When C. elegans emb yos ha ch in he absence o ood,
de elopmen a es s a he i s la al s age (L1). This
p ocess in ol es quiescence o he cells ha no mally
di ide a he beginning o pos emb yonic de elopmen .
When a es ed L1s encoun e ood, cell di isions
esume and pos emb yonic de elopmen p oceeds. Fo
his eason, his s age o a es is ou inely used in many
C. elegans labs o synch onize la a. L1 a es was
desc ibed as a non-aging s a e, since he ime spen on i
did no accoun owa ds he o al li espan once he
animals esumed de elopmen [1]. Howe e , Roux e al.
showed ha L1 la ae unde go a p ocess simila o
adul aging. Rema kably, he signals o aging
accumula ed du ing a es we e e ased upon eeding o
he a es ed la ae [2], explaining why he ime spen in
a es does no educe he li espan o he adul .
Clea ance o aging signs seemed necessa y o esume
de elopmen . Al hough i was somehow implici ha
he ex en o aging sings would ma k he ime necessa y
o eco e , he lack o quan i a i e me hods o assess he
iming o eco e y p e en ed es ing his idea.
Now, we ha e bene i ed om a quan i a i e me hod ha
we de eloped o measu e la al de elopmen al iming
[3] o quan i y he ime o eco e a e p olonged L1
a es . In a ecen publica ion [4], we ha e shown ha
ma ke s o aging ha accumula e du ing L1 a es
con ibu e o inc ease he ime needed o eco e a e
p olonged a es . Fu he mo e, inc eased ac i i y o he
ansc ip ion ac o DAF-16, as ha ound in he insulin
ecep o mu an da -2, led o as e eco e y.
Con e sely, da -16 mu an s showed s ong delays in
eco e y, e en a e sho pe iods o a es . This ole o
Insulin signaling was su p ising, as ac i a ion o DAF-
16 is commonly ela ed o ep ession o p oli e a ion.
da -16 mu an s a e de ec i e in L1 a es and a ac ion
o he la ae in he popula ion ini ia e pos emb yonic
cell di isions, wha was a ibu ed o a lowe ac i a ion
o he cyclin dependen kinase inhibi o cki-1 [5].
Howe e , his only happens when he e is e hanol
p esen in he media o a es ed L1, no mally used o
dilu e he choles e ol supplemen a ion o C. elegans.
Ins ead, we used media wi hou e hanol and obse ed
he same le els o cki-1 exp ession in he wild- ype
s ain and da -16 mu an s. Analysis o he ini ial
di isions o pos emb yonic de elopmen e ealed ha
he da -16 mu an no only did no show p ema u e
di isions, bu hey su e ed an impo an delay compa ed
Edi o ial
o he wild ype. Then, how do we explain he
ep ession o cell di isions in he da -16 mu an ? Ou
hypo hesis was ha insulin signaling modula es he a e
o aging du ing L1 a es , as i does o adul aging [6].
Indeed, we could con i m ha ac i a ion o DAF-16
educes he a e o L1 aging. The e o e, he delay in he
ini ia ion o pos emb yonic de elopmen in he da -16
mu an i is no ela ed o a di ec ole o his
ansc ip ion ac o in he con ol o cell di isions
du ing eco e y bu o he lack o ac i a ion o he s ess
esponse du ing L1 a es , leading o a as e a e o L1
aging. The as e accumula ion o L1 aging ma ke s
en ails longe eco e y imes o clea hem, delaying he
ini ia ion o pos emb yonic di isions [4].
