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Results of a recently released randomized and controlled dietary intervention trial lend support for the use of telomere length as a biomarker for diabetes risk, as well as the effectiveness of dietary interventions to mitigate this risk. Published in Cardiovascular Diabetology, this 5-year study in Spain included 462 participants in the CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) who did not have diabetes at baseline and for which telomere length data was available. Participants were ages 20-75 with established coronary heart disease (CHD) and were randomly assigned 1:1 to either a Mediterranean diet or to a low-fat diet (as recommended by the National Cholesterol Education Program, with <30% of total calories from fat).
With established CHD, these participants were at greater risk for developing type 2 diabetes, and roughly 23% of them did during the 5-year study. However, among those participants that had shorter telomeres (defined as <20% percentile), a higher percentage developed diabetes (27% vs. 17%), an 86% greater likelihood (odds ratio of 1.86). However, this risk was highly dependent on the dietary intervention. Among those with shorter telomere lengths who were assigned the low-fat diet, a hazard ratio of 2.43 for developing diabetes was observed, whereas no significant difference was found for people with shorter telomeres following the Mediterranean diet. In other words, the substantial increase in risk associated with having shorter telomeres completely disappeared when following a Mediterranean diet. An additional observation: people with shorter telomeres who developed diabetes during the study had lower HDL-C levels than people who did not. Previous publications from the CORDIOPREV study found that low telomere length is also associated with increased intima-media thickness of the common carotid arteries (IMT-CC, an important indicator of cardiovascular risk). A similar benefit of the Mediterranean diet vs a low-fat diet was again observed, marked by a reduction in the IMT-CC in all participants, but especially among those with a low telomere length.
While CORDIOPREV is not the first study to show an association between telomere length and cardiometabolic disease, it may be the first randomized trial to suggest that dietary interventions may reduce the telomere-associated diabetes risk (as well as IMT-CC), at least among people with preexisting CHD. Telomeres are DNA-protein complexes found at the end of chromosomes, stabilizing and shielding the exposed ends of genomic DNA. They are comprised of more than 2000 repetitions of a specific nucleotide (non-coding) sequence, and end with a single strand of guanine-rich (prone to damage) DNA. Shortening of telomeres is thought to result in part from oxidative damage, and telomere length has been proposed to be a sign of biological aging. Telomeres are involved in pathways related to cellular proliferation, regulating the lifespan of a cell, and therefore may serve as biological clocks, i.e., shorter telomeres indicate a cell has a limited number of divisions left. Telomeres naturally shorten with each cell division, but oxidative stress, lifestyle factors, diet, inflammation, etc., are all proposed to chip away more rapidly at telomeres. This promotes both senescence and apoptosis, thereby accelerating the pathological drivers for numerous diseases of aging, including cardiovascular disease, neurodegenerative diseases, type 2 diabetes, and osteoporosis. The lower HDL-C levels observed among the people who developed diabetes in this recent study may reflect a reduction in antioxidant and anti-inflammatory function.
Causality between telomere length or function and the subsequent development of disease or aging is difficult to determine. However, a few recent studies suggest that a direct effect is probable, though the direction of causality varies. For example, the results of Mendelian randomization (MR) using data from a European genome-wide association study (GWAS) recently published in Lipids in Health and Disease suggest that obesity is causally associated with a shortening of telomere length (a “robust causal association” was observed between BMI and telomere length shortening). The authors of this study point to the low-grade inflammation that accompanies obesity and the corresponding upregulation in the expression of inflammatory cytokines and M1-type macrophages as potential mediators of this effect. Similarly, MR of a large European GWAS found that smoking was robustly associated with shorter telomere length and, to a lesser degree, genetically predicted insomnia (but not sleep duration) was associated with shorter length as well. In contrast, moderate to vigorous physical activity was associated with longer telomere length, providing another potential mechanism for the general anti-aging effects attributed to exercise.
Other recently published MR studies suggest that telomere length is a driver for many aging-related biochemical hallmarks, with causal effects on testosterone, fasting insulin, and others. Telomere length has been associated with other signs of aging, such as bone loss, in addition to cardiometabolic disease. An MR of a GWAS that examined the expression of multiple markers of bone metabolism found only unidirectional causality, with shortening telomere length increasing the activity of osteocalcin and matrix metalloproteinases 3 and 12, suggesting that bone loss may be, at least in part, a result of shorter telomeres. It’s notable that higher consumption of extra virgin olive oil, emphasized as part of the Mediterranean diet, was associated with a lower fracture rate in the PREDIMED trial, with the highest tertile of consumption associated with roughly ½ the fracture risk. Hopefully more studies will evaluate telomere length both as a biomarker of risk as well as a biomarker for risk reduction with targeted interventions.
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