MARK-AGE population: From the human model to new insights

Capri, Miriam; Moreno-Villanueva, María; Cevenini, Elisa; Hervonen, Antti; Hurme, Mikko
MARK-AGE population: From the human model to new insights

Author: Capri, Miriam,Moreno-Villanueva, María,Cevenini, Elisa,Hervonen, Antti,Hurme, Mikko
Year: 2015
Source: https://trepo.tuni.fi/bitstream/10024/99897/1/MARK-AGE_population_2015.pdf
Mechanisms o Ageing and De elopmen 151 (2015) 13–17
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 popula ion: F om he human model o new insigh s
Mi iam Cap ia,b,∗,1, Ma ía Mo eno-Villanue ac,1, Elisa Ce eninia, Elisa Pinia,
Ma ia Scu ia, Vincenzo Bo ellia, Ma ia Gius ina Palmasb, Ma co Zolid, Ch is iane Schöne,
Anne Siepelmeye e, Jü gen Be nha d e, Simone Fiegl , Ge ben Zondagg,
An on J.M. de C aenh, An i He oneni, Mikko Hu mei, Ewa Siko aj, E s a hios S. Gonosk,
Kons an inos Vou e akisk, Oli ie Toussain l, Flo ence Debacq-Chainiauxl,
Bea ix G ubeck-Loebens einm, Alexande Bü klec, Claudio F anceschia,b
aDIMES-Depa men o Expe imen al, Diagnos ic and Special y Medicine, Alma Ma e S udio um, Uni e si y o Bologna, 40126 Bologna, I aly
bCIG-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
cMolecula Toxicology G oup, Depa men o Biology, Uni e si y o Kons anz, 78457 Kons anz, Ge many
dDepa men o Medical and Su gical Sciences, Uni e si y o Bologna and S. O sola-Malpighi Hospi al, Bologna, I aly
eBioTeSys GmbH, 73728 Esslingen, Ge many
UMIT P i a e Uni e si ä ü Gesundhei swissenscha en, Medizinische In o ma ik und Technik GmbH, 6060 Hall in Ti ol, Aus ia
gDNage BV, Leiden, The Ne he lands
hDepa men o Ge on ology and Ge ia ics, Leiden Uni e si y Medical Cen e, Leiden, The Ne he lands
iSchool o Medicine, Uni e si y o Tampe e, 33014 Tampe e, Finland
jLabo 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
kIns i u e o Biology, Medicinal Chemis y and Bio echnology, Na ional Hellenic Resea ch Founda ion, 48 Vas. Cons an inou A e. 116 35 A hens, G eece
lNARILIS URBC, Uni e si y o Namu (FUNDP), 61, ue de B uxelles, 5000 Namu , Belgium
mImmunology Di ision, Ins i u e o Biomedical Aging Resea ch, Uni e si ä Innsb uck, Rennweg 10, 6020 Innsb uck, Aus ia
a i c l e i n o
A icle his o y:
A ailable online 2 Ap il 2015
Keywo ds:
Human ageing
Bioma ke s
Rec ui men
MARK-AGE popula ion
Many ele an EU p ojec s we e unded du ing las decade and
MARK-AGE (Eu opean S udy o Es ablish Bioma ke s o Human
Ageing) was he ﬁ s ocused on he iden iﬁca ion o bioma k-
e s connec ing i sel wi h a p e ious unded p ojec , i.e. GEHA
(Gene ic o Heal hy Ageing) ha iden iﬁed Eu opean amilies wi h
longe i y componen (F anceschi e al., 2007). MARK-AGE was
mainly a c oss sec ional s udy, based on deﬁni e assump ions, as
Abb e ia ions: CS, Cockayne synd ome; DS, Down synd ome; GO, GEHA o -
sp ing; RASIG, andomly ec ui ed age-s a iﬁed indi iduals om he gene al
popula ion; SGO, spouses o GO; WS, We ne synd ome.
