New research in Aging Cell has identified senescence-associated biomarkers whose levels are altered by caloric restriction in humans [1].
Slowing down senescence with fewer calories
Multiple animal studies have found that reducing caloric intake without causing malnutrition (caloric restriction) has great lifespan-extending potential and can delay the onset of several age-related diseases [2]. These studies suggest that caloric restriction can delay the Hallmarks of Aging.[3], one of which is cellular senescence.
While the influence of caloric restriction on cellular senescence has been broadly studied in animals, the effect of caloric restriction on cellular senescence in humans is less explored. This is why the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study was conducted. It was a 2-year long randomized controlled trial for assessing the influence of caloric restriction on healthy, non-obese, young to middle-aged volunteers [4].
So far, CALERIE is the most rigorous study that has been conducted in this area. Its participants were able to obtain ~12% caloric restriction.
Senescence markers and metabolic changes
The authors investigated clinical data and plasma samples of 199 CALERIE participants, 128 of which practiced caloric restriction and 71 of which ate normally.
The researchers investigated 28 candidate senescence biomarkers, which included cytokines, chemokines, matrix remodeling proteins, and growth factors. They were carefully selected based on scientific literature, senescence model screens, and appearing in human blood “in contexts associated with increased senescent cell burden” [5,6,7].
They compared the levels of the biomarkers at baseline, 12 months, and 24 months. After 12 months of caloric restriction, the researchers observed a reduction in nine senescence biomarkers. Four of those were still reduced following 24 months of caloric restriction, joined by reduced levels of two more.
Only one biomarker, sclerostin (SOST), was increased after 12 months. SOST negatively regulates bone formation, which might suggest changes in bone metabolism [8].
After 24 months, only one biomarker was increased, but this time it was the receptor for advanced glycation end-products (RAGE), a protein implicated in DNA repair.
Researchers then used the obtained data regarding changes in these senescence biomarkers to assess whether these changes are associated with the changes in the metabolic measurements in study participants who followed caloric restriction.
Those metabolic measurements included homeostatic model assessment of insulin resistance (HOMA-IR), insulin sensitivity index, and resting metabolic rate (RMR) residual. RMR is the amount of energy the body uses when it is in the resting state. RMR residual is the difference between a person’s actual RMR and the RMR predicted based on that person’s fat mass and lean mass.
Senescence is linked to metabolism
The researchers identified that changes in several senescence biomarkers played a role as predictors of changes in metabolism. Baseline measurements of HOMA-IR, insulin sensitivity index, and RMR residual were good predictors of where these biomarkers would be in 12 and 24 months. Incorporating five key senescence-related biomarkers into the model led to a great improvement in its ability to predict all three metabolic measurements after a year. However, this is only an association, and the authors could not conclude if those changes are causally connected or only parallel observations.
The researchers also analyzed a “recently defined gene set of 125 secreted factors, transmembrane proteins, and intracellular proteins centered on cellular senescence and the SASP, named SenMayo” [9]. Gene expression data was derived from the adipose tissue of eight study participants at baseline, 12 months, and 24 months. The authors observed a reduced SenMayo response following caloric restriction.
Overall, this study adds another layer of evidence that dietary interventions can counter biological aging.
High-quality data with some weaknesses
While this study’s strength is the high-quality and rigorously obtained data from the CALERIE clinical trial, the study also has some limitations. As the authors say, this selection of biomarkers doesn’t “unequivocally and universally detect senescent cells.” While they were chosen to the best of current knowledge, further studies are necessary to validate them.
Furthermore, the models used in the study suggest an association between changes in several biomarker levels and changes in HOMA-IR, insulin sensitivity index, and RMR residual. However, this relationship cannot imply causation.
Additionally, stringent inclusion criteria for CALERIE study participants might imply that the results cannot be generalized to the entire population.
This study does not also provide information on the cause of the reduced levels of senescence-associated biomarkers. Authors speculate that it could be reduced accumulation of senescent cells, increased clearance, or the inhibition of their SASP.
In conclusion, our results show that 2 years of moderate CR with adequate nutrient intake reduces biomarkers of cellular senescence in healthy young to middle-aged humans without obesity. Additional research is needed to fully elucidate the senotherapeutic implications of CR, validate the biomarkers signatures that emerged as predictive of metabolic health outcomes, and determine the generalizability and durability of the observed effects. Our data further highlight the impact of lifestyle factors on fundamental mechanisms of aging.
Literature
[1] Aversa Z, White TA, Heeren AA, Hulshizer CA, Saul D, Zhang X, Molina AJA, Redman LM, Martin CK, Racette SB, Huffman KM, Bhapkar M, Khosla S, Das SK, Fielding RA, Atkinson EJ, LeBrasseur NK. Calorie restriction reduces biomarkers of cellular senescence in humans. Aging Cell. 2023 Nov 14:e14038. doi:10.1111/acel.14038. Epub ahead of print. PMID: 37961856.
[2] Balasubramanian, P., Howell, P. R., & Anderson, R. M. (2017). Aging and Caloric Restriction Research: A Biological Perspective With Translational Potential. EBioMedicine, 21, 37–44.
[3] Green, C. L., Lamming, D. W., & Fontana, L. (2022). Molecular mechanisms of dietary restriction promoting health and longevity. Nature reviews. Molecular cell biology, 23(1), 56–73.
[4] Ravussin, E., Redman, L. M., Rochon, J., Das, S. K., Fontana, L., Kraus, W. E., Romashkan, S., Williamson, D. A., Meydani, S. N., Villareal, D. T., Smith, S. R., Stein, R. I., Scott, T. M., Stewart, T. M., Saltzman, E., Klein, S., Bhapkar, M., Martin, C. K., Gilhooly, C. H., Holloszy, J. O., … CALERIE Study Group (2015). A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. The journals of gerontology. Series A, Biological sciences and medical sciences, 70(9), 1097–1104.
[5] Aversa, Z., Atkinson, E. J., Carmona, E. M., White, T. A., Heeren, A. A., Jachim, S. K., Zhang, X., Cummings, S. R., Chiarella, S. E., Limper, A. H., & LeBrasseur, N. K. (2023). Biomarkers of cellular senescence in idiopathic pulmonary fibrosis. Respiratory research, 24(1), 101.
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[7] Schafer, M. J., Zhang, X., Kumar, A., Atkinson, E. J., Zhu, Y., Jachim, S., Mazula, D. L., Brown, A. K., Berning, M., Aversa, Z., Kotajarvi, B., Bruce, C. J., Greason, K. L., Suri, R. M., Tracy, R. P., Cummings, S. R., White, T. A., & LeBrasseur, N. K. (2020). The senescence-associated secretome as an indicator of age and medical risk. JCI insight, 5(12), e133668.
[8] Delgado-Calle, J., Sato, A. Y., & Bellido, T. (2017). Role and mechanism of action of sclerostin in bone. Bone, 96, 29–37.
[9] Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., Pignolo, R. J., Robbins, P. D., Niedernhofer, L. J., Ikeno, Y., Jurk, D., Passos, J. F., Hickson, L. J., Xue, A., Monroe, D. G., Tchkonia, T., Kirkland, J. L., Farr, J. N., & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827.
