Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis

Belsky DW*, Huffman K, Pieper C, Shalev I, Kraus W. Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis. Journals of Gerontology A: Biological Sciences, glx096, Published online May 22, 2017.



ABSTRACT. Biological aging measures have been proposed as proxies for extension of healthy life span in trials of geroprotective therapies that aim to slow aging. Several methods to measure biological aging show promise but it is not known if these methods are sensitive to changes caused by geroprotective therapy. We conducted analysis of two proposed methods to quantify biological aging using data from a recently concluded trial of an established geroprotector, caloric restriction. We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank ( The CALERIE trial randomized N = 220 nonobese adults to 25% caloric restriction (n = 145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n = 75) for 2 years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera–Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans.

SUMMARY. We conducted intent-to-treat analysis of the CALERIE randomized trial to test if caloric restriction slowed biological aging over the course of a 2-year intervention. Tests using two different methods to quantify biological aging (Klemera–Doubal method Biological Age and homeostatic dysregulation) produced a consistent result: participants in the caloric-restriction arm of the trial experienced slowed biological aging as compared to participants in the ad libitum arm. Sensitivity analysis showed that slowed biological aging in the caloric restriction arm of the trial was not accounted for by weight loss during the intervention phase.

TAKE HOME MESSAGE. The main contribution of this study is to provide initial evidence that methods to quantify biological aging are sensitive enough to detect effects of geroprotective therapy delivered to middle-aged adults in a small randomized trial. This evidence adds to findings from observational studies that accelerated biological aging measured using the same methods predicts functional decline, morbidity, and mortality in older adults (manuscript refs 10,11,14,15,37,40). Together, this evidence argues for using methods to quantify biological aging as outcomes in trials of geroprotective therapies. For example, it is thought that pharmacotherapy may be able to replicate the geroprotective effects of caloric restriction (e.g. see manuscript ref 45). Methods for assessing biological aging used in this study provide benchmarks against which such pharmacotherapy might be evaluated.

FIGURE 1. CALERIE participants’ KDM Biological Ages were highly correlated with their chronological ages at the time of baseline assessment but tended to be slightly younger. The plotted line shows a one-to-one correspondence between biological age and chronological age. The larger number of plotted points below the line as compared to above the line indicates that CALERIE participants’ KDM Biological Ages tended to be slightly younger than their chronological ages. 


Figure 2. Change in KDM Biological Age from Baseline to 12- and 24-month follow-ups in the ad libitum (black dots) and caloric-restriction (blue dots) arms of the CALERIE trial. Panel A shows mean values with 95% confidence intervals calculated for each follow-up. Panel B shows slopes estimated from the growth model with the shaded areas indicating 95% confidence intervals. 

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