∗Co esponding au ho a : Depa men o Expe imen al, Diagnos ic and Special y
Medicine, Alma Ma e S udio um, Uni e si y o Bologna, Via S. Giacomo, 12 40126
Bologna, I aly.
E-mail add ess: [email p o ec ed] (M. Cap i).
1These au ho s con ibu ed equally o his wo k
i will be desc ibed below, and ocused on an age ange be ween
34 and 75 yea s, in o de o iden i y ea ly bioma ke s o biolog-
ical s. ch onological age, po en ially capable o p edic ing he
a e o ageing la e in li e. Complemen a ily, many an i-ageing
s a egies ha e been p oposed, such as hose ela ed o immune
sys em emodelling (Cap i e al., 2006b), bu a new e a begun on
di e en issues-speciﬁc epigenomics (Ho a h, 2013; Romanoski
e al., 2015), ood/nu i ion science, die in e en ion (San o o e al.,
2014; Bacalini e al., 2014; Me cken e al., 2013; Ce enini e al.,
2013;Be endsene al.,2014)andi sin e ac ion wi h genomic back-
g ound (Co ella and O do ás, 2014) and gu mic obio a emodeling
(O a iani e al., 2011; Biagi e al., 2013; Collino e al., 2013). These
ecen ﬁndings oge he wi h MARKAGE bioma ke s no only gi e a
new pe spec i e in e m o ageing a e measu emen , bu also new
insigh s o molecula - a ge ed in e en ions o slow down human
ageing p ocess and likely, age- ela ed pa hologies onse .
h p://dx.doi.o g/10.1016/j.mad.2015.03.010
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/).
14
M.
Cap i
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
13–17
1.
Ageing
o
Eu opean
Coun ies
The
p opo ion
o
elde ly
people
o e
65
yea s
in
Eu ope
(EU-
28Coun ies)
is
p edic ed
o
inc ease
om
18.2%
in
2013
o
28.7%
by
2080
(Eu os a
sou ce).
The
sha e
o
hose
aged
80
yea s
o
abo e
in
he
EU-28’s
popula ion
is
p ojec ed
o
almos
iple
be ween
2013
and
2080.
Thus,
o e
he
coming
decades,
Eu ope’s
demog aphic
makeup
will
change
ha shly.
Ou
popula ions
a e
becoming
olde
han
e e
be o e
due
o
h ee
majo
ends.
Fi s ,
he
baby-boom
gene a ion
app oaches
e i emen
age
hus
olde
people
will
ise
apidly;
second,
bi h
a es
ha e
emained
low
o
se e al
decades;
and
hi d,
Eu opean
people,
bu
no
only,
a e
li ing
longe
li es,
e en
i
como bidi es
and
disabili ies
a e
inc easing,
especially
a e
62
yea s
(Eu os a
sou ce).
In
2011
he
numbe
o
heal hy
li e
yea s
a
bi h
was
es ima ed
a
a ound
62
yea s
o
men
and
61
yea s
o
women
in
EU-28,
meaning
ha
app oxima ely,
16%
and
21%
o
unheal hy
li e
o
men
and
women,
espec i ely,
a e
expec ed.
This
demog aphic
emodelling
emphasises
he
c i ical
impo ance
o
iden i ying
new
s a egies
able
o
coun e ac
o
slow
down
age-
ing
and
he
onse
o
age- ela ed
diseases
and
disabili ies.
These
new
s a egies
can
con ibu e
o
inc ease
he
numbe
o
elde ly
ci izens
in
good
heal h,
and
educing
age- ela ed
medical
and
social
cos s.
The e o e
he
iden iﬁca ion
o
bioma ke s
o
heal hy
o
unheal hy
ageing
(see
Bü kle
e
al.,
his
issue)
and
he
adop ion
o
heal hy
li e
s yles
be o e
he
use
o
d ug-based
he apies
a e
necessa y.
