Calorie restriction and mimetics in aging
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Published:
Apr 22, 2025
Keywords:
Restriction, calories, mimetics, aging, drugs, longevity
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Abstract
Introduction. The aging of the world's population has prompted the search for strategies to prolong health and delay age-related diseases. Calorie restriction (CR), which reduces caloric intake without malnutrition, is the most studied geroprotective dietary intervention. However, the difficulty of maintaining it has directed research towards drugs that mimic its effects, known as calorie restriction mimetics (CRMs). Objective. To examine the potential of CR and its mimetics to delay aging, assessing their impact on health and longevity, and analyzing their scientific basis and possible therapeutic applications. Methodology. Qualitative literature review based on literature on CR and CRM in relation to aging. Data was collected from scientific databases such as PubMed, LILACS and Cochrane, focusing on clinical studies from the last five years. The findings are summarized in a narrative review. Results. CR showed significant improvements in health and longevity in experimental and human models, reducing weight, insulin levels, body temperature and oxidative stress. It promoted autophagy through mTOR inhibition and AMPK activation. MRCs, such as metformin and rapamycin, also demonstrated anti-aging effects by modulating nutrient-sensing pathways and reducing oxidative damage, suggesting their potential as alternatives to CR. Conclusion. CR and its mimetics, such as rapamycin, improve longevity and muscle quality by activating key pathways such as AMPK and SIRT1. Although they act differently, both promote autophagy and antioxidant protection, suggesting the need for combined approaches to optimize anti-aging effects. General Area of Study: Medicine. Specific area of study: Endocrinology. Type of study: Bibliography Review.
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Díaz Núñez, K. P., & Cevallos Teneda, A. C. (2025). Calorie restriction and mimetics in aging. Anatomía Digital, 8(2), 69-88. https://doi.org/10.33262/anatomiadigital.v8i2.3395
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Articulos de revisión bibliográfica
References
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14. Chung K, Chung H. The Effects of Calorie Restriction on Autophagy: Role on Aging Intervention. Nutrients [Internet]. 2019 [cited 2024 September 15]; 11(12): 2923. Available from: https://pubmed.ncbi.nlm.nih.gov/31810345/
15. Shintani T, Shintani H, Sato M, Ashida H. Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension. GeroScience [Internet]. 2023 [cited 2024 September 15]; 45(6): 3475-3490. Available from: https://pubmed.ncbi.nlm.nih.gov/37389698/
16. Ingram D, Roth G. Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics. GeroScience [Internet]. 2021 [cited 2024 September 15]; 43(3): 1159-1169. Available from: https://pubmed.ncbi.nlm.nih.gov/33184758/
17. Mohammed I, Hollenberg M, Ding H, Triggle C. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Frontiers in endocrinology [Internet]. 2021 [cited 2024 September 15]; 12:718942. Available from: https://pubmed.ncbi.nlm.nih.gov/34421827/
18. La Grotta R, Frigé C, Matacchione G, Olivieri F, de Candia P, Ceriello A, et al. Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms. International journal of molecular sciences [Internet]. 2022 [cited 2024 September 15]; 23(20): 12325. Available from: https://pubmed.ncbi.nlm.nih.gov/36293181/
19. Hoong C, Chua M. SGLT2 Inhibitors as Calorie Restriction Mimetics: Insights on Longevity Pathways and Age-Related Diseases. Endocrinology [Internet]. 2021 [cited 2024 September 15]; 162(8): bqab079. Available from: https://pubmed.ncbi.nlm.nih.gov/33857309/
20. Orenduff M, Coleman M, Glenny E, Huffman K, Rezeli E, Bareja A, et al. Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle. Experimental gerontology [Internet]. 2022 [cited 2024 September 15]; 165:111841. Available from: https://pubmed.ncbi.nlm.nih.gov/35623538/
21. Ros M, Carrascosa J. Current nutritional and pharmacological anti-aging interventions. Biochimica et biophysica acta. Molecular basis of disease [Internet]. 2020 [cited 2024 September 15]; 1866(3):165612. Available from: https://pubmed.ncbi.nlm.nih.gov/31816437/
22. Serna E, Mastaloudis A, Martorell P, Wood S, Hester S, Bartlett M et al. A Novel Micronutrient Blend Mimics Calorie Restriction Transcriptomics in Multiple Tissues of Mice and Increases Lifespan and Mobility in C. elegans. Nutrients [Internet]. 2020 [cited 2024 September 15]; 12(2):486. Available from: https://pubmed.ncbi.nlm.nih.gov/32075050/
