Epigenetic Clock Data from the CALERIE Trial of Calorie Restriction
The practice of calorie restriction extends life notably in short-lived mammals, but not in long-lived mammals, despite the short-term benefits to health appearing quite similar in mice and humans. This may be because many of the beneficial shifts in metabolism triggered by a low calorie intake are already built in to long-lived species, as a part of the history of evolutionary change that led to those species becoming long-lived. Since calorie restriction alters near every aspect of cellular biochemistry, coming up with a comprehensive understanding of the important mechanisms has been a slow process, never mind how those differences might then generate the large variation in effects on life span across species.
In today's open access paper, researchers apply epigenetic clocks to samples from a noted human study of calorie restriction that was conducted a while back. The clocks show little to no effect on biological age, but do suggest improvement in health that is on a par with the better lifestyle choices, such as choosing not to smoke or avoiding obesity. In the short term calorie restriction does indeed produce significant improvement in a range of markers of health related to inflammation, cardiovascular risk, and so forth. It is interesting that the presently favored epigenetic clocks are largely insensitive to this intervention.
Calorie restriction slows pace of aging in healthy adults
The CALERIE Phase-2 randomized controlled trial, funded by the US National Institute on Aging, is the first ever investigation of the effects of long-term calorie restriction in healthy, non-obese humans. The trial randomized 220 healthy men and women at three sites in the US to a 25 percent calorie-restriction or normal diet for two years. To measure biological aging in CALERIE Trial participants, the team analyzed blood samples collected from trial participants at pre-intervention baseline and after 12- and 24-months of follow-up. The team analyzed methylation marks on DNA extracted from white blood cells. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with aging.
In the primary analysis researchers focused on three measurements of the DNA methylation data, sometimes known as epigenetic clocks. The first two, the PhenoAge and GrimAge clocks, estimate biological age. The third measure studied by the researchers was DunedinPACE, which estimates the pace of aging, or the rate of biological deterioration over time. "In contrast to the results for DunedinPace, there were no effects of intervention on other epigenetic clocks. The difference in results suggests that dynamic 'pace of aging' measures like DunedinPACE may be more sensitive to the effects of intervention than measures of static biological age." The intervention effect on DunedinPACE represented a 2-3 percent slowing in the pace of aging, which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention.
The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm), and is established to increase healthy lifespan in multiple species. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 years.
We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies, and contrasting with reports that biological aging may not be modifiable. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality.