22
5 Future Directions 26
References 27

1 Introduction

In the 200,000 year history of anatomically modern humans, we have never lived
remotely as long as we do today. The rate of change in our life expectancy has been
breathtaking. For the past 175 years, the mean age-at-death has increased steadily
by about 2.5 years per decade, or 6 h per day, among the longest-lived countries [1].
While in the early part of the twentieth century, the rise in life expectancy was

S.N. Austad, Ph.D. (*)

Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA
e-mail: austad@uab.edu

© Springer International Publishing 2016 1

F. Sierra, R. Kohanski (eds.), Advances in Geroscience,
DOI 10.1007/978-3-319-23246-1_1
2 S.N. Austad

5000

2000 (82)

4000
Deaths per 100,000

3000

2000

1000

0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110+
Age

10,000

1900 (54)
8000
Deaths per 100,000

6000

4000

2000

0
0 20 40 60 80 100
Age

Fig. 1 Distribution of deaths as a function of age among Swedish women from the years 1900 and
from 2000. Birth and death data from Swede are among the most reliable in the world. Note that
more than 90 % of the population reached age 65 in the year 2000 compared with only 50 % reach-
ing that age in 1900. Numbers in parentheses are life expectancies at birth (Data from the Human
Mortality Database (downloaded November 2014))
The Geroscience Hypothesis: Is It Possible to Change the Rate of Aging? 3

driven mainly by reduced infant and young adult mortality, more recently bigger
advances have been made in combating later life diseases (Fig. 1). As a consequence
chronic health problems associated with aging, such as sarcopenia, osteoporosis,
and Alzheimer’s disease, which were once rare, have become common. As the
global population continues to age over the coming decades, maladies of aging
threaten to overwhelm our healthcare infrastructure, disrupt our national econo-
mies, and potentially poison relations among generations. Fortunately, understand-
ing of the basic biology of aging has also progressed rapidly in the past several
decades such that the promise of medical interventions that enhance and lengthen
healthy life is no longer an empty promise promulgated only by avaricious quacks
and charlatans. The economic impact of generalized health extension could be stun-
ning. According to one analysis, slowing the rate of human aging by 20 % would be
worth more than $7 trillion over the next 50 years in the United States alone [2].
The likelihood that we will ultimately be able to slow human aging depends on
our understanding of underlying processes. I have claimed that such understanding
has progressed rapidly in recent decades. What is the evidence for such a claim?
How realistic is the promise of medically extended healthy life? Those are the topics
of this chapter.

2 Aging and Its Relation to Disease

No 60 year old – even the healthiest, hardest-training, and most disease-free 60 year
old – can sprint as fast or throw as far as she could as a healthy 25 year old. This is
prima facie evidence that aging, the progressive decline in physical function that
accompanies growing older, occurs even in the absence of disease. However aging
is so intimately intertwined with numerous diseases and disabling conditions that
almost any discussion that begins with aging ends on disease. Although aging occurs

Table 1 Death rates from selected diseases in the United States (2010) * indicates the disease is
essentially nonexistent at this age.
Age group
35–44 45–54 55–64 65–74 75–84 85+
Malignant neoplasms 29 112 300 666 1202 1730
Diabetes mellitus 4 13 32 68 144 286
Diseases of the heart 26 82 187 409 117 4285
Alzheimer’s disease * 0.3 2 20 185 987
Parkinson’s disease * 0.2 1 12 75 166
Influenza & Pneumonia 2 4 10 28 102 426
COPD 2 10 39 146 370 691
Stroke 5 13 30 82 288 994
Data from Murphy et al. [3]
Rates are per 100,000 population in the specific age group based on the 2010 U.S. Census
4 S.N. Austad

even in the absence of disease, it clearly increases vulnerability to multiple diseases.

