Textbook of Aging Skin

2158 Pages·59.659 MB·English

by  Miranda A. Farage, Kenneth W. Miller, Howard I. Maibach (eds.)

An Overview of the Histology of Aging
Skin in Laboratory Models
Tapan K. Bhattacharyya
Contents Abstract
This article is an overview of
Introduction.......................................... 1
histomorphological changes documented dur-
TheHumanScenario:SkinAgingHistology...... 2 ing various stages of life in many laboratory
AginginRodentModels............................. 3 modelsutilizedinskinagingstudies.Abewil-
deringvarietyincutaneousagingresponsehas
MorphologicalChangeswithAginginOther
Species............................................. 7 been observed in different strains. The com-
monlyusedlaboratorymodelsliketheratand
CalorieRestriction(CR)andSkinAging.......... 7
the mouse show dissimilar aging changes in
Conclusion............................................ 7 skin. There are a few mouse models which
References............................................ 10 seem to resemble the general trend of skin
attrition related to advancing age observed in
some human studies. Caloric restriction has
beenobservedtomodulateskinagingchanges
in the rat and the mouse. Despite the wide
variation in observational studies related to
agingchanges,somerodentmodelsareuseful
toagingresearchandexperimentalresponseof
agingskin.
Introduction
Human populations worldwide are living longer,
andskinfromolderpeoplebecomesmoresuscep-
tible to diseases and malformations apart from
“Whatliesbeneaththisagingskin?Theuntolddestruction beingravagedbyenvironmentaltraumalikeultra-
stealthycreeping,Thebonestheorgansthenerves,the violetradiation.Thescienceofclinicaldermatol-
brain,Iambreathing,Iamfunctioning,AmIliving?” ogydocumentsnumerousdiseasesofhumanskin,
JulieA.Crippin,2008
but scant information has been paid to basic
T.K.Bhattacharyya(*) researchinthemicroanatomyofagingskin.This
Otolaryngology-Head&NeckSurgery,Universityof
isasubjectthatinvokesbiologicalandevolution-
Illinois,Chicago,IL,USA
ary interest about age-induced involution of the
e-mail:[email protected]
#Springer-VerlagBerlinHeidelberg2015 1
M.A.Farageetal.(eds.),TextbookofAgingSkin,
DOI10.1007/978-3-642-27814-3_1-2
2 T.K.Bhattacharyya
integumentary system. It is logical to introspect fewdecades.Skinatrophyismarkedonlyafterthe
aboutthephenomenonofchronologicalagingof fifthdecadeofhumanlifeandshowsaplethoraof
animal skin from other mammalian species. morphologicalchangesincludingepidermalthin-
Despite many descriptive studies published in ning,flatteningofthedermal-epidermaljunction,
early literature, there are still many gaps in our loss of melanocytes, and immunocompetent
knowledgeaboutthepatternsofintrinsicagingin Langerhans cells; some physiological functions,
various laboratory models. Although animal suchassurfacelipidproduction,andthermoregu-
models may not fully corroborate biochemical lation are also affected by the aging process
data of aging skin and may show inconsistent (reviewinRittieandFisher[3]).
results, they are still useful tools to interpolate Therearealsodermalchangessuchasreduced
the fundamental etiologies of skin aging and fibroblastpopulationandsebaceousglands.These
antiagingeffects[1]. histopathologic events have been reviewed
One reason for the lack of documentation in [4]. Morphometric measurement of collagen
thisareaofresearchisscantavailabilityofanimal fibers from stained human skin biopsies further
models of skin aging with clear documentation showedthatcollagenfiberdensitystarteddecreas-
regardingageorthestagesofthelifecycle.Ani- ing from around 30–40 years, with thinner and
mal husbandry for long-term maintenance of morespacedfibers[5].Otherinvestigatorsfound
aginganimalsinadisease-freecolonyisacostly nodifferenceinepidermalordermalthicknessina
project and is usually beyond the reach of an study of wound healing comparing skin from
average laboratory. The aging human skin with young and elderly volunteers [6]. The biochemi-
increasedroughnessandwrinklingissagging,and calprofileofcollagenmetabolismofhumanskin,
inelastic,andshowsmanysignsofatrophy,such however, changes with age. A steady decline in
as epidermal thinning or abnormal collagen and synthesis of hydroxyproline in human skin up to
elastic fibers. It is logical to ask if similar or thefourthdecadehasbeendescribed[7].