This
si ua ion
has
pushed
EU
go e nance
o
iden i y
scien iﬁc
p ojec s
able
o
ﬁnd
solu ions
o
moni o
and
coun e ac
unheal hy
ageing,
hus
p omo ing
a
heal hy
and
ac i e
ageing.
2.
F om
popula ion
o
indi idual
le el
On
he
o he
side,
he
a e
o
ageing
in
humans
is
no
uni o m
due
o
he
complexi y
o
gene ics
and
epigene ics
(Cap i
e
al.,
2006a,
2014),
which
in e ac
wi h
en i onmen
(Biagi
e
al.,
2013;
Ga m
e
al.,
2013)
and
s ochas ici y
wi h
di e se
weigh s
a
di -
e en
phases
o
li e
aking
in o
accoun
also
emb yonic
and
oe al
de elopmen
(Ce enini
e
al.,
2010).
Fu he ,
hese
main
ac o s
could
di e en ly
a ec
he
a e
o
ageing
a
he
le els
o
cells,
is-
sues
o
body
sys ems
wi hin
he
same
o ganism
acco ding
o
he
hypo hesis
o
he
“mosaic
o
ageing”
(Ce enini
e
al.,
2008).
Tissues
and
o gans
migh
age
a
di e en
a e
and
u he mo e,
indi idu-
als
o
same
ch onological
age
migh
ha e
di e en
biological
age.
This
complexi y
makes
mo e
di ﬁcul
he
iden iﬁca ion
o
a
unique
comp ehensi e
mechanism
o
ageing
and
ela ed
bioma ke s
(Deelen
e
al.,
2013).
3.
The
human
model
in
MARK-AGE:
inno a i e
concep s
MARK-AGE
aimed
a
he
iden iﬁca ion
o
bioma ke s
o
age-
ing
capable
o
dis inguishing
be ween
ch onological
and
biological
ageing
(see
Giampie i
e
al.,
his
issue)
looking
a
sys emic
pa am-
e e s
assessed
in
he
blood/u ine
and
buccal
mucosa
cells
(BMC)
o
olun ee s,
likely
mi o ing
he
en i e
o ganism.
To
achie e
his
objec i e
a
obus
human
model
wi h
deﬁni e
assump ions
was
concep ualised
acco dingly
(see
Bü kle
e
al.,
his
issue),
as
b ieﬂy
desc ibed:
1.
Subjec s
ep esen ing
he
“no mal”
aging:
andomly
ec ui ed
age-s a iﬁed
indi iduals
om
he
gene al
popula ion
o
RASIG,
co e ing
he
age
ange
35–74
yea s;
2.
Subjec s
ep esen ing
he
success ul
o
“decele a e”
aging:
sub-
jec s
bo n
om
a
long-li ing
pa en
belonging
o
a
amily
wi h
long
li ing
sibling(s)
al eady
ec ui ed
in
he
amewo k
o
he
GEHA
-Gene ic
o
Heal hy
Ageing-
p ojec
(Sky he
e
al.,
2011).
These
indi iduals
(“GEHA
o sp ing”
o
GO)
we e
ec ui ed
oge he
wi h
hei
spouses
o
SGO
ep esen ing
he
bes
con ol
o
e alua e
possible
li e
s yle
e ec s,
since
hey
ha e
sha ed
he
same
en i onmen al
ac o s
o
many
yea s
wi h
hei
pa ne s.
3.
Subjec s
ep esen ing
accele a ed
aging:
pa ien s
wi h
p oge oid
synd omes
(Cockayne,
We ne
and
Down
synd omes),
cha ac-
e ised
by
accele a ed
“segmen al”
ageing.
4.
Independen
a iables
in
MARK-AGE
MARK-AGE
model
ook
in o
accoun
essen ial
independen
a i-
ables,
i.e.
gende ,
age,
geog aphy
and
popula ions.
The
selec ion
o
hese
a iables
was
done
on
he
basis
o
speciﬁc
assump ions
such
as
he
majo
ole
o
gende
in
he
ageing
p ocess,
he
need
o
iden i y
bioma ke s
be o e
he
la e
phase
o
li e
and
he
ole
o
en i onmen /geog aphy/cul u e
in
he
popula ion
ageing
wi h
a
consis en
numbe
o
indi iduals.).
