Ebook Textbook of aging skin: Part 1

(BQ) Part 1 book Textbook of aging skin presents the following contents: Histology, physiology, specialized skin - Genital, rheology, metabolism, molecular biology, endocrinology, stratum corneum, endogenous and exogenous factors in skin aging.

Textbook of Aging Skin

Miranda A Farage, Kenneth W Miller and Howard I Maibach Editors

Textbook of Aging Skin

With 366 Figures and 156 Tables

Miranda A Farage, Ph.D

Principal Scientist

The Procter & Gamble Company

6110 Center Hill Avenue

Cincinnati, OH 45224

USA

Kenneth W Miller, Ph.D

Associate Director

The Procter & Gamble Company

6110 Center Hill Avenue

This publication is available also as:

Electronic publication under ISBN 978-3-540-89656-2

Print and electronic bundle under ISBN 978-3-540-89935-8

This work is subject to copyright All rights are reserved, whether the whole or part of the material isconcerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,reproduction on microfilm or in any other way, and storage in data banks Duplication of this publication orparts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in itscurrent version, and permission for use must always be obtained from Springer Violations are liable toprosecution under the German Copyright Law

ß Springer-Verlag Berlin Heidelberg 2010

The use of general descriptive names, registered names, trademarks, etc in this publication does not imply,even in the absence of a specific statement, that such names are exempt from the relevant protective lawsand regulations and therefore free for general use

Product liability: The publishers cannot guarantee the accuracy of any information about dosage andapplication contained in this book In every individual case the user must check such information byconsulting the relevant literature

Springer is part of Springer Science+Business Media

www.springer.com

Publishing Editor: Tobias Kemme

MRW Editor: Sandra Fabiani

Printed on acid‐free paper

Dedicated to those on a forgotten and sometimes lonely and scary aging journey—much more dignity and respect are deserved for all of you.

– MAF, KWM and HIM

When things go wrong as they sometimes will,

When the road you’re trudging seems all uphill,

When the funds are low and the debts are high,

And you want to smile but you have to sigh,

When care is pressing you down a bit

Rest if you must, but don’t you quit.

Success is failure turned inside out,

The silver tint on the clouds of doubt,

And you can never tell how close you are,

It may be near when it seems afar.

So, stick to the fight when you’re hardest hit

It’s when things go wrong that you mustn’t quit.

—Unknown

Deep appreciation and grateful thank-yous are extended to the significant efforts of many people who contributed bothknowingly and indirectly to this book, by dedicating their valuable time in preparing their chapters This bookrepresents the fruits of a jointly conceived and executed venture, and has also benefited from global and diverse partners

A special thank-you to Dr Mark Dato and Mr Ron Visscher for generously offering their time and expertise in reviewing the relevant chapters and extending their immense support to this book No praise is excessive for theirefforts, and our heartfelt gratitude goes to them

peer-We would like to single out Mr Anil Joseph Chandy (Springer Reference Editorial Office) for a special recognition ofhis great effort, time, discipline, and dedication in moving this book forward in a timely and organized manner Weextend our appreciation to Ms Marion Philipp and Ms Ellen Blasig (Springer Heidelberg) too for the same

Last but not least, we acknowledge the assistance provided by Dr Deborah A Hutchins, Ms Zeinab Schwen,

Ms Wendy Wippel, Ms Gayle Entrup, Ms Jan Tremaine, Ms Peggy Firth, and Dr T L Nusair for this book Theircollective recommendations and input have vastly improved the texts assembled here

Above all, we extend our everlasting gratitude and love to our parents, who inspired us and to our families andchildren, who supported and encouraged us all the way with their incredible patience Only their continuous care,unconditional love, and incomparable sacrifice made all this possible, and easy to achieve

Howard I Maibach

The population is aging rapidly Centenarians are no longer a rarity The fastest growing segment of the population inthe United States is people over 80 In the next 25 years, half of the population in the United States will be aged over 50.These shifts will have a tremendous impact on the delivery of healthcare to the elderly and will require a newawareness of how cutaneous disorders affect the quality of life, comprising a heavy burden on health and wellbeing.Physicians and healthcare workers are woefully ignorant of the distress, discomfort, and anxieties of people afflicted

by disorders of the skin There exists a widespread misconception that skin disorders are simply cosmetic nuisances thatcan be self-treated by a great assortment of anti-aging creams and lotions available at the local drug store Most of theseinclude high-sounding ingredients such as antioxidants, vitamins, nutrients, botanicals, and ancient folkloristicremedies, the efficacy and safety of which have never been tested They offer little more than hope in a bottle Thefact is that common skin diseases may not often be lethal but can ruin enjoyment of life Chronic itchy rashes can bemaddening, lowering one’s self-esteem, embarrassing, interfering with sleep, and often accompanied by depression,social isolation, and deterioration of appearance; they can also be uncomfortable, and, not least, costly to treat.The elderly commonly take 15–20 oral supplements daily to fight the ailments of old age These are generally uselessand may be harmful, often interacting adversely with prescription drugs The elderly often resort to alternativemedicines instead of seeing their doctor to obtain FDA-approved drugs, and also often skip their daily doses to savemoney Noncompliance is common Misdiagnosis and mistreatment of the elderly by health-care workers are common.National surveys show that skin diseases increase steadily throughout our lifespan Old people may have as many as 5–10coexistent cutaneous problems that are worthy of medical attention Moreover, the clinical manifestations of skindiseases in the aged often have different appearances than in the young, confounding diagnosis Importantly, healing ofchronic lesions, especially ulcers, is impaired in the elderly Immunity is weakened, increasing susceptibility toinfections Response to treatment is slower, leading to noncompliance Adverse drug reactions are common and toocommonly not suspected Management of chronic conditions is difficult and frustrating