differentconditionsareobservedwhenacompar- Reports of dermal elastic fiber changes with
ativeanatomical analysis isextendedtodifferent age including abnormalities and disintegration
models from the mammalian kingdom. This havebeenpublishedbysomeauthors.Asperthe
review explores whether intrinsic aging also study of Vitellaro-Zuccarello et al. [5], elastic
affects skin histology in laboratory models in a fiber distribution has a different aging pattern in
comparablemanner.Thedataareverylimitedand men and women. While the density of elastic
wereacquiredthroughpainstakinginvestigations fibersinthepapillarydermisisnotmodifiedasa
by researchers dating back to several decades function of age, in the reticular dermis of both
using classical histological techniques; the sexes, the fiber density increases in the first
reported quantitative data were often decade, followed by a drop only in the female.
uncorroboratedbystatisticalmethodology. Biochemically,elastinbiosynthesisisstableupto
approximately the fourth decade of life
[7]. Although reports by different investigators
TheHuman Scenario: Skin Aging vary in detail due to different kinds of sampling
Histology and histological methods employed, a general
trend of attrition of the dermal connective tissue
Morphologicalchangesofthehumanintegument fibersisnotedasacorrelateoftheagingprocess.
due to intrinsic aging caused by time-induced Histopathologicchangesintheepidermisandder-
physiological changes are understandable, but mis of human skin in sun-exposed and
canbealteredduetopersonalandenvironmental sun-protected areas have been reviewed by
factors,canvaryindifferentanatomicalsites,and Monteiro-Riviere[8].
are also linked to endocrine factors [2]. Despite
theseproblems,severalaccountsofintrinsicaging
of human skin have been published over the last
AnOverviewoftheHistologyofAgingSkininLaboratoryModels 3
Aging inRodentModels detailed study in young and old C57B1/6NNia
mice[13].Infact,theepidermisfromtheearand
Someaccountsofhistologicalandcellularkinetic footpadshowedastatisticallysignificantincrease
changesthroughoutthelifespanorrepresentative inthicknessandaugmentedcellsize.Theindexof
stages of rodent life span are available. Most of labeling with tritiated thymidine showed no dif-
thestudieswereconductedonthehairlessmouse, ference between young and old mice. Moreover,
otherstrainsofmice(CBA,C57131/6NNia,Balb/ inC57BL/6Nmice,thenumberofepidermalcell
c),andrats(Wistarrat,Fischer344).Itisdifficult layersandtheepidermalthicknessremainedcon-
tomake ameaningful comparisonbetween older stantfrom1to22monthsofage[14].
studies related to skin aging histopathology, as Most of the reported studies on mouse skin
different authors have reported data on both were mainly concerned with the aging effect on
sexes of various mouse models, which were theepidermalcellsizeorcellkinetics,andscarce
often based upon limited samplenumbers.Some attention has been devoted to the morphological
of these important articles lack statistical evalua- changes of the dermal constituents in aging ani-
tion. However, some noteworthy findings from mals. CBA mouse skin was investigated in three
early literature on different rodent models are age groups (1, 6, and 27 months) from animals
summarizedhere. procured from NIH colonies [15]. As the rate of
The hairless mouse owes its hairlessness to a skin aging differs in different areas of the body
homozygous recessive genetic condition, and [13], samples were studied from the dorsal, ven-
structural changes of skin accompanying devel- tral, and pinna skin and the footpad of these
opment of hairlessness in this animal were young,youngadult,andoldanimals.Anegative
describedintheolderliterature.Age-relatedmod- linear effect of age on epidermal depth with a
ificationsinepidermalcellkineticsinthisspecies significant reduction in cell count (cell/mm) and
were described by Iverson and Schjoelberg pilosebaceousunitprofilesindorsalskinsamples
[9]. Using autoradiography, it was shown that andfootpadwasobserved.Thesebaceousglands
epidermal cell proliferation increased from birth appeared atrophied with pyknotic nuclei (Figs. 1
to approximately 20 weeks of age and remained and 2). No consistent change in depth of the
steady. This detailed study could not confirm dermisorareafractionofcollagenasdetermined
whether epidermal thickness or cell proliferation by histomorphometry was noticed. The dermal
ratedecreasessystematicallywithincreasingage. elastic fibers in the dorsal skin and footpad
Ontheotherhand,Haratakeetal.[10]presented showedproliferationinhigheragegroups inthis
datashowingthatthethicknessoftheepidermisin mousemodel.Thiscanbecomparedwithastudy
hairlessmicedecreaseswithintrinsicaging.There in the C57/B16 mice from NIH colonies [16]
wasalsolessincorporationoftritiatedthymidine wheredecreaseddermalcellularityandthickness
intheepidermisinoldermice. and decreased epidermal proliferation were
The tritiated thymidinetechnique was usedin reported.
