MARK-AGE biomarkers of ageing

Bürkle, Alexander; Moreno-Villanueva, María; Bernhard, Jürgen; Hervonen, Antti; Hurme, Mikko
MARK-AGE biomarkers of ageing

Author: Bürkle, Alexander,Moreno-Villanueva, María,Bernhard, Jürgen,Hervonen, Antti,Hurme, Mikko
Year: 2015
Source: https://trepo.tuni.fi/bitstream/10024/99896/1/MARK_AGE_biomakers_2015.pdf
Mechanisms o Ageing and De elopmen 151 (2015) 2–12
Con en s lis s a ailable a ScienceDi ec
Mechanisms o Ageing and De elopmen
jou nal homepage:www.else ie .com/loca e/mechagede
MARK-AGE bioma ke s o ageing
Alexande Bü klea,∗, Ma ía Mo eno-Villanue aa, Jü gen Be nha db, Ma ía Blascoc,
Ge ben Zondagd, Jan H.J. Hoeijmake se, Oli ie Toussain , Bea ix G ubeck-Loebens eing,
Eugenio Mocchegianih, Sebas iano Collinoi, E s a hios S. Gonosj, Ewa Siko ak,
Daniela G adina ul, Ma ijn Dollém, Michel Salmonn, Pe e K is enseno,
Helen R. G i ﬁ hsp, Claude Libe q, Tilman G une ,s, Nicolle B eusing , And eas Simm ,
Claudio F anceschiu, Mi iam Cap iu, Duncan Talbo , Paola Caia aw, Be and F igue x,
P. Eline Slagboomy, An i He onenz, Mikko Hu mez, Richa d AspinallA
aMolecula Toxicology G oup, Depa men o Biology, Box 628, Uni e si y o Kons anz, 78457 Kons anz, Ge many
bBioTeSys GmbH, 73728 Esslingen, Ge many
cSpanish Na ional Cance Resea ch Cen e (CNIO), 3 Melcho Fe nandez Almag o, 28029 Mad id, Spain
dDNage BV1, Leiden, The Ne he lands
eDepa men o Gene ics, E asmus Uni e si y Medical Cen e , P.O. Box 1738, 3000 DR Ro e dam, The Ne he lands
Uni e si y o Namu , Resea ch Uni on Cellula Biology, Rue de B uxelles, 61, Namu B-5000, Belgium
gResea ch Ins i u e o Biomedical Aging Resea ch, Uni e si y o Innsb uck, Rennweg, 10, 6020 Innsb uck, Aus ia
hT ansla ional Resea ch Cen e o Nu i ion and Ageing, IRCCS-INRCA, Via Bi a elli 8, 60121 Ancona, I aly
iNes lé Ins i u e o Heal h Sciences SA, Molecula Bioma ke s, EPFL Inno a ion Pa k, 1015 Lausanne, Swi ze land
jNa ional Hellenic Resea ch Founda ion, Ins i u e o Biology, Medicinal Chemis y and Bio echnology, A hens, G eece
kLabo a o y o he Molecula Bases o Ageing, Nencki Ins i u e o Expe imen al Biology, Polish Academy o Sciences, 3 Pas eu s ee , 02-093 Wa saw, Poland
lAna Aslan – Na ional Ins i u e o Ge on ology and Ge ia ics, Bucha es , Romania
mNa ional Ins i u e o Public Heal h and he En i onmen (RIVM), Cen e o P e en ion and Heal h Se ices Resea ch, P.O. Box 1, 3720 BA Bil ho en, The
Ne he lands
nS a icell, Science Pa k C ealys, Rue Jean Sone 10, 5032 Les Isnes, Belgium
oDepa men o Enginee ing – BCE P o ein Enginee ing, Gus a Wieds ej 10, 8000 Aa hus, Denma k
pLi e and Heal h Sciences, As on Resea ch Cen e o Heal hy Ageing, As on Uni e si y, Bi mingham, UK
qDepa men o Molecula Biomedical Resea ch, VIB, Ghen , Belgium
Ins i u e o Nu i ional Medicine, Uni e si y o Hohenheim, 70593 S u ga , Ge many
sDepa men o Nu i ional Toxicology, F ied ich Schille Uni e si y Jena, Do nbu ge S . 24, 07743 Jena, Ge many
Depa men o Ca dio ho acic Su ge y, Uni e si y Hospi al Halle, E ns -G ube S . 40, 06120 Halle (Saale), Ge many
uCIG-In e depa men al Cen e “L.Gal ani”, Alma Ma e S udio um, Uni e si y o Bologna, 40126 Bologna, I aly
Unile e Co po a e Resea ch, Sha nb ook, UK
wDepa men o Cellula Bio echnologies and Hema ology, Facul y o Pha macy and Medicine, “Sapienza” Uni e si y Rome, V.le Regina Elena 324, 00161
Rome, I aly
xSo bonne Uni e si és, UPMC Uni Pa is 06, UMR UPMC CNRS 8256, Biological adap a ion and ageing – IBPS, INSERM U1164, F-75005 Pa is, F ance
yDepa men o Molecula Epidemiology, Leiden Uni e si y Medical Cen e, Leiden, The Ne he lands
zMedical School, Uni e si y o Tampe e, 33014 Tampe e, Finland
ARegene a i e Medicine G oup, C anﬁeld Heal h, C anﬁeld, UK
a i c l e i n o
A icle his o y:
Recei ed 2 Decembe 2014
Recei ed in e ised o m 19 Ma ch 2015
Accep ed 21 Ma ch 2015
A ailable online 24 Ma ch 2015
Keywo ds:
Ageing bioma ke s
Human s udies
MARK-AGE
a b s a c
Many candida e bioma ke s o human ageing ha e been p oposed in he scien iﬁc li e a u e bu in all
cases hei a iabili y in c oss-sec ional s udies is conside able, and he e o e no single measu emen has
p o en o se e a use ul ma ke o de e mine, on i s own, biological age. A plausible eason o his is he
in insic mul i-causal and mul i-sys em na u e o he ageing p ocess. The ecen ly comple ed MARK-AGE
s udy was a la ge-scale in eg a ed p ojec suppo ed by he Eu opean Commission. The majo aim o his
p ojec was o conduc a popula ion s udy comp ising abou 3200 subjec s in o de o iden i y a se o
bioma ke s o ageing which, as a combina ion o pa ame e s wi h app op ia e weigh ing, would measu e
biological age be e han any ma ke in isola ion.
© 2015 The Au ho s. Published by Else ie I eland L d. This is an open access a icle unde he CC
BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
∗Co esponding au ho . Tel.: +49 7531 884035; ax: +49 7531 884033.
E-mail add ess: [email p o ec ed] (A. Bü kle).
h p://dx.doi.o g/10.1016/j.mad.2015.03.006
0047-6374/© 2015 The Au ho s. Published by Else ie I eland L d. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/
licenses/by-nc-nd/4.0/).
A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
3
1.
In oduc ion
Ageing
has
been
deﬁned
as
he
ime-dependen
decline
o
unc-
ional
capaci y
and
s ess
esis ance,
associa ed
wi h
inc eased
isk
o
mo bidi y
and
mo ali y.
Ageing
is
a
p ocess
ha
a ec s
mos
i
no
all
issues
and
o gans
o
he
body.
Mo eo e ,
c oss- alk
can
occu
be ween
mul iple
physiological
sys ems,
e.g.
me abolic
sys ems
may
inﬂuence
he
ageing
o
he
immune
sys em.
The
mechanisms
unde lying
he
ageing
p ocess
a e
beginning
o
be
un a elled
a
he
molecula
le el
(López-O ín
e
al.,
2013),
ye
he e
is
clea
e idence
ha
he
a e
o
ageing
di e s
signiﬁcan ly
be ween
membe s
o
he
same
animal
species,
including
humans.
In
o he
wo ds,
he
“biological
age”
may
di e
om
he
ch onological
age.
The
classical
quan i a i e
assessmen
o
“ he
a e
o
ageing”
elies
on
he
analysis
o
mo ali y
cu es
(Gompe z
unc ion)
o
popula ions.
In
o he
wo ds,
indi iduals
ha e
o
be
ollowed
up
un il
he
end
o
hei
li es
in
o de
o
de e mine
hei
“biologi-
cal
age”
a
any
ime
poin
du ing
li e.
The e o e,
a
he
le el
o
a
li ing
indi idual,
a
eliable
o
assessmen
o
he
s a e
o
ageing,
i.e.
he
s a e
o
he
abo e-men ioned
unc ional
decline,
and
a
p edic-
ion
o
he
isk
o
he
onse
o
mo bidi y
and
he
esidual
indi idual
li e
expec ancy
a e
no
possible
wi h
his
me hod.
One
s a egy
o
sol e
his
p oblem
is
he
iden iﬁca ion
o
(an)
age- ela ed
change(s)
in
body
unc ion
o
composi ion
ha
could
se e
as
a
measu e
o
“biological”
age
and
p edic
he
u u e
onse
o
age- ela ed
diseases
and/o
esidual
li e ime
mo e
accu a ely
han
ch onological
age.
Such
pa ame e s
a e
e med
“bioma ke s
o
age-
ing”
(Bake
and
Sp o ,
1988).
This
e m
has
been
coined
in
analogy
o
bioma ke s
o
speciﬁc
ch onic
diseases,
such
as
HIV
in ec ion,
o
bioma ke s
o
exposu e
o
oxins.
The
Ame ican
Fede a ion
o
Aging
Resea ch
has
p oposed
he
ollowing
c i e ia
o
a
bioma ke
o
ageing:
1.
I
mus
p edic
he
a e
o
ageing.
In
o he
wo ds,
i
would
ell
exac ly
whe e
a
pe son
is
in
hei
o al
li e
span.
I
mus
be
a
be e
p edic o
o
li e
span
han
ch onological
age.
2.
I
mus
moni o
a
basic
p ocess
ha
unde lies
he
ageing
p ocess,
no
he
e ec s
o
disease.
3.
I
mus
be
able
o
be
es ed
epea edly
wi hou
ha ming
he
pe son,
o
example,
a
blood
es
o
an
imaging
echnique.
4.
I
mus
be
some hing
ha
wo ks
in
humans
and
in
labo a o y
animals,
such
as
mice.
This
is
so
ha
i
can
be
es ed
in
lab
animals
be o e
being
alida ed
in
humans.
The
ou h
o
he
abo e
c i e ia
may,
howe e ,
be
ques ioned
as
he e
a e
ce ainly
some
pa ame e s
whose
impo ance
o
he
ageing
p ocess
may
di e
be ween
mammalian
species.
One
exam-
ple
would
be
elome e
sho ening
in
humans
and
in
labo a o y
mice:
While
in
human
soma ic
issues
elome e
sho ening
can
eadily
be
de ec ed,
his
is
no
he
case
in
wild- ype
labo a o y
mouse
s ains
owing
o
hei
much
g ea e
o e all
leng h
o
elom-
e es.
The e o e
elimina ing
some
candida e
pa ame e s
jus
based
on
hei
lack
o
ele ance
in
some
model
sys ems
may
lead
o
an
exclusion
o
pa ame e s
ha
a e
po en ially
in e es ing
o
he
human
sys em.
I
should
be
no ed
ha
many
candida e
bioma ke s
o
human
ageing
ha e
been
p oposed
in
he
scien iﬁc
li e a u e
bu
in
all
cases
hei
a iabili y
in
c oss-sec ional
s udies
is
conside able,
and
he e o e
no
single
measu emen
has
p o en
o
se e
a
use ul
ma ke
o
de e mine,
on
i s
own,
biological
age.
A
plausible
eason
o
his
is
he
in insic
mul i-causal
(Holliday,
2006)
and
mul i-
sys em
na u e
o
he
ageing
p ocess.