The above litany of problems makes this textbook edited by Farage, Miller, and Maibach a welcome addition to theliterature It is invaluable as a reference resource covering exhaustively an enormous number of clinical conditions Notopic is neglected including cosmetic treatments The numerous contributions are by highly qualified experts who have

a published record of expertise

This comprehensive volume is also practical and relevant to the everyday world of clinical practice The informationwill be useful to physicians, manufacturers of drugs and skincare products, educators, investigators, nursing homepersonnel, estheticians, and federal regulators

This first edition is up-to-date, including much new material that belongs to the shelves of every library, which dealswith geriatric problems Dermatologists especially will be remiss if they do not put this volume within easy reach forconsultation as they encounter a swelling clientele of aging patients

Albert M Kligman M.D., Ph.D

Professor EmeritusUniversity of Pennsylvania

Philadelphia, PA

USA

The skin is a portal of knowledge on aging From its softness and smoothness in infancy, through its suppleness in youth,

to its wrinkled texture in elders, the skin displays the most visible and accessible manifestations of aging

Due to falling birth rates and rising life expectancies in industrialized countries, the average age of the population isincreasing Research interest in the process of aging has grown and people are becoming obsessed with looking and

“staying” young

Although excellent compendia exist on the subject of aging skin, the body of knowledge is burgeoning quently, this handbook compiles information into one comprehensive reference It covers a range of topics, from thebasics of skin structure and function, to the cellular and molecular mechanisms of aging, to the latest bioengineeringinstruments used to assess age-related changes in the skin The Nobel Prize in Physiology and Medicine awarded in 2009

Conse-to Drs E H Blackburn, C W Greider and J W Szostak will stimulate research that will ameliorate the effects of aging

on the organ systems of both humans and animals

This textbook will simplify approaches when the skin may be an efficient approach to aging based on Dr Blackburn’steam research The skin approachability and the opportunities to work on humans will provide us in the near futurewith rapid therapeutic and preventive applications

Contributors are internationally recognized experts from multiple disciplines germane to this topic We gratefullyacknowledge all contributors for sharing their time and expertise

We expect this handbook to be valuable to researchers and students with an interest in aging skin Because researchprogress in this area is so rapid, we hope to update this compendium periodically as advances in the field dictate.The editors welcome suggestions for the second edition

Miranda A Farage, Kenneth W Miller, and Howard I Maibach

October 2009

Table of Contents

Editors xxiii

List of Contributors xxv

Part 1 Basic Sciences 1

Histology 3

1 Skin Aging in Animal Models: Histological Perspective 5

Tapan K Bhattacharyya 2 Histology of Microvascular Aging of Human Skin 13

Peter Helmbold 3 Basophilic (Actinic) Degeneration of the Dermis: An Easy Histological Scoring Approach in Dermal Photoaging 19

Peter Helmbold Physiology 23

4 Degenerative Changes in Aging Skin 25

Miranda A Farage Kenneth W Miller Howard I Maibach 5 Skin Aging: A Brief Summary of Characteristic Changes 37

Christina Raschke Peter Elsner 6 Physiological Variations During Aging 45

Ge´rald E Pie´rard Philippe Paquet Emmanuelle Xhauflaire-Uhoda Pascale Quatresooz 7 The Stratum Corneum and Aging 55

Anthony V Rawlings 8 The Importance of Extracellular Matrix Protein 1 as Basement Membrane Protein in Maintaining Skin Function 77

Sandy Sercu Noritaka Oyama Joseph Merregaert 9 Pathomechanisms of Endogenously Aged Skin 93

Evgenia Makrantonaki Christos C Zouboulis 10 Pathomechanisms of Photoaged Skin 101 Jean Krutmann

11 Proteoglycans in Skin Aging 109Franc¸ois-Xavier Maquart Ste´phane Bre´zillon Yanusz Wegrowski

12 Possible Involvement of Basement Membrane Damage by Matrix Metalloproteinases

and Serine Proteinases in Skin Aging Process 121Satoshi Amano

13 Aging and Intrinsic Aging: Pathogenesis and Manifestations 129Hanan Assaf Mohamed A Adly Mahmoud R Hussein

14 Buffering Capacity Considerations in the Elderly 139Jacquelyn Levin Howard I Maibach

15 Neurotrophins and Skin Aging 147Mohamed A Adly Hanan Assaf Mahmoud R Hussein

16 Considerations for Thermal Injury: The Elderly as a Sensitive Population 159Donald L Bjerke

17 Skin Reactivity of the Human Face: Functional Map and Age Related Differences 173Slaheddine Marrakchi Howard I Maibach

18 Cluster of Differentiation 1d (CD1d) and Skin Aging 183Mohamed A Adly Hanan Assaf Mahmoud R Hussein

19 Aging of Epidermal Stem Cells 191Alexandra Charruyer Ruby Ghadially

20 Adipose-derived Stem Cells and their Secretory Factors for Skin Aging 201Byung-Soon Park Won-Serk Kim

21 Peroxisome Proliferator-activated Receptors: Role in Skin Health and Appearance

of Photoaged Skin 213Stacy S Hawkins William Shingleton Jean Adamus Helen Meldrum

22 Hyaluronan and the Process of Aging in Skin 225Robert Stern

23 Changes in Nail in the Aged 239Nelly Rubeiz Ossama Abbas Abdul Ghani Kibbi

Specialized Skin: Genital 245

24 Vaginal Secretions with Age 247Paul R Summers

25 Unique Skin Immunology of the Lower Female Genital Tract with Age 253Paul R Summers

xiv Table of Contents

26 Aging Genital Skin and Hormone Replacement Therapy Benefits 257William J Ledger

32 Fibulin-5 Deposition in Human Skin: Decrease with Aging and UVB Exposure

and Increase in Solar Elastosis 333Satoshi Amano

Endocrinology 341

33 Sebum Production 343Claudine Pie´rard-Franchimont Pascale Quatresooz Ge´rald E Pie´rard

34 Climacteric Aging and Oral Hormone Replacement Therapy 353Pascale Quatresooz Claudine Pie´rard-Franchimont Ge´rald E Pie´rard

