EDITORIAL

Do refined carbohydrates, glycemic index, subclinical hypothyroidism, and insulin resistance contribute to the brain senescence of subjective cognitive decline in aging in man and animals? Here is what the lab rats are saying

Orien L Tulp 

Professor of Medicine and Graduate Studies, University of Science Arts and technology, Montserrat

Corresponding Author: Orien L Tulp, Professor of Medicine and Graduate Studies, University of Science Arts and technology, Montserrat, British West Indies, PO Box 506, MSR1110; East West College of Natural Medicine, Sarasota, FL USA. 34234, and Universidad de Sevilla, Seville, Spain, 41004. E-mail: [email protected], [email protected]

Received: June 22, 2025                                              Published: July 25, 2025

Citation: Tulp OL. Do refined carbohydrates, glycemic index, subclinical hypothyroidism, and insulin resistance contribute to the brain senescence of subjective cognitive decline in aging in man and animals? Here is what the lab rats are saying. Int J Complement Intern Med. 2025;6(3):408–417. DOI: 10. 58349/IJCIM. 4. 6. 2025. 00154

Copyright: ©2025 Tulp OL. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially.

Abstract 

The onset and progression of subjective cognitive decline (SCD) in aging typically occurs gradually over an extended duration, often escaping recognition by friends and family during the early stages of the disorder. The incidence of SCD in developed counties, where the abundant consumption of refined carbohydrate sources is also commonplace, is virtually staggering, currently approaching over 10% of the population over age 45 with no definitive end in sight.1 The development of SCD has been associated with factors of socioeconomic, educational, metabolic and pathophysiological comorbidities, including diet and impaired insulin sensitivity common to obesity, Type 2 and 3 diabetes (T2DM; T3DM). While early intervention is preferable for the treatment of many illnesses and disorders, effective remedies for the senescence of aging and SCD remain a challenge for the practicing clinician, in part because the metabolic and nutritional factors which initiate the process remain largely unclear. The development of symptoms consistent with subclinical hypothyroidism (SCHT) are also commonplace among the aged. The independent contributions of thyroidal dysregulation and insulin resistance to dysregulation of energy balance, although strongly linked, some aspects remain unclear and incompletely known. Several recent studies have now associated obesity and insulin resistance (IR) to brain senescence in aging congenic obese rats. Several studies also support a link between chronic hyperinsulinemia, epigenetic expression of obesity, brain shrinkage and decreased brain protein and cellular deoxyribose nucleic acid (DNA) content in a congenic rodent model of early onset obesity.

Aging congenic obese LA/Ntul//-cp rats develop obesity and hyperinsulinemia soon after weaning regardless of diet and which pathophysiologic stigmata persist throughout their lifespan. The stigmata of insulin resistance may become further aggravated when fed a high glycemic index diet. Groups of lean and obese rats were fed USDA-formulated nutritionally complete isoenergetic diets continuing cornstarch (ST) or sucrose (SUC) asthe only carbohydrate source from weaning until 10.5 months of age. Longevity of obese << lean in both sexes. Obese rats were found to exhibit SCHT and decreased brain mass associated with IR, and accompanied with proportionate decreases in brain lipid, protein and DNA content in the obese but not the lean phenotype. In addition, the decreases in brain mass, protein and DNA composition were of greater magnitude when fed the SUC vs the ST diets in both phenotypes. These observations are suggestive of an increased potential for a contribution of the metabolic sequelae of insulin resistance as a pathophysiologic factor in the progression of brain shrinkage and presumed cognitive decline in the aging obese, hyper insulinemic rat, analogous to clinical observations which may occur in senescence, dementia and Alzheimer’s disease in aging populations and implicate the glycemic index of the refined carbohydrate source as a contributory factor. 

Keywords: carbohydrates, glycemic index, subclinical hypothyroidism, insulin resistance, epigenetics, rats, aging, nootropics, senescence.

References 

1. Yi SY, Steffen LM, Jacobs DR, et al. Dietary carbohydrate quality is associated with epigenetic age acceleration: a crosssectional study of the CARDIA cohort. J Nutr. 2025;155(4):1210-1217. 

2. Bray GA. Energy and Fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people. Adv Nutr. 2013;4:220-225. 

3. Martins IJ. Nutrition therapy regulates caffeine metabolism with relavabce to NAFLD and induction of Type 3 diabetes. HSOA J of Diabetes & Metabolic Disorders. 2017. 

4. Martins, IJ. Single gene inactivation with implications to diabetes and multiple organ dysfunction syndrome. J Clin Epigentics. 2017;3(3). 

5. Soták M, Clark M, Suur BE, et al. Inflammation and resolution in obesity. Nat Rev Endocrinol. 2024. 

6. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017;127:1–4. 