MARK-AGE
was
a
la ge-scale
in eg a ed
p ojec
suppo ed
by
he
Eu opean
Commission.
The
majo
aim
o
his
p ojec
was
o
conduc
a
popula ion
s udy
com-
p ising
abou
3200
subjec s
in
o de
o
iden i y
a
se
o
bioma ke s
o
ageing
which,
as
a
combina ion
o
pa ame e s
wi h
app op ia e
weigh ing,
would
measu e
biological
age
be e
han
any
ma ke
in
isola ion.
2.
MARK-AGE
conso ium
In
o de
o
ackle
he
scien iﬁc
p oblem
o
es ablishing
powe -
ul
bioma ke s
o
human
ageing,
he
MARK-AGE
conso ium,
which
consis ed
o
26
Pa ne s
comp ising
21
non-p oﬁ
o ganisa ions
(uni e si ies
and
public
esea ch
ins i u es),
3
small
and
medium
sized
en e p ises
(SMEs),
and
2
la ge
companies,
was
o med.
The
scien iﬁc
g oups
in ol ed
a e
a
he
o e on
in
he
ﬁeld
o
ageing
esea ch,
and
some
Pa ne s
a e
in e na ional
leade s
e en
in
wide
ﬁelds
such
as
Gene ics.
The
MARK-AGE
conso ium
was
cha ac-
e ised
by
a
high
deg ee
o
in e disciplina i y:
The
a ay
o
expe ise
anged
om
Ge ia ics,
Epidemiology
and
Human
Gene ics
o
Clin-
ical
Chemis y,
Biochemis y,
Cell
Biology,
Immunology,
Molecula
Gene ics,
Bioin o ma ics
and
Ma hema ical
Modelling.
Such
a
le el
o
in e disciplina i y
is
essen ial
o
he
success
o
a
p ojec
o
his
la ge
scale.
The
lead
esea che s
a e
he
au ho s
on
his
documen .
3.
The
MARK-AGE
s a egy
In
he
La ge-Scale
In eg a ing
P ojec
MARK-AGE,
he
Pa ne s
p oposed
o
pe o m
a
comp ehensi e
and
cohe en
Eu ope-
wide
popula ion
s udy
aiming
a
he
iden iﬁca ion
o
powe ul
bioma ke s
o
human
ageing
ac oss
a
ange
o
physiological
Fig.
1.
Schema ic
ep esen a ion
o
he
managemen
s uc u e
o
he
MARK-AGE
p ojec .
4
A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
Table
1
MARK-AGE
wo k
packages.
Wo k
package
numbe
Wo k
package
i le
1
Rec ui men
o
p obands
and
physiological
ma ke s
2
DNA-based
ma ke s
3
Ma ke s
based
on
p o eins
and
hei
modiﬁca ions
4
Immunological
ma ke s
5
Clinical
chemis y,
ho mones
and
ma ke s
o
me abolism
6
Oxida i e
s ess
ma ke s
7
Eme gen
bioma ke s
o
ageing
om
model
sys ems
and
no el
me hodological
app oaches
8
Da a
analysis
and
bioin o ma ics
9
Dissemina ion
and
aining
10
P ojec
managemen
and
e hical
issues
sys ems.
The
s udy
popula ion
comp ised
o
abou
3200
subjec s
and
ep esen ed
se e al
di e en
geog aphical
egions
o
Eu ope.
The
s udy
popula ion
co e ed
he
age
ange
o
35–74
yea s,
as
his
is
he
ime
span
du ing
which
p ophylaxis
/
in e en ion
o
coun e
age- ela ed
diseases
may
be
possible
and
p omising.
A
wide
ange
o
candida e
bioma ke s
was
es ed,
including
(1)
“classical”
ones
o
which
da a
om
se e al
smalle
s udies
ha e
been
published;
(2)
“new”
ones,
based
on
p elimina y
da a
ob ained
in
small-scale
s udies,
as
well
as
(3)
“no el”
ones,
based
on
ecen
esea ch
on
mechanis ic
aspec s
o
ageing,
conduc ed
by
p ojec
Pa ne s.
I
is
easonable
o
assume
ha
a
combina ion
o
se e al
bioma ke s
will
p o ide
a
much
be e
ool
o
measu e
biologi-
cal
age
han
any
single
bioma ke
in
isola ion.
I
has
o
be
aken
in o
accoun ,
hough,
ha
no
all
bioma ke s
a e
o
equal
weigh .
The e o e
a e aging
all
possible
candida e
bioma ke s
may
no
app op ia e.
A
majo
ask
o
his
p ojec
was,
he e o e,
o
op i-
mise
he
weigh ing
o
he
di e en
ma ke s,
by
using
mul i- a ia e
analysis,
wi h
he
aim
o
educing
a iance
and
o
de i e
a
ma he-
ma ical
o mula
ha
will
yield
a
“biological
age
sco e”.
I
should
be
men ioned
ha
wo k
pe o med
in
he
con ex
o
he
“MacA hu
s udies
o
success ul
aging”
on
a
coho
o
171
adul s
aged
70–79
had
al eady
p o ided
p oo -o -concep
by
showing
ha
an
“allo-
s a ic
load
sco e”,
inco po a ing
10
biological
ma ke s,
can
be
p edic i e
o
mo ali y
isk
(Seeman
e
al.,
1995).
The
MARK-AGE
p ojec
p o ided
a
sys ema ic
app oach:
The
Conso ium
es ablished
S anda d
Ope a ing
P ocedu es
o
he
ec ui men
o
subjec s
and
p ocessing
o
samples
(see
Mo eno-
Villanue a
and
Cap i
e
al.,
his
issue),
as
well
as
quali y
con ol
measu es
(Jansen
e
al.,
his
issue).
I
was
deemed
essen ial
o
ec ui
a
new
popula ion
o
subjec s,
since
p e ious
ec ui men
e o s
pe o med
in
many
Eu opean
coun ies
nei he
ha e
co -
e ed
he
age
ange
o
in e es
no
ha e
hey
p o ided
he
biological
ma e ials
o
be
s udied,
including
c yop ese ed
blood
cells.
The
ac i i ies
wi hin
he
MARK-AGE
p ojec
we e
dis ibu ed
in
Wo k
Packages
(Table
1)
3.1.
WP1:
ec ui men
o
subjec s
and
assessmen
o
physiological
ma ke s
Two
la ge
g oups
o
subjec s
we e
ec ui ed.
A e
exclusion
o
138
hepa i is
posi i e
subjec s,
he
ﬁ s
g oup
comp ised
o
2262
andomly
ec ui ed
age-s a iﬁed
indi iduals
om
he
gen-
e al
popula ion
(RASIG)
om
se e al
di e en
geog aphical
egions
o
Eu ope.
Equal
numbe s
o
men
and
women
we e
en olled,
com-
p ising
simila
numbe s
o
indi iduals
in
he
ollowing
age
classes:
35–39
y s,
40–44
y s,
45–49
y s,
50–54
y s,
55–59
y s,
60–64
y s,
65–69
y s,
70–74
y s.
This
g oup
was
hough
o
be
display
he
“a e age
popula ion
ageing
a e”.
The
second
g oup
comp ised
o
subjec s
bo n
om
a
long-li ing
pa en
belonging
o
a
amily
wi h
long-li ing
sibling(s),
such
as
he
“90+
sibpai s”
ec ui ed
wi hin
he
amewo k
o
he
EU
In eg a ed
P ojec
GEHA,
and
hence o h
designa ed
GEHA
o sp ing
(GO)
(528
subjec s).
GO
co e
he
age
ange
o
55–74
yea s.
Acco ding
o
da a
om
he
ecen
li e a u e,
indica ing
ha
o sp ing
o
long-li ing
pa en s
age
in
a
“be e ”
way
han
con ols
bo n
om
non
long-
li ing
pa en s,
GO
a e
p edic ed
o
age
a
a
slowe
a e
han
he
a e age
popula ion.
Wi hin
he
MARK-AGE
p ojec ,
he
GO
subjec s
we e
he e o e
compa ed
wi h
hei
spouses,
hence o h
designa ed
spouses
o
GEHA
o sp ing
(SGO)
(305
subjec s).
Sys ema ic
compa ison
o
GO
and
SGO
coho s
should
p o ide
a
unique
oppo uni y
o
a
ﬁ s
al-
ida ion
o
he
bioma ke s
iden iﬁed
in
he
c oss-sec ional
s udy
o
he
RASIG
subjec s.
I
is
expec ed
ha
GO
display
a
lowe
biological
age
han
SGO.
The
p ojec
also
ook
ad an age
o
he
ac
ha
some
ela i ely
a e
‘segmen al
p oge oid
synd omes’
p esen
cha ac e is ics
o
d ama ically
accele a ed
ageing
and
p ema u e
dea h
om
ypi-
cal
ageing-associa ed
diseases.
This
is
he
case
o
subjec s
a ec ed
by
Down’s
synd ome
(DS)
o
We ne ’s
synd ome
(WS).
Due
o
he
(ex eme)
a i y
o
hese
synd omes,
only
a
small
numbe
o
DS
subjec s
we e
ec ui ed,
while
biological
ma e ial
(se um,
plasma,
u ine
and
blood)
om
WS
pa ien s
was
s o ed
in
he
MARK-AGE
biobank.
The
ageing
p ocess
o
DS
and
WS
subjec s
is
being
com-
pa ed
wi h
RASIG
and
GO/SGO
subjec s.
I
is
expec ed
ha
hei
bioma ke s
indica e
a
highe
biological
age,
and
so
his
compa ison
is
expec ed
o
p o ide
an
addi ional
alida ion
o
he
bioma ke s
iden iﬁed
in
he
c oss-sec ional
analysis
o
RASIG.
In
o de
o
asce ain
he
biological
and
analy ical
obus ness
o
he
measu emen s
o
candida e
bioma ke s,
97
dono s
om
he
whole
s udy
popula ion
ha e
been
e-sampled
wi hin
3–6
mon hs.
In
such
a
sho
ime
pe iod,
no
signiﬁcan
change
in
he
biological
age
s a us
o
he
subjec s
is
expec ed;
he e o e
an
ideal
bioma ke
essen ially
should
yield
he
same
esul s.
Finally,
a
limi ed
andom
sample
o
subjec s
was
ollowed-up
in
a
small
longi udinal
s udy,
compa ible
wi h
he
ime
and
budge a y
cons ain s
o
he
p ojec .
We
e- es ed
12%
o
he
ec ui ed
sub-
jec s
RASIG,
GO,
SGO
(389
subjec s
in
o al)
a e
3
yea s.
I
was
expec ed
ha
hose
subjec s
whose
bioma ke
p oﬁle
indica ed
an
ad anced
biological
age
a
baseline
should
display
a
simila
o
accele a ed
pa e n
a
he
3-yea
ollow-up,
and
ice
e sa
o
he
biologically
younge
indi iduals.
F om
all
subjec s
en olled,
an h opome ic,
clinical
and
demo-
g aphic
da a
ha e
been
collec ed
in
a
s anda dised
ashion.
Upon
w i en
in o med
consen ,
he
ollowing
se
o
in o ma ion
was
ob ained
by
using
a
s anda dised
ques ionnai e:
•Demog aphic
in o ma ion:
amily
composi ion,
ma i al
s a us,
educa ion,
occupa ion,
and
housing
condi ions.
•Li es yle:
use
o
obacco
and
alcohol,
daily
ac i i ies.
•Func ional
s a us:
Ac i i ies
o
Daily
Li ing
(ADL)
and
No on
Scale.
•Cogni i e
s a us:
STROOP
es ,
15-pic u e
lea ning
es .
