Blood Glucose Is a Biomarker of Aging

Glucose is the second most influential biomarker on the rate of aging, according to Aging.ai’s age prediction platform. Glucose control is vital to human health, and uncontrolled high glucose results in diabetes.

In the United States, one in ten individuals are diabetic, and one in three are prediabetic. The incidence of type 2 diabetes among young people has been increasing 5% per year since 2002, and the average 50-year-old man is prediabetic [1,2].

Glucose is associated with rapid aging and mortality

Increasing levels of glucose are associated with greater biological age and increased risk of death from all causes [3]. The best range for glucose is between 80 and 94 milligrams per deciliter of serum. At greater or lesser values, the hazard ratio for all-cause mortality increases. For example, a person with a fasting glucose level of 140 would be 40% more likely to die at any time than a person with an optimal glucose level.

What is glucose, and what does it do?

Glucose is a six-carbon sugar that all nucleus-containing cells use for energy. The breaking down of glucose, known as glycolysis, leads to the production of adenosine triphosphate (ATP). ATP is the energy currency of the cell.

When there is an excess of glucose, the individual glucose molecules can be linked together to create a storage form called glycogen. Glycogen is mostly stored in muscles and the liver. On average, the body can store about 15 grams of glycogen for every kilogram of body weight. Excess glucose can also be turned into fat in a process called lipogenesis, which is the main way that the human body stores energy [4].

Products of glucose metabolism, apart from ATP, are used to make other molecules that perform many metabolic functions. These include glucuronic acid and advanced glycation end-products (AGEs).

Glucuronic acid functions in the liver as a detoxification agent and is used in the production of many glycosaminoglycans, including hyaluronic acid, chondroitin sulfate, and heparin [5]. Almost all chemical reactions in the body involve the use of biological catalysts called enzymes. AGEs, on the other hand, are formed without the aid of enzymes.

AGEs are a significant aspect of aging, and some researchers hold that they should be among the Hallmarks of Aging [6]. One of these AGEs is A1C, which is created when the blood protein hemoglobin reacts with glucose. The amount of A1C in blood is proportional to the average glucose level over time, making it a useful diagnostic tool for diabetes [7].

Symptoms of high glucose and the development of diabetes

The symptoms of high glucose include increased thirst, frequent urination, unexpected weight loss, ketones in the urine, fatigue and weakness, irritability, blurry vision, slowly healing sores, and frequent infections [8].

Type 1 diabetes, also known as juvenile diabetes, occurs when the immune system attacks the insulin-producing cells of the pancreas. The death of these pancreatic cells often leads to dependence on insulin injections.

Although many diabetic people still inject themselves with insulin, a growing number (63% in the United States and 5-15% in Europe) use insulin pumps. These are medical devices that monitor blood glucose and automatically inject insulin when necessary.

People who have type 2 diabetes and prediabetes have elevated glucose levels and begin to show signs of insulin resistance. This is when the pancreas can produce normal amounts of insulin but the insulin produced is ineffective at shuttling glucose into glucose-deficient cells. Fortunately, type 2 diabetes can be controlled through lifestyle changes 90% of the time [9,10].

High glucose damages the body and accelerates aging

The metabolisms of people with diabetes differ in small but significant ways from the metabolisms of people without diabetes. People with type 2 diabetes often experience declining insulin production over time and later develop features of type 1 diabetes as well [11].

Chronically elevated blood glucose causes cardiovascular disease, nerve damage, kidney damage, eye damage, loss of hearing, neurodegenerative disease, and mood disorders over time [8].

Diet, exercise, weight loss, and drugs can prevent type 2 diabetes

Researchers pooled data from 21 clinical trials that looked at diet, exercise, and drug intervention. The study showed that lifestyle interventions reduced risk by 49%.

Lifestyle interventions included diet, exercise, or both [11]. Drug-based interventions reduced risk by 56% on average. However, all drugs were not equally effective. Another meta-analysis of 4864 people found that lifestyle changes could reduce the likelihood of developing type II diabetes by up to 58%. However, individuals had to lose 5-7% of their body weight to gain this benefit [11].

A clinical review of antidiabetic medications showed that patients who took them had 30% less risk. The effectiveness of individual medications varied, and some patients needed to try several medications before finding the one that worked best [12].

Strategies for controlling blood glucose

Continuous glucose monitoring (CGM) systems inform users about how specific foods, sleeping patterns, exercise, and other variables affect their glucose levels in real time [13].

Increasing and maintaining muscle mass throughout aging has been shown to improve glucose control by providing a “sink” to store excess ingested glucose [14,15].

Zone 2 conditioning reduces insulin resistance while increasing mitochondrial density, function, and flexibility [16,17], which for mitochondria is the ability to use fat or glucose for energy. Dysfunctional mitochondria are associated with type 2 diabetes, metabolic syndrome, and cardiovascular disease [18].