23. Ham D, Börsch A, Chojnowska K, Lin S, Leuchtmann A, Ham A, et al. Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle Nature communications [Internet]. 2022 [cited 2024 September 15]; 13(1): 2025. Available from: https://pubmed.ncbi.nlm.nih.gov/35440545/
24. Orenduff M, Coleman M, Glenny E, Huffman K, Rezeli E, Bareja A. Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle [Internet]. 2022 [cited 2024 September 15]; 165:111841. Available from: https://pubmed.ncbi.nlm.nih.gov/35623538/
25. Ferreira-Marques M, Carvalho A, Cavadas C, Aveleira C. PI3K/AKT/MTOR and ERK1/2-MAPK signaling pathways are involved in autophagy stimulation induced by caloric restriction or caloric restriction mimetics in cortical neurons. Aging [Internet]. 2021 [cited 2024 September 15]; 13(6):7872-7882. Available from: https://pubmed.ncbi.nlm.nih.gov/33714946/
26. Park J, Jeong J, Bae Y. Protein Kinase CK2 Is Upregulated by Calorie Restriction and Induces Autophagy. Molecules and cells [Internet]. 2021 [cited 2024 September 15]; 45(3): 112-121. Available from: https://pubmed.ncbi.nlm.nih.gov/34949740/
27. Matt K, Hochecker B, Schöller-Mann A, Bergemann J. mRNA expression of ageing-associated genes in calorie reduction is subject to donor variability and can be induced by calorie restriction mimetics. Nutrition and health [Internet]. 2020 [cited 2024 September 15]; 26(3): 253-262. Available from: https://pubmed.ncbi.nlm.nih.gov/32552390/
28. Masraloudis A, Shenth C, Hester S, Wood S, Prescot A, McGlade E, et al. Supplementation with a putative calorie restriction mimetic micronutrient blend increases glutathione concentrations and improves neuroenergetics in brain of healthy middle-aged men and women. Free radical biology & medicine [Internet]. 2020 [cited 2024 September 15]; 153:112-121. Available from: https://pubmed.ncbi.nlm.nih.gov/32335159/
2. Liu J. Antiaging agents: safe interventions to slow aging and healthy life span extension. Natural products and bioprospecting [Internet]. 2022 [cited 2024 September 15]; 12(1):18. Available from: https://pubmed.ncbi.nlm.nih.gov/35534591/
3. Mehdi M, Solanki P, Singh P. Oxidative stress, antioxidants, hormesis and calorie restriction: The current perspective in the biology of aging. Archives of gerontology and geriatrics [Internet]. 2021 [cited 2024 September 15]; 95:104413. Available from: https://pubmed.ncbi.nlm.nih.gov/33845417/
4. Hofer S, Carmona-Gutierrez D, Mueller M, Madeo F. The ups and downs of caloric restriction and fasting from molecular effects to clinical application. EMBO molecular medicine [Internet]. 2022 [cited 2024 September 15]; 14(1): e14418. Available from: https://pubmed.ncbi.nlm.nih.gov/34779138/
5. Napoleão A, Fernandes L, Miranda C, Marum A. Effects of Calorie Restriction on Health Span and Insulin Resistance: Classic Calorie Restriction Diet vs. Ketosis-Inducing Diet. Nutrients [Internet]. 2021 [cited 2024 September 15]; 13(4): 1302. Available from: https://pubmed.ncbi.nlm.nih.gov/33920973/
6. Kraus W, Bhapkar M, Huffman K, Pieper C, Krupa D, Redman L, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. The lancet. Diabetes & endocrinology [Internet]. 2019 [cited 2024 September 15]; 7(9): 673-683. Available from: https://pubmed.ncbi.nlm.nih.gov/31303390/
7. Martel J, Chang S, Wu C, Peng H, Hwang T, Ko Y, et al. Recent advances in the field of caloric restriction mimetics and anti-aging molecules. Ageing research reviews [Internet]. 2021 [cited 2024 September 15]; 66: 101240. Available from: https://pubmed.ncbi.nlm.nih.gov/33347992/
8. Madeo F, Carmona D, Hofer S, Kroemer G. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell metabolism [Internet]. 2019 [cited 2024 September 15]; 29(3): 592-610. Available from: https://pubmed.ncbi.nlm.nih.gov/30840912/
9. Most J, Redman L. Impact of calorie restriction on energy metabolism in humans. Experimental gerontology [Internet]. 2020 [cited 2024 September 15]; 133:110875. Available from: https://pubmed.ncbi.nlm.nih.gov/32057825/
10. Ros M, Carrascosa J. Current nutritional and pharmacological anti-aging interventions. Biochimica et biophysica acta. Molecular basis of disease [Internet]. 2020 [cited 2024 September 15]; 1866(3):165612. Available from: https://pubmed.ncbi.nlm.nih.gov/31816437/
11. Pifferi F, Aujard F. Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies. Progress in neuro-psychopharmacology & biological psychiatry [Internet]. 2019 [cited 2024 September 15]; 95: 109702. Available from: https://pubmed.ncbi.nlm.nih.gov/31325469/