The lack o homogenei y o L1 a es esembles he
p ocess o quiescence deepening unde gone by mam-
malian cells. Capaci y o quiescen cells o eco e
p oli e a ion po en ial depends on he dep h o
quiescence. This p ocess has been s udied in de ail in
Ra Emb yonic Fib oblas s. Cells in shallow quiescence
espond as e o g ow h s imuli han hose in deep
quiescence, which need s onge s imuli and longe
imes o ini ia e p oli e a ion. Deep quiescen cells sha e
gene-exp ession signa u es wi h senescen and aged
cells, wha sugges s quiescence deepening as a
ansi ional s a e owa d senescence and aging. Cells
cul u ed o long pe iods unde quiescence condi ions
mo e om shallow o deep quiescence and, ul ima ely,
hey i e e sibly a es as senescen cells [7]. Simila o
wha we ha e desc ibed in C. elegans o a es ed L1s
[4], accumula ion o signs o aging du ing p olonged
pe iods o quiescence delays he eac i a ion o cell
p oli e a ion. Lysosomal unc ion con ols quiescence
deepening by educing he accumula ion o Reac i e
oxygen species (ROS) [7]. Cells subjec ed o long- e m
se um s a a ion unde wen lysosomal unc ion
impai men leading o a highe ROS accumula ion,
esul ing in a loss o capaci y o een e cell cycle [7]. In
his way, when quiescen cells we e pha macologically
ea ed o inhibi lysosomal unc ion o o induce
oxida i e s ess, hey we e pushed in o a deepe
quiescen s a e and hey needed s onge s imula ion o
eco e [7]. As ROS, accumula ion o p o ein agg e-
ga es also leads o quiescence deepening. Lysosomal
ac i a ion is also impo an o clea p o ein agg ega es
in quiescen cells o keep hem in a shallowe quiescen
s a e [8]. This is in conco dance wi h ou indings,
Aging du ing C. elegans L1 quiescence
Alejand o Ma a-Cabana, F ancisco Ja ie Rome o-Expósi o, Ma ía Olmedo
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whe e a es ed la ae wi h highe le els o ROS and
p o ein agg ega ion needed longe imes o eco e and
o ini ia e pos -emb yonic de elopmen . This leads us o
aise he idea o he quiescence dep h in he con ex o
C. elegans and o p opose a es ed L1 la ae as a model
o he s udy o his p ocess. The con ol o he
quiescence dep h is undamen al o main ain he issue
egene a i e po en ial, bu also, he dys egula ion o he
cellula quiescence can esul in hype p oli e a ion ha
leads o cance . The e o e, he unde s anding o he
molecula mechanisms unde lying his phenomenon is
o special in e es and he C. elegans model is a use ul
ool o gain knowledge abou hese p ocesses (Figu e 1).
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Figu e 1. Pa allelisms be ween quiescence deepening and L1 ageing. (A) Upon emo al o g ow h ac o s, REF (Ra
Emb yonic Fib oblas ) en e cell quiescence, a e e sible, non-p oli e a i e s a e. Cells p og essi ely unde go quiescence
deepening as hey accumula e ROS and p o ein agg ega es. A e p olonged quiescence, cells equi e s onge s imula ion and
ake longe o exi quiescence and e u n o p oli e a ion. E en ually cells each senescence, an i e e sible s a e o cell a es . (B)
L1 a es ed C. elegans la ae show a simila p ocess o quiescence deepening. P olonged a es en ails a p ocess named L1 aging,
ha also in ol es accumula ion o ROS and p o ein agg ega es. We ha e shown ha p olonged quiescence leads o a delay in he
ini ia ion o pos emb yonic cell di isions. Be o e dying as a es ed L1, la ae lose he capaci y o eco e om L1 a es , a p ocess
ha could be compa ed o cell senescence. (C) Insulin signalling modula ed he p ocess o L1 aging. Ac i a ion o he ansc ip ion
ac o DAF-16, as ha sound in da -2 mu an s, leads o a slowe a e o L1 aging. As a consequence, a e he same ime in L1
a es , da -2 mu an s accumula e less ma ke s o aging. This allows a as e eco e y once la ae encoun e ood. da -16 mu an s,
show as e L1 ageing and he ini ia ion o pos emb yonic di isions upon eeding is delayed compa ed o he wild ype.
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Ma ía Olmedo: Depa amen o de Gené ica, Facul ad de
Biología, Uni e sidad de Se illa, Se illa 41012, Spain
Co espondence: Ma ía Olmedo
Email: ma iaolme[email p o ec ed]
Keywo ds: L1 aging, quiescence, C. elegans, insulin
signalling
Copy igh : © 2020 Ma a-Cabana e al. This is an open
access a icle dis ibu ed unde he e ms o he C ea i e
Commons A ibu ion License (CC BY 3.0), which pe mi s
un es ic ed use, dis ibu ion, and ep oduc ion in any
medium, p o ided he o iginal au ho and sou ce a e
c edi ed
Recei ed: Augus 18, 2020
Published: Sep embe 27, 2020
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