Abou
5%
o
ec ui ed
ol-
un ee s
we e
no
classiﬁed
as
“success ully
ec ui ed”
MARK-AGE
indi idual,
ei he
because
exclusion
c i e ia
such
as
posi i e
esul s
o
HBV,
HCV
i uses
sc eening
o
due
o
e o s
in
da a
en y
in o
he
pheno ypic
da abase.
The
a
GENDER.
Males
and
emales
we e
ec ui ed
close
o
50%
in
each
age
class,
gi ing
he
possibili y
o
analyse
age-gende
e ec s.
Li e a u e
s ongly
sugges s
a
gende
e ec
on
mo ali y
a e.
Females
li e
longe
e en
wi h
a
highe
equency
o
disabili-
ies
and
como bidi ies
(Oksuzyan
e
al.,
2008).
This
di e ence
be ween
males
and
emales
seems
o
be
a
pa adox
and
he
bio-
logical
causes
a e
no
ye
unde s ood,
bu
many
da a
sugges
he
in ol emen
o
sexual
ch omosomes
and
hei
age-dependen
me hyla ion
pa e n
(Cap i
e
al.,
2014;
Gen ilini
e
al.,
2012,
2013).
Fu he mo e,
p ospec
demog aphic
s udies
show
ha
he
gap
o
li e
expec ancy
be ween
gende s
will
become
smalle
in
he
nex
40
yea s,
e en
i
an
analysis
compa ing
heal hy
li e
yea s
be ween
he
gende
a
he
age
o
65
shows
he e
we e
9
EU
Mem-
be
S a es
in
2011
whe e
men
could
expec
mo e
heal h
li e
yea s
han
women
(Eu os a
sou ce).
b
AGE.
An
age
ange
be ween
34
and
75
yea s
was
hough
o
be
c ucial
o
iden i y
ea ly
bioma ke s
o
ageing.
Humans
unde go
di e en
phases
o
li e
and
15
yea s
beyond
50–60
yea s,
i.e.
he
ansi ion
be ween
adul
age
and
he
beginning
o
he
consis en
ageing
p ocess
appea
o
be
a
c i ical
empo al
window.
Indeed,
Table
1
Indi iduals
classiﬁed
as
“success ully
ec ui ed”
RASIG,
GO,
SGO
and
DS
olun ee s
ﬁnally
inse ed
in
he
da abase
and
conside ed
o
MARK-AGE
analysis.
Cen es
RASIGM
RASIGF
GOM
GOF
SGOM
SGOF
DSM
DSF
MissedCodes
Sub
o al
BioTeSys
162
188
8
358
FUNDP
121
135
33
42
17
21
8
377
LUMC
52
68
58
44
0
222
NENCKI
192
189
25
51
30
17
2
506
NHRF
200
203
5
17
4
2
1
432
UIBK
200
190
0
390
UNIBO
193
199
52
42
22
33
27
20
0
588
UTA
27
63
53
88
24
33
8
296
To al
1095
1167
220
308
155
150
27
20
27
3169
M.
Cap i
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
13–17
15
Table
2
S a egies
o
MARKAGE
dissemina ion
applied
by
all
he
cen es
in ol ed
in
he
ec ui men .
Cen es
Popula ion
Dissemina ion
and
s a egy
o
ec ui men
BioTeSys
GmbH
(DE)
RASIG
Newspape
a icles,
in o ma ion
e ening
a
he
own
hall
oge he
wi h
he
go e ning
mayo ;
egis a ion
o ﬁce
(le e /ﬂye ),
olun ee s
known
om
o he
ials
conduc ed
a
BioTeSys
a
li le
wo d-o -mou h
ecommenda ion.