35 Biological Effects of Estrogen on Skin 361Zack Thompson Howard I Maibach

38 Aging and Melanocytes Stimulating Cytokine Expressed by Keratinocyte

and Fibroblast 385Mutsumi Okazaki

39 Cyanoacrylate Skin Surface Strippings 393Claudine Pie´rard-Franchimont Jorge Arrese-Estrada Pascale Quatresooz Ge´rald E Pie´rard

40 Biology of Stratum Corneum: Tape Stripping and Protein Quantification 401Ali Alikhan Howard I Maibach

Endogenous and Exogenous Factors in Skin Aging 409

41 Effect of Ozone on Cutaneous Tissues 411Giuseppe Valacchi

42 Infrared A-induced Skin Aging 421Peter Schroeder Jean Krutmann

43 Global Warming and its Dermatologic Impact on Aging Skin 427Young Hui Haw-Yueh Thong Howard I Maibach

44 Skin Photodamage Prevention: State of the Art and New Prospects 429Denize Ainbinder Elka Touitou

45 Environmental and Genetic Factors in Facial Aging in Twins 441David J Rowe Bahman Guyuron

46 Tobacco Smoke and Skin Aging 447Akimichi Morita

Biomarkers 451

47 DNA Biomarkers in Aging Skin 453Kimberly G Norman Alex Eshaghian James E Sligh

In vitro Techniques 459

48 The Use of Reconstructed Skin to Create New In Vitro Models of Skin Aging

with Special Emphasis on the Flexibility of Reconstructed Skin 461Daniel Asselineau Sylvie Ricois Herve´ Pageon He´le`ne Zucchi Sole`ne Mine Sarah Girardeau

Flore Nallet Se´verine Teluob Gae¨lle Claviez-Homberg

49 In vitro Method to Visualize UV-induced Reactive Oxygen Species in a

Skin Equivalent Model 477Akira Date Tomohiro Hakozaki

50 Aging of Skin Cells in Culture 487Suresh I S Rattan

xvi Table of Contents

Malignant Skin Conditions 543

55 Neoplastic Skin Lesions in the Elderly Patient 545Miranda A Farage Kenneth W Miller Enzo Berardesca Howard I Maibach Isaac M Neuhaus

56 Carcinogenesis: UV Radiation 567Douglas E Brash Timothy P Heffernan Paul Nghiem

57 Melanoma and Skin Aging 579Salina M Torres Marianne Berwick

58 Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis 587Davina A Lewis Jeffrey B Travers Dan F Spandau

59 Non-surgical Modalities of Treatment for Primary Cutaneous Cancers 601Ossama Abbas Salah Salman

60 Sunlight Exposure and Skin Thickness Measurements as a Function of Age:

Risk Factors for Melanoma 609Panthea Heydari Andia Heydari Howard I Maibach

Non-Malignant Skin Conditions 617

61 Influence of Race, Gender, Age, and Diabetes on the Skin Circulation 619Jerrold Scott Petrofsky Gurinder Singh Bains

62 Atopic Dermatitis in the Aged 639Alexandra Katsarou Melina C Armenaka

Table of Contents xvii

63 Dry Skin in Diabetes Mellitus and in Experimental Models of Diabetes 653Shingo Sakai Hachiro Tagami

64 Cutaneous Effects and Sensitive Skin with Incontinence in the Aged 663Miranda A Farage Kenneth W Miller Enzo Berardesca Howard I Maibach

Part 3 Techniques and Methods 673 Bioengineering Methods and Tools 675

65 Bioengineering Methods and Skin Aging 677Francesca Giusti Stefania Seidenari

66 Hydration of the Skin Surface 687Hachiro Tagami

67 Transepidermal Water Loss and Aging 695Ali Alikhan Klaus-Peter Wilhelm Fatima S Alikhan Howard I Maibach

68 Corneocyte Analysis 705Tetsuji Hirao

69 The Structural and Functional Development of Skin During the First Year of Life:

Investigations Using Non-invasive Methods 715Georgios Stamatas

70 Structure of Stratum Corneum Lipid Studied by Electron Paramagnetic Resonance 725Kouichi Nakagawa

71 Molecular Concentration Profiling in Skin Using Confocal Raman Spectroscopy 735Jonathan M Crowther Paul J Matts

72 The Measurement and Perception of Uneven Coloration in Aging Skin 749Paul J Matts

xviii Table of Contents

Gianfranca Miconi Luisa Di Marzio Maria Grazia Cifone Maurizio Giuliani

Part 4 Toxicological/Safety and General Considerations 821 Safety Evaluation for the Elderly Population 823

79 Irritant Contact Dermatitis 825Florian Seyfarth Peter Elsner

80 Susceptibility to Irritation in the Elderly: New Techniques 833Miranda A Farage Kenneth W Miller G Frank Gerberick Cindy A Ryan Howard I Maibach

81 Safety Evaluation in the Elderly via Dermatological Exposure 845Mario Bramante

82 Dermal Safety Evaluation: Use of Disposable Diaper Products in the Elderly 857Prashant Rai Daniel S Marsman Susan P Felter

Scales and Typing System 919

87 Assessing Quality of Ordinal Scales Depicting Skin Aging Severity 921Fabien Valet Khaled Ezzedine Denis Malvy Jean-Yves Mary Christiane Guinot