•Heal h
s a us:
p esen
and
pas
diseases,
sel -pe cei ed
heal h,
numbe
and
ype
o
p esc ibed
d ugs.
•Mood:
ZUNG
dep ession
scale.
A
physical
examina ion
o
all
subjec s
comp ised
measu emen
o
he
ollowing
“classical”
candida e
bioma ke s:
•Body
mass
index.
•Wais
and
hip
ci cum e ence.
•Blood
p essu e
a
es .
•Hea
a e
a
es .
A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
5
•Lung
unc ion
–
o ced
expi a o y
olume
in
1
s
(FEV1).
•Lung
unc ion
–
o ced
i al
capaci y
(FVC).
•Fi e- imes
chai
s anding.
•Handg ip
s eng h.
All
subjec s
we e
asked
o
dona e
blood
(55
ml)
by
enipunc u e
a e
o e nigh
as ing.
The
blood
sample
was
p ocessed
o
ob ain
plasma,
se um
and
pe iphe al
blood
mononuclea
cells
(PBMC).
PBMC
we e
c yop ese ed
and
all
he
o he
componen s
we e
ozen
down.
Buccal
mucosal
cells
we e
also
collec ed
(using
a
ki )
as
well
as
spo
u ine
samples
(see
Mo eno-Villanue a
and
Cap i
e
al.,
his
issue).
3.2.
WP
2:
DNA-based
ma ke s
The
in eg i y
o
he
nuclea
genome
and
he
epigenome
is
o
i al
impo ance
o
he
p ope
unc ion
o
cells,
issues
and
o gans.
The e
is,
howe e ,
a
cons an
a ack
by
exogenous
and
endogenous
compounds
and
agen s
(including
eac i e
oxygen
species
[ROS])
ha
can
damage
DNA
and/o
dis u b
epigene ic
egula ion.
Possible
consequences
a e
mu a ion
and
dys egula ion
o
gene
exp ession,
which
ei he
can
lead
o
cell
dea h
o
cellula
senescence
o
o
malignan
ans o ma ion
o
he
cells
ul ima ely
esul ing
in
can-
ce .
P o ec ion
and
main enance
sys ems
ha e
e ol ed
ha
help
main ain
a
sus ainable
s eady-s a e
le el
o
molecula
damage,
and
hese
include
DNA
epai
sys ems
and
DNA
me hyl
ans e ases.
Fu he mo e
elome ic
DNA
unde goes
a i ion
wi h
each
eplica-
ion
cycle
and
also
as
a
consequence
o
DNA
damage.
A
c i ical
loss
o
elome e
epea
sequences
has
been
shown
o
p e en
u he
cell
p oli e a ion
and
in
some
cell
ypes
induces
cellula
senescence.
Mi ochond ial
DNA
is
an
especially
ulne able
a ge
o
mu a-
genesis,
in
iew
o
he
high
local
le els
o
endogenous
ROS
in
mi ochond ia.
Damage
and
mu a ion
o
mi ochond ial
DNA
is
iewed
as
a
majo
mechanism
d i ing
he
ageing
p ocess
(Niemi
e
al.,
2003;
Wong
e
al.,
2009;
Al ilia
e
al.,
2012).
Ne e he-
less
D-loop
egion
con ains
le el
o
he e oplasmy
associa ed
wi h
longe i y,
as
p e iously
iden iﬁed
(Rose
e
al.,
2007),
sugges ing
also
m DNA
a ian s-
based
mechanisms
o
p o ec ion
(Raule
e
al.,
2014).
Fu he ,
APOE
geno ype,
which
is
conside ed
a
gold
s an-
da d
o
he
gene ics
o
longe i y
and
was
ecen ly
e-conﬁ med
(Deelen
e
al.,
2014),
was
aken
in o
accoun
wi h
he
basic
idea
o
iden i y
possible
subg oups
o
indi iduals
wi h
bes
o
wo s
heal h
condi ions
(ex eme
pheno ypes).
Ou
o e a ching
hypo hesis
was
ha
he
p esence
o
p oﬁ-
cien
sys ems
o
p e en / epai
damage
and
mu a ion
(Beneke
and
Bu kle,
2007)
o
he
nuclea
genome
(Reale
e
al.,
2005;
Caia a
and
Zampie i,
2005;
Za do
e
al.,
2002),
including
elome e
sho ening
(Canela
e
al.,
2007;
Bene i
e
al.,
2007;
Flo es
e
al.,
2005;
Gonzalo
e
al.,
2006),
and
o
he
mi ochond ial
genome
(Bellizzi
e
al.,
2006;
De
Benedic is
e
al.,
1999)
should
help
e a d
he
ageing
p ocess
in
many
i
no
all
issues.
The e o e
hese
cellula
unc ions
ha e
a
po en ial
o
se e
as
bioma ke s
o
ageing.
The
ollowing
esea ch
asks
ha e
speciﬁcally
been
add essed:
•We
ha e
s udied
he
main enance
o
he
epigenome
by
analysing
gene
exp ession
pa e ns
in
PBMC
and
cy osine
me hyla ion
s a-
us.
DNA
me hyla ion
was
o
be
co ela ed
wi h
he
possible
age-dependen
exp ession
le el
o
some
genes
whose
exp ession
has
been
associa ed
wi h
ageing
o
longe i y.
•The
ageing-dependen
decline
o
DNA
epai
was
e alua ed
by
unc ional
analysis
o
he
epai
o
DNA
s and
b eaks
induced
by
X- ays
and
in
s udies
on
cellula
poly(ADP- ibosyl)a ion
capaci y
and
PARP-1
exp ession
le els.
•A en ion
was
also
di ec ed
owa ds
elome e
leng h,
which
is
being
co ela ed
wi h
modiﬁca ions
o
sub elome ic
DNA
me hy-
la ion
pa e n.
•The
ques ion
o
an
age- ela ed
accumula ion
o
mu a ions
in
m DNA
was
o
be
add essed
by
quan i ying
he
le el
o
he e o-
plasmy.
Special
a en ion
was
paid
o
he e oplasmy
o
he
m DNA
con ol
egion.
•Dono s
we e
s a iﬁed
o
hei
APOE
geno ype
o
co ela e
his
wi h
he
ype
o
ageing,
i.e.
success ul
o
unsuccess ul
ageing.
3.3.
WP
3:
ma ke s
based
on
p o eins
and
hei
modiﬁca ions
One
impo an
physiological
pos ansla ional
modiﬁca ion
o
sec e ed
p o eins
is
addi ion
o
N-linked
oligosaccha ides
(N-
glycans).
Since
mos
N-glycans
a e
on
he
ou e
su ace
o
cellula
and
sec e ed
mac omolecules,
hey
can
modula e
o
media e
a
wide
a ie y
o
e en s
in
cell-cell
and
cell-ma ix
in e ac ions
c ucial
o
he
de elopmen
and
unc ion
o
complex
mul icellula
o ganisms.
Because
he
biosyn hesis
o
glycans
is
no
con olled
by
in e ac-
ion
wi h
a
empla e
bu
depends
on
he
complica ed
conce ed
ac ion
o
glycosyl ans e ases,
he
s uc u es
o
glycans
a e
much
mo e
a iable
han
hose
o
p o eins
and
nucleic
acids,
and
hey
can
be
easily
al e ed
by
he
physiological
condi ions
o
he
cells.
Acco dingly,
s udying
age- ela ed
al e a ions
o
he
glycans
could
be
ele an
o
unde s anding
he
complex
physiological
changes
in
ageing
indi iduals
(Vanhoo en
e
al.,
2010).
The
objec i e
o
his
sub- ask
was
o
de e mine
he
changes
in
he
blood
N-glycome
du -
ing
human
ageing
o
heal hy
humans
and
o
de elop
me hodology
o
p oﬁling
u ine
N-glycans
(Vanhoo en
e
al.,
2007).
The
apolipop o ein
J/Clus e in
(ApoJ/CLU)
is
a
highly
conse ed
mul i unc ional
glycop o ein.
Amongs
i s
mul iple
physiological
unc ions,
his
p o ein
is
a
chape one
ha
s abilizes
s essed
p o-
eins
in
a
olding-compe en
s a e.
P e ious
wo k
had
shown
ha
ApoJ/CLU
is
associa ed
wi h
human
ageing
and
wi h
ageing
o
human
cells
in
i o,
and
ha
i s
le el
is
inc eased
in
pa ien s
wi h
ype
II
diabe es,
co ona y
hea
disease,
and
myoca dial
in a c ion.
The e o e
ApoJ/CLU
may
ep esen
a
aluable
ageing
bioma ke .
Non-enzyma ic
p o ein
glyca ion
is
a
common
pos ansla ional
modiﬁca ion
o
p o eins
in
i o,
esul ing
om
eac ions
be ween
glucose
and
amino
g oups
on
p o eins;
his
p ocess
is
e med
“Mail-
la d
eac ion”
and
leads
o
he
o ma ion
o
Ad anced
Glyca ion
Endp oduc s
(AGEs).
Du ing
no mal
ageing,
he e
is
accumula ion
o
AGEs
o
long-li ed
p o eins
such
as
collagens
and
ca ilage.
AGEs,
ei he
di ec ly
o
h ough
in e ac ions
wi h
hei
ecep o s,
a e
in ol ed
in
he
pa hophysiology
o
nume ous
age- ela ed
diseases
(Simm
e
al.,
2014),
such
as
ca dio ascula
and
enal
diseases
and
neu odegene a ion.
Howe e ,
in
a
coho
s udy
on
human
ageing,
he
co ela ion
o
AGEs
wi h
human
age
emained
deba able.
By
analysing
o e all
pa ame e s
o
AGEs
as
well
as
speciﬁc
AGEs,
i
was
o
be
de e mined
i
hese
modiﬁca ions
co ela e
wi h
age
indepen-
den ly
o
disease
and
i
he e
a e
gende
di e ences
(Scheubel
e
al.,
2006;
Simm
e
al.,
2004).
I
is
well
known
ha
le els
o
oxidised
p o eins
inc ease
wi h
age,
due
o
inc eased
p o ein
damage
induced
by
ROS,
dec eased
elimina ion
o
oxidised
p o ein
(i.e.
epai
and
deg ada ion),
o
a
combina ion
o
he
wo.
Since
he
p o easome
is
in
cha ge
o
bo h
gene al
p o ein
u no e
and
he
selec i e
emo al
o
oxidized
p o-
ein,
i s
a e
du ing
ageing
has
ecei ed
conside able
a en ion,
and
e idence
has
been
p o ided
o
an
impai men
o
p o easome
unc ion
wi h
age
in
di e en
cellula
sys ems
(Chond ogianni
and
Gonos,
2010;
Ba aiba
and
F igue ,
2013),
including
human
PBMC
(Chond ogianni
e
al.,
2003,
2005;
Ca a d
e
al.,
2003;
F igue ,
2006).
Apa
om
o
being
deg aded,
ce ain
oxidised
p o eins
can
be
epai ed.
Howe e ,
epai
is
limi ed
o
he
e e sion
o
a
ew
oxida i e
modiﬁca ions
o
sulphu -con aining
amino
acids,
such
as
he
educ ion
o
me hionine
sul oxide
by
he
me hionine
sul oxide
educ ase
(Ms )
sys em.
Ms
ac i i y
is
known
o
be
impai ed
du -
ing
ageing
and
eplica i e
senescence.
The e o e,
he
s a us
o
bo h
p o easome
and
Ms s
A
and
B
in
human
PBMC
om
he
ec ui ed
6
A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
dono s
o
di e en
ages
was
o
be
assessed.
These
pa ame e s
had
p e iously
been
shown
o
be
key
playe s
in
oxidised
p o ein
deg a-
da ion
and
epai
and
o
exhibi
a
declining
ac i i y
wi h
age
(Pico
e
al.,
2004,
2007).
