Edi o ial: Molecula and
epigene ic mechanisms in
neu oinflamma ion and
neu odegene a ion
Isaac F ancos-Quijo na
1
*
†
, Elisa Ca asco
2
*
†
and
En ique Gabandé-Rod íguez
3
*
†
1
Depa men o Molecula Biology, Facul y o Sciences, Uni e sidad Au ónoma de Mad id (UAM), Mad id,
Spain,
2
Depa men o Biology, Facul y o Sciences, Uni e sidad Au ónoma de Mad id, Mad id, Spain,
3
Tissue and O gan Homeos asis P og am, Cen o de Biología Molecula Se e o Ochoa (CBMSO), Consejo
Supe io de In es igaciones Cien íficas (CSIC), Mad id, Spain
KEYWORDS
aging, neu odegene a ion, epigene ics, neu oinflamma ion, age-associa ed diseases
Edi o ial on he Resea ch Topic
Molecula and epigene ic mechanisms in neu oinflamma ion and
neu odegene a ion
In oduc ion
The sus ained inc ease in li espan expec ancy achie ed du ing he las yea s has
c i ically inc eased he in e es in unde s anding he molecula and cellula mechanisms
igge ing age- ela ed diseases. Aging is a na u al biological p ocess ha leads o a
p og essi e decline in physiological unc ions, making indi iduals mo e suscep ible o
a ious age- ela ed diseases.
In his Resea ch Topic, Lee e al. e iew and emphasize he con ibu ion o
immunosenescence o he unc ional decline o he immune sys em du ing aging.
Among o he ea u es, senescen cells ypically accumula ed in he issues du ing aging
a e cha ac e ized by he p o-inflamma o y senescence associa ed sec e o y pheno ype
(SASP), con ibu ing o d i e local and sys emic ch onic s e ile inflamma ion h ough
he sec e ion o mul iple cy okines and chemokines. Among he senescen signa u es ha
appea in he majo popula ions o immune cells, p e ious epo s unco e ed he dec eased
ex en o ype I IFN esponses d i en by inna e immune cells is highligh ed as a isk ac o o
i al in ec ions in aged indi iduals (Bas a d e al., 2020). In pa allel, ine ficien an ibody
p oduc ion by B cells is coupled wi h age-associa ed al e a ions in he unc ion o ollicula
helpe T cells (Almanan e al., 2020), oge he wi h de ec i e clea ance o senescen cells om
he issues and excessi e and p omiscuous p oduc ion o cy o oxic molecules by cy o oxic
T cells (Sua ez-Ál a ez e al., 2017;Pe ei a e al., 2020). Al oge he , hese age-associa ed
al e a ions in di e en senescen immune cell popula ions con ibu e o immune
dys unc ion du ing aging. The au ho s highligh ha apa om cell-au onomous
esponses, he al e ed aged en i onmen can nega i ely a ec immune cell unc ion. The
exposu e o i al and bac e ial agen s exemplified by SARS-CoV-2 can also ins iga e
OPEN ACCESS
EDITED AND REVIEWED BY
Consuelo Bo as,
Uni e si y o Valencia, Spain
*CORRESPONDENCE
Isaac F ancos-Quijo na,
[email p o ec ed]s
Elisa Ca asco,
[email p o ec ed]
En ique Gabandé-Rod íguez,
[email p o ec ed]
†
These au ho s ha e con ibu ed equally
o his wo k
RECEIVED 02 Augus 2023
ACCEPTED 08 Augus 2023
PUBLISHED 14 Augus 2023
CITATION
F ancos-Quijo na I, Ca asco E and
Gabandé-Rod íguez E (2023), Edi o ial:
Molecula and epigene ic mechanisms in
neu oinflamma ion
and neu odegene a ion.
F on . Aging 4:1271714.
doi: 10.3389/ agi.2023.1271714
COPYRIGHT
© 2023 F ancos-Quijo na, Ca asco and
Gabandé-Rod íguez. 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). The use, dis ibu ion o
ep oduc ion in o he o ums is
pe mi ed, p o ided he o iginal au ho (s)
and he copy igh owne (s) a e c edi ed
and ha he o iginal publica ion in his
jou nal is ci ed, in acco dance wi h
accep ed academic p ac ice. No use,
dis ibu ion o ep oduc ion is pe mi ed
which does no comply wi h hese e ms.
F on ie s in Aging on ie sin.o g01
TYPE Edi o ial
PUBLISHED 14 Augus 2023
DOI 10.3389/ agi.2023.1271714
senescence and con ibu e o immune cell dys unc ion ha a ou s
inc eased mul imo bidi y, wi h highe impac on he elde ly.