88 The Baumann Skin Typing System 929Leslie S Baumann

Part 5 Global Skin Aging and its Management: Perception, Needs,

Differences and Responses to Skin Aging 945 Psychosocial Implications 947

89 Psychological and Social Implications of Aging Skin: Normal Aging and the

Effects of Cutaneous Disease 949Miranda A Farage Kenneth W Miller Enzo Berardesca Howard I Maibach

90 Aging Skin: Some Psychosomatic Aspects 959Madhulika A Gupta

Aging Perception 971

91 Facial Skin Attributes and Age Perception 973Alex Nkengne Georgios Stamatas Christiane Bertin

Gender, Ethnicity and Lifestyle Differences 981

92 Determinants in the Rate of Skin Aging: Ethnicity, Gender, and Lifestyle

Influences 983Miranda A Farage Kenneth W Miller Howard I Maibach

93 Gender Differences in Skin 999Sarah Fitzmaurice Howard I Maibach

94 Aging in Asian Skin 1019Low Chai Ling

Sensitive Skin and Aging 1025

95 Perceptions of Sensitive Skin with Age 1027Miranda A Farage

96 Aging and Skin Sensitivity 1047Michael K Robinson

Ingredients and Products for Aging Skin 1053

97 Aging and Anti-aging Strategies 1055Giuseppina Candore Giovanni Scapagnini Calogero Caruso

xx Table of Contents

98 Cosmetics and Aging Skin 1063Robert L Bronaugh Linda M Katz

99 Cosmetic Anti-aging Ingredients 1069Donald L Bissett Mary B Johnson

100 Topical Growth Factors for Skin Rejuvenation 1079Vijayeta Rangarajan Frank Dreher

101 Topical Peptides and Proteins for Aging Skin 1089Farzam Gorouhi Howard I Maibach

Fem Care Products 1119

102 Solutions and Products for Managing Female Urinary Incontinence 1121David J Caracci

103 Changes in Vulvar Physiology and Skin Disorders with Age and

Benefits of Feminine Wipes in Postmenopausal Women 1127Miranda A Farage Kenneth W Miller William J Ledger

Part 6 Global Market Place for the Aged 1185

107 Marketing and Product Design of Anti-aging Skin Care Products 1187Nancy C Dawes

108 Key Trends Driving Anti-aging Skin Care in 2009 and Beyond 1197Mary Carmen Gasco-Buisson

Subject Index 1207

Table of Contents xxi

Miranda A Farage, Ph.D.

Principal Scientist

The Procter & Gamble Company

6110 Center Hill Avenue

The Procter & Gamble Company

6110 Center Hill Avenue

USA MaibachH@Derm.ucsf.edu

Kesariani, AthensGreece

Jorge Arrese-EstradaLaboratory of Skin Bioengineering and ImagingDepartment of Dermatopathology

University Hospital of Lie`geLie`ge

BelgiumHanan AssafDepartment of Dermatology and VenereologyFaculty of Science

Sohag UniversitySohag

EgyptDaniel AsselineauL’Ore´al Life Sciences ResearchClichy

FranceGurinder Singh BainsDepartment of Physical TherapySchool of Allied Health ProfessionsLoma Linda University

Loma Linda, CAUSA

Leslie S BaumannDepartment of Dermatology andBaumann Cosmetic Medicine and Research InstituteUniversity of Miami

Miami, FLUSAThomas BlattSkin Research CentreBeiersdorf AGHamburgGermany

Division of Epidemiology and Biostatistics

Department of Internal Medicine

University of New Mexico

Albuquerque, NM

USA

Tapan K Bhattacharyya

Department of Otolaryngology-Head & Neck Surgery

University of Illinois, Chicago

Procter & Gamble Service GmbH

Schwalbach am Taunus, Hesse

Germany

Douglas E BrashDepartments of Therapeutic Radiology, Geneticsand Dermatology

School of MedicineYale UniversityNew Haven, CTUSA

Robert L BronaughCFSAN Food and Drug AdministrationCollege Park, MD

USASte´phane Bre´zillonLaboratory of Biochemistry and Molecular BiologyFaculty of Medicine

University of Reims Champagne-ArdenneReims

FranceGiuseppina CandoreDepartment of Pathobiology and BiomedicalMethodologies

University of PalermoPalermo

ItalyDavid J CaracciThe Procter & Gamble CompanyCincinnati, OH

USA

Calogero CarusoDepartment of Pathobiology and BiomedicalMethodologies

University of PalermoPalermo

ItalyDuane L CharbonneauThe Procter and Gamble CompanyCincinnati, OH

USAAlexandra CharruyerDepartment of Dermatology and Institute forRegeneration Medicine

University of California, San FranciscoSan Francisco, CA

USAxxvi Contributors

Maria Grazia Cifone

Department of General Pathology

Faculty of Medicine and Surgery

San Francisco, CAUSA

Kimberly M EickhorstProcedural Dermatology FellowMorristown, NJ

USAPeter ElsnerDepartment of Dermatology and AllergologyUniversity of Jena

JenaGermanyAlex EshaghianDepartment of Internal MedicineUniversity of New MexicoAlbuquerque, NMUSA

Khaled EzzedineDepartment of DermatologyCHU Saint-Andre´

BordeauxFranceMiranda A FarageThe Procter & Gamble CompanyCincinnati, OH

USASusan P FelterThe Procter & Gamble CompanyCincinnati, OH

USASarah FitzmauriceSchool of MedicineUniversity of California, DavisSacramento, CA

USASara FloresDepartment of DermatologySchool of Medicine

University of California, San FranciscoSan Francisco, CA

USA

Contributors xxvii

Mary Carmen Gasco-Buisson

The Procter and Gamble Company

University of California, San Francisco and

Veteran’s Affairs Medical Center

Neuilly-sur-SeineFrance

Madhulika A GuptaDepartment of PsychiatrySchulich School of Medicine and DentistryUniversity of Western Ontario