In other words, aging is a risk factor for diseases. In fact, it is by far the biggest risk
factor for virtually all of the chronic diseases that strain our health care system today
and it increases the chances that a given disease will be fatal (Table 1). For instance
in 2010, an American 75–84 years old had a 42-fold greater chance of dying of can-
cer, and a 45-fold greater chance of dying of heart disease, than a 35–44 year old.
The chances of dying from Alzheimer’s disease increase more than 600-fold between
age 50 and 80 [3]. For comparison, smoking only increases overall mortality rate by
threefold compared with nonsmokers (http://www.cdc.gov/tobacco/data_statistics/
fact_sheets/health_effects/tobacco_related_mortality/) and having two copies of the
ApoE4 allele, the most common genetic risk factor for Alzheimer’s disease, increases
an individual’s chances of contracting that disease by only 12-fold relative to those
with two copies of the ApoE3 allele [4]. Looked at from this perspective, aging is by
far the biggest threat to human health in the developed world today. Geroscience, the
topic of this book, is an interdisciplinary field seeking to understand the basis for the
relationship between aging and disease vulnerability.
The Geroscience Hypothesis posits that, because aging underlies so many dis-
eases and disabling conditions, interventions that would retard aging would also
simultaneously prevent or delay the onset of multiple chronic diseases. In recent
years there has been success at delaying cardiovascular diseases. Over the first
decade of the twenty-first century, the age-adjusted death rate from heart diseases
fell by more than 30 % and for stroke fell by more than 35 % [5, 3]. One contribut-
ing factor is the discovery of treatments that address underlying risk factors such as
high blood pressure and high cholesterol. There has also been progress against a
major behavioral risk factor – smoking. Importantly though, aging is a bigger risk
to health than high blood pressure, cholesterol, and smoking combined. If we could
similarly learn to treat the risk factor of aging, the health benefits would be enor-
mous, not only for delaying fatal diseases but in delaying many nonfatal conditions
such as hearing and vision loss, osteoporosis, and arthritis that degrade the quality
of later life.

3 Experimental Organisms in Aging Research

3.1 Uses and Caveats in the Use of Model Organisms

For most of its history, basic aging research relied on standard laboratory animals
such as fruit flies, mice, and rats. The chief advantage of these animals was that their
laboratory husbandry was established and that they were short-lived. That is, rats
and mice are short-lived among mammals, fruit flies are relatively short-lived
among insects. Initially, basic aging research focused on describing physiological
changes occurring during aging in the hope that the nature of these changes would
reveal underlying aging mechanisms. Short-lived animals were useful because indi-
viduals could be monitored throughout their lives and the longevity of different
The Geroscience Hypothesis: Is It Possible to Change the Rate of Aging? 5

groups could be compared and contrasted. Until recently, lengthening of life was
assumed to be sufficient evidence that aging had been slowed. This view has recently
been questioned as will be discussed later, but it has dominated the history of exper-
imental aging research.
After dietary restriction (DR), simply reducing the amount of available food, was
discovered to lengthen life in many laboratory rats and mice, attention shifted to
searching for mechanism(s) by which DR had these effects and also searching for
other methods of life extension. Again, the rate limiting step for such studies was the
length of the animals’ lives. But even the shortest-lived species commonly used in
this research lived months (fruit flies) or years (mice and rats), and because the
focus was on increasing lifespan, aging studies were particularly time-consuming
compared with other areas of biomedical research.
It is important to understand why the focus so quickly fell on lengthening life
rather than shortening it. In principle, understanding basic aging processes could
be studied much more quickly by accelerating them rather than retarding them.
The practical difficulty with this logical approach is that there are many ways to
shorten animals’ lives by inducing pathological processes that may have nothing to
do with normal aging processes. The problem is how would we know the differ-
ence between those aberrant pathologies and normal aging processes? This doesn’t
mean that so-called accelerated aging models, which do exist, are not informative.
It does mean that such models are difficult to evaluate with respect to normal aging
and findings from them need to be interpreted with considerable care. For instance,
the so-called Senescence Accelerated Mouse (SAM mouse) is a series of excep-
tionally short-lived mouse strains, created by accidental outbreeding of an AKR/J
inbred strain with an unknown other strain. Despite their short lives – most live
less than 1 year – they have had virtually no impact on the larger mouse aging
research field, because like all so-called accelerated aging models, they replicate at
best a few of the features of normal aging and the fidelity of that replication is not
clear.
Experiments that lengthen life are much less problematic to interpret. Animals
are unlikely to live longer if we haven’t retarded at least some normal aging process,
such as the increasing susceptibility to cancer. We may not have retarded them all
(however many that may be), but we must have retarded some. To verify that one
had identified a mechanism regulating aging, generally, the mantra for many years
was that both mean (or median) and maximum longevity must be extended.
Maximum longevity is generally defined as the mean longevity of the oldest x% of
the starting population, where x often equals 10 %. The focus on maximum longev-
ity implies that ameliorating a specific disease process may impact mean longevity,
but only by affecting aging itself would both the mean and the length of life of the
longest-lived animals be longer. For example, if group A displays longer mean or
median survival, but no difference in maximum survival than group B, then group
A must have experienced higher mortality rate than group B in the latter part of life.
Higher mortality late in life is not a trait that one would associate with slower aging.
For this reason exercise, which consistently increases mean longevity in both rats
and people [6, 7] and has manifold beneficial health-preserving effects, is not gen-
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 A folding table frame, designed as a support for a circular split-
bamboo tray, is shown in the photographs reproduced and detailed
in the working drawing. It is a serviceable and inexpensive piece of
furniture, and can be constructed readily by the home mechanic. As
the trays vary in size, the frame must be made to correspond, those
from 24 to 28 in. in diameter being satisfactory. The tray may be
made by the ambitious craftsman or purchased at stores dealing in
Oriental goods. A wooden top may, of course, be substituted. The
frame is made preferably of soft wood. The following finished pieces
are required for a 24-in. tray: 4 legs, ⁷⁄₈ by 3 by 30 in.; 4 crosspieces,
1 by 2 by 25 in. Mortise the legs to the ends of the crosspieces, one
set of mortises being ⁷⁄₈ in. below the other. Assemble the parts and
fasten the joints with glue and 2-in. flat-head screws, countersunk.
 This Tray Table Is Readily Portable, and Useful in the House and on the
Porch or Lawn

