Magnesium is an essential nutrient
Magnesium is a mineral which is of great abundance in the human body. Along with enzymes, it is important for protein synthesis, muscle regulation and a host of other important cellular factors such as oxidative phosporylation, energy production which involves production and utilization of ATP and glycolysis. Additionally, Magnesium is required to assist in different cellular processes such as DNA replication and transcription and RNA translation(Barbagallo, 2012).
Magnesium is found usually in the bones and or in the soft tissues of humans. Next to Potassium, it is the most abundant ion in the body. The plasma actually contains less than 0.5% of the total Magnesium in the body (Swaminathan, 2003). However, such is the basis for measuring the Magnesium status of an individual.
Magnesium is present in food, of which about 30% of dietary magnesium intake is absorbed by the body through the gut. According to the Dietiticians of Canada, male adults aged 19-50 years old require an Expected Average Requirement (EAR) of 400-420 mg of Mg daily while women of the same age range would have an EAR of 310mg. However, the Center for Community Health Survey of Canada has found that adults ages 19-50 fall below their required daily dosage of the mineral(CCHS, 2004).
Magnesium Absorption, Distribution, Excretion
Magnesium is present in most commonly consumed foods. Being the mineral ion of the green pigment found in plants, the chlorophyll, Magnesium can be found in vegetables such as spinach, lettuce, leafy greens, and in most cereals. Hard water also contains a noticeable amount of Magnesium, about 5mmol per liter, much higher than the content in other foods. On one hand, Magnesium is depleted in processed foods (Swaminathan, 2003).
Magnesium absorption usually takes places in the intestine, highlighting the importance of dietary Mg intake. Of the usual dietary intake of 12mmol, about 6 mmol is absorbed in the intestine . Absorption of magnesium however is slowed down by fiber, due to the binding action of the fiber’s phosphate structure. Also, higher than 142 mg daily intake of Zinc has been found to impair the body’s absorption of Magnesium (Spencer et al, 1994).
Two distinct transport systems are involved in the absorption of the mineral. One is an active transport, the other is the passive transport of Magnesium. The passive form of Magnesium transport moves bulk of the mineral in the body. The large intestine also reabsorbs some Magnesium, while the remaining is secreted back into the small intestine. Kidneys play a central role in the homeostasis of Magnesium. Seventy five percent of Magnesium then in plasma concentration is filtered through the glomeruli, the capillaries which are found in the nephron, the basic cells composing the kidney. After which, it is reabsorbed into the proximal tubule, particularly the loop of Henle. Finally, Magnesium reaches the distal tubules and is reabsorbed through active transcellular absorption. The remaining Magnesium is then excreted through the urinary tract.(Yu, 2001)
Effect of Calcium on Magnesium Reabsorption
Magnesium is required in the active transport of Calcium and Sodium. Studies have shown that excessive Calcium intake along with Sodium ingestion increase concentration of Magnesium in the urine, signalling higher excretion rates (Greger et al,1981).
In 1975, the effect of Calcium on Magnesium absorption was studied by Bejar. In the course of the research, it has been found that an increase in absorption of Calcium in the ileum of the rat results to parallel decreases in the concentration of Magnesium and Sodium in the plasma. (Bejar, 1975)
Meanwhile, in 1994, a study conducted by Spencer et al, the corollary was tested, that is whether Magnesium has an effect on Calcium absorption. Using five adult males, it was found that Magnesium does not affect the intestinal absorption rate of calcium. However, one takeaway from the study was, there was an increase in the plasma concentration of Calcium. Thus, although absorption was unchanged, concentrations levels were altered(Spencer et al, 1994).
In a much recent study, rats were fed with differing concentrations of Calcium in their diet. Consonant with the earlier findings that higher Calcium absorption likewise decreases Magnesium levels, the study focused on rats who were already Magnesium deficient. After being exposed to a high Ca diet, the Mg levels measured in their femur were even more depressed as compared to their beginning Mg levels. The study further found that a mere 54% increase of calcium intake significantly lowers the Mg level of rats. As can be gleaned from the data, when Mg levels are low, Mg utilization is highly dependent on Ca dietary intake (Bertinato, 2014).
The Mg concentration in the urine of rats fed with a high Ca diet was higher versus those with a lower Ca diet. The data suggests that, with the higher Mg excreted with higher Ca intake, Calcium then plays a major role in the reabsorption of Mg in the kidneys.