These
p o ein
main enance
sys ems,
iewed
as
po en ial
bioma ke s
o
ageing,
we e
o
be
moni o ed
a
he
le els
o
enzyma ic
ac i i y,
p o ein
exp ession,
and
RNA
exp ession.
The
ollowing
esea ch
asks
ha e
speciﬁcally
been
add essed:
•Analysiso
he
N-glycomic
changes
in
glycop o eins
om
blood
o
all
dono s.
U ine
glycop o ein
changes
we e
o
be
s udied
in
a
subse
o
subjec s.
•ApoJ/CLU
le els
in
se um
om
all
dono s.
•AGEs
in
plasma
by
ﬂuo escence
spec oscopy
and
by
immuno-
logical
analysis
o
ca boxy-me hyllysine,
pen osidine,
a g-
py imidine
and
imidazolone.
•P o ein
damage
in
blood
a
di e en
le els,
i.e.
ac i i ies
o
p o-
easome
and
me hionine
sul oxide
educ ases
in
PBMC
lysa es;
RNA
le els
o
ep esen a i e
p o easome
subuni s
(ca aly ic
and
egula o y)
and
me hionine
sul oxide
educ ases
A
and
B;
and
p o ein
le els
o
ep esen a i e
p o easome
subuni s
and
me hi-
onine
sul oxide
educ ases
A
and
B
in
PBMC
lysa es.
3.4.
WP
4:
immunological
ma ke s
Thymic
ou pu
is
known
o
decline
wi h
age;
u he mo e
he
a e
o
decline
is
dependen
on
gende ,
wi h
g ea e
hymic
ou -
pu
o
longe
in
emales
compa ed
wi h
males
(Aspinall
e
al.,
2007).
Females
o en
de elop
be e
immune
esponses
han
males,
which
may
ela e
o
hei
longe
li espan.
Wi hin
MARK-AGE,
signal
join
T-cell
ecep o
ea angemen
excision
ci cles
(sjTREC)
we e
assessed
as
a
candida e
bioma ke
o
ageing
and
hymic
in olu ion,
by
analysing
sjTREC
le els
in
indi iduals
a
a ious
ages
(Aspinall
e
al.,
2007).
A
obus
immunological
memo y
is
known
o
be
a
gua an o
o
heal h
in
adul s
and
in
pa icula
in
elde ly
pe sons,
while
ch onic
la en
in ec ions,
such
as
CMV
in ec ion,
ha e
been
shown
o
be
associa ed
wi h
sho e
li e
expec ancy.
Au o-immune
esponses
may
also
es ic
he
di e si y
o
immune
esponsi eness
o
o -
eign
an igens.
We
he e o e
e alua ed
long- e m
and
sho - e m
immunological
memo y
and
au oimmune
esponses
as
po en ial
bioma ke s
o
ageing
(Almanza
e
al.,
2005;
Ko aiou
e
al.,
2007;
Weinbe ge
e
al.,
2007;
He ndle -B ands e e
e
al.,
2005).
In
i o,
wo
ypes
o
senescence
ha e
been
desc ibed.
One
is
elome e-dependen
eplica i e
senescence
and
he
second
is
s ess-induced
p ema u e
senescence
(SIPS)
(Siko a
e
al.,
2014).
In
iew
o
p e ious
esul s
we
hypo hesised
ha
du ing
age-
ing,
ch onic
an igenic
load
as
well
as
oxida i e
s ess
may
cause
dec eased
lymphocy e
suscep ibili y
o
Damage-Induced
Cell
Dea h
(DICD)
and,
on
he
o he
hand,
inc eased
suscep ibili y
o
Ac i a ion-Induced
Cell
Dea h
(AICD).
As
an
in ac
equilib ium
be ween
su i al
and
elimina ion
o
immune
cells
may
be
deci-
si e
o
in ac
immune
unc ion
and
heal h
we
s udied
DICD
and
AICD
in
T
cells
om
dono
samples
(see
Siko a
e
al.,
his
issue).
The
ollowing
esea ch
asks
ha e
speciﬁcally
been
add essed:
•Analysis
o
o al
IgG,
IgE,
IgM
and
IgA;
se um/plasma
concen-
a ions
o
14
cy okines;
blood
coun s
and
di e en ial
blood
coun s
(pe o med
by
he
ec ui e s
locally);
and
pheno yping
o
T
cells,
B
cells
NK
cells
and
monocy es
by
immunoﬂuo escence
in
p oband
samples.
•Analysis
o
he
numbe
o
sjTRECs;
i
was
o
pa icula
in e es
o
analyse
whe he
sjTREC
concen a ions
di e
in
pe sons
wi h
and
wi hou
la en
i al
in ec ions
such
as
CMV,
HHV-6
and
HHV-7.
•Analysis
o
an ibodies
and
cellula
immuni y
(IFN
gamma
p o-
duc ion
by
Elispo )
agains
measles
and
mumps
i us
( ypically
childhood
exposu e)
in
o de
o
assess
long- e m
immunological
memo y.
•Analysis
o
an ibodies
and
cellula
immuni y
o
highly
con-
se ed
p o eins
o
he
inﬂuenza
i us
(NP
and
M
p o eins)
as
well
as
e anus
(an
agen
agains
which
mos
adul
pe sons
a e
accina ed
a
egula
in e als)
in
o de
o
assess
sho - e m
immunological
memo y.
•Analysis
o
immune
esponses
agains
CMV,
in
o de
o
assess
he
e ec
o
la en
i al
in ec ion.
•Analysis
o
au oan ibodies
agains
hy oglobulin
(as
an
exam-
ple
o
a
issue-speciﬁc
an igen)
and
an inuclea
an ibodies
(as
example
o
a
sys emic
immune
esponse).
•Analysis
o
suscep ibili y
o
Damage-Induced
Cell
Dea h
(DICD)
and
Ac i a ion-Induced
Cell
Dea h
(AICD),
espec i ely,
by
using
apop osis
ma ke s.
3.5.
WP
5:
clinical
chemis y,
ho mones
and
ma ke s
o
me abolism
In
he
li e a u e
a
ple ho a
o
classical
clinical
chemis y
pa am-
e e s
ha e
been
p oposed
as
po en ial
bioma ke s
o
ageing.
P ominen
examples
a e
pa ame e s
o
ca bohyd a e
and
lipid
me abolism
o
ho mones.
We
ha e
selec ed
he
mos
p omising
ones
o
inclusion
in
he
MARK-AGE
p ojec
and
we
ha e
added
se -
e al
new
po en ial
bioma ke s
ela ed
wi h
me abolism
ha
ha e
eme ged
in
he
ecen
wo k
o
some
Pa ne s
(Al-Delaimy
e
al.,
2006;
Rezzi
e
al.,
2007a,b;
Kochha
e
al.,
2006;
Heijmans
e
al.,
2006;
Mooijaa
e
al.,
2006;
Hu me
e
al.,
2005,
2007;
Ron u
e
al.,
2006;
Leh imaki
e
al.,
2007).
The
ollowing
candida e
bioma ke s
ha e
speciﬁcally
been
add essed:
Sys emic
me abolism
and
oxici y
pa ame e s
•Blood
u ea
ni ogen
and
c ea inine,
used
o
he
e alua ion
o
enal
unc ion.
•Me al
binding
p o eins
including
ans e in,
e i in,
␣2-
mac oglobulin
and
ce uloplasmin,
in
o de
o
complemen
me al
ion
de e mina ions
(see
below).
•Fas ing
glucose
and
as ing
insulin
as
a
measu e
o
glucose
homeos asis,
insulin
esis ance
and
diabe ic
condi ions.
•Glycosyla ed
hemoglobin
(A1C)
as
a
measu e
o
he
long- e m
sys emic
glucose
load,
in
o de
o
de ec
(p e)
diabe ic
condi ions.
•Some
basic/ e e ence
pa ame e s,
including
albumin
and
se um
p o ein
concen a ion.
Fa y
acid
and
choles e ol
me abolism
pa ame e s
•Fas ing
iglyce ides
and
ee
a y
acids
we e
measu ed
o
de ec
me abolic
diso de s
in
lipid
me abolism.
•To al
choles e ol,
HDL
and
LDL-choles e ol
we e
measu ed
( oge he
wi h
iglyce ides)
o
isk
assessmen
o
ca dio ascula
diseases.
•Concen a ions
o
lipop o ein
pa icle
size
classes
by
NMR.
Sys emic
inﬂamma ion
pa ame e s
•C- eac i e
p o ein
(CRP),
homocys ein,
u ic
acid
and
ﬁb inogen
a e
inﬂamma o y
ma ke s
associa ed
ca dio ascula
disease
and
hype ension.
•Se um
amyloid
A
and
P,
and
pen axin
3
we e
amongs
he
acu e
phase
p o eins
s udied.
•Adiponec in
is
co ela ed
wi h
an
an i-inﬂamma o y
s a e
and
supp esses
me abolic
de angemen s
ha
may
esul
in
ype
II
diabe es,
obesi y,
a he oscle osis
and
non-alcoholic
a y
li e
disease.

A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
7
Addi ional
candida e
bioma ke s
•Tes os e one,
he
p incipal
male
sex
ho mone
whose
le els
a e
known
o
decline
g adually
wi h
age
in
males.
•P os a e
speciﬁc
an igen
(PSA)
was
measu ed
o
he
de ec ion
o
(p e)
neoplas ic
p ocesses
in
he
p os a e
and
p os a e
cance
in
pa icula .
•Vi amin
D,
a
ecen ly
iden iﬁed
p omising
candida e
ela ed
o
ageing
and
se e al
ch onic
diseases,
was
also
s udied.
•Dehyd oepiand os e one
sul a e
(DHEAS)
is
known
o
decline
wi h
age
and
is
a
classical
candida e
bioma ke
o
human
ageing
(Lane
e
al.,
1997).
No el
bioma ke s
o
be
de i ed
om
me abonomics
analysis
•Nuclea
Magne ic
Resonance
(NMR)-based
me abolic
p oﬁling
o
se um/plasma
samples
and
u ine
samples
om
p obands.
NMR
p oﬁles
display
a
se
o
esonances
a ising
om
majo
low-
molecula
weigh
molecules,
such
as
ke one
bodies,
o ganic
acids,
amino
acids,
and
a oma ic
me aboli es
(Oos endo p
e
al.,
2006;
Rezzi
e
al.,
2007a,b;
Ramadan
e
al.,
2007)
3.6.
WP
6:
oxida i e
s ess
ma ke s
I
has
been
pos ula ed
ha
oxida i e
s ess
is
causal
o
he
age-
ing
p ocess.
Oxida i e
s ess
e e s
o
an
imbalance
be ween
ROS
o ma ion
and
an ioxidan
de ence.
In
human
beings
la ge
amoun s
o
oxidan s
a e
o med
in
a ious
physiological
me abolic
eac ions
and
e en
a
wide
a ie y
o
pa hophysiological
condi ions.
The
body
is
able
o
espond
o
such
enhanced
oxidan
o ma ion
wi h
com-
pensa o y
an ioxidan
eac ions.
These
eac ions
a e
also
complex
and
a
la ge
a ie y
o
di e en
enzymes
a e
in ol ed.
I
an ioxi-
dan
p o ec ion
is
insu ﬁcien ,
oxida i e
s ess
wi h
an
enhanced
o ma ion
o
oxida i e
s ess
ma ke s
occu s.
Oxida i e
damage
accumula ion
in
mac omolecules
has
been
conside ed
causa i e
o
cellula
damage
and
pa hology.
Such
dam-
age
seems
o
be
closely
ela ed
o
he
ageing
p ocess.