Adjust the crosspieces of each set so that their centers match, and
fasten them in this position with screws, from the under side. The
two parts of the frame revolve on them when the table is “knocked
down.” On the ends of the lower crosspieces of each set, fasten
blocks to level the support for the tray. Finish the frame to harmonize
with the furniture of the room. Conceal the screw heads under bands
of hammered or oxidized copper, fastened with copper or brass pins.
A second tray may be placed on the lower crosspieces.—F. E. Tuck,
Nevada City, Calif.
 Small Desk Lamp Supported by Paper Weight
Those who wish a small desk light that may be pushed back out of
the way in the daytime, will find the accompanying sketch of interest.
When in use on a roll-top desk, the lamp is placed on top near the
edge, so that the bulb overhangs. A 25-watt lamp will light the bed of
the desk, and the small metal shade is so placed that no part of the
bulb is visible to the eye of the worker. By providing a suitable base,
the lamp may be adapted to other uses. A stock paper weight, about
2 in. in diameter and covered with green felt, was used as a base. An
ordinary drop-cord socket is provided, and to one side of the top cap
a strip of brass, ¹⁄₁₆ by ¹⁄₂ in., is soldered. A hole is drilled near the
end of this strip so that the screw which holds the knob will also hold
the socket. Connect the flexible cord in the usual manner.
 The shade is made of sheet metal, bent in the form of a cone,
having the front shorter than the opposite edge. Make a sketch of the
bulb, and determine the lengths of the two sides A and B, and then
draw two concentric circles of corresponding radii on paper, as
indicated in the small diagram. The proper curve for the shade will
then lie between these two circles. Cut a paper pattern, and form it
into a cone. After the proper shape is determined, mark it on the
metal, cut it to shape, and solder it. A small spring clip, C, engages
the tip of the bulb; the back of the shade is held by a piece of spring
wire, D. It is easy to spring the shade off in replacing the bulb. The
outside of the shade should be enameled an olive-green.—John D.
Adams, Phoenix, Arizona.
 Device Frightens Flies at Screen Door