miceupto19monthsofage,andthedatarevealed Further investigation of the CBA mice from
anage-dependentdeclineinthecellproliferation NIH colonies as described in the previous para-
rate[11].ThedatareportedfromBalb/cmice[12] graph [15] was made to compare epidermal mor-
seemed to indicate epidermal atrophy with age. phometryandtheindexofproliferatingcellnuclear
Theepidermiswasthinner,withsmallernuclei,in antigen (PCNA-I) by immunohistochemistry in
20-month-old animals compared to 2-month-old respect to the dorsal and pinna skin, ventral skin,
animals,althoughtherewasnodecreaseinmitotic and the footpad fromother areas ofaging experi-
activity and DNA labeling index. The loss of mental animals (Bhattacharyya, unpublished
epidermal mass was related to a decrease in pro- observations).Therewasanattritionofepidermal
teinandRNAcontentoftheepidermis.However, thicknessindorsalandventralskinandthefootpad
similarepidermalchangeswerenotobservedina in relation to aging. PCNA-I showed a reduction
4 T.K.Bhattacharyya
Fig.1 Histologicalpreparationofthedorsalskininaging shrinkageofsebaceousfollicles.Dermalelasticfiberscan
CBA mice in young (a), young adult (b), and old (c) beseeninc.Verhoeff-vanGiesenstain
animals,showingincreasingatrophyoftheepidermisand
Fig.2 Errorbarchartof Three age groups: young, adult, old
epidermalwidth
measurementsinthree
groupsofCBAmice m) 15.00
µ
h (
pt 12.50
e
d
pi
e
D 10.00
S
1
±
n 7.50
a
e
M
5.00
1.00 2.00 3.00
Age
across the ages only in the pinna skin and dorsal murinespecies.InanearlystudyofWistarInstitute
surface(Table1;Figs.3a–c). rats,nosignificantage-relatedalterationwasnoted
The aging skin in the rat shows nonuniform althoughtheauthordescribedmanyqualitativedif-
patternsindifferentstrainswhenitcomestoepider- ferences in epidermal layers [17]. In Sprague
mal and dermal thickness, and the age-associated Dawley rats, the foot epidermis was explored to
changes seem to differ from the trend noted in determine age-related changes in cell kinetics
AnOverviewoftheHistologyofAgingSkininLaboratoryModels 5
Table1 PCNA-IandepidermalthicknessdatafromagingCBAmice
PCNA-I EPIwidth(μm)
DS
Y 31.9+5.0 16.3+0.8
AD 32.6+5.4 14.1+1.0
O 24.1+4.3 12.3+0.7
*F5.46,P0.01 *F32.43,P0.0005
PS
Y 37.0+7.2 15.6+1.5
AD 26.8+5.3 14.1+1.3
O 31.2+5.9 13.3+3.2
*F4.01,P0.04
FP
Y 40.8+12.2 88.7+11.8
AD 32.6+6.5 72.9+8.1
O 40.9+6.1 55.3+8.7
*F17.28P0.0001
VS
Y 35.0+4.8 14.6+0.6
AD 34.8+2.7 12.1+0.9
O 32.1+3.1 9.8+0.9
*F54.91P0.0005
DSdorsalskin,PSpinnaskin,FPfootplate,VSventralskin,Yyoung,ADadult,Oold
usingsingle-pulse[3H]-thymidinelabelingandthe increase is greatly diminished with aging. This is
percentlabeledmitosistechnique[18]andledtothe duetoreducedcollagenbiosynthesisandincreased
conclusionthatthereisaprogressivedeclineinthe degradation of macromolecules, but the balance
ratesofcellproliferationassociatedwithage.How- betweensynthesisanddegradationremainspositive
ever,thesedatawerepresentedfromratsonlyupto inrats.
