Calorie restriction reduces biomarkers of cellular senescence in humans

Authors: AVERSA, ZAIRA - Mayo Clinic; WHITE, THOMAS - Mayo Clinic; HEEREN, AMANDA - Mayo Clinic; HULSHIZER, CASSONDRA - Mayo Clinic; SAUL, DOMINIK - Mayo Clinic; ZHANG, XU - Mayo Clinic; MOLINA, ANTHONY - University Of California; REDMAN, LEANNE - Pennington Biomedical Research Center; MARTIN, CORBY - Pennington Biomedical Research Center; RACETTE, S - Washington University School Of Medicine; HUFFMAN, K - Duke University; BHAPKAR, M - Duke University; KHOSLA, SUNDEEP - Mayo Clinic; DAS, SAI KRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FIELDING, ROGER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ATKINSON, ELIZABETH - Mayo Clinic; LEBRASSEUR, NATHAN - Mayo Clinic

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/2023
Publication Date: 11/15/2023
Citation: Aversa, Z., White, T.A., Heeren, A.A., Hulshizer, C.A., Saul, D., Zhang, X., Molina, A.J., Redman, L.M., Martin, C.K., Racette, S.B., Huffman, K.M., Bhapkar, M., Khosla, S., Das, S., Fielding, R.A., Atkinson, E.J., LeBrasseur, N.K. 2023. Calorie restriction reduces biomarkers of cellular senescence in humans. Aging Cell. https://doi.org/10.1111/acel.14038.
DOI: https://doi.org/10.1111/acel.14038

Interpretive Summary: Senescent cells can build up in the body and release harmful biological products that speed up aging. Current research supports calorie restriction as a possible way to slow the speed of aging, but its effects on these specific types of cells are not fully understood. Using measurements obtained from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIETM), calorie restricted participants had significantly lower levels of harmful biological products from senescent cells compared to participants who were not restricting calorie intake. These lower levels of senescence products were also significantly associated with improved insulin sensitivity and reduced insulin resistance, among other beneficial biological effects.

Technical Abstract: Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young to middle aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging-related conditions. Using plasma specimens from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIETM) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA-IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA-sequencing data from a subset of participants, we observed a significant reduction in a senescence-focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.