Such study resounds to those individuals taking Ca supplements. With an increase in Ca intake, Mg excretion is quickened. Moreover, in Bertinato’s study, rats with higher Ca in their diets were also less energy efficient. They needed to consume more food to increase their weight. This finding is consistent with the study done which concluded that Mg depletion has been shown to increase energy requirement (Lukaskiet al, 2002)
Biomarkers of Mg Status
Currently, there exists no determination of the average levels of Mg among American adults, aside from dietary estimation of the subject. The only way to clinically ascertain Mg blood levels meanwhile is through serum samples, a method not maintained in routine electrolyte testing among health institutions
Since about half of Magnesium is in the bone, and the other half is in the tissues, less than 1% can be found in extracellular sites. This makes blood serum Magnesium detection
an imperfect reflection of the level of the mineral in the body.
However, among normal individuals, a balance exists between the absorption of Magnesium in the intestine versus its excretion via urine. Urinary levels of Mg increase whenever the intake of the mineral is excessive whereas during periods of Magnesium depletion, the kidney reabsorbs and conserves excretion. Thus Magnesium levels in the urine more accurately provide insight on a person’s Magnesium status.
Another study made a systematic review of the various methods used to assess Magnesium levels in an individual. Bulk of the studies reviewed used serum and plasma levels. It was found that plasma and serum concentrations were responsive to increased Magnesium intake, but levels were unaltered when the subjects were under a Magnesium deficient condition (Witkowski et al, 2011).
Similarly, assessment using erythrocyte Magnesium concentration significantly reflected increased intake of the mineral .However in studies that used ionized blood magnesium and albumin bound magnesium, there were no conclusive results to determine the usefulness of such tests. Three researchers also used saliva Magnesium levels, but not enough samples were made to reach a definite conclusion.
On the other hand, urinary magnesium levels were found to be an effective biomarker as both depletion and supplementation studies showed responsive urine Magnesium levels.
The above mentioned biomarkers measure Magnesium levels through interpolation. However, no direct method exists to measure Magnesium levels at present.
Mg intakes in North America
Recommended intakes of Magnesium which differ by age group and gender are provided for by the Food and Nutrition Board. Estimated Average Requirements state that newborns only need 30mg of Magnesium up until they reach 6 months. One year olds meanwhile need 80mg of the mineral, regardless of gender. For adult males, the recommended daily allowance for the 19-30 age range is 400 mg, while those in the 31-50 age group require 420 mg. Females meanwhile require lower Magnesium intakes. Females aged 19-30 need 300 mg daily, while it is increased to 310 mg daily for those aged 31 until 50.
Although Magnesium is found in almost all kinds of foods such as vegetables, fruits, animal products and in beverages, the intake of individuals is lower than the average daily requirement. Processing of foods which significantly lower its Magnesium content is thought to be responsible for the phenomena (Institute of Medicine, 1997).
On average, supplementation augments the intake for men to reach 449 mg daily and 387 for women (Bailey et al, 2011). Meanwhile, as expected, thelevels of those who ingest supplements are slightly above their average requirement.
Currently, population Magnesium levels are measured through dietary intake. No serum nor concentration level assessment were made( Rosanoff et al, 2012) . Moreover, as discussed previously, serum concentration can sometimes be inaccurate due to the least bioavailability of Magnesium in the blood and plasma. Therefore, among Americans, since dietary intake of Magnesium is lower than the requirement, the population can be said to be possibly Magnesium deficient.
Mg deficiency is associated with chronic diseases and health conditions
Early signs of magnesium deficiency remain undetected as the kidney regulates its excretion of the mineral. Generally, slight Mg deficiency is asymptomatic. However, significantly low levels of Mg manifest as weakness, loss of appetite fatigue, and a general feeling of malaise. Among patients with more severe Mg deficiency, muscular cramps and numbness are observed. Likewise, sever Mg deficiency affects homeostasis, thus hypokalemia or low potassium levels and hypocalcemia, low calcium levels are also present(Rude et al, 2010).