the age of 52 weeks. The authors of this chapter Aging changes in cells other than epidermal
referred to five reports published earlier, which keratinocytes, such as melanocytes or cells of
showed that rodent epidermal cell proliferation Langerhans,havealsobeendocumentedinsome
decreasedinmiddleageandthenremainedconstant studies.Ultravioletradiationhasimportanthealth
or increased in senile animals. Skin from aging consequences on the Langerhans cells of human
Wistarratsuptotheageof34monthswasstudied skin.ThenumericaldensityofLangerhanscellsin
using histomorphometric analysis by Voros and aging inbred mice was studied from epidermal
Robert [19]. Average epidermal and dermalthick- sheets and showed reduction when compared to
nessdidnotshowappreciablechangewithsenility thatinyounganimals,althoughcutaneousimmu-
inthisspecies.InagingFischer344rats,epidermal noreactivity was not compromised [23].
thicknessremainedconstantfrom3monthsofage Age-relatedneurodegenerativechangesinperiph-
onward[14].However,increasingvaluesinepider- eralnervesareawidespreadphenomenonofclin-
maldepthandnuclearpopulationwerenotedinthe ical importance, and rat studies have attested to
ventral and dorsal skin and footplate skin samples thisinhibitorypattern.Age-associatedlossinsize
from young, 1-year-old, and 2-year-old Fischer ofMeissner’scorpuscles,withsmalleranddisor-
344rats[20,21].Earlier,Lapiere[22]commented ganized axonal processes, was reported in the
thatinsteadofbecomingatrophic,ratskinincreases digital pads of mice aged to the maximum life
in size, with more collagen, although the rate of expectancy[24].
6 T.K.Bhattacharyya
a Bar graph CBA mice pcna/epi width
DSPCNAI
120.00 DSEPlum
PSPCNAI
PSEPIUM
FPPCNAI
100.00 FPEPIUM
VSPCNAI
VSEPIUM
80.00
n
ea 60.00
M
40.00
20.00
0.00
Young Adult Old
AGEGROUP
Error bars: +/- 1 SD
b c
Fig.3 (a)Acompositebardiagramshowingepidermal specimen shows PCNA staining in epidermis (EPI,
width and PCNA-I (PCNA index) in skin samples from arrow). CT cartilage. (c) Pinna skin immunostained for
dorsalandventralareas,footpad,andthepinnainthreeage PCNAinanoldspecimenshowsabsenceofreactivenuclei
groups. (b). Pinna skin section from a CBA young inathinnerepidermis(EPI)
Interpretation of morphological changes of changesinagingmice,rats,rabbits,andhamsters
aging skin has many limitations, as discreet bio- havebeenpublished.Onlyafewpapersarecited
chemicalchangesunderlyingsuchalterationscan- here[25,26].Oxidativedamagetothelipidsand
notbevisualized.Incontrasttosparselyavailable DNA increases with age in Fischer 344 rats,
accountsofdermalhistochemicalormorphologi- which was studied by measuring antioxidant
cal transformations in relation to life history in enzymeactivity[27].Inthehairlessmouse,how-
laboratory models, biochemical studies showing ever, skin aging was not accelerated due to
quantitative changes in dermal glycosaminogly- decreasedantioxidantcapacity[28].Suchmolec-
cans, hydroxyproline concentration, acid muco- ularchangesoftheskininintrinsicallyagedlab-
polysaccharides, and skin collagen and elastin oratory animals can only be revealed by
AnOverviewoftheHistologyofAgingSkininLaboratoryModels 7
immunohistochemistry as more suitable anti- dermalcollagen, elastic fibers, fibroblast density,
bodiesbecomeavailableforresearch. capillaryprofiles,andstainingintensityofdermal
glycosaminoglycans). The Fischer 344 rat
showed many age-related skin changes, and
Morphological Changes withAging thesewerepreventedordelayedbyCR,presum-
inOtherSpecies ably due tometabolic alterations imposed by the
dietaryregimen(Fig.4).
