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Cited by 10Genetics, Aging, and Longevity in Model OrganismsComplement system in diseasesAdipokines, Inflammation, and Metabolic Diseases

Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging

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Mishra, Manish, Kim, Hee-Hoon, Youm, Yun-Hee, Gonzalez-Hurtado, Elsie, Zaitsev, Konstantin, Dlugos, Tamara, Shchukina, Irina, Gliniak, Christy +6 more·2026·Nature Aging
DOI 10.1038/s43587-026-01107-0PMC PMC13190345

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Abstract

Abstract Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.

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  • 238 metabolically healthy adults (BMI 22.0-27.9 kg/m2, age 25-45) were enrolled in CALERIE Phase 2 and randomized to a 25% calorie restriction intervention versus an ad-libitum control group.

    “238 metabolically healthy adults (BMI: 22.0– 27.9 kg/m2, Age: 25–45) were enrolled in the study from Pennington Biomedical Research Center (PBRC, Baton Rouge, LA), Washington University (St. Louis, MO) and Tufts University (Boston, MA) (NCT00427193)”

    From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [67]

    Methods > Human participants identifies CALERIE-II as a multicenter randomized trial involving healthy, non-obese adults. Results > CR rewires the directionality of the human exoproteome toward longevity pathways identifies a Pennington cohort, but the paper describes 42 participants in its proteomics analysis, not the claimed 238 enrollees. Our copy does not substantiate the exact BMI and age ranges, the Washington University and Tufts sites, or a 25% restriction assignment; it reports 14% calorie restriction after two years. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • CALERIE Phase 2 is a multi-center, parallel-group, randomized controlled trial recruiting non-obese healthy individuals.

    “CALERIE Phase 2 is a multi-center, parallel group, randomized controlled trial recruiting non-obese healthy individuals.”

    From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [67]

    The Methods section (“Human participants”; page not specified) describes CALERIE-II as a multicenter randomized controlled trial and identifies its sampled participants as non-obese and healthy. It does not specify a parallel-group design, so that part of the claim is not verified by our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • CALERIE Phase 2 calorie restriction group participants accomplished 14% of the intended calorie restriction.

    “CR group participants accomplished 14% of CR.”

    From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [67]

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Authors
Mishra, M., Kim, H.-H., Youm, Y.-H., Gonzalez-Hurtado, E., Zaitsev, K., Dlugos, T., Shchukina, I., Gliniak, C., Ravussin, E., Mohanty, S., Shaw, A. C., Scherer, P. E., Artyomov, M. N., & Dixit, V. D.
Affiliations
  • Yale University (US)
  • ITMO University (RU)
  • Washington University in St. Louis (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Dixit, Vishwa Deep
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2026-04-13
Volume
6
Issue
5
Pages
1064-1078
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-026-01107-0
PMC
PMC13190345
OpenAlex
W4413017146
Cited by
10
References
13
Citations by year
2026: 10
FWCI
16.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Aging (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion)
Funders
  • Cure Alzheimer's Fund
  • National Institutes of Health
  • National Institute on Aging (R01AG045712, R01AG031797, P01AG051459)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070811)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
caloric restriction, exoproteome, complement system, C3a, inflammaging, healthspan, immunometabolism, ERK signaling, FGF21, PLA2G7, aging, lifespan extension, plasma proteomics

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