Significantly lower Mg levels are associated with diseases that are considered biological hallmarks of aging. Subjects who had conditions such as Celiac disease and Type 2 diabetes were found to have had lower Mg blood levels. Among diabetics, increased glucose results to urine output and an increase in Mg excretion (Larsson et al, 2012) .Moreover, they had higher incidence of muscular weakness, fatigue and cramps
Some groups are also more prone to having lower than the required Mg levels due to their condition or dietary intake. Due to hampered absorption and increased renal excretion, along with medications that affect Magnesium balance, older adults have a higher incidence of deficiency(Barbagallo et al, 2009).
Although short term Mg deficiency is said to have no significant effect, prolonged deficiency alters the body’s biochemistry, exacerbating the risk of illnesses and diseases.
Higher Magnesium intake of 100mg daily for instance may lower the risk of ischemic stroke by 8% (Larsson et al, 2012).
Migraine sufferers are also deemed to benefit from improved Mg intake. Magnesium regulates neurotransmitters and vasoconstriction of vessels. However, such claim is not solidified yet by numerous research. So far, studies conducted found that an additional 300 mg of Mg in the diet daily reduces the instance of migraines (Shurks et al, 2012)
Since Magnesium is usually found in the bone and soft tissues, it is not surprising that it is actively involved in bone formation and homeostasis. It regulates the parathyroid hormone and Vitamin D levels in the blood, which are key players in bone growth. A certain study found that female osteoporosis patients have significantly lower Mg serum levels as compared with the population (Aydin et al, 2012)
Genome stability, cellular senescence and aging
Aging is characterized by various physiological changes. Such changes occur in the cellular level of the organism, manifested through outward appearance, gait, mental sharpness and other biomarkers. From a cellular level, aging is incidental to an organism’s growth and is brought about by cell division,
One theory termed the senescence theory proposes that aging is a result of the accumulation of cells which are past their maximum diploid stage, or past its replication stage. It thus results to the physical manifestation of aging due to the inability of the affected senescent cells to renew itself.
A proposal that most scientists have agreed upon is that, aging is a molecular process inherent in every species and is caused not only by a single factor, but by a multitude of variables. However, one plausible and most supported claim is that aging is largely due to the shortening of the telomeres. Telomeres are nucleoprotein DNA structures located at the end of a DNA strand. Cell division which is an indication of growth and at the same time aging causes the telomeres shorten.
Oxidative damage though considered incidental to cell senescence is further enhanced by oxidative stress. The oxygenation occurs when free radicals bind with the DNA. The identified biomarkers associated with oxidation are 8-hydroxyguanosine and 8-hydroxy-2′-deoxyguanosine (8-OHDG). Such biomarkers were detected in abnormally high levels from serum samples taken from subjects with diseases such as hypertension, diabetes and other degenerative diseases (Montuschi et al, 2012). Further, such diseases have been found to have been exacerbated by Mg deficiency. (Bertinato, 2014)
Since oxidation of the DNA easily occurs at the guanosine base, the latter is easily converted to 8-hydroxyguanine, 8-hydroxyguanosine or 8-OHdG. Therefore, the, measurement of 8-OHdG in urine reflects the level of oxidative stress of an organism. The detection of 8-OHdG urinary levels were first used by Shigenaga in 1989. A study supporting the claim that 8-OHdG levels increase after exposure to stress was conducted in 2004. It has been found that post shift workers exposed to residual oil fly ash exhibited higher 8-OHdG in their urine as compared with their pre-shift levels (Kim et. Al, 2004).
The shortening of telomeres seems well backed by the scientific community, but as to what exactly brings about the phenomena remains unresolved. Telomeres are located at the end of the chromosomes. During cell proliferation or growth, cells are replicated. However, DNA polymerases are unable to completely and exactly replicate cells. Thus, for each round of cell division, strands become shorter, and so do telomeres. Telomeres which contain significantly higher guanines are sensitive to oxidative stress. Senescent cells were found to have higher levels of modified guanines (von Zglinicki, 2005).
In a study by Nakashima et al in 2004, telomere length was found to be shorter in those with vascular and or metabolic diseases (Nakashima, 2004), indicating the role of telomeres as biomarkers of senescence.
In a study by Shah et al in 2014, correlated telomere length with senescence. The cardiac muscles tested for telomerase included the aorta, and the left and right ventricles. Among those subjects which increased Mg intake, there was an observed 70-88% downregulation or decrease in telomerase levels , an indication that telomere shortening is well combatted.