Al hough
he
ela ionship
be ween
oxida i e
damage
and
he
ageing
p ocess
has
been
es ablished
in
a ious
model
sys ems,
only
ew
s udies
epo ed
a
sys ema ic
analysis
o
oxida i e
s ess
pa ame e s
in
heal hy
humans
ela ed
o
age
o
indi iduals
(Pandey
and
Riz i,
2010;
Gil
e
al.,
2006).
The
pu pose
o
his
wo k
package
was
o
analyse
a
se
o
pa am-
e e s
o
oxida i e
s ess
pa ame e s
(Gil
e
al.,
2006),
i amins
and
ace
elemen s
(Mazza i
e
al.,
2007;
Mala ol a
e
al.,
2006;
Mocchegiani
e
al.,
2006)
in
human
blood,
se um,
u ine
and
buc-
cal
mucosa
cells.
P e e ence
was
gi en
o
new
echnologies
o
he
assessmen
o
oxida ion
ma ke s
and
o
ma ke s
al eady
es ab-
lished
and
sui able
o
adap a ion
o
high- h oughpu
o ma s.
The
ollowing
candida e
bioma ke s
ha e
speciﬁcally
been
add essed:
•Malondialdehyde.
•Ca bonyla ed
and
ni a ed
p o eins.
•Oxida ion
o
LDL.
•NO
me abolic-pa hway
p oduc s
(NOx)x.
•Isop os anes.
•Cellula
glu a hione.
•Vi amin
con en
(␣- ocophe ol,
␣-ca o ene
and
asco ba e)
o
se um
and
buccal
mucosal
cells.
•T ace
elemen s
(Zn,
Cu,
Se
and
Fe)
in
blood/se um.
3.7.
WP
7:
eme gen
bioma ke s
o
ageing
om
model
sys ems
and
no el
me hodological
app oaches
Whils
con en ional
bioma ke s
o
disease
ha e
been
es ab-
lished
by
hypo hesis-d i en
app oaches
based
on
an
unde lying
knowledge
o
he
disease
p ocess
o
se endipi y,
s udies
which
ocus
on
iden iﬁca ion
o
bioma ke s
o
heal hy
ageing
a e
con-
s ained
in
hei
abili y
o
ollow
indi iduals
o e
p olonged
pe iods
o
ime
un il
hei
ch onological
age
de ia es
om
hei
biological
age.
To
o e come
his
p oblem,
we
adop ed
pa allel,
sys ema ic
app oaches
o
in es iga e
pu a i e
bioma ke s
in
speciﬁc
ageing
coho s
(as
deﬁned
in
WP1)
alongside
he
s udy
o
models
o
accel-
e a ed
ageing,
such
as
p oge oid
synd omes
(in
humans
and
mice)
and
induced
senescence
in
leukocy es
om
subjec s
o
di e en
ages.
We
used
bo h
es ablished
and
no el
app oaches
o
sea ch
o
bioma ke s
o
ageing
in
an
i e a i e
p ocess,
whe e
ma ke s
de i ed
om
models
would
in o m
in
i o
bioma ke
sea ches.
(a)
Model
Sys ems
P oge oid
mouse
models
P oge oid
synd omes
a e
a e
diso de s
wi h
p ema u e
ageing
and
a
sho ened
li e
expec ancy.
These
condi ions
a e
cha ac e -
ized
by
ex emely
accele a ed
ageing,
showing
many
hallma ks
o
no mal
ageing
including
cessa ion
o
g ow h,
li e ,
kidney
and
bone
abno mali ies,
e inopa hy,
hea ing
loss,
sa copenia,
neu-
odegene a ion,
sensi i i y
o
UV
ligh ,
and
a
p ema u e
aged
appea ance
due
o
kyphosis,
baldness,
loss
o
subcu aneous
a ,
and
d y
w inkled
skin.
Cockayne
synd ome
(CS),
Hu chinson-
Gil o d
synd ome,
We ne ’s
synd ome
(WS),
Bloom’s
synd ome,
and
icho hiodys ophy
a e
all
au osomal
ecessi e
diso de s
wi h
p oge oid
symp oms.
Al hough
some
di e ences
exis
in
he
pa hology
o
hese
condi ions
i
is
s iking
ha
he
causal
ac-
o
o
all
hese
synd omes
lies
in
impai ed
genome
main enance
due
o
DNA
epai
deﬁciencies
o
genome
ins abili y.
One
aim
o
he
p ojec
was
he
iden iﬁca ion
o
bioma ke s
o
ageing
in
CS,
a
a e
human
diso de ,
in
which
pa ien s
su e
om
segmen-
al
bu
bona
ﬁde
accele a ed
ageing.
The
mean
age
a
dea h
o
CS
pa ien s
is
12.5
yea s.
The e
is
cu en ly
no
ea men
o
CS
and
ela ed
diso de s
a ailable
and
he
clinical
managemen
o
pa ien s
is
pu ely
suppo i e.
CS
is
an
au osomal
ecessi e
diso de
caused
by
mu a ions
in
he
CSA
o
CSB
genes,
which
a e
in ol ed
in
ansc ip ion-coupled
nucleo ide
and
base
excision
epai
(TCER).
The
TCER
sub-pa hway
selec i ely
emo es
lesions
om
he
an-
sc ibed
s and
ha
ac ually
block
ansc ip ion.
As
such
his
p ocess
is
impo an
o
p omo ing
eco e y
o
he
i al
p ocess
o
an-
sc ip ion
and
hus
cellula
su i al
om
ansc ip ion-blocking
DNA
lesions.
One
o
he
objec i es
o
he
p ojec
was
o
apply
he
bioma ke s
s udied
in
Wo k
Packages
2
h ough
6
o
p oge oid
pa ien s,
he eby
de e mining
o
which
ex en
p ema u e
and
no -
mal
ageing
esemble
each
o he
and
hei
sui abili y
o
iden i y
ageing
ea u es
independen
o
ch onological
age.
To
unde s and
he
ae iology
o
CS
and
o he
DNA
epai
dis-
o de s
such
as
icho hiodys ophy
(TTD)
and
he
cance -p one
condi ion
xe ode ma
pigmen osum
(XP),
an
ex ensi e
collec ion
o
DNA
epai -deﬁcien
ansgenic
mice
had
p e iously
been
gene -
a ed,
many
o
which
mimic
he
hallma ks
o
he
co esponding
human
epai
synd ome.
These
mice
display
ei he
a
s ong
can-
ce
p edisposi ion
(XP-like)
o
many
ea u es
o
p ema u e
ageing,
o
a
combina ion.
Al hough
he
Csbm/m mouse
model
eliably
eﬂec s
he
epai
de ec
and
UV-sensi i e
pheno ype
o
he
pa ien ,
animals
show
ela i ely
mild
g ow h
e a da ion
and
neu ological
abno mali ies,
accompanied
by
age- ela ed
e inal
degene a ion.
In e es ingly,
when
TCER-de ec i e
Csbm/m mice
we e
c ossed
wi h
comple ely
NER-deﬁcien
Xpa−/−animals
double
mu an s
phenocopy
human
CS
su p isingly
well,
including
i s
age- ela ed
8
A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
pa hology.
Al hough
Csbm/m/Xpa−/−pups
a e
de oid
o
any
o e
emb yonic
de elopmen al
pheno ype,
hey
display
se e e
pos -
na al
g ow h
e a da ion,
impai ed
psychomo o
de elopmen ,
a axia,
p og essi e
cachexia,
and
kyphosis.
Loss
o
e inal
pho-
o ecep o s
is
also
u he
accele a ed,
as
compa ed
o
Csbm/m
animals.
Mo eo e ,
mos
Csbm/m/Xpa−/−newbo ns
die
du ing
o
sho ly
a e
bi h,
whe eas
animals
ha
su i e
bi h
s ess
do
no
su i e
beyond
h ee
weeks.
Exploi ing
he
gene ic
and
en i-
onmen ally
ully
deﬁned
mouse
sys em
hese
and
o he
mouse
mu an s
o
XP,
XP/CS
and
TTD
p o ided
a
con enien
ool
o
deduce
speciﬁc
bioma ke s
in
a ious
o gans/ issues
including
se um.
Wi hin
MARK-AGE
a
se
o
mouse
bioma ke s
o
ageing
was
de eloped
and
e alua ed,
using
ansc ip omics,
immuno-
his ochemis y
and
se um/u ine
ma ke s
in
p ema u ely
ageing
mouse
models
wi h
di e en
li e
span
and
ageing- ela ed
pa hol-
ogy
o
deli e
uni e sal
ma ke s
o
ageing.
Biological
ma e ial
om
gene ically
and
en i onmen ally
con olled,
(his o)
pa hologically
well-deﬁned
coho
s udies
wi h
NER-deﬁcien
mouse
models,
se ed
o
iden i y
pa ame e s
ha
we e
expec ed
epo
on
he
biological
age
o
he
animals
and/o
he
onse
and
p og ession
o
ageing- ela ed
pa hology
in
a ious
issues
(e.g.
li e ,
b ain)
( an
de
Pluijm
e
al.,
2007;
de
Boe
e
al.,
2002;
Rossi
e
al.,
2007;
Niede nho e
e
al.,
2006).
S ess
induced
p ema u e
senescence
The e
a e
se e al
pa hways
ac i a ing
cellula
senescence;
hese
include
elome e
uncapping,
DNA
damage,
oxida i e
s ess
and
oncogene,
amongs
o he s
(Ben-Po a h
and
Weinbe g,
2005).
No -
mal
human
diploid
ﬁb oblas s
cul u ed
in
i o
i e e sibly
s op
di iding
a e
a
ce ain
numbe
o
cumula i e
popula ion
doublings
in
a
p ocess
known
as
eplica i e
senescence
(Hayﬂick,
1965).
This
limi ed
p oli e a i e
li e
span
has
been
obse ed
in
many
o he
euka yo ic
cell
ypes
and
has
been
in e p e ed
as
a
mani es a ion
o
cellula
ageing.
Random
me abolic
modiﬁca ions
appea
wi hin
hese
cells
o e
ime,
leading
o
andom
damage
o
he
cellula
com-
ponen s.
These
damaged
cellula
componen s
a e
no
comple ely
elimina ed
o
epai ed
and
he e o e
accumula e
wi h
ime
and
p og essi ely
impai
cellula
unc ions.
Cellula
senescence
can
be
also
ega ded
as
a
pe manen ly
main ained
DNA
damage
esponse
s a e
( on
Zglinicki
e
al.,
2005).
ROS
a e
impo an
con ibu o s
o
he
ageing
p ocess
and
we
ha e
conﬁ med
he
simila i ies
be ween
eplica i e
senescence
and
s ess
induced
p ema u e
senescence
(SIPS)
(Dumon
e
al.,
2000;
Die ick
e
al.,
2002;
Pascal
e
al.,
2005).
In
MARK-AGE,
we
used
SIPS
o
“age”
T
and
B
cells
om
he
subjec s
ec ui ed
in
WP1
and
sea ched
o
no el
bioma ke s
using
genomic
a ay
and
p o eomic
app oaches
desc ibed
below
(Debacq-Chainiaux
e
al.,
2005;
F ippia
e
al.,
2001).
•No el
me hodological
app oaches
Analysis
o
miRNAs
Mic oRNAs
(miRNAs)
a e
small,
abundan
non-coding
RNA
molecules
o
abou
21–23
nucleo ides
ha
ha e
been
shown
o
a ec
a
b oad
spec um
o
biological
ac i i ies.
In e es ingly,
he e
is
e idence
ha
a
ema kably
la ge
p opo ion
o
genes
(>30%)
a e
subjec
o
mic oRNA-media ed
egula ion.
