Long-term caloric restriction has a modest effect on DNA methylation measures of aging pace

In a recent letter published in natural aginginvestigators evaluated the impact of caloric restriction (CR) on biological aging in a comprehensive assessment of the long-term effects of reducing randomized controlled trial participants in energy intake (CALERIE). bottom.

Background

Several treatments have been identified that increase biological aging in humans. Interventional trials take months to years for clinical translation, whereas it takes years to decades for age-related processes to cause disease. Measures that can recapitulate changes in biological pathways with aging can overcome this challenge. Biological age quantification tools that can estimate future illness, morbidity, and mortality and detect age-related short-term changes can be used as surrogate endpoints for interventional trials on aging.

According to the geroscience hypothesis, therapeutics that can slow or reverse age-related molecular changes may prevent or delay the onset of chronic diseases and extend lifespan. Caloric restriction by reducing caloric intake without altering intake of key nutrients may alter age-associated molecular changes such as deoxyribonucleic acid (DNA) methylation (DNAm) and thus extend lifespan. there is.

About trial

In this study, researchers reported the results of the CALERIE trial. This study was conducted in healthy adults with a BMI less than 27.90 kg m to assess the effect of restricting calorie intake by 25.0% in her 2-year he.⁻²consisting of men aged 21–50 years and premenopausal women aged 21–47 years).

The CALERIE trial, conducted at three US clinical centers, provided a therapy known to slow aging in animals.The trial consisted of 220 nonobese adults randomized in a 2:1 ratio to receive a 25.0% calorie-restricted diet (intervention) and option Diet (control) diet for 2 years.

CR levels were quantified based on energy requirements (determined semi-annually based on a 2-week double-labeled water (DLW) period). Blood DNAm analysis information was obtained from 197 individuals, of whom 128 and 69 were on the CR and control diets, respectively. DNA methylation assays were performed using blood samples from CALERIE randomized controlled clinical trial participants and data were integrated with secondary information from clinical trials.

Biological aging was measured based on changes in blood DNA methylation using a previously published algorithm based on the molecular changes underlying age-related gradual loss of system integration. His DNAm clocks of the first generation, such as the Horvath clock and the Hannum clock, were used to compare samples of individuals of different ages.

Intent-to-treat (ITT) analyzes have improved the quantification of aging by emphasizing differences in mortality risk rather than age-related differences with second-generation DNA methylation clocks such as GrimAge and PhenoAge. , was performed using a 3rd generation DunedinPACE clock for measurements. Measure the rate of aging using the repeated measures analysis of covariance (ANCOVA) method.

A DNAm PC/PC clock was used to assess test-retest reliability. Follow-up assessments of dose-response and post-treatment (TOT) effects were performed at 1 and 2 years after the intervention. The TOT effect was assessed using an instrumental variable (IV) approach. The study participant also underwent her weekly individual and intensive group behavioral counseling sessions. Sensitivity analyzes evaluated changes in white blood cell counts with CALERIE therapy and gender differences in treatment effects. The extent of weight loss was compared to an estimated weight loss trajectory of 16% weight loss within 1 year with subsequent maintenance.

result

The average age of study participants was 38.0 years, 77.0% were Caucasian, and 70.0% were female. The method proposed to quantify biological aging used in this study was able to estimate age-related health deterioration and mortality. Although the CALERIE intervention slowed aging as determined using the DunedinPACE DNA methylation clock, no significant age-related changes were observed as measured using the PhenoAge and GrimAge clocks. The therapeutic effect was small. However, the small delay in aging observed could have significant public health implications.

CR treatment lowered participants’ DunedinPACE within one year, and the effect was maintained for more than two years. No dose-response effects were observed when using the Grimage and PhenoAge clocks. However, individuals who achieved greater CR experienced more severe DunedinPACE declines. A sensitivity analysis yielded similar results. DunedinPACE showed high test-retest reliability in validation studies and showed strong correlations with aging endpoints.

Most CALERIE trial participants failed to achieve the prescribed 25% calorie restriction. Despite incomplete adherence, participants in the treatment group showed significant weight loss and concomitant changes in body composition, improved cardiovascular health, and delayed age-related physiological changes. .

Conclusion

Overall, the results of this study indicated that the CALERIE trial intervention slowed the aging process as determined by the DunedinPACE clock, whereas the GrimAge and PhenoAge DNA methylation clocks were not significantly affected by CR. .

This finding supports the geroscience hypothesis and highlights that DunedinPACE is a reliable aging measurement for further clinical trials. However, long-term follow-up evaluations are needed to investigate whether the reduction of DunedinPACE by CR leads to longer life and prevention of disease.