London, ONCanadaBahman GuyuronDepartment of Plastic SurgeryUniversity Hospitals of Cleveland and CaseWestern Reserve University

Cleveland, OHUSA

Tomohiro HakozakiThe Procter & Gamble CompanyCincinnati, OH

USAStacy S HawkinsUnilever R&DTrumbull, CTUSA

Timothy P HeffernanDepartments of Therapeutic Radiology, Geneticsand Dermatology

School of MedicineYale UniversityNew Haven, CTUSA

Peter HelmboldDepartment of DermatologyUniversity of HeidelbergHeidelberg

GermanyFre´de´rique HenryLaboratory of Skin Bioengineering and ImagingDepartment of Dermatopathology

University Hospital of Lie`geLie`ge

Belgiumxxviii Contributors

Office of Research and Development

US Environmental Protection Agency

National Health and Environmental Effects Research

USA

Alexandra KatsarouDepartment of DermatologyUniversity of Athens

Kesariani, AthensGreece

Linda M KatzOffice of Cosmetics and ColorsCFSAN Food and Drug AdministrationCollege Park, MD

USA

Abdul Ghani KibbiDepartment of DermatologyAmerican University of Beirut Medical CenterBeirut

Lebanon

Won-Serk KimDepartment of DermatologyKangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoul

Korea

Jean KrutmannEnvironmental Health Research Institute (IUF)Heinrich-Heine-University

DuesseldorfGermany

Cristina La TorreDepartment of Health SciencesUniversity of L’Aquila

CoppitoItaly

Sampo LahtinenDanisco Health and NutritionKantvik

Finland

Contributors xxix

Samuel M Lam

Willow Bend Wellness Center and

Lam Facial Plastic Surgery Center & Hair Restoration

Institute

Plano, TX

USA

William J Ledger

Department of Obstetrics and Gynecology

Cornell University-Weill Medical College

Low Chai Ling

The Sloane Clinic

Departments of Dermatology, Venereology

Allergology and Immunology

Dessau Medical Center

Dessau

Germany

Denis MalvyDepartment of Internal Medicine andInfectious Diseases

CHU St.Andre´

BordeauxFranceFranc¸ois-Xavier MaquartLaboratoire Central de BiochimieHoˆpital Robert Debre´

ReimsFranceSlaheddine MarrakchiDepartment of DermatologyHedi Chaker HospitalSfax

Tunisia

Daniel S MarsmanThe Procter & Gamble CompanyCincinnati, OH

USA

Jean-Yves MaryINSERM

Department of Biostatistics andClinical Epidemiology

Saint-Louis HospitalParis

FranceLuisa Di MarzioDepartment of Health SciencesUniversity of L’Aquila

CoppitoItaly

Paul J MattsProcter & Gamble Technical Centres LtdEgham, Surrey

UK

Esterina MelchiorreDepartment of Health SciencesUniversity of L’Aquila

CoppitoItalyxxx Contributors

Laboratory of Molecular Biotechnology

Department of Biomedical Sciences

USA

Paul NghiemDepartments of Therapeutic Radiology, Geneticsand Dermatology

School of MedicineYale UniversityNew Haven, CTUSA

John NipUnilever R&DTrumbull, CTUSA

Alex NkengneJohnson & Johnson Consumer FranceIssy-les-Moulineaux

France

Kimberly G NormanVanderbilt University Medical CenterNashville, TN

USA

Mutsumi OkazakiDepartment of Plastic and Reconstructive SurgeryTokyo Medical and Dental University

Bunkyo-ku, TokyoJapan

Arthur C OuwehandDanisco Health and NutritionKantvik

Finland

Noritaka OyamaDepartment of DermatologySchool of Medicine

Fukushima Medical UniversityFukushima

Japan

Contributors xxxi

Jerrold Scott Petrofsky

School of Allied Health

Loma Linda University

University of California, IrvineIrvine, CA

USA

Pascale QuatresoozLaboratory of Skin Bioengineering and ImagingDepartment of Dermatopathology

University Hospital of Lie`geLie`ge

Belgium

Prashant RaiProcter and Gamble Japan KKHigashinada-ku

Japan

Vijayeta RangarajanNEOCUTIS Inc

San Francisco, CAUSA

Matthew J RanzerCenter for Wound Healing and Tissue RegenerationCollege of Dentistry

University of Illinois, ChicagoChicago, IL

USA

Christina RaschkeDepartment of Dermatology and AllergologyUniversity of Jena

JenaGermany

Suresh I S RattanLaboratory of Cellular AgeingDepartment of Molecular BiologyAarhus University

AarhusDenmark

Anthony V RawlingsAVR Consulting LtdNorthwich, CheshireEngland

UKxxxii Contributors

Basic Research Laboratory

Kanebo Cosmetics Inc

CampobassoItaly

Dwight ScarboroughDivision of DermatologyOhio State University HospitalColumbus, OH

USAPeter SchroederEnvironmental Health Research Institute (IUF)Heinrich-Heine-University

DuesseldorfGermanyStefania SeidenariDepartment of DermatologyUniversity of Modena and Reggio EmiliaModena

ItalySandy SercuLaboratory of Molecular BiotechnologyDepartment of Biomedical SciencesUniversity of Antwerp

AntwerpBelgiumFlorian SeyfarthDepartment of Dermatology and AllergologyUniversity of Jena

JenaGermanySusan N ShermanSNS ResearchCincinnati, OHUSA

William ShingletonUnilever R&DColworthUKJames E SlighSkin Diseases Research CenterVanderbilt University Medical CenterNashville, TN

USA

Contributors xxxiii

Jack D Sobel

Division of Infectious Diseases

Department of Internal Medicine

Wayne State University

USA

Haw-Yueh ThongDepartment of DermatologyUniversity of California, San FranciscoSan Francisco, CA