FUNDP/S a iCELL
(BE)
RASIG/GO/SGO
Con ac ed
an
open-uni e si y
o
pe sons
belonging
o
he
3 d
age
and
all
socie al
ho izons;
he
Se ices
o
he
Human
Resou ces
o
he
Ci y
o
Namu ,
he
Uni .
o
Namu ,
Uni .
Clinics
o
Mon -Godinne,
and
Regional
Hospi al
Cen e,
dealing
wi h
all
so s
o
pe sonnel;
o ganised
p ess
con e ence
a
Uni .
o
Namu
(many
p ess
a icles,
in e iews
on
na ional
adios,
local
TV
news,
na ional
TV
p og amme
on
ageing).
GEHA
e e ence
o
GO
lis
LUMC
(NL)
GO/SGO
D a ed
a
lis
wi h
a
numbe
o
picked
nomina i es
(GEHA
e e ence).
NHRF
(GR) RASIG/GO/SGO
Con ac
by
email
all
he
pe sonnel
o
Resea ch
Ins i u es
o
A hens.
i.
Con ac
by
phone,
call
all
he
GEHA
siblings
gi ing
in o ma ion
o
GO/SGO
on
MARK-AGE,
sending
hem
he
in o ma i e
shee
by
pos
o
ax.
ii.
Con ac
by
phone,
call
all
ou
pe sonal
acquain ances
gi ing
in o ma ion
on
MARK-AGE
NENCKI
(PL)
RASIG/GO/SGO
Ob ained
add esses
o
3200
RASIG
om
Minis y
o
In e io
and
Adminis a ion
(p esen ly
Minis y
o
In e io )
acco ding
o
PESEL
(Na ional
Elec onic
Census
Numbe
Sys em);
sen
1700
le e s
o
in i a ion,
he
esponde s
eedback
by
phone
o
e-mail
(22%).
GEHA
e e ence
o
GO
lis .
UIBK
(AT) RASIG
A icles
in
a
e y
common
Ty olean
daily
newspape ;
dissemina ion
on
local
TV
news
and
a icles
in
o he
newspape s
and
magazines.
UNIBO
(IT)
RASIG/GO/SGO/DS
GO/SGO
we e
ec ui ed
be o e
RASIG:
d a ed
a
lis
wi h
a
numbe
o
picked
nomina i es.
RASIG:
popula ion
o
PIANORO
(17,000
inhabi an s)
nea
Bologna;
con ac s
wi h
he
Mayo
Ci izen
and
he
Dis ic
o
Public
Heal h.
A
p esen a ion
o
he
p ojec
was
pe o med
o
all
he
popula ion
wi h
local
Go e nmen
and
gene al
p ac i ione s;
local
pape ,
in o ma ion
ﬂye s;
magazine
associa ed
o
ood
discoun s)
and
TV,
ec ui ed
also
pe sons
om
he
Uni e si y
o
Bologna.
DS
and
hei
amily
we e
con ac ed
by
speciﬁc
associa ion
in
Bologna
UTA
(FL)
RASIG/GO/SGO
Newspape s,
local
TV
announcemen s
his
pe iod
includes
he
menopause
in
women
and
he
pe iod
whe e
majo
age
ela ed
diseases
and
he
a e
o
mo ali y
s a
o
inc ease
(Rause
e
al.,
2006).
Acco dingly,
one
o
he
majo
cha ac e is ic
o
MARK-AGE
is
o
ocus
on
he
abo e
men ioned
age
ange
in
o de
o
iden i y
ea ly
bioma ke s
o
biological
s.
ch onological
age,
po en ially
capable
o
p edic ing
he
a e
o
ageing
la e
in
li e.
c
GEOGRAPHY.
11
di e en
Eu opean
beneﬁcia ies,
dis ibu ed
om
No h
o
Sou h,
we e
esponsible
o
he
ec ui men .
This
dis ibu ion
has
gi en
he
possibili y
o
s udy
en i onmen-
al/geog aphical/cul u al
popula ion
e ec s.
