INSIGHTS | PERSPECTIVESsciencemag.org SCIENCEto ChP organoids will allow further dissec-
tion of different ChP compartments and
their cross-talk. ChP organoids will thus be
an attractive system to investigate the sec-
retome of different choroidal cells and to
identify human-specific and evolutionarily
conserved signaling factors. The ChP is also
an important contributor to disease. A fur-
ther translational application will be the
generation of ChP organoids from induced
pluripotent stem cells from individual pa-
tients to investigate links between specific
mutations and ChP dysfunction.
An exciting next step is to probe the
functional implications of ChP epithelial
cell hetereogeneity, and of other ChP cell
types, including their in vivo distribution
and whether there are regional differences
between different brain ventricles, which
differ in their secretomes ( 3 ). Choroidal
epithelial cells may be specialized for dif-
ferent functions, given their many roles
in vivo, and use different modes of secre-
tion. The challenge now is to unravel how
the functions of each choroidal cell typeare regulated by different inputs to the
ChP. Indeed, the ChP lies at the interface
of blood and the central nervous system
and is therefore singularly poised to sense
and integrate signals from the periphery as
well as the brain and to dynamically adapt
its secretome in different physiological
states of homeostasis and disease. It is an
exciting time in the field to discover how
this system is orchestrated and dynami-
cally participates in brain function. jREFERENCES AND NOTES- J. F. Ghersi-Egea et al., Acta Neuropathol. 135 , 337
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ACKNOWLEDGMENTS
F. D. is supported by European Research Council (ERC)
Advanced Grant NeuroStemCircuit, Swiss National Science
Foundation Grant 31003A_163088, and the University of
Basel. We thank D. Thaler for comments.10.1126/science.abd0269PHYSIOLOGYExercising your mind
A circulating factor induced by exercise contributes
to keeping the brain young in mice
By Victor A. Ansere^1 and
Willard M. Freeman2,3,4A
lthough the beneficial effects of ex-
ercise on the brain and cognition are
generally accepted, the mechanisms
by which physically active people re-
main mentally sharp later in life have
been unclear. On page 167 of this is-
sue, Horowitz et al. ( 1 ) demonstrate that the
beneficial effects of exercise in mitigating
brain aging can be conveyed from exercis-
ing mice to sedentary mice through plasma
transfer. The authors also provide compelling
evidence that the positive effects of exercise
on brain aging are at least partially mediated
through hepatic mechanisms and identify a
promising target for further study.
The economic, social, and health conse-
quences of the growing aged population are
profound, thus necessitating interventions
that promote healthy aging. Interventions
to maintain health later into life, such as ra-
pamycin ( 2 ) and caloric restriction ( 3 ), have
been reported to improve memory and cog-
nition in animal models but are challenging
to translate to humans. Approaches such as
heterochronic parabiosis (the surgical join-
ing of young and aged animals resulting in
plasma exchange) or heterochronic plasma
transfer by infusion have gained consider-
able attention and also offer great promise
in rejuvenating the aged hippocampus in
mice ( 4 ). However, regular physical exercise
is arguably the most consistently effective
health-enhancing strategy to attenuate the
age-related deterioration in brain structure
and function in laboratory animals and hu-
mans ( 5 ). Using exercise to probe the mecha-
nisms of brain aging could also identify new
therapeutic avenues for the maintenance of
brain health throughout life.
Horowitz et al. transferred plasma from
regularly exercising adult or aged mice to
aged sedentary mice. This increased the
formation of new hippocampal neurons, in-
creased the concentrations of neurotrophicfactors, and improved cognition in behav-
ioral tests of the sedentary mice. Potential
circulating factors responsible for this ef-
fect were identified by a plasma proteomic
screen. Among these, the authors found
that the glycosylphosphatidylinositol-specific
phospholipase D1 (GPLD1), a protein abun-
dant in the liver, was induced by regular
exercise in mice. Higher plasma GPLD1 con-
centrations were also observed in physically
active older people (ages 66 to 78) compared
to inactive older people. Furthermore, induc-
tion of GPLD1 specifically in the mouse liver
through in vivo transfection was sufficient to
recapitulate the rejuvenative effects of exer-
cise in sedent ary mice.
GPLD1 hydrolyzes the inositol phos-
phate linkage in glycosylphosphatidylino-
sitol (GPI) that anchors proteins to mem-
branes, releasing them into the circulation.
Horowitz et al. found that this activity of
GPLD1 was necessary for the improved
cognition and increased hippocampal neu-
rogenesis observed after GPLD1 induction
in vivo. Intriguingly, neither liver nor circu-
lating GPLD1 concentrations were found to
decline with age, and GPLD1 did not appear
to enter the brain from the circulation. This
suggests that the beneficial effects of GPLD1
on the hippocampus may involve interme-
diary factors that are released by periph-
eral organs and are capable of entering the
brain to act directly on the hippocampus
(see the figure). This concept is supported
by studies such as those that demonstrated
the induction of muscle peroxisome pro-
liferator–activated receptor–g coactivator
1 a (PGC-1a) by exercise, which ultimately
results in increased circulating concentra-
tions of irisin, a myokine that acts directly
on the brain ( 6 , 7 ). Therefore, determining
tissue-level targets of circulating GPLD1 as
well as the resultant alterations in circulat-
ing factors that can cross the blood-brain
barrier is crucial to understanding the di-
rect mechanism of action on the brain.
Horowitz et al. identified coagulation and
complement signaling cascades as possible
intermediary factors mediating the effects
of GPLD1; however, additional investigation
is required to fully understand their role.
These findings integrate with the myriad
effects of exercise across organ systems that
may mediate the positive effects on brain ag-
ing ( 8 ). After exercise, circulating myokines(^1) Department of Physiology, University of Oklahoma Health
Sciences Center, Oklahoma City, OK, USA.^2 Genes and
Human Disease Program, Oklahoma Medical Research
Foundation, Oklahoma City, OK, USA.^3 Oklahoma City
Veterans Affairs Medical Center, Oklahoma City, OK, USA.
(^4) Department of Biochemistry and Molecular Biology,
University of Oklahoma Health Sciences Center, Oklahoma
City, OK, USA. Email: [email protected]
“A major challenge in medicine
is to deliver drugs to the
brain, owing to the blood-CSF
and blood-brain barriers.”
144 10 JULY 2020 • VOL 369 ISSUE 6500