Low glycemic index foods

The glycemic index is a number assigned to a given food that reflects the relative rise in blood glucose two hours after eating it. Glycemic index values range between 0 and 100.

A randomized, controlled study that compared low and high glycemic index diets found that the low glycemic index diet improved glucose control and use. It also improved lipid profiles (cholesterol numbers and triglycerides) and the ability to break down blood clots. Diabetics are more prone to blood clots, a major contributing factor to early mortality [19].

Weight loss and fasting

Modest continuous energy restriction (CER) leads to improvements in glucose and fat metabolism [20]. These improvements can also be brought about by alterations in meal timing, and this effect is independent of weight loss [21]. Recently, several fasting variants have become popular, including intermittent energy restriction (IER) and time-restricted feeding (TRF).

IER is beneficial for improving serum glucose and lipid values in short to medium time frames [22]. However, there is a need to conduct longer-term studies to figure out if IER benefits are sustainable over the long haul.

TRF has shown demonstrable benefits in rodent studies but mixed results in human studies. Some fasting benefits are available without restricting caloric intake but only manipulating meal timing [22].

IER has been shown to improve liver insulin sensitivity and triglyceride metabolism. These benefits have not been seen on the same scale with mild caloric restriction. IER also improves circadian clock regulation, which leads to further improvements in glucose and lipid metabolism [22].

Coffee compounds favorably affect glucose metabolism

Green coffee beans have a group of polyphenols called chlorogenic acids, and green coffee extract is sold as supplements that provide a concentrated dose. These compounds reduce blood glucose levels and offer other health benefits [23]. Chlorogenic acids inhibit an enzyme called alpha-glucosidase that cells of the small intestine produce to break down complex carbohydrates and disaccharides, such as amylopectin (potato starch) and sucrose.

This allows glucose to be absorbed and reduces the uptake of glucose during digestion [24-27]. Furthermore, coffee contains caffeic acid, which reduces liver glucose output, improves glucose uptake by fat cells, and better controls insulin secretion [28]. However, too much caffeine can induce cardiac arrhythmias, disturb sleep, disrupt calcium balance, and increase insulin resistance [29].

Probiotics that improve glucose metabolism

Existing data strongly suggest that the gut microbiota affect glucose homeostasis [30]. Possible mechanisms linking the gut microbiota to glucose homeostasis may include changes in the production of short-chain fatty acids (SCFAs), increased intestinal permeability, and low-grade endotoxemia. Changes related to branched-chain amino acids may alter bile acid metabolism and/or affect the secretion of gut hormones [30].

Bacterial species such as Ruminococcus and Faecalibacterium produce SCFAs. Studies have implicated short-chain fatty acids in the regulation and secretion of several gut hormones, including GLP-1 and anorectic hormone peptide, which regulate glucose metabolism, nourish gut cells, and improve their ability to maintain barrier function [31].

Poor barrier function is associated with increased Intestinal permeability, which enables toxic chemicals from Gram-negative bacteria to pass through the intestinal wall and into the bloodstream. Probiotics not only crowd Gram-negative bacteria out of the gut, they prevent increases in intestinal permeability induced by inflammatory cytokines. Streptococcus thermophilus and Lactobacillus acidophilus are two such probiotics [31].

Some research, although controversial, shows evidence that bacterial synthesis and later absorption by the body of branched-chain amino acids may result in insulin resistance [32].

The gut microbiome also plays a key role in bile acid metabolism [33,34]. The liver makes primary bile acids from cholesterol and amino acids such as glycine and taurine. The liver secretes these acids, when needed, into the small intestine. About 5% go on to the large intestine where they undergo bacterial transformation to secondary bile acids, including deoxycholic acid and lithodeoxycholic acid [31,32].

Secondary bile acids are known to affect both insulin sensitivity and glycemic control. The research community has yet to uncover all the mechanisms underlying these effects [33]. One mechanism is mediated through the enzyme GLP-1, which is known to have favorable effects on glucose metabolism and weight loss. Several diabetes drugs, such as Ozempic, target this molecule to improve glucose metabolism.

Alpha-lipoic acid

A 2018 meta-analysis showed that alpha-lipoic acid administration led to improvements in fasting glucose, insulin concentrations, A1C, and HOMA-IR. A1C measures the amount of blood protein in circulation that has reacted with glucose to form advanced glycation end products, making it a useful marker of long-term glucose levels. HOMA-IR is a way of measuring insulin resistance. There were also improvements in cholesterol and triglycerides [34].

Stress management

Chronic stress causes hormonal changes due to its effects on the hypothalamus along with the pituitary and adrenal glands. Additionally, it activates the stress response system, which connects the nervous system to the area of the hormonal system that releases “fight or flight” hormones.