Somesporadicaccountshavealsobeenpublished CR reduces cell proliferation in some tissues,
relatingtomammalsotherthancommonlyavail- with inhibited pace of DNA replication, and this
able laboratory rodent models. Age-induced makesthosetissueslesssusceptibletoDNAdam-
reduction in sebaceous glands was described in age by carcinogens. Epidermal cell proliferation
sheepbyWarrenetal.[29].Epidermalflattening, as quantified by immunohistochemistry was also
fewer hair follicles and sebaceous glands, and a correlated to age-related changes in epidermal
decreaseinmelanocyteswereage-relatedchanges thicknessinthesecolony-raisedFischer344rats.
in the hairless dog [30]. Veterinary textbooks Just as CR somewhat inhibited the trend of
describe aging changes in skin of domesticated increasing epidermal width in aging rats, the
dogs and cats. Senile changes in the skin of old keratinocyte proliferation rate as measured by
cats and dogs include alopecia, callus formation staining of proliferating cell nuclear antigen
over pressure points, orthokeratotic hyperkerato- (PCNA)wascorrespondinglylowerinagingCR
sis of the epidermis, and atrophied hair follicles rats.Thistrendwasobservedintheepitheliumof
[31]. Due to certain structural similarities with thedorsalskinaswellasthefootplate(Figs.5and
humanskin,thepigskinmodelhasbeenusedin 6)[34].InC57BL/6Jmice,epidermalcellprolif-
many experiments for studying responses to sur- eration was reduced by CR and alternate-day
gicalandphysiologicalmanipulations[32],butno fastingregimens[36].AstudyinSENCARmice
account is available on aging morphological also shows that dietary calorie restriction may
changesinthisspecies. inhibitgeneexpressioninskintissuesrelevantto
cancerrisks[37].CRhasbeenreportedtoreduce
theleveloffreeradicalsandpreventaccumulation
CalorieRestriction(CR)andSkinAging of advanced glycation products and thus may be
beneficialtoagedskin.Ontheotherhand,lossof
Calorie restriction (CR) can reverse subdermal adipose tissue stores, with restricted
age-associated alterations in many organs like feeding, may accentuate fine wrinkles in human
the heart, the liver, and the brain [33] and has facial skin. CR can diminish subdermal adipose
been shown to exert beneficial effects on many tissue [21]; therefore, its aesthetic effect on the
skin disorders, although its morphological effect profile of the aging human face remains to be
on the aging skin has not been thoroughly seen.
explored. Whether CR can modify age-related
histomorphological features of the skin in
colony-raised rats was evaluated with morpho- Conclusion
metric procedures in Fischer 344 rats. [20, 21,
34, 35]. Three age groups (young, adult, old) of Duetotheeaseofstudyingskinagingphenomena
thisstrainbelongingtoadlibitumandCRfeeding and age-associated progressive changes in short-
regimens were obtained from NIH colonies, and lived mammals, published studies were mostly
skin samples from the dorsum, footpad, and confined to laboratory rodent models. Unfortu-
abdominalskinwereanalyzedwithmorphometric nately,manyearlierdescriptionsofthehistopath-
procedurestoevaluatevariousskincompartments ologic changes in aging skin in such models did
(thicknessofstratumcorneum,epidermis,PCNA notconsideroldorsenilespecimensandtherefore
index, dermis, fat layer, percentage fraction of lackaproperpopulationsampling.Thus,thestory
8 T.K.Bhattacharyya
Dermis depth in abdominal skin in CR rats
700
600
500
s
er 400
et Mean value
m
o sd
cr 300
Mi
200
100
0
1 2 3 4 5 6
Mean value 402 585.3 622.1 418.8 375.36 429.73
sd 49.86 189 170.1 72.8 103.2 114.65
ALY ALAD ALO CRY CRAD CRO
Fig.4 BargraphrepresentationofthedermisdepthfromFischer344ratsinCRstudy.Threeagegroupsofadlibitum
(AL)andcalorie-restricted(CR)animalsarerepresented
Fig.5 Representationof Title RAT CR Study FP EpiW vs PCNA