Thus,
geog aphical
o
en i onmen al
ac o s
could
inﬂuence
pa ame e s,
such
as
me hyla ion
pa e ns
(Pi azzini
e
al.,
2012),
bu
di e ences
among
di e se
la i udes
can
be
e ealed
and
ad
hoc
analysed.
d
POPULATIONS.
One
o
he
main
goal
o
MARK-AGE
was
o
ec ui
consis en
g oups
o
subjec s
assumed
o
ha e
di e se
a es
o
ageing,
as
desc ibed
abo e.
On
he
whole
3337
subjec s
we e
ini ially
ec ui ed
and
he
ec ui men
o
GO/SGO
was
he
mos
challenging
due
o
la ge
dis ances
be ween
subjec s
esidence
and
labo a o y
place,
hus
i
was
mo e
ime
consuming,
mo e
expensi e
and
mo e
e o
needed
o
ulﬁl
equi emen s
o
anspo
o
biological
samples.
Fu he mo e,
he
numbe
o
SGO
was
abou
hal
o
GO
since
somebody
declined,
di o ced
o
passed
away.
53
Down
Synd ome
indi iduals
we e
ec ui ed
by
UNIBO
wi h
a
speciﬁc
s a egy
commi ed
o
amily
in ol emen
and
he
employmen
o
specialized
human
esou ces,
such
as
psychologis s
and
psychia is s.
Fu he
a
speciﬁc
ba e y
o
es s
ocused
on
beha iou ,
neu opsychological,
neu opsychia ic
and
cogni i e
assessmen
was
se
up
(see
Mo eno-Villanue a,
Cap i
e
al.,
his
issue)
in
o de
o
e alua e
he
unc ional
and
cogni i e
s a us
o
hese
people.
DNage
B.V.
and
la e
on
Uni e si y
o
Con-
s ance
(UKON,
Ge many)
we e
esponsible
o
collec ion
o
abou
59
exis ing
blood
samples
om
WS
pa ien s
and
a
mino
num-
be
o
CS
pa ien s
ec ui ed
by
ex e nal
collabo a o s.
In
iew
o
he
complexi y
and
he
size
o
he
MARK-AGE
p ojec ,
d opou s
we e
expec ed.
Ne e heless,
abou
95%
o
ec ui ed
subjec s
(i.e.
3169)
could
be
included
in
he
MARK-AGE
popula ion
o
anal-
ysis
(Table
1
ﬁnal
numbe s
o
success ully
ec ui ed
olun ee s
and
also
inse ed
in
he
MARK-AGE
da abase
we e
he
ollowing:
2262
RASIG;
528
GO;
305
SGO
and
47
DS
as
shown
in
Table
1
(59
WS
pa ien s
samples
a e
no
included).
Technical
aspec s
a e
b ieﬂy
epo ed
in
Box
I
and
Table
2.
All
p ocedu es
o
da a
base
managemen
and
cleaning
a e
desc ibed
(see
Bau
e
al.,
his
issue).
Box
I:
P ac ical
aspec s
o
MARK-AGE.
-
MARK-AGE
RASIG
popula ion
was
ec ui ed
by
BioTeSys
GmbH
(Ge many),
Uni e si y
o
Namu
(FUNDP,
Belgium),
Ös e e-
ichische
Akademie
de
Wissenscha en
(UIBK,
Aus ia),
Ins i u e
o
Expe imen al
Biology
(NENCKI,
Poland),
Na ional
Hellenic
Resea ch
Founda ion
Cen e
(NHRF,
G eece),
Uni e si y
o
Tam-
pe e
(UTA,
Finland)
and
Uni e si y
o
Bologna
ALMA
MATER
STUDIORUM
(UNIBO,
I aly).
Subjec s
om
GO/SGO
coho s
we e
ec ui ed
by
Uni e si y
o
Leiden
(LUMC,
Ne he land),
Uni e si y
o
Tampe e
(UTA,
Finland),
NENCKI,
UNIBO,
FUNDP
and
NHRF.