Among these hormones are the glucocorticoids and catecholamines. These compounds enable the body to adjust to increasing energy demands by turning up metabolism. In the context of chronic stress, the body recalibrates metabolism to a new norm. Unfortunately, this causes alterations in glucose metabolism, including the development of insulin resistance and glucose intolerance [35].

The process of stress management has two major facets: the identification, evaluation, and potential removal or limitation of stressors along with the management of ongoing stressors, which may include improvements in eating, sleeping, exercise, and relaxation strategies (i.e. yoga and massage therapy) [36].

Medications

Used correctly, various medications can effectively treat diabetes, and individuals are encouraged to work with their physicians when trying to manage their glucose levels.

Berberine is a popular supplement for people with suboptimal glucose readings who are not diabetic but wish to have better control over their blood glucose. Interestingly, berberine is sold as a supplement while having the same mechanism of action as the prescription drug metformin. Berberine causes cells in the liver and gut to use glucose inefficiently, resulting in energy loss and lower serum glucose. Some individuals may experience abdominal discomfort [37].

Literature

[1] J. Divers, E. Mayer-Davis, and J. Lawrence, “Trends in Incidence of Type 1 and Type 2 Diabetes Among Youths – Selected Counties and Indian Reservations, United States, 2002-2015,” MMWR Morb Mortal Wkly Rep 2020;69161-165, no. 69, pp. 161–165, 2020.

[2] E. Putin et al., “Deep biomarkers of human aging: Application of deep neural networks to biomarker development,” Aging (Albany. NY)., vol. 8, no. 5, pp. 1021–1033, May 2016

[3] S.-W. Yi, S. Park, Y. Lee, H.-J. Park, B. Balkau, and J.-J. Yi, “Association between fasting glucose and all-cause mortality according to sex and age: a prospective cohort study,” Sci. Rep., vol. 7, no. 1, p. 8194, 2017

[4] M. Serda et al., “Modern nutrition in health and disease: Eleventh edition,” Uniw. śląski, vol. 7, no. 1, pp. 343–354, 2012

[5] E. Montell, P. Contreras-Muñoz, A. Torrent, M. de la Varga, G. Rodas, and M. Marotta, “Mechanisms of action of chondroitin sulfate and glucosamine in muscle tissue: in vitro and in vivo results. A new potential treatment for muscle injuries?,” Osteoarthr. Cartil., vol. 26, no. 2018, p. S404, 2018

[6] A. Fedintsev and A. Moskalev, “Stochastic non-enzymatic modification of long-lived macromolecules – A missing hallmark of aging” Ageing Res Rev. Sept. 2020

[7] A. Cerami, “The unexpected pathway to the creation of the HbA1c test and the discovery of AGE’s,” J. Intern. Med., vol. 271, no. 3, pp. 219–226, Mar. 2012

[8] A. Ramachandran, “Know the signs and symptoms of diabetes,” Indian J. Med. Res., vol. 140, no. 5, pp. 579–581, Nov. 2014

[9] T.H. Chan School of Public Health, “Simple Steps to Preventing Diabetes | The Nutrition Source | Harvard T.H. Chan School of Public Health.”

[10] K. I. Galaviz, K. M. V. Narayan, F. Lobelo, and M. B. Weber, “Lifestyle and the Prevention of Type 2 Diabetes: A Status Report,” Am. J. Lifestyle Med., vol. 12, no. 1, pp. 4–20, Nov. 2015

[11] C. L. Gillies et al., “Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis,” BMJ, vol. 334, no. 7588, p. 299, Feb. 2007

[12] A. Chaudhury et al., “Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management ,” Frontiers in Endocrinology , vol. 8. 2017

[13] R. A. Ajjan, “How Can We Realize the Clinical Benefits of Continuous Glucose Monitoring?,” Diabetes Technol. Ther., vol. 19, no. S2, p. S-27-S-36, May 2017

[14] J. L. Gamboa, M. L. Garcia-Cazarin, and F. H. Andrade, “Chronic hypoxia increases insulin-stimulated glucose uptake in mouse soleus muscle,” Am. J. Physiol. Regul. Integr. Comp. Physiol., vol. 300, no. 1, pp. R85–R91, Jan. 2011

[15] J. Yang, “Chapter Five – Enhanced Skeletal Muscle for Effective Glucose Homeostasis,” in Glucose Homeostatis and the Pathogenesis of Diabetes Mellitus, vol. 121, pp. 133–163Y.-X. B. T.-P. in M. B. and T. S. Tao, Ed. Academic Press, 2014

[16] T. Stöggl and B. Sperlich, “Polarized training has greater impact on key endurance variables than threshold, high intensity, or high volume training,” Frontiers in Physiology , vol. 5. 2014