In
gene al,
miR-
NAs
unc ion
pos - ansc ip ionally
by
inhibi ing
ansla ion
om
speciﬁc
a ge
mRNAs.
Up
o
now,
abou
600
miRNAs
ha e
been
cha ac e ized
in
humans.
These
small
RNA
molecules
we e
hough
o
con ibu e
o
ageing
o
C.
elegans.
I
has
been
p e iously
shown
ha
miRNA
cause
a
gene al
educ ion
o
message-speciﬁc
ansla-
ional
inhibi ion
du ing
ageing.
Reducing
he
ac i i y
o
a
speciﬁc
miRNA
lin-4
sho ened
li e
span
and
accele a ed
issue
aging,
whe eas
o e exp essing
lin-4
o
educing
he
ac i i y
o
lin-14
ex ended
li e
span
o
C.
elegans,
equen ly
used
as
a
model
sys-
em
o
mammalian
ageing
(Boehm
and
Slack,
2005).
S udies
on
miRNA
exp ession
le els
in
issues
o
young
and
old
mice
showed
he
di e en ial
and
clea ly
issue
speciﬁc
exp ession
o
some
miR-
NAs
(Smi h-Vikos
and
Slack,
2012).
On
he
le el
o
cells,
i
was
also
shown
ha
such
di e en ial
exp ession
can
di ec ly
inﬂu-
ence
cellula
ageing.
miR-21
was
ound
up- egula ed
by
eplica i e
and
s ess-induced
senescence
in
human
endo helial
cells.
miR-
21
o e -exp ession
educes
he
eplica i e
li espan,
while
s able
knock-down
ex ends
he
eplica i e
li espan
o
hese
endo helial
cells
(Dellago
e
al.,
2013).
On
he
o gan
le el,
i
is
clea
ha
no
all
miRNAs
ha
a e
up-
o
down- egula ed
du ing
ageing
neces-
sa ily
play
c ucial
oles
du ing
ageing.
As
no
“key
egula o ”
on
issue
ageing
was
iden iﬁed
ye
in
mammalians,
one
has
o
cla i y
which
miRNAs
a e
ac i a ed
o
ep essed
especially
in
degene a-
i e
disease
con ex s
and
which
a e
eally
associa ed
wi h
aging
pe
se.
The e o e
we
a e
e alua ing
miRNA
exp ession
as
a
“no el”
bioma ke
o
ageing
using
he
leukocy es
o
subjec s
ec ui ed
in
WP1.
Phage
an ibodies
agains
no el
ma ke s
o
endo helial
and
T
cell
ageing
The
phage
display
an ibody
lib a y
echnology
has
been
ound
o
be
a
use ul
me hod
o
isola e
an igen-speciﬁc
an ibody
ag-
men s,
since
he
epe oi e
o
an ibody
speciﬁci ies
is
b oad
and
since
i
bypasses
he
need
o
immuniza ion.
When
applied
as
a
disco e y
ool,
he
phage
display
echnology
can
be
conside ed
a
complemen a ion
o
adi ional
p o eomic
app oaches
using
2-
D
gel
elec opho esis
and
mass
spec ome y,
which
qui e
o en
ha e
p oblems
in
iden i ying
p o eins
which
a e
e y
hyd ophobic
(Gonzalez-Dosal
e
al.,
2006;
Jensen
e
al.,
2003).
Du ing
ageing,
bo h
in
i o
and
in
i o,
changes
in
he
p o eomic
p oﬁle
a e
obse ed.
By
pe o ming
sub ac i e
selec ion
o
ecombinan
an i-
bodies
binding
o
e.g.
endo helial
cells
allowed
o
age
in
i o,
whe e
young
cul u ed
endo helial
cells
is
applied
as
compe i o ,
an ibod-
ies
binding
po en ial
bioma ke s
o
ageing
can
be
ob ained
(Boisen
e
al.,
2010;
Boisen
and
K is ensen,
2010)
Such
app oaches
ha e
enabled
he
de elopmen
o
a
panel
o
an ibodies
ecognizing
in
i o
ageing
human
endo helial
cells
du -
ing
he
p e ious
EU
p ojec
P o eomage,
in
pa icula
he
sec e ome
o
endo helial
cells.
Wi h
age
he e
is
a
dec ease
in
he
abili y
o
o m
new
blood
essels,
which
is
a
bioma ke
o
ageing.
The
pu -
pose
o
he
wo k
in
he
MARK-AGE
p ojec
was
o
e alua e
he
in
i o
signiﬁcance
o
endo helial
sec e ome
bioma ke s
iden i-
ﬁed
om
in
i o
models
o
hei
in
i o
ele ance
by
sc eening
plasma
om
subjec s
ec ui ed
in
WP1
o
hese
ma ke s.
Mo e
speciﬁcally
i
was
ound
ha
he
in e media e
ﬁlamen
p o ein,
imen in,
is
ound
in
he
se um.
As
s udies
wi hin
he
EU
unded
p ojec ,
P o eomage,
es ablished
ha
ex acellula
imen in
can
exe
unc ional
changes
o
he
abili y
o
o m
new
blood
essels,
i
has
been
o
pa icula
in e es
o
see
i
he e
is
an
age
speciﬁc
co -
ela ion
wi h
he
amoun
o
imen in
in
se um.
This,
in
pa ,
migh
explain
why
in
gene al
olde
people
exhibi
dec eased
abili y
o
o m
new
blood
essels.
Using
a
ba e y
o
an ibodies
aised
agains
endo helial
p ogeni o
cells,
i
was
u he
p oposed
o
e alua e
whe he
he
numbe
o
endo helial
p ogeni o
cells
in
se um
qual-
iﬁes
as
a
bioma ke
o
ageing
(Be elsen
e
al.,
2014;
Williamson
e
al.,
2012).
This
again
could
ha e
implica ions
o
he
gene ally
dec eased
abili y
o
olde
subjec s
o
o m
new
blood
essels.
Mic oa ay
and
p o eomics
Genomics
and
p o eomics
o e
he
oppo uni y
o
an
unbiased
sys ema ic
disco e y
ou e
o
no el
bioma ke s
and
a e
becom-
ing
inc easingly
popula
(G i ﬁ hs
e
al.,
2002;
G i ﬁ hs
e
al.,
2006;
Ald ed
e
al.,
2006;
G an
e
al.,
2007).
Ne e heless,
only
ew
g oups
ha e
unde aken
p o eomic
s udies
o
ei he
plasma
p o eins
o
mononuclea
cells
in
heal hy
human
ageing.
The
ﬁ s
o
hese,
published
by
Thambie y
e
al.
in
2010,
desc ibed
a
di e en ial
plasma
p o ein
pa e n
be ween
57
olde
adul s
wi h
and
wi hou
amyloid
deposi ion
in
he
b ain
(Thambise y
e
al.,
2010).
Subse-
A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
9
quen ly,
di e en ial
exp ession
o
ApoE
and
an ioxidan
p o eins
was
obse ed
in
he
plasma
o
10
Japanese
supe cen ena ians
com-
pa ed
wi h
10
young
people
(Miu a
e
al.,
2011).
In
2012,
some
o
us
desc ibed
al e a ions
in
ans e in
glycosyla ion
du ing
heal hy
ageing
(Duns on
e
al.,
2012).
The
ad an ages
o
applying
such
an
app oach
in
he
MARKAGE
popula ion
is
he
g ea e
powe
o
e alu-
a e
he
alidi y
o
no el
bioma ke s
disco e ed
h ough
p o eomics
when
compa ed
wi h
small
sample
size
disco e y
p og ammes.
A e
he
comple ion
o
MARKAGE,
one
o he
s udy
has
analysed
by
ELISA
he
le els
o
p o ein
bioma ke s
ha
we e
no
disco e ed
using
p o eomics
in
plasma
du ing
heal hy
ageing
in
compa ison
wi h
olde
adul s
ha
de elop
ail y
synd omes.
These
au ho s
showed
ha
highe
le els
o
ans e in
ﬁb inogen
and
in e leukin-
6
we e
associa ed
wi h
ail y
s a us
and
ail y
sco e
(Da in
e
al.,
2014).
E e
since
he
concep
o
MARK-AGE
has
been
de eloped
mic oa ay
has
been
used
ex ensi ely
o
cha ac e ise
ageing-
ela ed
changes
in
gene
exp ession.
Indeed,
he
sys ema ic
analysis
o
miR,
single
nucleo ide
polymo phisms
and
deep
sequencing
app oaches
ha e
led
o
u he
insigh
in o
exp ession
changes
in
speciﬁc
cell
ypes
(Lau ie
e
al.,
2012;
Smigielska-Czepiel
e
al.,
2014;
an
de
B ug
e
al.,
2010).
The
la e
a e
by
necessi y
c oss-sec ional
s udies.
The
app oach
aken
by
MARK-AGE
was
o
in es iga e
exp ession
changes
wi hin
unique
accele a ed
mod-
els
o
ageing
he
conso ium
had
access
o.
Sys ema ic
mic oa ay
analysis
o
p oge oid
mu an s
has
al eady
yielded
new
po en ial
bioma ke s:
using
ull-genome
mic oa ay
analysis
some
o
us
ha e
ecen ly
iden iﬁed
a
‘su i al’
esponse
in
he
p oge oid
mouse
models
di ec ed
by
down- egula ion
o
he
IGF1
soma o ophic
axis
ha
boos s
an ioxidan
de ence,
down- egula es
me abolism
and
edi ec s
ene gy
esou ces
om
g ow h
and
de elopmen
o
p o ec ion,
main enance
and
epai .
This
adap i e
swi ch
aims
o
slow
down
ageing- ela ed
pa hology
and
pos pones
dea h,
he eby
p omo ing
success ul
ageing.
I
is
cons i u i ely
u ned
on
in
he
epai -comp omised
mouse
mu an s
as
a
u ile
a emp
o
ex end
li espan
and
explains
hei
dwa
pheno ype.
In
no mal
mice
he
same
p incipally
beneﬁcial
esponse
can
be
ansien ly
igge ed
by
ch onic
exposu e
o
DNA-damaging
agen s
and
ROS-p oducing
compounds.
We
hypo hesise
ha
no mal
ageing
is
also
associ-
a ed
wi h
a
simila
esponse
due
o
age-dependen
accumula ion
o
damage.
The
exis ence
o
such
a
esponse
allows
p edic ions
o
shi s
in
le els
o
speciﬁc
p o eins,
ac i i ies,
pa hways
and
me aboli es
ha
could
se e
as
bioma ke s.
As
he
p o eome
is
a
mo e
ex ensi e
han
he
ansc ip ome,
i
o e s
a
iche
sou ce
o
po en ial
bioma ke s
bu
also
poses
inc eased
p oblems
in
e ms
o
dynamic
ange,
pa icula ly
in
plasma.
This
is
being
add essed
using
quali y-assu ed
sub ac iona ion
s eps
and
es ic ed
IPG
ange
in
he
ﬁ s
dimension.
In
MARK-AGE,
p o eomics
was
o
be
adop ed
in
acco dance
wi h
HUPO
guidelines,
in
he
sea ch
o
bioma k-
e s
in
plasma
om
subjec s
ec ui ed
in
WP1,
in
CS/p oge ia
and
in
T
and
B
cells
subjec ed
o
SIPS
in
subjec s
ec ui ed
in
WP1.
The
iden iﬁca ion
o
pu a i e
ma ke s
was
o
be
conﬁ med
by
sequence
analysis
and
hei
alida ion
as
bioma ke s
o
ageing
con-
ﬁ med
by
al e na i e
app oaches
such
as
ELISA
whe e
possible.