UNIBO
addi ionally
ec ui ed
DS
pa ien s,
DNage
B.V.
(Ne he land)
and
Uni e si y
o
Cons ance
(UKON,
Ge many)
we e
esponsi-
ble
o
collec ion
o
exis ing
blood
samples
om
CS
and
WS
pa ien s
ec ui ed
by
ex e nal
collabo a o s.
A
speciﬁc
ques-
ionnai e
was
de eloped
o
RASIG/GO/SGO
popula ion,
which
was
adap ed
by
UNIBO
o
he
DS
pa ien s.
All
he
ques ion-
nai es
and
biological
samples
ha e
been
desc ibed
in
he
a icle
dedica ed
o
MARK-AGE
s anda d
ope a ing
p ocedu es
(see
Mo eno-Villanue a,
Cap i
e
al.,
his
issue).
Rec ui men
s a egies
a e
de ailed
in
Table
1.
Reasonably,
GO/SGO
ec ui men
was
ca -
ied
ou
by
Beneﬁcia ies
who
we e
in ol ed
in
GEHA
p ojec
since
hey
had
al eady
con ac ed
hese
amilies
be o e
(F anceschi
e
al.,
2007).
-
Inclusion
and
exclusion
c i e ia
RASIG
we e
andomly
ec ui ed
age-s a iﬁed
indi iduals
om
he
gene al
popula ion
(bo h
sexes)
aged
35–74
and
able
o
gi e
in o med
consen .
Conce ning
GO
sub-
jec s,
hey
we e
sons
o
daugh e s
o
GEHA
indi iduals
and
SGO
we e
GO
spouses
in
age- ange
55–74
yea s.
As
well
as
RASIG,
all
o
hem
should
be
able
o
gi e
hei
in o med
consen .
Exclu-
sion
c i e ia
we e
he
ollowing:
i.
sel - epo ed
se oposi i i y
o
HIV,
HBV
(excep
se oposi i i y
by
accina ion)
and
HCV
(HBV
and
HCV
se oposi i i y
assessed
a e
blood
collec ion).
ii.
p esence
o
ac ual
cance
and
cu en
use
o
an i-cance
d ugs
o
glucoco i-
coids;
iii.
less
han
50%
o
li e ime
spen
in
coun y
o
esidence.
i .
inabili y
o
gi e
in o med
consen .
5.
Robus
da a,
longi udinal
componen
and
p og ess
MARK-AGE
was
a
g ea
oppo uni y
o
ad ancemen
in
knowl-
edge.
To
asce ain
he
biological
and
analy ical
obus ness
o
he
measu emen s
o
candida e
bioma ke s,
100
dono s
om
he
whole
s udy
popula ion
we e
e-sampled
wi hin
3–6
mon hs.
Fu -
he ,
wi hin
he
li e ime
o
he
p ojec
(66
mon hs),
a
limi ed
(12%)
andom
sample
o
p obands
we e
e- es ed
in
o de
o
es ablish
16
M.
Cap i
e
al.
/
Mechanisms
o
Ageing
and
De elopmen
151
(2015)
13–17
Fig.
1.
Ch onological
s
biological
age.
Dis ances
om
bisec o
(Y
=
X)
a e
only
indica i e.
Basic
assump ion
o
MARK-AGE
highligh s
he
possibili y
o
iden i y
sys emic
bioma ke s
which
co ela e
wi h
age
and
signiﬁcan ly
sepa a e
RASIG,
GO
and
DS
popula ions
o
di e en
age
a es.
RASIG:
Randomly
ec ui ed
Age-S a iﬁed
Indi iduals
om
he
gene al
popula ion
(age
ange:
34–75
yea s);
GO:
GEHA
o sp ing
(age
ange:
54–75
yea s);
DS:
Down
synd ome
(age
ange:
19–68
yea s)
a
longi udinal
componen
wi hin
he
s udy.