[17] T. M. H. Eijsvogels, S. Molossi, D. Lee, M. S. Emery, and P. D. Thompson, “Exercise at the Extremes: The Amount of Exercise to Reduce Cardiovascular Events,” J. Am. Coll. Cardiol., vol. 67, no. 3, pp. 316–329, 2016

[18] D. A. Chistiakov, T. P. Shkurat, A. A. Melnichenko, A. V Grechko, and A. N. Orekhov, “The role of mitochondrial dysfunction in cardiovascular disease: a brief review,” Ann. Med., vol. 50, no. 2, pp. 121–127, Feb. 2018

[19] S. Rizkalla, “Whole-Body Glucose Utilization , and Lipid Profile on a Low – Glycemic Index Diet in Type 2 Diabetic Men A randomized controlled trial,” vol. 27, no. 8, 2004

[20] NICE, “Obesity : identification , assessment and management,” September, 2022.

[21] G. D. M. Potter, J. E. Cade, P. J. Grant, and L. J. Hardie, “Nutrition and the circadian system,” Br. J. Nutr., vol. 116, no. 3, pp. 434–442, 2016

[22] R. Antoni, K. L. Johnston, A. L. Collins, and M. D. Robertson, “Effects of intermittent fasting on glucose and lipid metabolism,” Proc. Nutr. Soc., vol. 76, no. 3, pp. 361–368, 2017

[23] P. LIczbiński and B. Bukowska, “Tea and coffee polyphenols and their biological properties based on the latest in vitro investigations,” Ind. Crops Prod., vol. 175, p. 114265, 2022

[24] H. E. Lebovitz, “Alpha-glucosidase inhibitors,” Endocrinol. Metab. Clin. North Am., vol. 26, no. 3, pp. 539–551, 1997

[25] W. Benalla, S. Bellahcen, and M. Bnouham, “Antidiabetic Medicinal Plants as a Source of Alpha Glucosidase Inhibitors,” Current Diabetes Reviews, vol. 6, no. 4. pp. 247–254, 2010

[26] C.-Y. Yang, Y.-Y. Yen, K.-C. Hung, S.-W. Hsu, S.-J. Lan, and H.-C. Lin, “Inhibitory effects of pu-erh tea on alpha glucosidase and alpha amylase: a systemic review,” Nutr. Diabetes, vol. 9, no. 1, p. 23, 2019

[27] J. M. Tunnicliffe, L. K. Eller, R. A. Reimer, D. S. Hittel, and J. Shearer, “Chlorogenic acid differentially affects postprandial glucose and glucose-dependent insulinotropic polypeptide response in rats,” Appl. Physiol. Nutr. Metab., vol. 36, no. 5, pp. 650–659, Oct. 2011

[28] U. J. Jung, M.-K. Lee, Y. B. Park, S.-M. Jeon, and M.-S. Choi, “Antihyperglycemic and Antioxidant Properties of Caffeic Acid in db/db Mice,” J. Pharmacol. Exp. Ther., vol. 318, no. 2, pp. 476 LP – 483, Aug. 2006

[29] J. dePaula and A. Farah, “Caffeine Consumption through Coffee: Content in the Beverage, Metabolism, Health Benefits and Risks,” Beverages , vol. 5, no. 2. 2019

[30] K. M. Utzschneider, M. Kratz, C. J. Damman, and M. Hullarg, “Mechanisms Linking the Gut Microbiome and Glucose Metabolism,” vol. 101, no. April, pp. 1445–1454, 2016

[31] J. M. Ridlon and P. B. Hylemon, “Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium,” J. Lipid Res., vol. 53, no. 1, pp. 66–76, 2012

[32] D. H. Mallonee, J. L. Adams, and P. B. Hylemon, “The bile acid-inducible baiB gene from Eubacterium sp. strain VPI 12708 encodes a bile acid-coenzyme A ligase,” J. Bacteriol., vol. 174, no. 7, pp. 2065–2071, 1992

[33] F. Kuipers, V. W. Bloks, and A. K. Groen, “Beyond intestinal soap—bile acids in metabolic control,” Nat. Rev. Endocrinol., vol. 10, no. 8, pp. 488–498, 2014

[34] M. Akbari et al., “The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials,” Metabolism, vol. 87, pp. 56–69, 2018

[35] H. Yajurvedi, “Stress and Glucose metabolism: A Review,” Imaging J. Clin. Med. Sci., pp. 008–012, Mar. 2018

[36] K. Kassymova, N. Kosherbayeva, S. Sangilbayev, and H. Schachl, “Stress management techniques for students BT – Proceedings of the International Conference on the Theory and Practice of Personality Formation in Modern Society (ICTPPFMS 2018),” pp. 47–56 Sep. 2018

[37] J. Yin, H. Xing, and J. Ye, “Efficacy of berberine in patients with type 2 diabetes mellitus,” Metabolism., vol. 57, no. 5, pp. 712–717, May 2008