Majo age-associa ed pa hologies include neu odegene a i e
diso de s like Alzheime ’s disease (AD). One o he key
challenges in diagnosing neu odegene a i e diseases is he
di ficul y in dis inguishing be ween physiological aging and
pa hological aging. Iden i ying bioma ke s ha flag his ansi ion
would p o ide an ea lie de ec ion and he apeu ic op ions. In his
ega d, ecen findings poin o a p ominen ole o
neu oinflamma ion in igge ing neu odegene a i e diseases.
While he ole o myeloid cells, and specially mic oglia, was well
es ablished, how he adap i e immune sys em con ibu es o
neu odegene a i e diseases is p og essi ely acqui ing mo e
ele ance in his esea ch field. Indeed, ecen findings ha e
e idenced ha cy o oxic T cells accumula e in he b ain o
mouse models and pa ien s wi h pa hologies like AD,
Amyo ophic la e al scle osis o Pa kinson’s disease (Ca asco
e al., 2022).
In his opic, Cox e al. e iewed he po en ial o glu ama e, a
c ucial neu o ansmi e in he b ain, as a bioma ke o iden i ying
his pa hological ansi ion in AD. Du ing heal hy aging, has been
epo ed a dec ease in glu ama e gic synapses and neu ons mainly in
he hippocampus, p e on al co ex and mo o senso y a eas which
in combina ion wi h g ey ma e hinning helps o explain he
subsequen cogni i e, mo o and senso y decline in heal hy aging
(Sego ia e al., 2001;Gasio owska e al., 2021). Howe e , con a y o
heal hy aging, esea ch on bo h human pa ien s and animal models
(Minke iciene e al., 2008;Mu a e al., 2012;Hascup e al., 2016;
Hascup e al., 2021) showed ha ea ly s ages o AD a e associa ed
wi h hype ac i e glu ama e signaling in hippocampus, p eceding o
coinciding wi h amyloid and/o au accumula ion, while la e s ages
show educed glu ama e le els due o neu onal loss. The e o e, as
Cox e al. highligh in hei e iew, he use o non-in asi e imaging
me hods o moni o glu ama e le els, such as ce eb ospinal fluid
analysis, PET imaging, MRS, and GluCEST migh open a enues o
ea ly he apeu ic in e en ions aimed a mi iga ing cogni i e decline
in AD pa ien s.
Rega ding neu oinflamma ion, Zhuang e al. in es iga ed he
in ol emen o immune cell- ela ed genes and bioma ke s in AD
de elopmen and p og ession. They used bioin o ma ic me hods o
find di e en ially exp essed genes (DEGs) be ween AD and con ol
samples in h ee di e en da abases, and by CIBERSORT algo i hm
hey co ela ed hose genes wi h di e en ially infil a ed immune
cells (DIICs) (Zhuang e al.). They epo ed ha , in line wi h ecen
li e a u e da a (Heneka e al., 2015;Chen and Hol zman, 2022),
se e al immune cell ypes, including NK cells, mac ophages,
dend i ic cells, and T cells, showed significan di e ences in
infil a ion be ween AD and con ol samples. Nex , a e u he
na owed down he ocus o immune cell- ela ed DEGs ha we e
highly co ela ed wi h specific immune cell ypes by WGNA
analysis, hen machine lea ning me hods we e employed o
iden i y a se o en obus immune cell- ela ed genes (CMTM2,
DDIT4, LDHB, NDUFA1, NDUFB2, NDUFS5, RPL17, RPL21,
RPL26, and NDUFAF2) as po en ial bioma ke s o AD. Then,
a e alida ing he exp ession ends o hese genes in pe iphe al
blood samples om AD pa ien s and heal hy olun ee s by qPCR,
au ho s cons uc ed a diagnos ic nomog am by di e en bioma ke
combina ion, as a ool o es ima e he p obabili y o disease p esence
showing p omising esul s in diagnos ic accu acy. Finally, hey
p edic ed some chemicals, including es e a ol, ha could a ge
he iden ified genes and po en ially se e as he apeu ic agen s in AD
ea men using he Compa a i e Toxicogenomics Da abase (CTD)
and bioin o ma ic app oaches. In conclusion, Zhuang e al.’s epo
iden ified se e al immune-cell- ela ed genes as eliable bioma ke s
in AD pa hogenesis, and hei diagnos ic monog am o e s an
impo an ool o ea ly AD diagnosis despi e he need o
addi ional esea ch and alida ion s udies.