To
make
s onges
he
esul s
eme ging
om
MARK-AGE
i
would
be
impo an
o
pe o m
a
mo e
obus
longi udinal
s udy
on
all
he
ec ui ed
subjec s.
Ne -
e heless,
hose
pa ame e s,
which
co ela e
wi h
age
and
hose,
which
signiﬁcan ly
sepa a e
coho s
o
di e en
age
a es
a e
hose
able
o
moni o
he
sys emic
age- ela ed
changes
o
he
body.
Fig.
1
depic s
he
concep s
which
MARK-AGE
aced
and
he
basic
ma he-
ma ical
app oach
om
which
algo i hms
ha e
been
de eloped.
The
s onges
MARK-AGE
bioma ke s
and
hose
ela ed
o
he
epigene ic
clock
(353CpG
si es
shaping
an
ageing
clock
in
e ms
o
ch oma in
s a es
and
issue
a iance),
ecen ly
aised
up
om
s udies
on
di e en ly
aged
human
issues,
human
obesi y
and
Down
Synd ome
(Ho a h,
2013;
Ho a h
e
al.,
2014,
2015),
e eal
powe ul
issue
-speciﬁc
bioma ke s
mi o ing
he
sys emic
con-
di ion.
These
ﬁndings
open
new
ques ions
on
he
u u e
ole
o
he
bioma ke s
ne wo k
which
suppo s
in o ma ion
o
heal hy
s a us
and
likely
could
also
“ anspo
communica ion”
among
di e en
cell,
o gans
o
issues.
Thus,
new
insigh s
a e
expec ed
by
bioma k-
e s
ne wo k,
no
only
highligh ing
issue-speciﬁc
and/o
sys emic
molecula
pa hways,
bu
also
moni o ing
he
issue-speciﬁc
and/o
sys emic
a e
o
ageing,
bo h
a
indi idual
and
popula ion
le els,
and
e en ually
a ge ing
genes
o
hei
p oduc s
o
age- ela ed
pa hology
in e en ions.
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
g a e ul
o
D .
Lau a
Celani,
D .
Anna
Lau a
Ba bie i,
D .
Claudia
Be a elli,
D .
C is ina
Fabb i,
Massimo
Izzi
oge he
wi h
all
he
UNIBO
eam
o
hei
essen ial
con ibu ion
on
olun ee s’
ec ui men
and
labo a o y
p ocedu es
in
Bologna
(I aly).
We
would
like
o
hank
he
BioTeSys
eam
Jen-
ni e
Schweika ,
Simone
Sie e ,
Annabel
S ie lin,
Ka ha ina
Halle
and
Am ei
Ge ull
o
hei
e o
in
ec ui men
managemen
and
documen a ion
as
well
as
sample
p ocessing.
O.
Toussain
and
F.
Debacq-Chainiaux
a e,
espec i ely
Senio
Resea ch
Associa e
and
Resea ch
Associa e
o
he
FNRS,
Belgium
and
acknowledge
he
Région
Wallonne
o
he
Ne wo k
II
Senegene
I
and
Senegene
p ojec s
II,
he
Pole
o
Excellence
Nano oxico
p ojec
#
516252,
and
Complemen
‘QNano’
p ojec
#
1117448.
We
a e
g a e ul
o
D .
Do o a
Janiszewska,
D .
Magdalena
Dudkowska,
Ms.
Anna
Ka pa,
Ms.
Ma a
Wincenciak
om
he
Nencki
eam
and
all
nu ses
o
hei
con ibu ion
on
olun ee s’
ec ui men
and
labo a o y
p oce-
du es
in
Wa saw
(Poland).
We
would
like
also
o
hank
D .
G azyna
Mosieniak
o
he
aluable
inpu
in
he
p ojec
o ganisa ion.
Las ly,
we
would
like
o
hank
all
s udy
pa icipan s
who
olun a ily
o e ed
hei
ime
and
suppo
o
he
beneﬁ
o
he
MARK-AGE
p ojec .
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M.G.,
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P.,
2014.
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u u e
o
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