The Scalloped Roller is Revolved Rapidly When the Door is Opened,

Frightening Flies

An effective means of frightening flies away from a screen door

may be made from a spring curtain rod and cotton duck. Scallops of
8-oz. duck, 6 in. long, are fastened to the pole, on opposite sides, as
shown. The ratchet on the end of the pole is arranged so as not to
catch. A small cord is wound around the pole and fastened to the
screen door. The rod supports are fixed near the top of the door
frame.—Josef H. Noyes, Paris, Tex.
Porch Swing Made from Automobile Seat
The Seat Discarded from a Rebuilt Car was Put to Good Use
 When an obsolete type of automobile was converted into a truck
for marketing purposes, a leather-upholstered seat, discarded, was
utilized as an attractive and comfortable porch swing. Hooks were
secured to the front corners of the seat and to the upper edge of the
back, for the chains attached to suitable supports.—George L.
Ayers, Washington, D. C.
 Linoleum Panels for a Homemade Chest
A strong packing box was converted into a useful and not
unsightly chest by covering it with panels of linoleum left over from a
job of covering a floor. Strips, ¹⁄₂ by 2 in. wide, were nailed around
the corners of the box to form a panel on the top, sides, and ends.
The wood and the linoleum were shellacked, and made a good
appearance.

¶The lower corner of an envelope may be used as a small funnel.

Camera for Bird Photography
 Bird Images Large Enough to Show Identification Markings are Obtained
with This Camera

A reasonably large image must be obtained in photographing bird

life, or the details of plumage and identification are lost, reducing the
value of the pictures. The “gun camera” shown in the photograph
was devised for this purpose, and with it exposures may be made
more quickly than with the telephoto type of camera, a feature of
great value in this class of photography. The device consists of an
ordinary reflecting-type camera, mounted on a carriage for ready
portability and quick adjustment. The bellows is supplemented with a
tube, permitting the use of lenses of upward of 30-in. extreme focus.
This gives a larger image without loss in speed. A ¹⁄₄-in. image of a
bird was obtained with a 7¹⁄₂-in. extreme-focus lens, as against a 2-
in. image with one of 30-in. focus, from the same position. The lens
is set near the rear end of the tube, giving a deep hood for shading
the sunlight. Lenses of an old type, known as “Long Toms,” were
used. They are inexpensive compared with newer types with iris
diaphragms, and give good results even at ¹⁄₁,₀₀₀ exposures.—Arthur
Farland, New Orleans, La.
 Electric Fan an Aid to Heating Room
The electric fan is useful not only for cooling the air in summer, but
also for distributing the warm air to advantage in the winter. An
efficient way of warming a room fairly uniformly is to place an electric
fan near a radiator, so that its breeze passes through the heating
coils, or near another source of heat. The heat is circulated around
the room, instead of being kept in a limited area.—Peter J. M. Clute,
Schenectady, N. Y.
Cat-and-Bells Scarecrow
 A scarecrow resembling a living animal is often more effective
than other devices, and the cat-and-bells arrangement shown in the
sketch was found especially so. The hide of a cat was stretched over
a hollow frame and suspended by a cord from a large weather vane.
Several bells were attached to the cord, and when the vane shifts in
the wind, the movement of the hide and the rattling of the bells
combine to frighten the birds.—F. H. Sweet, Waynesboro, Va.

¶A coating of five parts of coal tar, one part gasoline, and one part
japan drier will make canvas nearly water-tight.
 A Small Hydraulic Turbine
By FRANK D. BELL

C onsiderable power and speed can be developed under ordinary

water-supply pressure by the turbine, or water motor, shown in
the sketch and detailed in the working drawings. The parts are of
simple construction, and the machine may be assembled or taken
down easily. It is useful for either belt or direct connection to
electrical generators, small machines, etc., the direct connection
being preferable for a generator. The wheel is built up of sheet metal
and provided with curved buckets set in the saw-tooth edge. The
water is admitted through an opening in the lower part of the housing
and passes out at the opposite end into a suitable drain pipe. The
housing is made of two sections, the main casting and a cover plate.
Bearings for the shaft are cast into the housing, which is reinforced
on the back by ribs radiating from the center.
View of the Water Turbine with the Cover Plate Removed, Showing Inlet and
Drain

Wooden patterns are made for the housing, the main casting and
the cover plate being cast separately. The pattern for the cover plate
should provide for the bearing lug, as shown in the sectional detail,
and for the angle forming a support at the bottom. Special attention
should be given to allowance for proper draft in making the pattern
for the main casting; that is, the edges of the reinforcing ribs, and the
sides of the shell should be tapered slightly to make removal from
the sand convenient. The advice of a patternmaker will be helpful to