In
iew
o
he
s ong
pa allels
be ween
he
mouse
mu an s
and
he
human
synd omes,
down- egula ion
o
he
IGF1
soma o ophic
axis
bioma ke s
is
likely
o
be
ins umen al
o
iden iﬁca ion
o
co -
esponding
ma ke s
in
human
pa ien s
and
e en
no mal
ageing
and
will
be
e alua ed
in
WP1
subjec s.
3.8.
WP
8:
da a
analysis
and
bioin o ma ics
In
iew
o
he
la ge
amoun s
o
clinical
and
biochemical
da a,
which
ha e
been
collec ed
in
he
amewo k
o
he
MARK-AGE
p ojec
an
app op ia e
and
cohe en
s a egy
o
da a
analysis
and
model
building
is
manda o y.
In
o de
o
ex ac
a
obus
se
o
bioma ke s
o
human
ageing
and
o
de i e
a
model
o
heal hy
ageing,
he
ollowing
asks
we e
pe o med:
•Da ap ope y
analysis.
Pa ial
knowledge
abou
suspec ed
co -
ela ions
be ween
measu emen s
is
a ailable
and
being
used
o
judge
he
noise
a io
wi hin
some
o
hese
measu emen s
using
classical
s a is ical
echniques.
We
also
applied
co ela ion
measu es
o
iden i y
addi ional
ela ionships
be ween
measu e-
men s.
Repea ed
sampling,
i.e.
ob aining
samples
a e
6
mon hs
om
97
subjec s,
was
done
o
u he
in es iga e
biological
and
analy ical
a iabili y
in
he
measu emen s.
•Modelling.
Bo h,
s a is ical
models
as
well
as
machine
lea n-
ing/da a
mining
me hods
we e
o
be
used
in
o de
o
build
models
aiming
o
p edic
biological
age
om
he
a ailable
measu e-
men s.
We
used
classical
echniques,
such
as
eg ession
analysis
bu
also
aim
o
in oduce
addi ional
knowledge
(mono onici y)
o
imp o e
hose
models.
Neu al
Ne wo ks
and
Decision/Reg ession
T ees
we e
o
be
used
o
ﬁnd
mo e
local
ela ionships
wi hin
he
da a,
o
ins ance
e ealing
p ope ies
ha
a e
ele an
only
o
a
subse
o
he
chosen
popula ion.
•Va iance
educ ion.
Th ough
dimensionali y
educ ion
ech-
niques
(p incipal
componen
analysis
and
o he s)
we
aim
a
educing
he
numbe
o
equi ed
measu emen s
while,
a
he
same
ime,
educing
he
a iance
in
he
p edic ions
gene a ed.
Machine
Lea ning
o e s
ensembles
o
models
o
his
pu pose,
which
allows
combining
di e en ,
di e se
p edic o s
o
gene a e
models
wi h
lowe
a iance.
•Clus e ing/ isualisa ion.
We
expec
o
disco e
p e iously
unknown
o
unexpec ed
ela ionships
in
he
da a
ha
deﬁne
success ul
ageing.
Da a
isualisa ion
echniques
and
in e ac i e
me hods
such
as
isual
clus e ing
models
may
help
unco e
some
o
hese
ela ionships.
I
is
expec ed
ha
some
measu emen s
will
ha e
highe
co ela ions
wi h
he
biological
age
han
o he s
in
pa s
o
he
popula ion.
Finding
such
clus e s
is
u he
helping
educe
a iance
in
he
gene a ed
models
since
we
will
be
able
o
be e
model
cha ac e is ics
o
subg oups.
3.9.
WP
9
and
WP
10
WP
9
and
WP
10
we e
dedica ed
o
dissemina ion,
aining,
p ojec
managemen
(Fig.
1)
and
e hical
issues.
4.
Discussion
Bioma ke s
o
human
ageing
a e
u gen ly
needed
o
a i-
e y
o
easons,
including
he
iden iﬁca ion
o
indi iduals
a
high
isk
o
de eloping
age-associa ed
disease
o
disabili y.
This
would
p omp
a ge ed
ollow-up
examina ions
and,
i
a ailable,
p o-
phylac ic
in e en ion
(e.g.
changes
in
li es yle)
o
ea ly-s age
ea men
o
age- ela ed
disease.
Fu he mo e,
he
a ailabili y
o
powe ul
bioma ke s
would
allow
he
assessmen
o
he
e ﬁcacy
o
o hcoming
pha macological
and
o he
in e en ions
(including
op imisa ion
o
mic onu ien
in ake
and
o he
die a y
componen s
o
physical
ac i i y)
cu en ly
being
de eloped
wi h
he
aim
o
lowe
he
isk
o
age-associa ed
disease
e en
in
indi iduals
wi hou
accele a ed
ageing.
In
iew
o
he
apidly
inc easing
a e age
li e
expec ancy
o
human
beings
wo ld-wide,
he
p e alence
o
age- ela ed
diseases
is
likely
o
inc ease
as
well.
This
necessi a es
e ec i e
new
s a egies
o
p e en ion
and
ea ly
diagnosis
o
such
condi ions.
I
should
be
no ed
ha
di e en
ypes
o
bioma ke s
ha e
been
en isaged:
(1)
“neu al”
ma ke s
o
age
(also
called
ma ke s
o
“ch onological
ageing”)
possibly
lacking
he
powe
o
di ec ly
p e-
dic ing
disease
isk,
as
he
unde lying
physiological
change
may
pe
10
A.
Bü kle
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
2–12
se
be
ha mless
and
wi hou
unc ional
comp omise;
(2)
ma ke s
o
(global)
isk
o
age- ela ed
diseases.
Those
in
ca ego y
#2
a e
o
ob ious
and
di ec
in e es .
Ne e heless,
he
use ulness
o
hose
in
ca ego y
#1,
especially
as
a
combina ion
o
ma ke s,
should
no
be
dismissed,
as
hey
could
eﬂec
he
a e
o
ageing
ha
has
p e ailed
o e
a
ce ain
ime
pe iod
in
he
pas
and
he
cumula i e
change
i
has
p oduced
in
he
body.
The
de ec ion
o
a
p e ious
as e - han-
no mal
a e
o
ageing
in
a
gi en
indi idual
should
also
be
ala ming
and
call
o
addi ional
diagnos ic
and
p e en i e
measu es.
Disclaime
Unile e
PLC
con ibu ed
only
o
he
human
wo k
–
wi hin
Wo k
Packages
5
(Clinical
chemis y,
ho mones
and
ma ke s
o
me abolism)
and
6
(Oxida i e
s ess)
as
well
as
analysis
o
human
s udy
da a
wi hin
Wo k
Package
8
(Da a
analysis
and
bioin o ma -
ics).
Acknowledgemen s
We
wish
o
hank
he
Eu opean
Commission
o
ﬁnancial
sup-
po
h ough
he
FP7
la ge-scale
in eg a ing
p ojec
“Eu opean
S udy
o
Es ablish
Bioma ke s
o
Human
Ageing”
(MARK-AGE;
g an
ag eemen
no.:
200880).
We
a e
e y
g a e ul
o
D .
Bea -
ice
Luca oni
(Eu opean
Commission
Scien iﬁc
O ﬁce
in
cha ge
o
he
MARK-AGE
p ojec )
o
he
excellen
suppo
and
ad ice
du ing
all
phases
o
he
p ojec .
Re e ences
Al-Delaimy,
W.K.,
Jansen,
E.H.,
Pee e s,
P.H.,
an
de
Laan,
J.D.,
an
Noo d,
P.A.,
Boshuizen,
H.C.,
an
de
Schouw,
Y.T.,
Jenab,
M.,
Fe a i,
P.,
Bueno-de-Mesqui a,
H.B.,
2006.
Reliabili y
o
bioma ke s
o
i on
s a us,
blood
lipids,
oxida i e
s ess,
i amin
D,
C- eac i e
p o ein
and
uc osamine
in
wo
Du ch
coho s.
Bioma ke s
11
(4),
370–382.
Ald ed,
S.,
Sozzi,
T.,
Mudway,
I.,
G an ,
M.M.,
Neube ,
H.,
Kelly,
F.J.,
G i ﬁ hs,
H.R.,
2006.
Alpha
ocophe ol
supplemen a ion
ele a es
plasma
apolipop o ein
A1
iso o ms
in
no mal
heal hy
subjec s.
P o eomics
6
(5),
1695–1703.
Almanza ,
G.,
Schwaige ,
S.,
Jenewein,
B.,
Kelle ,
M.,
He ndle -B ands e e ,
D.,
Wu zne ,
R.,
Schoni ze ,
D.,
G ubeck-Loebens ein,
B.,
2005.
Long- e m
cy omegalo i us
in ec ion
leads
o
signiﬁcan
changes
in
he
composi ion
o
he
CD8+ T-cell
epe oi e,
which
may
be
he
basis
o
an
imbalance
in
he
cy okine
p oduc ion
p oﬁle
in
elde ly
pe sons.
J.
Vi ol.
79
(6),
3675–3683.
Al ilia,
S.,
San o o,
A.,
Malagoli,
D.,
Lanza ini,
C.,
Balles e os
Al a ez,
J.A.,
Galazzo,
G.,
Po e ,
D.C.,
C occo,
P.,
Rose,
G.,
Passa ino,
G.,
Roninson,
I.B.,
F anceschi,
C.,
Sal ioli,
S.,
2012.
TP53
codon
72
polymo phism
a ec s
accumula ion
o
m DNA
damage
in
human
cells.
Aging
(Albany
N.Y.)
4
(1),
28–39.
Aspinall,
R.,
Pido-Lopez,
J.,
Imami,
N.,
Henson,
S.M.,
Ngom,
P.T.,
Mo e,
M.,
Niphuis,
H.,
Rema que,
E.,
Rosenwi h,
B.,
Heeney,
J.L.,
2007.
Old
hesus
macaques
ea ed
wi h
in e leukin-7
show
inc eased
TREC
le els
and
espond
well
o
inﬂuenza
accina ion.
Reju ena ion
Res.
10
(1),
5–17.
Bake
3 d,
G.T.,
Sp o ,
R.L.,
1988.
Bioma ke s
o
aging.
Exp.
Ge on ol.
23
(4–5),
223–239.
Ba aiba ,
M.A.,
F igue ,
B.,
2013.
Oxida i e
p o eome
modiﬁca ions
a ge
speciﬁc
cellula
pa hways
du ing
oxida i e
s ess,
cellula
senescence
and
aging.
Exp.
Ge on ol.
48
(7),
620–625.
Bellizzi,
D.,
Ca alcan e,
P.,
Ta e na,
D.,
Rose,
G.,
Passa ino,
G.,
Sal ioli,
S.,
F anceschi,
C.,
De
Benedic is,
G.,
2006.
Gene
exp ession
o
cy okines
and
cy okine
ecep o s
is
modula ed
by
he
common
a iabili y
o
he
mi ochond ial
DNA
in
cyb id
cell
lines.
Genes
Cells
11
(8),
883–891.
Ben-Po a h,
I.,
Weinbe g,
R.A.,
2005.
The
signals
and
pa hways
ac i a ing
cellula
senescence.
In .
J.
Biochem.
Cell
Biol.
37
(5),
961–976.
Beneke,
S.,
Bu kle,
A.,
2007.
Poly(ADP- ibosyl)
a ion
in
mammalian
ageing.
Nucleic
Acids
Res.
35
(22),
7456–7465.
Bene i,
R.,
Ga cia-Cao,
M.,
Blasco,
M.A.,
2007.
Telome e
leng h
egula es
he
epigene ic
s a us
o
mammalian
elome es
and
sub elome es.
Na .
Gene .
39
(2),
243–250.
