Welcome to part 2 of ODX's "Biological Age Biomarkers" Series. In the second post, you'll learn how fasting glucose and glucose dysregulation are associated with cognitive decline and an increased risk of morbidity and mortality.
Chronic exposure to high glucose levels results in numerous physiological and pathophysiological changes, affecting cells, tissues, and organ systems. Hyperglycemia exacerbates its toxic effects through several pathways, including inducing oxidative stress, upregulating the polyol pathway, activating protein kinase C (PKC), enhancing the hexosamine biosynthetic pathway (HBP), and promoting the formation of advanced glycation end-products (AGEs), which ultimately alter gene expression.
Prolonged hyperglycemia damages pancreatic β-cells and induces insulin resistance, leading to severe diabetic conditions. Diabetes is associated with various complications, such as cardiovascular and reproductive system dysfunction, nephropathy, retinopathy, neuropathy, and diabetic foot ulcers. Elevated glucose levels also encourage the proliferation of cancer cells and the development of osteoarthritis and create a favorable environment for infections. Hyperglycemia-induced reactive oxygen species (ROS) production leads to DNA damage and an inflammatory response, further contributing to its toxicity.
Chronic hyperglycemia is linked to both microvascular and macrovascular complications, including nephropathy, retinopathy, neuropathy, atherosclerosis, and an increased susceptibility to infections. Additionally, other complications such as hypothyroidism, hyperthyroidism, non-alcoholic fatty liver disease, limited joint mobility, and edema may arise.
Overall, the detrimental effects of hyperglycemia on various biomolecules, organelles, and cells highlight the importance of managing glucose levels to prevent the extensive damage caused by prolonged exposure to high glucose concentrations. The progression of glucose-induced physiological changes includes (Giri 2018):
Diabetes is a known risk factor for cognitive impairment and dementia. In the Atherosclerosis Risk in Communities (ARIC) study, nearly 13,000 participants were assessed over 20 years using neuropsychological tests.
The study found that low levels of 1,5-anhydroglucitol (1,5-AG), indicating glycemic peaks, were associated with an increased risk of dementia and more significant cognitive decline in persons with diabetes. Each 5 µg/mL increase in 1,5-AG was linked to a 16% higher risk of dementia. Among those with diabetes and HbA1c levels below 7%, more glucose peaks correlated with greater cognitive decline, although this finding was not statistically significant (Rawlings 2017).
The study suggests that glycemic variability, characterized by glucose peaks, may contribute to cognitive decline more than sustained hyperglycemia. This highlights the importance of targeting glucose peaks and average glycemia to prevent cognitive decline and dementia in diabetes patients. Further research is needed to confirm these findings and explore the mechanisms involved
Chronological age (CA) is determined by the time of birth, while biological age (BA) is based on cellular changes and strongly correlates with morbidity, mortality, and longevity. In type 2 diabetes (T2D), increased morbidity and mortality are associated with a higher BA, calculated from routine clinical biomarkers. Studies found that the BA of individuals with T2D was, on average, 12.02 years higher than that of non-diabetics and 16.32 years higher in type 1 diabetes (T1D).
The biomarkers A1c and systolic blood pressure showed the strongest correlations with increased BA in T2D. The study validated these findings with mortality data, showing a significant correlation between higher BA and decreased survival.
Elevated BA in T2D and T1D indicates that glucose metabolism dysregulation accelerates aging rather than peripheral insulin resistance alone. Hyperglycemia contributes to oxidative stress, cellular senescence, and vascular aging, thereby promoting accelerated aging and increased risks for complications like cardiomyopathy, as reflected by elevated systolic blood pressure.
Even when A1c was excluded from analysis, the increase in BA persisted, suggesting that other diabetes-related cellular mechanisms contribute to accelerated aging. Understanding the relationship between glucose levels and biological age is crucial for predicting and managing age-related diseases in diabetic patients (Bahour 2022).
Approximately 25% of individuals with prediabetes will develop diabetes within 3 to 5 years, and as many as 70% will progress to diabetes in their lifetime. Progression from prediabetes to diabetes is associated with a higher risk of death. In a large cohort study of 45,782 individuals with prediabetes, it was found that reversion from prediabetes to normoglycemia within three years did not lower the risk of death compared to those with persistent prediabetes.
However, reversion to normoglycemia combined with healthy behaviors, such as higher physical activity levels and no smoking, was linked to a substantially lower risk of death and increased life expectancy. Evidence supports that lifestyle modifications like regular physical activity, a healthy diet, and maintaining a desirable weight are beneficial for stabilizing prediabetes and achieving normoglycemia. The primary reason for the reduced risk of death in those who reverted to normoglycemia is attributed to lifestyle changes (Cao 2023).
Bahour, N., et al. "Diabetes mellitus correlates with increased biological age as indicated by clinical biomarkers." *Geroscience*, vol. 44, no. 1, 2022, pp. 415-427, doi:10.1007/s11357-021-00469-0.
Cao, Z., et al. "Risk of Death Associated With Reversion From Prediabetes to Normoglycemia and the Role of Modifiable Risk Factors." *JAMA Network Open*, vol. 6, no. 3, 2023, doi:10.1001/jamanetworkopen.2023.4989.
Giri, Biplab et al. “Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 107 (2018): 306-328. doi:10.1016/j.biopha.2018.07.157
Rawlings, Andreea M., et al. "Glucose Peaks and the Risk of Dementia and 20-Year Cognitive Decline." *Diabetes Care*, vol. 40, no. 7, 2017, pp. 879-886.