Further, several studies were made strengthening the theory that Mg deficiency increases the incidence of inflammatory chemicals or cytokines. One research has demonstrated that Mg deficient animals have higher TNF-Alpha levels. TNF-Alpha is indicative of lower telomerase levels and is associated with shorter telomeres.
A particular gene, the CDKN2A or the cyclin dependent kinase inhibitor 2A is said to be a tumor regulator. It belongs to the cyclin dependent kinase family which binds with the protein kinase to regulate the cell cycle. CDKN2A slows down the transition of a cell from G1 phase to S phase where in the former the cells increase in size and in the latter, the cells are replicated.
The CDKN2A is also responsible for the production of the tumor suppressors, P16 and P14 proteins. Both proteins regulate the growth of cells, such that it prevents a cell from growing too rapidly, thereby slowing cell growth and suppressing tumors. The protein P16 binds with CDK4 and CDK6, both responsible for cell growth. With the hampered ability to stimulate the cell cycle, P16 indirectly slows down cell growth.
The TP63 gene is a protein responsible for encoding enzymes which suppress tumor growth, thus the name tumor protein gene. Also called P63, it has been associated with developmental problems among rodents and bladder cancer in humans. Being a tumor limiting gene, it affects the cell cycle by inhibiting it.
The P14 protein meanwhile guards another protein, the P53. The latter inhibits mutation of a cell by promoting stability. It thus regulates the cell cycle and acts as a tumor suppressant. Aside from arresting growth, it prohibits DNA proliferation, thus defective cells are inhibited from multiplying. On one hand, the P53 protein also promotes apopstosis or cell death, whenever mutated cells cannot be aborted through its first two functions. . Thus, excessive P53 may accelerate aging (McCormick, 2001).
In a study done in 2014 by Serra et al, the p16INK4a was used as a marker for cell senesence. Various researches have used such as a marker for cell ageing since it has been found to accumulate as rodents and humans age. Further, it inhibits the cell cyle. . The rats exposed to radiation exhibited several cell senescence markers, and in increase in CDKN proteins such as P21 and P16. An analysis of liver proteins showed the presence of p21 among rats which were irradiated prior to the study, similar to the group which received further radiation in the later part. Likewise, an increase in P16 presence was found among irradiated rats (Serra et al, 2014).
Another marker used to determine the level senescence are splenocytes. The study by Connoy et al measured the presence of P16 among mice and correlate it with cellular senescence. Using flow cytometry, it was found that CD19 increased with age among rats. Moreover, P16INK4a, as an inhibitor was found to increase with age, along with increased presence of CD19. This strengthens the finding of previous researches that P16INK4a indeed accumulates with age.(Connoy, 2014)
The above mentioned studies strengthen the claim that telomerase shortening is an indicator of cell senescence. Further, the shortening is due to the inhibition of the cell cycle, due to P16INK4a and CDKN2A, the latter responsible for regulating tumor growth.
References
Allen Smith, A. Z.-T.-D. (2007). Intestinal inflammation caused by magnesium deficiency alters basal and oxidative stress-induced intestinal function.Springer Science Business Media, LLC 200.
Altura BM, S. N.-A. (2010). Short-term magnesium deficiency upregulates sphin-gomyelin synthase and p53 in cardiovascular tissues and cells: relevance to de novo synthesis of ceramide. American Journal of Physicians, H2046-H2055.
Aydin H, Deyneli O, Yavuz D, Gözü H, Mutlu N, Kaygusuz I, Akalin S. (2010). Short-term oral magnesium supplementation suppresses bone turnover in postmenopausal osteoporotic women. Biology Trace Elementary Research,133:136-43.
Bailey RL, Fulgoni III VL, Keast DR, Dwyer JD.(2011) Dietary supplement use is associated with high intakes of minerals from food sources. American Journal of Clinical Nutrition,1376-81.
Barbagallo, M., & Dominguez, L. J. (2012). Magnesium and the Cardiometabolic Syndrome . Current Nutrition Reports .
Barbagallo M., Belvedere M., Dominguez LJ. (2009) Magnesium homeostasis and aging. Magnesium Research,22:235-46.
CDKN2A. Retreived from https://ghr.nlm.nih.gov/gene/CDKN2A
Canadian Community health Survey. Retrieved from https://www.hc-sc.gc.ca/fn-an/surveill/nutrition/commun/art-nutr-adult-eng.php
Chaudhary DP1, B. R. (2007 Oct ). Implications of oxidative stress in high sucrose low magnesium diet fed rats. European Journal of Nutrition, 46(7):383-90.
