DNA methylation data shows calorie restriction slows pace of ageing

The CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trial tested the effects of a 25% calorie-restricted diet over two years at the molecular level – where ageing processes originate. The researchers did this by measuring biological ageing from blood DNA using algorithms designed to capture the molecular changes that underlie the progressive decline in system integrity that occurs with advancing age.

Explaining the background to the study, Daniel Belsky, associate professor of epidemiology at Columbia Mailman School and scientist with Columbia’s Butler Aging Center, told this publication: “Our prior work on the CALERIE trial showed evidence of improved cardiometabolic health and slowed ageing at the organ-system level. Combined with the evidence from laboratory animals that caloric restriction modifies biological hallmarks of ageing, this evidence motivated our hypothesis that CALERIE intervention would slow the pace of ageing.”

An international team of researchers led by the Butler Aging Center at the Columbia University Mailman School of Public Health tested this hypothesis in a sample of 220 healthy adults.

Study design

Participants in the randomised controlled trial were assigned to either a normal (control) diet or a 25% calorie-restricted (intervention) diet. To measure biological ageing, the research team analysed blood samples collected from trial participants at pre-intervention baseline and after 12 and 24 months of follow-up.

They used methylation marks on DNA extracted from white blood cells to measure the pace and advancement of ageing over the duration of the study. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with ageing.

The researchers used three algorithms to analyse the DNA methylation data. The DunedinPACE DNAm algorithm estimates the pace of ageing, or the rate of biological deterioration over time, whereas the older PhenoAge and GrimAge clocks estimate the biological age.

Results: 2-3% slower pace of ageing

The team found that the intervention slowed the pace of ageing by between 2-3%, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by the PhenoAge and GrimAge clocks.

The researchers attributed this apparent discrepancy to the fact these algorithms were developed using different methods and reflect different models of ageing.

“The PhenoAge and GrimAge clocks were developed to predict mortality risk at a single time point in mixed-age and older adults. This approach quantifies ageing as a static construct of risk accumulated across the lifetime. In contrast, DunedinPACE was developed to predict multi-system physiological decline over two decades of follow-up from early adulthood to midlife. This approach quantifies ageing as a dynamic construct reflecting change in risk accumulation,” wrote the researchers in the journal Nature Aging.

They said that DunedinPACE may therefore be more sensitive to changes induced by two years of calorie restriction.

The scientific community responds…

There have been several reactions to the study from the academic community. Professor Neil Mabbott, personal chair in immunopathology at The Roslin Institute, University of Edinburgh, said: “Although a reduction in calorie intake appeared to have reduced the pace of ageing, it is important to note that this did not translate to an increase in estimated lifespan.”

In response to this comment, Belsky told Vitafoods Insights: “Because we only had access to data collected during the two years of intervention, we were unable to examine long-term impacts, for example, on survival. However, the magnitude of reduction in DunedinPACE is consistent with reduced mortality risk. Ultimately, impact of the intervention on lifespan will depend on whether the effects we observe during the intervention persist over the long term.”

The researchers cited previous studies that suggested that a 2-3% slower pace of ageing corresponded to a reduction in mortality risk of as much as 10-15%, similar in magnitude to the effect of giving up smoking. They also said that in previous observational studies with long-term follow-up, slower DunedinPACE was associated with reduced risk for heart disease, stroke, disability, and dementia.

Follow-up to track long-term health impacts

The team confirmed that a follow-up of trial participants was ongoing to determine whether the slower pace of ageing induced by calorie restriction translated into long-term effects on healthy ageing.

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Another academic, Naveed Sattar, professor of metabolic medicine at the University of Glasgow, questioned the need to carry out more studies to show that eating fewer calories leads to a longer lifespan, saying that this should be evident from national datasets from Japan.

However, Belsky argued that observational data and evidence from randomised controlled trials are complementary sources of evidence.

“The specific contribution of our analysis of data from CALERIE was new evidence that calorie restriction may slow the pace of biological ageing,” he said.

CALERIE and beyond

In addition to the follow-up, Belsky said the team’s ongoing work on the CALERIE trial was focused on understanding whether biological pathways modified by calorie restriction in laboratory animals were also modified by calorie restriction in humans.

And outside of the CALERIE trial, Belsky confirmed that he was working on developing and validating novel ageing biomarkers and exploring other ways to modify the pace of ageing.