Be elsen,
L.B.,
Bohn,
A.B.,
Smi h,
M.,
Molgaa d,
B.,
Molle ,
B.,
S odkilde-Jo gensen,
H.,
K is ensen,
P.,
2014.
A e
endo helial
ou g ow h
cells
a
po en ial
sou ce
o
u u e
e- ascula iza ion
he apy?
Exp.
Ge on ol.
58,
132–138.
Boehm,
M.,
Slack,
F.,
2005.
A
de elopmen al
iming
mic oRNA
and
i s
a ge
egula e
li e
span
in
C.
elegans.
Science
310
(5756),
1954–1957.
Boisen,
L.,
K is ensen,
P.,
2010.
Con on ing
cellula
he e ogenei y
in
s udies
o
p o ein
me abolism
and
homeos asis
in
aging
esea ch.
Ad .
Exp.
Med.
Biol.
694,
234–244.
Boisen,
L.,
D asbek,
K.R.,
Pede sen,
A.S.,
K is ensen,
P.,
2010.
E alua ion
o
endo helial
cell
cul u e
as
a
model
sys em
o
ascula
ageing.
Exp.
Ge on ol.
45
(10),
779–787.
Caia a,
P.,
Zampie i,
M.,
2005.
DNA
me hyla ion
and
ch oma in
s uc u e:
he
puzzling
CpG
islands.
J.
Cell
Biochem.
94
(2),
257–265.
Canela,
A.,
Ve a,
E.,
Kla ,
P.,
Blasco,
M.A.,
2007.
High- h oughpu
elome e
leng h
quan iﬁca ion
by
FISH
and
i s
applica ion
o
human
popula ion
s udies.
P oc.
Na l.
Acad.
Sci.
U.
S.
A.
104
(13),
5300–5305.
Ca a d,
G.,
Dieu,
M.,
Raes,
M.,
Toussain ,
O.,
F igue ,
B.,
2003.
Impac
o
ageing
on
p o easome
s uc u e
and
unc ion
in
human
lymphocy es.
In .
J.
Biochem.
Cell
Biol.
35
(5),
728–739.
Chond ogianni,
N.,
Gonos,
E.S.,
2010.
P o easome
unc ion
de e mines
cellula
homeos asis
and
he
a e
o
aging.
Ad .
Exp.
Med.
Biol.
694,
38–46.
Chond ogianni,
N.,
S a o d,
F.L.,
T ougakos,
I.P.,
F igue ,
B.,
Ri e ,
A.J.,
Gonos,
E.S.,
2003.
Cen al
ole
o
he
p o easome
in
senescence
and
su i al
o
human
ﬁb oblas s:
induc ion
o
a
senescence-like
pheno ype
upon
i s
inhibi ion
and
esis ance
o
s ess
upon
i s
ac i a ion.
J.
Biol.
Chem.
278
(30),
28026–28037.
Chond ogianni,
N.,
Tza elas,
C.,
Pembe on,
A.J.,
Nezis,
I.P.,
Ri e ,
A.J.,
Gonos,
E.S.,
2005.
O e exp ession
o
p o easome
be a5
assembled
subuni
inc eases
he
amoun
o
p o easome
and
con e s
amelio a ed
esponse
o
oxida i e
s ess
and
highe
su i al
a es.
J.
Biol.
Chem.
280
(12),
11840–11850.
Da in,
K.,
Randolph,
A.,
O alles,
S.,
Halade,
D.,
B eeding,
L.,
Richa dson,
A.,
Espinoza,
S.E.,
2014.
Plasma
p o ein
bioma ke s
o
he
ge ia ic
synd ome
o
ail y.
J.
Ge on ol.
A
Biol.
Sci.
Med.
Sci.
69
(2),
182–186.
De
Benedic is,
G.,
Rose,
G.,
Ca ie i,
G.,
De
Luca,
M.,
Falcone,
E.,
Passa ino,
G.,
Bona e,
M.,
Mon i,
D.,
Baggio,
G.,
Be olini,
S.,
Ma i,
D.,
Ma ace,
R.,
F anceschi,
C.,
1999.
Mi ochond ial
DNA
inhe i ed
a ian s
a e
associa ed
wi h
success ul
aging
and
longe i y
in
humans.
FASEB
J.
13
(12),
1532–1536.
de
Boe ,
J.,
And essoo,
J.O.,
de
Wi ,
J.,
Huijmans,
J.,
Beems,
R.B.,
an
S eeg,
H.,
Weeda,
G.,
an
de
Ho s ,
G.T.,
an
Leeuwen,
W.,
Themmen,
A.P.,
Me adji,
M.,
Hoeijmake s,
J.H.,
2002.
P ema u e
aging
in
mice
deﬁcien
in
DNA
epai
and
ansc ip ion.
Science
296
(5571),
1276–1279.
Debacq-Chainiaux,
F.,
Bo lon,
C.,
Pascal,
T.,
Roye ,
V.,
Eliae s,
F.,
Ninane,
N.,
Ca a d,
G.,
F igue ,
B.,
de
Longue ille,
F.,
Bo e,
S.,
Remacle,
J.,
Toussain ,
O.,
2005.
Repea ed
exposu e
o
human
skin
ﬁb oblas s
o
UVB
a
subcy o oxic
le el
igge s
p ema u e
senescence
h ough
he
TGF-be a1
signaling
pa hway.
J.
Cell
Sci.
118
(P
4),
743–758.
Deelen,
J.,
Beekman,
M.,
Uh,
H.W.,
B oe ,
L.,
Aye s,
K.L.,
Tan,
Q.,
Kama ani,
Y.,
Benne ,
A.M.,
Tamm,
R.,
T ompe ,
S.,
Gue hbja sson,
D.F.,
Flachsba ,
F.,
Rose,
G.,
Vik o in,
A.,
Fische ,
K.,
Nygaa d,
M.,
Co dell,
H.J.,
C occo,
P.,
an
den
Akke ,
E.B.,
Boh inge ,
S.,
Helme ,
Q.,
Nelson,
C.P.,
Saunde s,
G.I.,
Al e ,
M.,
Ande sen-Ranbe g,
K.,
B een,
M.E.,
an
de
B eggen,
R.,
Caliebe,
A.,
Cap i,
M.,
Ce enini,
E.,
Colle on,
J.C.,
Da o,
S.,
Da ies,
K.,
Fo d,
I.,
Gampe,
J.,
Ga agnani,
P.,
de
Geus,
E.J.,
Ha ow,
J.,
an
Heems ,
D.,
Heijmans,
B.T.,
Heinsen,
F.A.,
Ho enga,
J.J.,
Ho man,
A.,
Jeune,
B.,
Jonsson,
P.V.,
La h op,
M.,
Lechne ,
D.,
Ma in-Ruiz,
C.,
McNe lan,
S.E.,
Mihailo ,
E.,
Mon esan o,
A.,
Mooijaa ,
S.P.,
Mu phy,
A.,
Noh ,
E.A.,
Pa e nos e ,
L.,
Pos mus,
I.,
Ri adenei a,
F.,
Ross,
O.A.,
Sal ioli,
S.,
Sa a ,
N.,
Sch eibe ,
S.,
S e ansson,
H.,
S o ,
D.J.,
Tiemeie ,
H.,
Ui e linden,
A.G.,
Wes endo p,
R.G.,
Willemsen,
G.,
Samani,
N.J.,
Galan,
P.,
So ensen,
T.I.,
Boomsma,
D.I.,
Jukema,
J.W.,
Rea,
I.M.,
Passa ino,
G.,
de
C aen,
A.J.,
Ch is ensen,
K.,
Nebel,
A.,
S e ansson,
K.,
Me spalu,
A.,
Magnusson,
P.,
Blanche,
H.,
Ch is iansen,
L.,
Ki kwood,
T.B.,
an
Duijn,
C.M.,
F anceschi,
C.,
Houwing-Duis e maa ,
J.J.,
Slagboom,
P.E.,
2014.
Genome-wide
associa ion
me a-analysis
o
human
longe i y
iden iﬁes
a
no el
locus
con e ing
su i al
beyond
90
yea s
o
age.
Hum.
Mol.
Gene .
23
(16),
4420–4432.
Dellago,
H.,
P eschi z-Kamme ho e ,
B.,
Te lecki-Zaniewicz,
L.,
Sch eine ,
C.,
Fo schegge ,
K.,
Chang,
M.W.,
Hackl,
M.,
Mon e o e,
R.,
Kuhnel,
H.,
Schosse e ,
M.,
G ube ,
F.,
Tschachle ,
E.,
Scheidele ,
M.,
G illa i-Voglaue ,
R.,
G illa i,
J.,
Wiese ,
M.,
2013.
High
le els
o
oncomiR-21
con ibu e
o
he
senescence-induced
g ow h
a es
in
no mal
human
cells
and
i s
knock-down
inc eases
he
eplica i e
li espan.
Aging
Cell
12
(3),
446–458.
Die ick,
J.F.,
Kalume,
D.E.,
Wende s,
F.,
Salmon,
M.,
Dieu,
M.,
Raes,
M.,
Roeps o ,
P.,
Toussain ,
O.,
2002.
Iden iﬁca ion
o
30
p o ein
species
in ol ed
in
eplica i e
senescence
and
s ess-induced
p ema u e
senescence.
FEBS
Le .
531
(3),
499–504.
Dumon ,
P.,
Bu on,
M.,
Chen,
Q.M.,
Gonos,
E.S.,
F ippia ,
C.,
Maza a i,
J.B.,
Eliae s,
F.,
Remacle,
J.,
Toussain ,
O.,
2000.
Induc ion
o
eplica i e
senescence
bioma ke s
by
suble hal
oxida i e
s esses
in
no mal
human
ﬁb oblas .
F ee
Radic.
Biol.
Med.
28
(3),
361–373.
Duns on,
C.R.,
Choudhu y,
K.,
G i ﬁ hs,
H.R.,
2012.
Te minal
galac ose
esidues
on
ans e in
a e
inc eased
in
midli e
adul s
compa ed
o
young
adul s.
P o eomics
12
(21),
3147–3153.
Flo es,
I.,
Cayuela,
M.L.,
Blasco,
M.A.,
2005.
E ec s
o
elome ase
and
elome e
leng h
on
epide mal
s em
cell
beha io .
Science
309
(5738),
1253–1256.
F igue ,
B.,
2006.
Oxidized
p o ein
deg ada ion
and
epai
in
ageing
and
oxida i e
s ess.
FEBS
Le .
580
(12),
2910–2916.
F ippia ,
C.,
Chen,
Q.M.,
Zdano ,
S.,
Magalhaes,
J.P.,
Remacle,
J.,
Toussain ,
O.,
2001.
Subcy o oxic
H2O2s ess
igge s
a
elease
o
ans o ming
g ow h
ac o -be a
1,
which
induces
bioma ke s
o
cellula
senescence
o
human
diploid
ﬁb oblas s.
J.
Biol.
Chem.
276
(4),
2531–2537.
Gil,
L.,
Siems,
W.,
Mazu ek,
B.,
G oss,
J.,
Sch oede ,
P.,
Voss,
P.,
G une,
T.,
2006.
Age-associa ed
analysis
o
oxida i e
s ess
pa ame e s
in
human
plasma
and
e y h ocy es.
F ee
Radic.
Res.
40
(5),
495–505.
Gonzalez-Dosal,
R.,
So ensen,
M.D.,
Cla k,
B.F.,
Ra an,
S.I.,
K is ensen,
P.,
2006.
Phage-displayed
an ibodies
o
he
de ec ion
o
glyca ed
p o easome
in
aging
cells.
Ann.
N.
Y.
Acad.
Sci.
1067,
474–478.
MARK-AGE biomarkers of ageing

Abstract

MARK-AGE biomarkers of ageing
