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ACKNOWLEDGMENTS
We thank Rukmini S, S. Ramani, V. Radhakhrishnan, A. Saikia,
M. Alavi, S. Das, P. Vardhan, and D. Rajendran, who were crucial in
filing petitions to access the various data sources. No individual-
level patient data were used in the analyses. Unity Health,
St. Michael’s Hospital, Toronto provided ethics approval (REB 15-231).
The opinions expressed are those of the authors and not
necessarily the institutions to which they are affiliated.Funding:
Canadian Institutes of Health Research; Emergent Ventures.
Author contributions:P.J. conceived the study. Y.D., W.S., C.T.,
A.B., S.S., and S.H.F. contributed to statistical analyses. P.J.,
H.G., and P.N. wrote the first draft, and all authors contributed.
Competing interests:The authors declare no competing interests.
Y.D. is the director and founding editor of CVoter. No external
funding was received for the CVoter COVID Tracker survey or
substudy.Data and materials availability:The data used for the
main facility and CRS deaths are in the supplementary materials
(table S6); the primary CVoter data showing daily results are
available at https://cvoterindia.com/trackers, and the substudy
data are in table S3. All input data are available at https://github.
com/cghr-toronto/Indian_Covid_Mortality ( 29 ). This work is
licensed under a Creative Commons Attribution 4.0 International
(CC BY 4.0) license, which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is
properly cited. To view a copy of this license, visit https://
creativecommons.org/licenses/by/4.0/. This license does not
apply to figures/photos/artwork or other content included in thearticle that is credited to a third party; obtain authorization from
the rights holder before using such material.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abm5154
Materials and Methods
Figs. S1 to S5
Tables S1 to S6
References ( 30 – 35 )
MDAR Reproducibility Checklist
Movie S123 September 2021; resubmitted 18 November 2021
Accepted 4 January 2022
Published online 6 January 2022
10.1126/science.abm5154AGINGCaloric restriction in humans reveals
immunometabolic regulators of health span
O. Spadaro1,2,3, Y. Youm1,2,3, I. Shchukina^4 , S. Ryu1,2,3, S. Sidorov1,2,3, A. Ravussin1,2,3, K. Nguyen1,2,3,
E. Aladyeva^4 , A. N. Predeus^4 , S. R. Smith^5 , E. Ravussin^6 , C. Galban^7 ,
M. N. Artyomov^4 , V. D. Dixit1,2,3,8,9*The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth,
reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic
targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and
was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in
adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses,
and longevity. Expression of the genePla2g7encoding platelet activating factor acetyl hydrolase (PLA2G7)
is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy,
protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved
metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and
could potentially be harnessed to lower inflammation and extend the health span.T
he beneficial effects of caloric restriction
(CR) include enhanced longevity and re-
duced disease burden ( 1 ). However, 40%
reduction of calories from a normal ad
libitum state in many rodent studies show-
ing life-span extension is associated with in-
creased severity of viral and parasitic infections
( 2 , 3 ), including mortality from polymicrobial
sepsis ( 4 ). Impaired immunity may result be-
cause energetically expensive functions are dis-
pensed with severe CR as energy resources are
diverted toward somatic cell maintenance ( 5 , 6 ).In addition to host defense, the resident im-
mune system in every organ is required for in-
tegration of cellular metabolism, tissue repair,
and function. Thus immunological trade-offs
may make it difficult to identify clinically rele-
vant beneficial CR mimetics ( 7 ). Furthermore,
forced extreme CR in nonconsenting animals
may elicit stress responses evidenced by in-
creased production of glucocorticoids ( 5 , 8 ),
which can further compromise the immune sys-
tem by causing thymocyte death and thymic in-
volution ( 9 ). To address the relevance of CR on
human physiology, the Comprehensive Assess-
ment of Long-term Effects of Reducing Intake of
Energy (CALERIE) clinical trial was designed to
test the long-term effects of 2 years of moderate
CR on physiology, aging biomarkers, and pre-
dictors of health span and longevity in healthy
volunteers ( 10 ). The energy intake at baseline
(ad libitum state) was evaluated by two con-
secutive 14-day measures of total daily energy
expenditure (TDEE) using doubly labeled water
( 11 ). Average %CR over 6-month intervals was
retrospectively calculated using the intake-
balance method, which involves simultaneousSCIENCEscience.org 11 FEBRUARY 2022¥VOL 375 ISSUE 6581 671
(^1) Department of Pathology, Yale School of Medicine,
New Haven, CT, USA.^2 Department of Immunobiology, Yale
School of Medicine, New Haven, CT, USA.^3 Department of
Comparative Medicine, Yale School of Medicine, New Haven,
CT, USA.^4 Department of Pathology and Immunology,
Washington University School of Medicine, St. Louis, MO,
USA.^5 Translational Research Institute for Metabolism and
Diabetes, AdventHealth, Orlando, FL, USA.^6 Pennington
Biomedical Research Center, LSU, Baton Rouge, LA, USA. 7
Department of Radiology, Michigan Medicine, University of
Michigan, Ann Arbor, MI, USA.^8 Yale Center for Molecular
and Systems Metabolism, Yale School of Medicine, New
Haven, CT, USA.^9 Yale Center for Research on Aging, Yale
School of Medicine, New Haven, CT, USA.
*Corresponding author. Email: [email protected]
RESEARCH | REPORTS