USA

Kirsti TiihonenDanisco Health and NutritionKantvik

Finland

Salina M TorresDivision of Epidemiology and BiostatisticsDepartment of Internal Medicine

University of New MexicoAlbuquerque, NMUSA

Elka TouitouSchool of PharmacyFaculty of MedicineThe Hebrew University of JerusalemJerusalem

IsraelJeffrey B TraversDepartment of DermatologySchool of Medicine

Indiana UniversityIndianapolis, INUSA

Joel TsevatDepartment of Internal MedicineCollege of Medicine

University of CincinnatiCincinnati, OH

USAGiuseppe ValacchiDepartment of Biomedical SciencesUniversity of Siena

SienaItalyxxxiv Contributors

University Hospital of Lie`geLie`ge

BelgiumDaniel B YaroshEstee Lauder CompaniesMelville, NY

USAChristos C ZouboulisInstitute of Clinical Pharmacology &

Department of ToxicologyCharite´ Universitaetsmedizin BerlinCampus Benjamin FranklinBerlin

GermanyHe´le`ne ZucchiL’Ore´al Life Sciences ResearchClichy

France

Contributors xxxv

20 Adipose-derived Stem Cells and their

Secretory Factors for Skin Aging

Byung-Soon Park Won-Serk Kim

Introduction

The term ‘‘stem cell’’ has attracted increasing attention of

the scientific community as well as of the general public

In many aspects, however, it is still confusing and difficult

to understand and interpret information about stem cells

They are vital to humans for numerous reasons Groups

of stem cells in some adult tissues give rise to replacement

cells for the tissues that are destroyed through injury,

disease, or aging [1] Knowledge relating to how healthy

cells replace diseased or otherwise damaged cells, would

allow development of medical therapies focusing on

crea-tion of compatible cell lines to replace aged or diseased

cells in the body The concept of regenerative medicine

using the body’s own stem cells and growth factors to

repair tissue may be realizable as science and clinical

experience converge to develop alternative therapeutic

strategies to treat the damaged or diseased tissue Stem

cell-based therapies are also being tried in tissue

engineer-ing: The aim of tissue engineering is to repair and

regen-erate damaged organs or tissues using a combination of

cells, biomaterials, and cytokines [1 4]

This chapter addresses the human subcutaneous

adi-pose tissue as a promising source of adult stem cells

Adipose-derived stem cells (ADSCs) may offer a solution

for the problem of limited availability of human cells that

are capable of self-renewal and differentiation ADSCs can

be easily obtained from liposuction of human adipose

tissue, cultured in a large scale, and display multi-lineage

developmental plasticity In addition, ADSCs secrete

vari-ous cytokines and growth factors, which control and

manage the damaged neighboring cells, and this has

been identified as essential functions of ADSCs [5 7]

As reviewed elsewhere in this book, aging and photoaging

are complex processes involving the wound-healing

cascade and/or repetitive oxidative stress Conventional

anti-aging skin treatments such as light-based or

radio-frequency devices and/or peelings have been less than

satisfactory because their primary mechanism is mainly

inducing new collagen synthesis via activation of dermal

fibroblasts On the basis of previous studies that

demonstrated wound healing, antioxidant, antiwrinkle,and antimelanogenic effects of ADSCs and their secretoryfactors, they may be good candidates for the treatment

of aging [5 9] Therefore, this chapter describes theauthors’ recent research and clinical developments on theanti-aging effects of ADSCs and their secretory factors

Stem Cells and ADSCsStem cells are a population of immature tissue precursorcells capable of self-renewal and provision of multi-lineagedifferentiable cells for tissues Although embryonic stemcell has multi-potency, there are many limitations such asdifficulties in control of differentiation and issues relating

to ethics As a result, use of adult stem cells with fewerimplicating issues is becoming an area of increased inter-est in stem cell medicine Given the vast potential oftreatments utilizing stem cells, validation and evaluationregarding safety and efficacy will result in greater benefits

ADSCs and Regeneration

Due to the lack of a specific and universal molecularmarker for adult stem cells, functional assays for multipledifferentiations must be used to identify stem cells in atissue Mesenchymal stem cells (MSCs) were first charac-terized in bone marrow, but many studies have reportedthe existence of MSCs in the connective tissue of severalorgans [10,11] The role of these cells is not entirely clear,but they are generally believed to constitute a reserve fortissue maintenance and repair It was recently demon-strated that the most abundant and accessible source ofadult stem cells is adipose tissue The yield of MSCs fromadipose tissue is approximately 40-fold greater than thatfrom bone marrow [12–14]

The following are the highly consistent, although notidentical, expression profiles of cell-surface proteins onADSCs [2,15]: adhesion molecules, receptor molecules,surface enzymes, extracellular matrix (ECM) proteins,

M A Farage, K W Miller, H I Maibach (eds.), Textbook of Aging Skin, DOI 10.1007/978-3-540-89656-2_20,

