Calorie restriction improves biological aging markers Original paper

Calorie restriction (CR), defined as eating a diet that contains approximately 25% fewer calories than normal, is one of the most reliable methods of extending lifespan and slowing aging in animals. Can CR also affect the rate of aging in humans?

In this randomized controlled trial called the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE), 220 men and women (average age of 38, normal weight or slightly overweight BMI) were prescribed a 25% reduction in calorie intake or a nonrestricted diet for 2 years.

The 25% CR was based on each participant’s individual energy requirements, which were estimated at the beginning of the study.

The primary study outcomes were biological age and the rate of biological aging, which were estimated using three different biological aging clocks: PhenoAge, GrimAge, and DunedinPACE. Biological aging measures were assessed at baseline, 12 months, and 24 months.

CR reduced the pace of biological aging by 2%–3%, as measured using DunedinPACE. Biological age measured using PhenoAge and GrimAge was not affected by CR.

There have been multiple studies published from the CALERIE trial in which CR has been reported to reduce cholesterol, systolic and diastolic blood pressure, inflammation, and metabolic syndrome score and increase insulin sensitivity.^[1] Furthermore, CR resulted in an average weight loss of 7.5 kg, reductions in waist circumference, and a preferential loss of visceral adipose tissue.^[2][3] Thus, CR can improve risk factors for cardiometabolic disease, even in a cohort of normal weight to slightly overweight, yet otherwise healthy, middle-aged adults. These measurable changes in health outcomes are important to complement and validate the changes in measures of biological aging reported in the current study. It’s another question entirely whether the health improvements actually translate to reduced morbidity and mortality — outcomes that take much longer to assess and won’t be realized for decades.

The “geroscience hypothesis” is the idea that interventions that slow or reverse molecular changes (i.e., DNA methylation) can delay or prevent the incidence of disease of aging and extend healthspan and lifespan. CR has been at the forefront of investigations into the geroscience hypothesis, yet unfortunately, most studies to date have been conducted in animal models. This is why CALERIE is such an important step for longevity research. It’s the first study to rigorously investigate long-term CR in humans.

Based on the DunedinPACE clock, participants assigned to CR reduced their rate of biological aging at 12 months, a pattern that continued through 24 months. In other words, CR participants were aging slower than their peers who were eating freely. The 2%–3% decline in the rate of aging is suggested by the authors to correspond to as much as a 10%–15% reduction in mortality risk.

One of the main limitations of CALERIE was that participants assigned to CR didn’t achieve the prescribed 25% reduction in calories over the course of the 2-year intervention. The average reduction of approximately 11.9% was less than half of the original goal and corresponds to about a 180 calorie per day reduction, or about 2 tablespoons of peanut butter.

For this reason, the authors ran two additional analyses on the data. One of these involved separating participants into those who achieved more than a 10% reduction in calories and those who achieved less than a 10% reduction. This dose–response analysis revealed that the pace of biological aging (DunedinPACE) slowed more in participants who achieved a greater level of CR, with no effect on the other measures of biological age.

Effects of 2-year calorie restriction on biological age and the pace of aging

The second analysis was called a effect of treatment-on-the-treated (TOT) analysis, in which the expected effects of achieving a 20% reduction in calories was investigated. In other words, what might have happened if participants had achieved 20% CR? The effect size for DunedinPACE in the TOT analysis was 0.4, higher than the 0.25 from the original analysis. The other two measures of biological age were not affected by CR in this analysis either.

Despite not achieving 25% CR, participants still experienced several health-related improvements (mentioned above) and a slowing of biological age. That’s promising and suggests that CR interventions need not be so “extreme” to benefit health — even a modest reduction in calories will do. However, the failure of many participants to meet the CR goal underscores one of the downfalls of CR as a potential longevity intervention. Specifically, adherence and sustainability may be difficult. CALERIE was only a 2-year study, and even then, the participants’ ability to restrict calories waned at 12 months and continued to decline at 24 months. Had the study been extended, it’s not clear whether any level of CR would have been maintained. Longer-term studies, if possible, will be needed to determine the feasibility of sustaining CR over years to decades.