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

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 (https://calerie.duke.edu/). 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.

Quantification of the pace of biological aging in humans through a blood test: The DunedinPoAm DNA methylation algorithm

“…Finally, to ascertain the potential usefulness of mPoA as a measure for trials of anti-aging treatments, we applied the algorithm to DNA methylation data from a randomized trial of caloric restriction, CALERIE . Earlier we reported from this trial that Belsky mPoA 12-30-19 7 the intervention (two years of prescribed 25% caloric restriction) slowed the rate of biological aging as measured by a blood-chemistry biological-age composite measure (Belsky et al, 2017b). Here, using newly generated methylation data from blood drawn at the CALERIE baseline assessment, we tested if (a) mPoA from blood drawn before caloric restriction could predict the future rate of biological aging of participants during the two-year trial, and (b) if this prediction was modified in participants who underwent caloric restriction, but not among control participants.…”

Cardiac changes associated with vascular aging

“…It has long been established in animal models that caloric restriction extends longevity and may attenuate CV aging changes . Data from the Comprehensive Assessment of Long‐Term Effects of Reducing Intake of Energy (CALERIE) study indicates that 2 years of moderate caloric restriction in healthy, nonobese adults 21‐50 years old reduces the rate of biologic aging, including lowering blood pressure, increasing insulin sensitivity, and improving lipid profiles . Whether caloric restriction is similarly effective at older ages remains unproven but worthy of future evaluation.…”

“…Mutated wild-type transthyretin protein has been detected in up to 25% of heart autopsies in older adults. 42 47,48 Whether caloric restriction is similarly effective at older ages remains unproven but worthy of future evaluation. At a cellular level, caloric restriction increases phosphorylation and activation of AMP-activated protein kinase (AMPK) which in turn triggers autophagia, an intrinsic process of cellular regeneration, which is known to be cardioprotective against myonecrosis via ischemic preconditioning.…”

Parsing metabolic heterogeneity in mood disorders: A hypothesis‐driven cluster analysis of glucose and insulin abnormalities

“…Data were derived from completed clinical trials conducted by the same group of investigators (RBM, EB and RSM) [13][14][15][16][17][18][19][20][21] or the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) [22][23][24][25][26][27] (Table 1). The clinical cohorts (studies 1-7) were comprised of individuals with MDD or BD, in a depressive episode or euthymic, recruited for clinical trials or observational studies.…”