epidermalwidthandPCNA
indexfromfootplate(FP)in 175
FPEWidth
ratsfromCRstudy.Three
agegroupsfromALandCR FPPcnal
animalsarerepresented
150
125
D
S 100
1
–
+
n
a
e 75
M
50
25
0
Young Adult OLD Young Adult OLD
AnOverviewoftheHistologyofAgingSkininLaboratoryModels 9
Fig.6 PCNAstaininginfootplateepidermisfromadult observed. (b) CR rat, old group. The footplate section
(a)andold(b)CRrats.(a)CRrat,adultgroup,footplate showsregressionoftheepidermisandfewerPCNAposi-
section.Abroadepidermiswithathickcornifiedlayerand tivecells
brownstainedPCNAreactivecellsinthebasallayercanbe
issomewhatincompletewhencomparedtogeron- underproperhusbandryconditionsandmaybea
tologic cutaneous changes studied from skin more suitable animal for studying the process of
biopsysamplesof90-year-oldhumanpatients!It senescenceoftheintegumentarysystem.Virtually
shouldbenotedthatrodentlifespanisalsohighly nodataareavailableonhistologicalchangesfrom
variable in different strains. Early literature has intrinsic aging in other animals like the dog, the
recordedthatamonginbredmicestrainsusedfor domesticpig,ortherabbit,althoughsuchspecies
aging research,ameanlifespancanvaryfroma are extensively used for biomedical and physio-
lowof276daysintheAKR/Jstraintoamaximum logicalstudies.
of 799 days in the LP/J strain [38]. The lack of Wrinkle formation is a vexing problem of
availability of suitably aged rodent models is a aging human facial skin, and there is little infor-
handicaptosuchresearch.Thisreview,however, mationaboutskinwrinklesinanyanimalmodelat
showsthatthemousemodelmaybemoresuitable the senile state. Suitable models for studying the
fordocumentingage-relatedhistologicalchanges histophysiologyofwrinklesortheirreversalhave
that can be compared to human data, despite the not been reported, except for one study. Cross-
caveat that comparing skin from laboratory- breedingbetweentheWistarandthewildratwas
grown rodents with a short life span with the reportedtogeneratearatmodel(theIshibashirat)
human skin assaulted by years of disease and in which skin aging, with wrinkles and furrows,
environmental challenge is a rather risky appeared at 12 weeks. Wrinkle formation in this
endeavor. Histological deficits in intrinsically new model was due to a reduction in elastin and
aged human skin affect the epidermis, dermal collagencontentsoftheagingskin[40].Thiskind
thickness, cellularity, and elastic fiber system. of experimental model would prove useful to
Efforts should be made to search for analogous define the underlying anatomical correlates of
chronologicalchanges inanimal modelsthat can skin wrinkleformation,tostudy its profilometry,
beutilizedforstudiesaimedatrejuvenationofthe andtotesttheeffectoftopicalanti-wrinkleprod-
aged skin. Similarities between human and uctsforitsamelioration[41].
murine skin have been reported in many studies, Inrecentyears,stemcellsinskinhaveattracted
makingmouseskinasuitablematerialforstudy- alotofscientificintrospectionduetotheirpoten-
ing inflammatory skin diseases. Apart from cer- tial clinical application in wound healing, burns,
tain similarities in basic molecular and andalopecia[42],andthesecellscangothrough
physiological processes between the mouse and self-renewalandterminaldifferentiationandmay
the human [39], the mouse can be maintained regulate tissue aging [43]. It remains to be
10 T.K.Bhattacharyya
determined whether stem cells in aging mouse HI,editors.Dermatoxicology.NewYork:CRCPress;
skincanshowtemporalregression.Invitrostud- 2008.p.39–49.
9.IversenOH,SchjoelbergAR.Agerelatedchangesof
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epidermalcellkineticsinthehairlessmouse.Virchows
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alterations in barrier function. J Invest Dermatol.
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