Effect of Long-Term Caloric Restriction on Epigenetic Proxies of Inflammaging - CALERIE™ 2 Trial Analysis

Sep 29, 2026

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Inflammaging, the age-linked rise in systemic inflammation, is a key target for epigenetic proxies derived via machine learning, such as InflammAge and InflClock. Concerns persist about whether these measures reflect true change beyond age-related immune cell redistribution and whether they respond to gero-protective interventions. This analysis implements a panel of inflammatory epi-scores within the CALERIE™ trial to test longitudinal concordance with serum inflammation and oxidative stress markers and immune-cell distributions. Mixed-effect modeling evaluates intervention effects; results show modest or non-significant effect sizes despite improved sensitivity from deconvolution references.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages1

Reading Time3 min

AccessFree to download

Background

Methods

Results

Conclusions

1118 Innovation in Aging, 2025, Vol. 9, No. S2 Abstract citation ID: igaf122.3753 EFFECT OF LONG-TERM CALORIC RESTRICTION ON EPIGENETIC PROXIES OF INFLAMMAGING: CALERIE™ 2 TRIAL ANALYSIS Waylon Hastings, Texas A&M University, College Station, Texas, United States Background: Inflammaging, the age-related increase in systemic inflammation, has received particular attention as a target for epigenetic proxies derived using machine learning approaches. Examples include InflammAge, a translational epigenetic biomarker derived from 120+ distinct epi-scores representing various inflammatory biomarkers and/or diseases, and InflClock, a measure developed to predict differences between healthy aging volunteers and patients with chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. Initial reports support the ability of these proxies to distinguish inflammaging phenotypes, but concerns remain about whether such measures capture meaningful change above and beyond age-related redistribution of immune cell populations. Moreover, their responsiveness to gero-protective interventions also remains untested. Methods: To address this gap, we are implementing a panel (n=130) of inflammatory-related epi-scores in the CALERIE™ clinical trial (n=594), including three proxies assessing global inflammaging. The overarching goal of this research proposal is to assess longitudinal concordance between epi-scores and serum biomarkers of inflammation (e.g., CRP, IL-6,TNFa), oxidative stress (e.g., isoprostanes), and immune cell distributions. Further, we leverage mixed-effect modeling to test treatment effects of the CALERIE™ intervention on these epigenetic proxies for inflammaging. Results: Preliminary analyses support associations between epigenetic proxies and some, but not all inflammatory biomarkers, and nearly all measures are associated with complete blood count differentials. Although de-noising epigenetic proxies using DNA-methylation deconvolution references increases their measurement sensitivity, intervention effect sizes remained modest to insignificant. Conclusions: Although epigenetic proxies are gaining momentum as surrogate endpoints, additional methodological refinement is necessary to achieve the rigor necessary for clinical translation.

FAQs

What is the main objective of the CALERIE™ 2 trial analysis?

Assess longitudinal concordance between epigenetic (inflammatory) epi-scores and serum biomarkers of inflammation and oxidative stress, alongside immune cell distributions, while testing treatment effects over time.

Which biomarkers and measures are used to validate the epigenetic proxies?

Serum inflammation markers (e.g., CRP, IL-6, TNFα), oxidative stress markers (e.g., isoprostanes), and immune cell distribution data are used to evaluate concordance with the epi-scores.

What do the preliminary results indicate about the strength of associations and intervention effects?

Epi-proxies show associations with some inflammatory biomarkers and nearly all complete blood count differential measures. De-noising via DNA-methylation deconvolution improves sensitivity, but intervention effect sizes remain modest to insignificant.

Sep 29, 2026

Upload by Jasmine