7. Flores Cordero, JA, Perez Pérez A, Jiménez-Cortegana C, et al. Obesity as a Risk Factor for Dementia and Alzheimer’s Disease: The Role of Leptin. Int J Mol Sci. 2022;23(9):5202. 

8. Kelly T, Wang W, Chen CS, et al. Global burden of obesity in 2005 and projections to 2030. Int J Obes (London). 2008;32(9):1431-1437. 

9. World Health Organization, Obesity and Overweight. 2021. 

10. Jiang NM, Cowan M, Moonah SN. et al. The Impact of Systemic Inflammation on Neurodevelopment. Trends Mol Med. 2018;24(9):794-804. 

11. Tulp OL, Einstein GP. Review: Obesity and its associated inflammatory cytokines pose significant risk factors for COVID19 outcomes. Advances in Obesity, Weight Management and Control. 2022;12(1):14‒20. 

12. Huang C. Irwin MG, Wong GT, et al. Evidence of the impact of systemic inflammation on neuroinflammation from a nonbacterial endotoxin animal model. Journal of Neuroinflammation. 2018; 15:147. 

13. Tulp OL. Effect of the obese phenotype on brain composition in congenic lean and obese LA/Ntul//-cp rats. J Psychol & Clin Psychiatry. 2023:14(2):38-43.

14. Tulp OL. Effect of carbohydrate type on brain composition and senescence in aging, hyperinsulinemia-prone obese LA/Ntul//-cp rats. Asian J Med & Health. 2023. 

15. Tulp OL. Glucocorticoid Ablation Restores Glycemic and Thermogenic Parameters in Obesity, Chapter in: Cortisol: between Physiology and Pathology. Diana Loreta Păun Intech Open press. 2024. 

16. Nguyen TT, Ta QTH, Nguyen TKO, et al. Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int J Mol Sci. 2020;21(9):3165. 

17. Carter SU, Oakamoto K. Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes. Am J Physiol. 1987:252(4);E252-E453. 

18. Devlin, TM. Devlin’s textbook of biochemistry w clinical correlations, 7th Ed. Publisher: John Wiley &Sons. 2010. 

19. Nie N, Hull CH, Jenkins K, et al. Statistical package for the social sciences (2nd edn). McGraw Hill Pubs: New York. 1981. 

20. Tulp OL. Mechanistic contributors to Subclinical Hypothyroidism in obesity: Review of Molecular evidence for impaired thyroid hormone receptor affinity and actions from rat studies. Manuscript Number: 2025/BPR/5230 Book name: Medical Science: Recent Advances and Applications. 2025. Medical Science: Trends and Innovations. 2025;13(26):158-167. 

21. Tulp OL, Obidi OF, Oyesile TC, et al. Subclinical Hypothyroidism: does it occur in Obesity and Metabolic Syndrome? Evidence for impaired thyroid hormone receptor affinity from animal studies. African J Int Med. 2023;11(2):001-004. 

22. Tulp OL, Frantz Sainvil, Rolando Branly, et al. Metabolic contributions to subclinical hypothyroidism: does dysregulation of thyroid hormone receptor affinity play a role? AJCIM. 2023;4(1):152-156. 

23. Nguyen TT, Ta QTH, Nguyen TKO, et al. Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int J Mol Sci. 2020;21(9):3165. 

24. Tulp OL. Characteristics of obesity and longevity in the LA/Ntul//-cp rat. ILARJ. 1990;32(3):32-39. 

25. Tulp OL. Effects of glycemic index on neuroplasticity, systemic inflammation and epigenetic longevity in man and animals. Int J Comp Internal Med. 2025;6(3):293-299. 

26. Herskovitz AZ, Guarente L. Sirt1 in neurodevelopment and brain senescence. Neuron. 2014;81:471-482. 

27. Tulp OL. Impact of aging and obesity on insulin parameters, T4/T3 ratios, metabolic rats, sirftuins and longevity in congenic LA/Ntul//-cp rats. Ch 2 in: Medical Science. Trends and Innovations. 2025;5:p12-38. 

28. Tulp OL. Effect of aging and obesity on parameters of insulin, T4/T3 ratios, metaboli rates, sirtuins and longevity in congenic LA/Ntul//-cp rats. Suntext review of medical and clinical research. 2024;5(4):212.p. 1-9. 

29. Tulp OL. Effect of carbohydrate type on brain composition and senescence in aging, hyperinsulinemia prone obese LA/Ntul//-cp rats. Asian J Medicine and Health. 2023;21(8):80-91. 

30. Tulp OL. Does insulin resistance contribute to neuroinflammation, cognitive decline and brain senescence in obesity? Int J Psychiatry Res. 2023:6(5):1-7. 

31. Tulp OL. Effects of aging, phenotype, and carbohydrate feeding on caloric efficiency and adiposity in the LA/Ntul//- cp rat. Adv Obes Weight Control Manag. 2021:11(1):5-11.