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Modestly Increased Incidence of Ketosis in Caloric Restriction Does not Significantly Alter the Effects of Caloric Restriction



Caloric restriction (CR) has been shown to slow the aging processes in a number of preclinical studies and reduces expression of aging-associated biomarkers in human trials. We hypothesized that CR would lead to increased incidence of ketosis and that ketosis in CR individuals would alter the aging-protective effects of CR or biomarkers thereof.


We analyzed data from the “Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE, Phase 2)” Public Use Database available at In this study, non-obese adults between the ages of 21 and 50 were randomized to 25% CR or control (ad lib) diet groups and extensively monitored for two years. Given our focus on the effect of caloric restriction on ketosis, individuals with detectible ketones during the baseline visit (pre-randomization) and those with missing data for ketone testing were excluded from the analysis, leaving 71 control and 117 CR participants.


We analyzed the incidence of ketosis as well as ketosis free survival in control and CR participants and assessed the effect of ketosis on a number of clinical lab values, functional assessments, and participant survey data related to aging biology.


We report that CR was associated with modestly increased incidence of ketosis (4.4% in CR vs 1.9% in control), though CR-associated changes in T3, VO2, SUMPT-WT (weight normalized composite strength score — peak torque), physical functioning, and general health did not appear to be altered by the presence or absence of ketosis. Additional observations of interest include: 1) striking patterns of biomarker expression changes (MCP-1, TNFα, TGF-β1, GH) in both the control and CR participants between the baseline visit and the 24-month post-randomization visit and 2) pro-growth/anti-inflammatory baseline (pre-randomization) biomarker expression profile in CR individuals that later test ketone positive relative to other CR individuals.


CR modestly increases the incidence of ketosis in healthy adults, yet the increase in ketosis in CR patients did not significantly affect the aging-protective effects of CR. However, given the relatively small number of participants who were ketone positive, further investigation in larger study cohorts is still required for definitive conclusions.

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MS was supported by NIH AG056848, AHA 857280 and a local CCTS Voucher from CTSA RUL1TR02733 to fund biostatistics analysis by the OSU Center for Biostatistics. USDA NIFA Hatch-NEV00727, NEV00767, the Dennis Meiss & Janet Ralston Fund for Nutri-epigenetic Research, NIH P20 GM130459 and R15 HL143496, and NSF EPSCOR Track II (OIA-1826801) supported BSF.

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Correspondence to Matthew S. Stratton.

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Supplemental Table 1.

Statistical testing of select CALERIE endpoints.

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Ferguson, B.S., Sahoo, P., McGrail, E. et al. Modestly Increased Incidence of Ketosis in Caloric Restriction Does not Significantly Alter the Effects of Caloric Restriction. J Nutr Health Aging 26, 657–662 (2022).

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Key words

  • Caloric restriction
  • ketosis
  • CALERIE phase 2