# Springer-Verlag Berlin Heidelberg 2010

and glycoproteins However, hematopoietic cell markers

such as CD14, CD31, and CD45 are not expressed

Inter-estingly, the immunophenotype of ADSCs resembles that

reported for other adult stem cells prepared from human

bone marrow (bone marrow stromal cell [BMSC]) and

skeletal muscle [2] Differentiation of ADSCs is not

re-stricted to the adipocyte lineage, but they can be

differ-entiated into chondrocyte, osteocyte, cardiomyocyte,

neuron, etc [16, 17] In addition, activity comparison

with BMSC revealed a similar regenerative capacity

Therefore, this abundant and accessible cell population

has potential clinical utility for regenerating damaged or

aged tissue and tissue engineering

As with many rapidly developing fields, diverse names

have been proposed to describe the plastic-adherent

cell population isolated from collagenase digests of

adi-pose tissue: adiadi-pose-derived stem/stromal cells, adiadi-pose-

adipose-derived adult stem cells, adipose-adipose-derived adult stromal

cells, adipose stromal cells (ASCs), adipose mesenchymal

stem cells (AdMSCs), lipoblast, pericyte, preadipocyte,

and processed lipoaspirate (PLA) cells To address the

confusion due to diverse nomenclature, the International

Fat Applied Technology Society reached a consensus to

adopt the term ‘‘adipose-derived stem cells’’ to identify

the isolated, plastic-adherent, multipotent cell

popula-tion Questioning the validity of the term ‘‘stem cell’’, led

to the use of the acronym to mean ‘‘adipose-derived

stromal cells’’ [18]

Although studies are limited, the quality and quantity

of the ADSCs varies according to interperson differences,

the harvest site, harvesting method, and culture

condi-tions Age and sex are the most obvious of the interperson

differences Stem cell recovery varies between

subcutane-ous white adipose tissue depots [19,20] Yield and growth

characteristics of ADSC (>Fig 20.1) are also affected

by the type of surgical procedure used for adipose

tissue harvesting Resection and tumescent

liposu-ction seem to be preferable above ultrasound-assisted

liposuction [21]

Mechanism of Action for Regeneration

Stem cell therapy is a safe, practical, and effective source

for repair of damaged tissue [22,23] Despite rapid

trans-lation to the bedside, the mechanism of action for

regen-eration is not well characterized It was initially

hypothesized that immature stem cells migrate to the

injured area, differentiate into the phenotype of injured

tissue, repopulate the diseased organ with healthy cells,and subsequently repair the tissue (building-block func-tion) However, this theory has some drawbacks becausethe levels of engraftment and survival of engrafted cells aretoo low to be therapeutically relevant [24] In addition,acute stem cell-mediated improvement within days oreven hours makes it difficult to fully explain the mechan-isms by which regeneration occurs [25,26] Instead, much

of the functional improvement and attenuation of injuryafforded by stem cells can be repeated by treatment withcell-free conditioned media derived from ADSCs (ADSC-CM) [27] Thus, it can be deduced that ADSCs may exerttheir beneficial effects via complex paracrine actions(manager function) in addition to building-blockfunction

Figure 20.1

ADSCs display adherent and fibroblastic morphology They show abundant endoplasmic reticulum and large nucleus relative to the cytoplasmic volume (Reprinted with permission from Elsevier, Kim WS et al [ 6 ])

202 20 Adipose-derived Stem Cells and their Secretory Factors for Skin Aging

Proteomic Analysis of ADSCs and

Their Secretomes

Proteomics, large-scale studies of proteins, can be used to

analyze the intracellular and secretory proteins of ADSCs

For example, Roche et al., conducted a 2-DE gel analysis

of BMSCs and ADSCs, and confirmed the similarity [28]

Zvonic et al., also analyzed the ADSC-CM by 2-DE gel

electrophoresis, detected approximately 300 features from

ADSC-CM, and found that secretomes are

up-/down-regulated by induction of adipogenesis [29] Although

the intracellular and secretory proteins of ADSCs have

been analyzed through 2-DE-coupled mass spectrometry

or non-gel-based mass spectrometry, the active proteins

of ADSCs responsible for the tissue regeneration are

not fully identified This may be due to the fact that

studies using proteomics has limitations as this approach

is capable of analyzing highly abundant proteins only

Therefore, new mass spectrometry-based proteomic

anal-ysis techniques for stem cell proteins in correlation with

other state-of-the-art analytical tools and functional study

by neutralizing the candidate proteins are needed to

clearly characterize the active proteins of regeneration

Diverse Pharmacologic Actions of

ADSCs and Their Secretory Factors

Wound-Healing Effect of ADSCs

Several studies of the pathophysiology of photoaging have

detected similarities with certain aspects of acute and/or

chronic wounds Histologically, photoaged skin shows

marked alterations in ECM composition Skin wound

repair by adult stem cells was originally demonstrated

using BMSC Wu et al showed that BMSC injection

around the wound significantly enhanced wound healing

in normal and diabetic mice compared with that of

allo-geneic neonatal dermal fibroblasts [30] Sasaki et al

demonstrated that BMSCs can differentiate into multiple

skin cell types including keratinocytes, pericytes, and

en-dothelial cells, which contribute to wound repair [31]

Notably, analyses of proteins in conditioned medium of

BMSC (BMSC-CM) indicated that BMSCs secret

distinc-tively different cytokines and chemokines compared to

dermal fibroblasts [32] ADSCs have surface markers

and gene profiling similar to BMSCs and their soluble

factors are not significantly different [6,10] Given their

convenient isolation compared with BMSCs and extensive

proliferative capacities ex vivo, ADSCs hold great promise

for use in wound repair and regeneration However, there

is little evidence demonstrating the wound-healing effects

of ADSCs It was also demonstrated that ADSCs acceleratewound healing, especially with regard to fibroblast activa-tion [6] They promote proliferation of dermal fibro-blasts, not only by direct cell-to-cell contact, but also byparacrine activation through secretory factors This fibro-blast-stimulating effect of ADSCs was superior to that ofthe fibroblasts Furthermore, ADSC-CM enhanced secre-tion of type I collagen from dermal fibroblasts and stimu-lated fibroblast migration in in vitro wound-healingmodels ADSCs secreted a variety of growth factors such