Recen esea ch is ying o es ablish whe he
neu oinflamma ion is a p ocess occu ing exclusi ely h ough he
engagemen o cell-in insic molecula pa hways o whe he
ex insic o sys emic ac o s con ibu e o he ac i a ion o
immune cells. The ele ance o his ex ends beyond basic
scien ific knowledge as li es yle habi s can influence inflamma ion
and so, can unco e po en ial a ge s o pha macological
in e en ion in hese diseases. In his ega d, F aus o e al. epo
in his opic ha a mouse model o AD o ced o inges alcohol,
de elops abno mal in es inal pe meabili y and al e ed composi ion
o he gu mic obiome (in es inal dysbiosis). This co ela es wi h
inc eased sys emic le els o he p o-inflamma o y cy okine
in e leukin-6 (IL-6) and inc eased le els o p o-inflamma o y
ma ke s in hei b ains. Mo eo e , hey ound a significan
co ela ion o ce ain bac e ial species such as Lachnospi aceae
NK4A136 and Clos idium sensu s ic o 1 wi h he al e ed
beha iou and he appea ance o disease ma ke s in he b ain o
hese mice (F aus o e al.). These findings align wi h ecen epo s
ha ound ha al e ed gu mic obio a composi ion may be an
indica o o p eclinical AD in pa ien s (Fe ei o e al., 2023).
Finally, in his opic E ic Mayo e iews he po en ial
neu o ophic e ec s o calo ie es ic ion, exe cise p ac ice o
in e mi en as ing; sugges ing ha implemen a ion o any o
e en a combina ion o hese ac o s could con ibu e o imp o e
he ou come o pa ien s su e ing neu odegene a i e diseases.
In e es ingly, impo an molecula pa hways such as mTOR, NF-
ĸB, PGC-1α, MAPK o GSK-3βa e a ge s o hese in e en ions
(Mayo ). This highligh s ha esea ch on his field may b ing he
iden ifica ion o al e ed, po en ially d uggable, molecula pa hways
in hese diseases and no only he cha ac e iza ion o he e ec s o
hese in e en ions ha a e un o una ely no always easy o
implemen in hese kind o pa ien s.
Conclusion
This opic includes o iginal pape s and e iew a icles
summa izing he con ibu ion o di e en mechanisms anging
om exogenously inges ed damaging agen s, p o-inflamma o y
molecules o exace ba ed neu o ansmi e elease o
neu odegene a ion and age-associa ed cogni i e decline.
Mo eo e , he opic p o ides wi h po en ial he apeu ic op ions
ha could amelio a e he impai ed neu onal pe o mance, which is
cha ac e is ic o hese condi ions. On op o ha , he eade s will also
find esea ch on new ma ke s ha will e en ually help diagnosing
hese condi ions a ea lie s ages. Fu u e esea ch mus deepen in o
why common mechanisms a e al e ed du ing he p og ession o
diseases wi h di e en ae iology, wha could defini ely make an
impac in pa ien s’weelbeing.
F on ie s in Aging on ie sin.o g02
F ancos-Quijo na e al. 10.3389/ agi.2023.1271714
Au ho con ibu ions
IF-Q: Concep ualiza ion, Funding acquisi ion, In es iga ion,
P ojec adminis a ion, Supe ision, Valida ion, Visualiza ion,
W i ing–o iginal d a , W i ing– e iew and edi ing. EC:
Concep ualiza ion, Da a cu a ion, Fo mal Analysis, Funding
acquisi ion, In es iga ion, Me hodology, P ojec adminis a ion,
Resou ces, So wa e, Supe ision, Valida ion, Visualiza ion,
W i ing–o iginal d a , W i ing– e iew and edi ing. EG-R:
Concep ualiza ion, Da a cu a ion, Fo mal Analysis, Funding
acquisi ion, In es iga ion, Me hodology, P ojec adminis a ion,
Resou ces, So wa e, Supe ision, Valida ion, Visualiza ion,
W i ing–o iginal d a , W i ing– e iew and edi ing.
Funding
This s udy was suppo ed by he Y2020/
BIO6350 Nu iSION-CM g an unded by Comunidad de
Mad id. EG-R is suppo ed by ERC-2021-CoG-101044248-Le T
Be. IF-Q is suppo ed by a Juan de la Cie a (JC2020-044392)
con ac om he spanish minis y o science.
Conflic o in e es
The au ho s decla e ha he esea ch was conduc ed in he
absence o any comme cial o financial ela ionships ha could be
cons ued as a po en ial conflic o in e es .
Publishe ’s no e
All claims exp essed in his a icle a e solely hose o he au ho s and
do no necessa ily ep esen hose o hei a filia ed o ganiza ions, o
hose o he publishe , he edi o s and he e iewe s. Any p oduc ha
may be e alua ed in his a icle, o claim ha may be made by i s
manu ac u e , is no gua an eed o endo sed by he publishe .
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