Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

Authors: WAXIRY, REEM - Columbia University; RYAN, CALEN - Columbia University; CORCORAN, DAVID - University Of North Carolina; HUFFMAN, KIM - Duke University; KOBOR, MICHAEL - University Of British Columbia; KOTHARI, MEERAJ - Columbia University; GRAF, GLORIA - Columbia University; KRAUS, VIRGINIA - Duke University; KRAUS, WILLIAM - Duke University; LIN, DAVID - University Of British Columbia; PIEPER, CARL - Duke University; RAMAKER, MEGAN - Duke University; BHAPKAR, MANJUSHRI - Duke University; DAS, SAI KRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FERRUCCI, LUIGI - National Institute On Aging (NIA, NIH); HASTINGS, WAYLON - Pennsylvania State University; KEBBE, MARYAM - Pennington Biomedical Research Center; PARKER, DANIEL - Duke University; RACETTE, SUSAN - Washington University School Of Medicine; SHALEY, IDAN - Pennsylvania State University; SCHILLING, BIRGIT - Buck Institute For Age Research; BELSKY, DANIEL - University Of North Carolina

Submitted to: Nature Aging
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/22/2022
Publication Date: 3/1/2023
Citation: Waxiry, R., Ryan, C.P., Corcoran, D.L., Huffman, K.M., Kobor, M.S., Kothari, M., Graf, G.H., Kraus, V.B., Kraus, W.E., Lin, D.S., Pieper, C.F., Ramaker, M.E., Bhapkar, M., Das, S., Ferrucci, L., Hastings, W.J., Kebbe, M., Parker, D., Racette, S.B., Shaley, I., Schilling, B., Belsky, D.W. 2023. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging. https://doi.org/10.1038/s43587-022-00357-y.
DOI: https://doi.org/10.1038/s43587-022-00357-y

Interpretive Summary: In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy trial (CALERIE), 220 healthy men and women were randomly assigned to consume a calorie restriction (CR) diet or normal diet for two years. We measured the biological aging of participants by analyzing chemical tags called methylation marks on DNA and calculated their epigenetic clocks. These clocks predict how biologically old a person is or how fast they are aging. To test if CR diets slow biological aging, we compared epigenetic clock values for CALERIE participants at baseline with those at 12 and 24 months. We found that the CR diet slowed the rate of aging by about 2 to 3 percent, as measured by one epigenetic clock called the DunedinPACE DNA methylation algorithm. Previously published studies predict that by reducing the rate of aging by this percent, mortality risk also falls by about 10 to 15 percent.

Technical Abstract: 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 2yr. 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.