as basic fibroblast growth factor (bFGF), KGF, TGF-b,hepatocyte growth factor (HGF), and VEGF into theconditioned medium, which might mediate the wound-healing effect of ADSCs In addition to the in vitro evi-dence, the wound-healing effect of ADSCs was also ver-ified in an animal study, which showed that topicaladministration of ADSCs significantly reduced thewound size (34% reduction) and accelerated the re-epi-thelialization at the wound edge (>Fig 20.2) Similar toADSC treatment, ADSC-CM treatment also acceleratedwound healing in laser-induced burn mouse models(authors’ unpublished data) In this experiment, burnwounds were made by laser surgery in the epidermis andthey were significantly reduced by single and multipleadministration of ADSC-CM As ADSCs are physiologi-cally located beneath dermal fibroblasts, they may interactwith dermal fibroblasts However, ADSCs and secretomes

of ADSCs may reach the epidermis in wounded area andmay affect the recovery of this layer As such, ADSC-CMwas treated in cultured primary human keratinocytes andshown to increase the proliferation and migration ofkeratinocytes (authors’ unpublished data) This resultsuggests that secretomes of ADSC also accelerate the heal-ing of epidermal layer

Antioxidant and Antimelanogenic Effects of ADSC

Reactive oxygen species (ROS) produced in the catalyticreactions by many environmental stimuli may be involved

in the pathogenesis of a number of skin disorders ing photoaging, photosensitivity diseases, and some types

includ-of cutaneous malignancy Antioxidants, as a popular term

in drug and cosmetics, take the form of enzymes, mones, vitamins, and minerals In biological systems, thenormal processes of oxidation produce highly reactivefree radicals, which may continue to damage even theAdipose-derived Stem Cells and their Secretory Factors for Skin Aging 20 203

hor-body’s own cells Antioxidants scavenge free radicals fore they get a chance to harm the body As of now, thereare few reports on the antioxidant action of stem cells.However, some evidences support the protective role ofsecretomes of ADSCs against the skin damage induced byreactive oxygen species For example, IGF reportedly pro-tects fibroblasts and intestinal epithelial cells from freeradicals [33,34] HGF protects the retinal pigment epithe-lium against oxidative stress induced by glutathione deple-tion [35] Pigment epithelium-derived factor (PEDF) is ananti-angiogenic/neurotropic factor and has been shown tohave antioxidant effects [36] Interleukin-6 (IL-6) reducesthe epithelial cell death induced by hydrogen peroxide[37] In addition, subtypes of superoxide dismutase(SOD) are expressed and secreted from ADSC [38].Therefore, antioxidant function of ADSC was investigated

be-in dermal fibroblasts after be-inducbe-ing chemical oxidativestress by the tert-butyl hydroperoxide (tbOOH) Morpho-logical change and cell survival assay revealed that incu-bation with ADSC-CM aided dermal fibroblasts to resistfree radicals induced by tbOOH In addition, activities ofsuperoxide dismutase (SOD) and glutathione peroxidase(GPx) were enhanced in the dermal fibroblasts treatedwith ADSC-CM In a cell cycle analysis, ADSC-CM treat-ment reversed the apoptotic cell death induced by ROS,which was demonstrated by a significant decrease of sub-G1 phase of dermal fibroblasts [8]

Photoaging is believed to be responsible for up to almost80% of the skin changes commonly attributed to theaging process The study further investigated the antioxi-dant and protective effects of ADSCs in the photodamage

of the primarily cultured dermal fibroblasts (>Fig 20.3)

In this experiment, ADSC-CM pretreatment significantly

Figure 20.2

Wound healing effect of ADSCs in nude mice Artificial

wounds were made using a 6-mm punch biopsy and ADSCs

were topically applied The wound size was reduced

significantly in the ADSC-treated side (right side of the

back) 7 days after surgery (Reprinted with permission from

Elsevier, Kim WS et al [ 6 ])

Figure 20.3

Antioxidant effect of ADSCs in UVB-irradiated fibroblasts as shown by cell cycle analysis of DNA contents Untreated fibroblasts showed little or no sub-G1 phases (a) However, UVB irradiation significantly increased sub-G1 (apoptotic) cells (b), which were reversed by ADSC-CM pretreatment (c) (Reprinted with permission from Elsevier, Kim WS et al [ 5 ])

204 20 Adipose-derived Stem Cells and their Secretory Factors for Skin Aging

reduced the apoptosis of dermal fibroblasts from

UVB-induced damage, which was demonstrated by a significant

decrease of sub-G1 phase of dermal fibroblasts after

ADSC-CM pretreatment In addition, ADSC-CM

treat-ment increased the production of collagen and reduced

the expression of matrix metalloproteinase-1 in the

der-mal fibroblasts These results indicated that ADSCs can

play a key role in protecting dermal fibroblast from

UVB-induced oxidative stress [5]

As antioxidants inhibit the chemical reactions leading

to melanin formation, change the type of melanin formed,

and interfere with the distribution of pigment and nosome transfer, they are good candidates for skin white-ning resources As ADSC-CM is a free radical scavengerand has potent antioxidant activity, antimelanogenic effect

mela-of ADSC was investigated ADSC-CM treatment inhibitedthe synthesis of melanin and the activity of tyrosinase inmelanoma B16 cells In addition, expressions of tyrosinaseand tyrosinase-relating protein 1 were down-regulated byADSC-CM treatment, which indicated the mechanism ofaction for antimelanogenic effect of ADSCs and their solu-ble factors (>Fig 20.4) [9]

Figure 20.4

(a) Antimelanogenic effect of ADSC-CM Expression of MITF and TRP2 remained unchanged, but expressions of

tyrosinase and TRP1 were down-regulated by ADSC-CM treatment in B16 melanoma cells (b) The inhibitory effect of

ADSC on melanin synthesis is schematically represented (Reproduced with permission from Pharmacological Society of

Japan, Kim WS et al [ 9 ])

Adipose-derived Stem Cells and their Secretory Factors for Skin Aging 20 205