12. Erbaba B, Arslan-Ergul A, Adams M. Effects of caloric restriction on the antagonistic and integrative hallmarks of aging. Ageing research reviews [Internet]. 2021 [cited 2024 September 15]; 66:101228. Available from: https://pubmed.ncbi.nlm.nih.gov/33246078/
13. Flanagan E, Most J, Mey J, Redman L. Calorie Restriction and Aging in Humans. Annual review of nutrition [Internet]. 2020 [cited 2024 September 15]; 40:105-133. Available from: https://pubmed.ncbi.nlm.nih.gov/32559388/
14. Chung K, Chung H. The Effects of Calorie Restriction on Autophagy: Role on Aging Intervention. Nutrients [Internet]. 2019 [cited 2024 September 15]; 11(12): 2923. Available from: https://pubmed.ncbi.nlm.nih.gov/31810345/
15. Shintani T, Shintani H, Sato M, Ashida H. Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension. GeroScience [Internet]. 2023 [cited 2024 September 15]; 45(6): 3475-3490. Available from: https://pubmed.ncbi.nlm.nih.gov/37389698/
16. Ingram D, Roth G. Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics. GeroScience [Internet]. 2021 [cited 2024 September 15]; 43(3): 1159-1169. Available from: https://pubmed.ncbi.nlm.nih.gov/33184758/
17. Mohammed I, Hollenberg M, Ding H, Triggle C. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Frontiers in endocrinology [Internet]. 2021 [cited 2024 September 15]; 12:718942. Available from: https://pubmed.ncbi.nlm.nih.gov/34421827/
18. La Grotta R, Frigé C, Matacchione G, Olivieri F, de Candia P, Ceriello A, et al. Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms. International journal of molecular sciences [Internet]. 2022 [cited 2024 September 15]; 23(20): 12325. Available from: https://pubmed.ncbi.nlm.nih.gov/36293181/
19. Hoong C, Chua M. SGLT2 Inhibitors as Calorie Restriction Mimetics: Insights on Longevity Pathways and Age-Related Diseases. Endocrinology [Internet]. 2021 [cited 2024 September 15]; 162(8): bqab079. Available from: https://pubmed.ncbi.nlm.nih.gov/33857309/
20. Orenduff M, Coleman M, Glenny E, Huffman K, Rezeli E, Bareja A, et al. Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle. Experimental gerontology [Internet]. 2022 [cited 2024 September 15]; 165:111841. Available from: https://pubmed.ncbi.nlm.nih.gov/35623538/
21. Ros M, Carrascosa J. Current nutritional and pharmacological anti-aging interventions. Biochimica et biophysica acta. Molecular basis of disease [Internet]. 2020 [cited 2024 September 15]; 1866(3):165612. Available from: https://pubmed.ncbi.nlm.nih.gov/31816437/
22. Serna E, Mastaloudis A, Martorell P, Wood S, Hester S, Bartlett M et al. A Novel Micronutrient Blend Mimics Calorie Restriction Transcriptomics in Multiple Tissues of Mice and Increases Lifespan and Mobility in C. elegans. Nutrients [Internet]. 2020 [cited 2024 September 15]; 12(2):486. Available from: https://pubmed.ncbi.nlm.nih.gov/32075050/
23. Ham D, Börsch A, Chojnowska K, Lin S, Leuchtmann A, Ham A, et al. Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle Nature communications [Internet]. 2022 [cited 2024 September 15]; 13(1): 2025. Available from: https://pubmed.ncbi.nlm.nih.gov/35440545/
24. Orenduff M, Coleman M, Glenny E, Huffman K, Rezeli E, Bareja A. Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle [Internet]. 2022 [cited 2024 September 15]; 165:111841. Available from: https://pubmed.ncbi.nlm.nih.gov/35623538/
25. Ferreira-Marques M, Carvalho A, Cavadas C, Aveleira C. PI3K/AKT/MTOR and ERK1/2-MAPK signaling pathways are involved in autophagy stimulation induced by caloric restriction or caloric restriction mimetics in cortical neurons. Aging [Internet]. 2021 [cited 2024 September 15]; 13(6):7872-7882. Available from: https://pubmed.ncbi.nlm.nih.gov/33714946/
26. Park J, Jeong J, Bae Y. Protein Kinase CK2 Is Upregulated by Calorie Restriction and Induces Autophagy. Molecules and cells [Internet]. 2021 [cited 2024 September 15]; 45(3): 112-121. Available from: https://pubmed.ncbi.nlm.nih.gov/34949740/
27. Matt K, Hochecker B, Schöller-Mann A, Bergemann J. mRNA expression of ageing-associated genes in calorie reduction is subject to donor variability and can be induced by calorie restriction mimetics. Nutrition and health [Internet]. 2020 [cited 2024 September 15]; 26(3): 253-262. Available from: https://pubmed.ncbi.nlm.nih.gov/32552390/
28. Masraloudis A, Shenth C, Hester S, Wood S, Prescot A, McGlade E, et al. Supplementation with a putative calorie restriction mimetic micronutrient blend increases glutathione concentrations and improves neuroenergetics in brain of healthy middle-aged men and women. Free radical biology & medicine [Internet]. 2020 [cited 2024 September 15]; 153:112-121. Available from: https://pubmed.ncbi.nlm.nih.gov/32335159/