sciencemag.org SCIENCEIMAGE: J. NEVES AND P. SOUSA-VICTORINSIGHTS | PRIZE ESSAYa degenerating retina. Indeed, the low inte-
gration efficiency of replacement photore-
ceptors transplanted into congenitally blind
mice could be fully restored to match the
efficiency obtained in nondiseased mice by
supplying MANF as a co-adjuvant with the
transplants ( 2 ). This intervention improved
restoration of visual function in treated
mice, supporting the utility of this approach
in the clinic ( 7 ).USING MANF AS AN IMMUNE MODULATOR
Next, my colleagues and I decided to address
the question of whether the immune modu-
latory mechanism described above was rele-
vant for aging biology and whether we could
harness its potential to extend health span.
We found that MANF levels are systemically
decreased in aged flies, mice, and humans.
Genetic manipulation of MANF expression
in flies and mice revealed that MANF is
necessary to limit age-related inflammation
and maintain tissue homeostasis in young
organisms. Using heterochronic parabio-
sis, an experimental paradigm that involves
the surgical joining of the circulatory sys-
tems of young and old mice, we established
that MANF is one of the circulatory factors
responsible for the rejuvenating effects of
young blood. Finally, we showed that phar-
macologic interventions involving systemic
delivery of MANF protein to old mice are ef-
fective therapeutic approaches to reverse sev-
eral hallmarks of tissue aging ( 8 ).REGENERATIVE MEDICINE AS A
REJUVENATING INTERVENTION
The biological process of aging is multi-
factorial, necessitating combined and
integrated interventions that can simul-
taneously target several of the underlying
problems ( 9 ). The potential of immune
modulatory interventions as rejuvenat-
ing strategies is emerging and requires a
deeper understanding of its underlying
molecular and cellular mechanisms.
One expected outcome of reestablishing
a regulated inflammatory response is the
optimization of tissue repair capacity
that naturally decreases during aging ( 3 ).
Combining these interventions with SC-
based therapeutics holds potential to de-
liver on the promise of regenerative medi-
cine as a path to rejuvenation ( 1 ). jREFERENCES AND NOTES- J. Neves, P. Sousa-Victor, H. Jasper, Cell Stem Cell 20 , 161
(2017). - J. Neves et al., Science 353 , aaf3646 (2016).
- J. Neves, P. Sousa-Victor, FEBS J. 287 , 43 (2020).
- Y. Okabe, R. Medzhitov, Nat. Immunol. 17 , 9 (2016).
- J. Neves, M. Demaria, J. Campisi, H. Jasper, Dev. Cell 32 ,
9 (2015). - M. Lindahl, M. Saarma, P. Lindholm, Neurobiol. Dis. 97
(Pt B), 90 (2017). - J. Neves, D. Lamba, H. Jasper, U.S. Patent
US20170274048A1 (2017). - P. Sousa-Victor et al., Nat. Metab. 1 , 276 (2019).
- B. K. Kennedy et al., Cell 159 , 709 (2014).
10.1126/science.aba6114A confocal fluorescence microscope image of a giant macrophage shows MANF (mesencephalic astrocyte-
derived neurotrophic factor) expression in red.For a detailed brochure,
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