Connoy, A, Trader, M., High, K.(2006) Age-related changes in cell surface and senescence markers in the spleen of DBA/2 mice: A flow cytometric analysis. Experimental Gerontology,. 225–229
Dietiticians of Canada. Retrieved from http://www.dietitians.ca/Your-Health/Nutrition-A-Z/Minerals/Food-Sources-of-Magnesium.aspx
Grace L, H. S. (2009). Effect of exercise on learning and memory in a rat model of developmental stress. Metabolic Brain Disorders, 643-657.
High, K. (2004). Infection as a cause of age-related morbidity and mortality. Ageing Review.
High, K. (2011). Murine models of infectious diseases in the aged. Handbook of Models of Human Aging. New York, NY: Academic Press
Huang, J.-H., Tsai, L.-C., & Chang, Y.-C. (2014). High or low calcium intake increases cardiovascular disease risks in older patients with type 2 diabetes . Cardiovascular Diabetology, 120
von Zglinicki, T.; Martin-Ruiz, C.; Saretzki, G. (2005). Telomeres, cell senescence and human ageing. Signal Transduct. 3
Kim, M; Ngo, M. (2004). Urinary 8-hydroxy-2'-deoxyguanosine as a biomarker of oxidative DNA damage in workers exposed to fine particulates. Environmental Health Perspective.
Killilea DW, A. B. (2008). Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts. National Academy of Sciences USA. 5768-73.
Larsson SC, Orsini N, Wolk A. (2012) Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies. American Journal of Clinical Nutrition, 95:362-6.
McKeown, M. N., Jacques, F. P., & Zhang, L. X. (2008). Dietary magnesium intake is related to metabolic syndrome in older Americans. European Journal of Nutrition.
McCormick F. (2001) Cancer gene therapy: fringe or cutting edge? National Review of Cancer. 130-141
Montuschi,M, Mondino, P., Koch, G., Ciabattoni, P. J. Barnes, and G. Baviera. (2007) Effects of montelukast treatment and withdrawal on fractional exhaled nitric oxide and lung function in children with asthma. Chest, 1876–188
Nakashima, H., Ozono, R., Suyama, C., Sueda, T., Kambe, M., & Oshima, T. (2004). Telomere attrition in white blood cell correlating with cardiovascular damage. Hypertension Research ,27:319–325.
Nemoto T, M. H. (2006). Magnesium-deficient diet-induced reduction in protein utilization in rats is reversed by dietary magnesium supplementation. Magnesium Research. 19-27.
Rude RK, G. H. (2005). Dietary magnesium reduction to 25% of nutrient requirement disrupts bone and mineral metabolism in the rat.Bone. 211-219.
Rude, K. R., Gruber, E. H., & Wei, Y. L. (2005). Immunolocalization of RANKL is Increased and OPG Decreased During Dietary Magnesium Deficiency in the Rat. Nutrition & Metabolism .
Schürks M, Diener H, Goadsby P. (2008) Update on the prophylaxis of migraine. Current Treatment Options Neurology,20–9
Serra, P, Marongiu, F.(2014) Hepatocyte senescence induced by radiation and partial hepatectomy in rat liver. International Journal of Radiation Biology, 876–883
Shigenaga, MK. Gimeno, C. Ames, B.(1989). Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc National Academy of Science U S A. 9697–9701.
Spencer, H., Norris,C. & Williams, D. (1994). Inhibitory effect of zinc on magnesium balance and absorption in man. Journal of American College of Nutrition, 13: 479-484.
Spasov AA, I. I. ( 2008). Depression-like and anxiety-related behaviour of rats fed with magnesium-deficient diet.Zh Vyssh Nerv Deiat Im I P Pavlova. 476-85
Swaminanthan, R.(2003) Magnesium Metabolism and its Disorders. Clinical Biochemistry Review, 47-66.
von Zglinicki, T.; Martin-Ruiz, C.; Saretzki, G. (2005). Human cell senescence as a DNA damage response. Mechanisms of ageing and Development, 111-117
Yu, AS. ( 2001). Evolving concepts in epithelial magnesium transport. Current Opinion on Nephrology and Hypertension, 649-653.
