620 11 FEBRUARY 2022 • VOL 375 ISSUE 6581 science.org SCIENCE
lial cells adopt mesenchymal properties,
such as increased migratory capacity ( 7 , 8 ).
p53 induces expression of p21, causing
cell cycle arrest at the G 1 /S checkpoint.
Kozyrska et al. discovered that spontane-
ous leader cells expressed higher amounts
of p21, suggesting that p53 mediates the
leader cell phenotype through up-regula-
tion of p21 expression (see the figure). p21
inhibits cyclin-dependent kinases (CDKs),
and the authors found that cells inducibly
overexpressing p16, a CDK inhibitor struc-
turally unrelated to p21, also began exhib-
iting leader cell characteristics. Curiously,
upon treating leader-follower pairs with
CDK1 and CDK2 inhibitors, the authors
observed a decrease in migration. This sug-
gests that, although spontaneous leader
cell-directed collective cell migration de-
pends upon cell cycle arrest through p53
and p21-mediated CDK inhibition, the abil-
ity of leaders to migrate while leading fol-
lowers requires a disparity in CDK activity.
What is the relevance to injury?
Kozyrska et al. found that epithelial
scratch in their cell culture system gave
rise to leader cells with increased expres-
sion of p53 and p21. These cells underwent
cell cycle arrest, whereas cells that became
migrating followers had no evidence of cell
cycle changes. Activation of p53 along the
scratch was caused by activation of the
mechanical stress kinase p38. Moreover,
inhibiting p53 or ablating p21 delayed the
rate of wound closure, indicating that the
p53-p21 axis mediates epithelial injury re-
pair, a finding consistent with cutaneous
wound repair experiments in vivo ( 9 ).
Prior work showed that MDCK cells with
increased p53 expression become hyper-
sensitive to compaction, resulting in their
elimination from the epithelium as “los-
ers” in a form of mechanical cell competi-
tion (a process by which cells with higher
fitness expand whereas less fit ones are
eliminated) ( 5 ). Notably, increased p53 ex-
pression in this biological context was also
due to p38 activation. Kozyrska et al. found
that both spontaneous leaders and scratch-
induced leader cells underwent cell death
or extrusion as they became compacted by
follower cells. Curiously, this appeared to
be independent of p21. However, leader
cells inducibly overexpressing p21 failed
to undergo elimination during wound
resolution, instead exhibiting an aberrant
morphology that disrupted the repaired
epithelium. These findings underscore the
dual function of p53 activation in both
initiating and concluding wound repair,
as well as the importance of mechanical
cell competition during this process. The
epithelial disruption observed with leader
cell retention evokes the loss of cell elimi-
nation by mechanical cell competition that
is observed in the context of oncogenic
Ras expression in Drosophila melanogas-
ter ( 10 ). Intriguing questions remain to be
addressed about how leader cell induction
and elimination through cell competition
might differ in a hyperproliferative epithe-
lium, and in the event that inappropriate
injury resolution occurs, there may also
be important implications for wound re-
pair in tissue harboring cancer-associated
mutations.
These discoveries engender new ways of
conceptualizing both the process of tissue
reorganization and p53 regulation, includ-
ing the manner by which tissue and cel-
lular context determines how a common
signal (p53) may yield different responses.
Investigating these molecular regulators
will enable further insight into the prin-
ciples of cell behavior modulation, as well
as their applicability to other organismal
systems and complex tissues. For example,
during wound repair of mouse skin, epithe-
lial cells adjacent to injury become migra-
tory and nonproliferative, suggesting that
the same molecular mechanism may apply
( 11 ). Collectively, they may offer molecular
opportunities for therapeutic intervention,
including correcting aberrant wound heal-
ing. For example, chronic wounds fail to
re-epithelialize owing to various mesen-
chymal, basement membrane, and inflam-
matory derangements, including epider-
mal hyperproliferation without migration
( 12 ). In this tissue context, reactivation of
epithelial migratory pathways while ar-
resting cell cycling may correct defects in
this process. jREFERENCES AND NOTES- M. Poujade et al., Proc. Natl. Acad. Sci. U.S.A. 104 , 15988
(2007). - R. Mayor, S. Etienne-Manneville, Nat. Rev. Mol. Cell Biol.
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ACKNOWLEDGMENTS
V.G. and S.Y. are supported by a Howard Hughes Medical
Institute Scholar award and NIH grants (1R01AR063663-
01, 1R01AR067755-01A1, 1DP1AG066590-01 and
R01AR072668). S.Y. is supported by a Medical Scientist
Training Program grant from the NIH (T32GM136651).10.1126/science.abn7411INSIGHTS | PERSPECTIVES
By Timothy W. Rhoads^1 and
Rozalyn M. Anderson1,2C
aloric restriction (CR) has been a cor-
nerstone of aging biology for decades
( 1 ). A reduction of energy intake with-
out malnutrition delays aging and the
onset of age-associated diseases in
multiple species, including nonhuman
primates ( 2 ). Although there has been inter-
est in CR as a lifestyle recommendation for
humans, the real potential lies in understand-
ing the mechanisms and translating them. By
identifying critical factors and processes that
are causal in the beneficial effects of CR, it
could be possible to learn what is creating
vulnerability and what might be targeted to
change the pace of functional decline. On
page 671 of this issue, Spadaro et al. ( 3 ) pro-
filed adipose tissues from people undergoing
CR for 2 years and identified reduced expres-
sion of platelet-activating factor acetylhydro-
lase (PLA2G7). Poised at the intersection of
metabolism and immunity, PLA2G7 could be
a valuable target for correction of immuno-
metabolic dysfunction.
The importance of immune and inflam-
matory pathways in aging is well established
( 4 , 5 ). Multiple diseases and disorders of age
bear a signature of dysfunction in these path-
ways, which are critical for health, repair, and
continued fitness after infection or injury. Of
particular clinical relevance, these processes
are also associated with disease vulnerability
in the context of obesity. Metabolic dysfunc-
tion is thought to be a key driver of disease
vulnerability associated with age and with ex-
panded adipose depots, and there is a highlyAGINGCaloric
restriction
has a
new player
Reverse translation
of a human caloric
restriction trial finds an
immunometabolic regulator
(^1) Department of Medicine, School of Medicine and Public
Health, University of Wisconsin–Madison, Madison, WI,
USA.^2 Geriatric Research, Education, and Clinical Center,
William S. Middleton Memorial Veterans Hospital, Madison,
WI, USA. Email: [email protected]