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Magnesium and Longevity

A peer-reviewed article of this preprint also exists.

Submitted:

27 October 2024

Posted:

29 October 2024

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Abstract

Magnesium (Mg) is not prominent among the list of well known anti-aging agents. Yet the signs and symptoms of aging mimic those of Mg deficiency. Mg is a required cofactor for over 800 enzymatic reactions (as of 2022). This review does not correlate Mg status with clinical data on agents linked to longevity. The approach is physiologic and highlights specific Mg dependent reactions required by these longevity linked biomarkers. Many of these share common pathways to extend healthspan. Mg is a required cofactor in the synthesis of vitamin D and melatonin and activation of five of the eight B vitamins. It is a required cofactor for all CYP450 enzymes. It is directly responsible for the appropriate methylation of proteins and DNA, which control the epigenome. The MTHFR (methylenetetrahydrofolate reductase) 677T allele that compromises methylation is present in a majority of Americans. Aberrant methylation predicts the severity of Covid-19 and its persistence into long Covid. Mg is a silent benefactor that may indirectly link these longevity agents, but only if viewed in context with calcium (Ca), i.e., Ca:Mg. Both compete for the same receptor. To fully exploit these longevity agents sufficient Mg is required. The pertinent physiology is presented.

Keywords: 
histone deacetylase inhibitors
;  
methylation
;  
Ca:Mg
;  
MTHFR 677T
;  
gut microbiome
Subject: 
Biology and Life Sciences  -   Aging

Introduction

Optimal longevity involves extending healthspan, not just lifespan. Its pursuit has been energized by recent breakthroughs in our understanding of its pathobiology. The contribution of the gut microbiome to our general health is at the top of this list. Many elements are associated with longevity. Some are well known, e.g., high density lipoprotein cholesterol (HDL-C), heart rate variability (HRV), vitamin D, and telomeres. Others are less well known but well documented, e.g., aryl hydrocarbon receptors (AhRs), histone deacetylase inhibitors (HDACi). There are numerous molecules associated with longevity. Popular ones include short chain fatty acids (SCFAs), polyunsaturated fatty acids, and glucagon-like peptide-1 (GLP-1). Ozempic (semaglutide) is a GLP-1 agonist. Although well known for weight loss, it also brings longevity benefits. Almost all exhibit some connection to the gut microbiome. Many involve the epigenome and raise the question—can we control our genes to some extent by what we eat? Intake of Mg is critical. It is a requirement for over 800 enzymatic reactions1, not just the frequently quoted 300 enzymatic reactions. It is involved in over 80% of known metabolic functions2. The dominance of so many Mg dependent enzymes may in part explain why many Mg deficiency symptoms mimic those of aging3. Mg deficiency has long been connected to cellular senescence4. Mg potentiates each of the discussed longevity agents, either directly or indirectly by enhancing the precursors or metabolites of their designated biopathways. Half of Americans are deficient in Mg. This figure would be much higher if the lower limit of its acceptable range were to be slightly increased to eliminate normomagnesemia Mg deficiency, as indicated by intra-erythrocytic Mg5, now known as chronic latent Mg deficit.

DISCUSSION

I. Gut Microbiome

A healthy gut microbiome produces abundant longevity agents—secondary bile acids, indoles, and short chain fatty acids6. Each triggers secretion of GLP-17. GLP-1 agonists are also linked to longevity8,9, primarily because they preserve insulin sensitivity. This biomarker deteriorates with age, even in those with normal blood glucose and body weight10. Insulin resistance is an early hallmark of cancer, type 2 diabetes (T2DM), and dementia (T3DM)

A. Secondary Bile Acids

Primary bile acids are normally conjugated in the liver after hepatic degradation of cholesterol. This involves CYP450 enzymes, which are all Mg dependent11. These primary bile acids must be deconjugated before gut bacteria can dehydroxylate and dehydrogenate them to produce secondary bile acids12. A central pathway in the production of secondary bile acids by gut bacteria is 7-alpha dehydroxylation13. 7-dehydroxylated bile acids are the most potent agonists for host bile acid receptors14. This makes the subsequent 7-alpha dehydrogenation equally significant. This latter reaction is significantly enhanced by Mg15. The contribution of Mg to production of secondary bile acids is, therefore, operating in both the liver (CYP 450 enzymes) and the intestinal lumen (7-alpha dehydrogenase)
Gilbert’s syndrome, linked to longevity, is a genetic disorder characterized by an increase in unconjugated bilirubin16. It is characterized by less oxidative stress, less inflammaging, lower body mass index, stronger vagal tone and less risk for cardiovascular disease (CVD) or T2DM than healthy controls17. The longevity benefits in Gilbert’s Syndrome might be due to the fast tracking of unconjugated primary bile acids to secondary bile acids. Unconjugated primary bile acids normally compose less than 1% of total biliary acids18. Nonetheless, production of primary bile acids is critical and Mg deficiency compromises this. Bile acid production decreases with age19, as do Mg levels. Indeed the symptoms of Mg deficiency reflect those of aging3.

A. Indoles

The gut microbiome also produces indole/indole derivatives, longevity agents that also trigger release of GLP-1. Gut bacteria metabolize tryptophan, creating these indole derivatives. Down regulation of tryptophan dioxygenase (TDO) and indoleamine dioxygenase (IDO) increases tryptophan and decreases kynurenine, extending lifespan20 (see Figure 1).
Altered tryptophan metabolism (ATM) and increased kynurenine to tryptophan ratio are hallmarks of cancer, dementia, autoimmune disease, and obesity. In each tryptophan depletion is prominent, leaving less for indole synthesis. Indole derivative production also requires CYP 450 enzymes, all of which are Mg++ dependent11. Indoles also induce the release of GLP-1, known to suppress appetite, increase insulin secretion and slow gastric emptying8. Indoles are also ligands for aryl hydrocarbon receptors (see section IV), another longevity agent conduit.

A. Butyrate

Butyrate is another GLP-1 agonist21 and an aryl hydrocarbon ligand. Both are longevity indicators. Probiotics, rich in butyrogenic bacteria, are associated with longevity22 and Mg enhances probiotic efficacy23. Butyrate produced by gut bacteria via vagal afferents may improve HRV24,25. Candida and cancer cells are prominent secretagogues for HDAC26,27. Butyrate is an HDACi28 and may also mediate the efficacy of calorie restriction in enhancing longevity29. Gut microbiota cannot produce SCFAs in the absence of Mg30. Omega 3 fish oils upregulate SCFA production, especially butyrate31 and enhance biodiversity32.

I. Vitamin D

Vitamin D is another well recognized longevity agent33 and Mg is critical to its synthesis34. The active forms of vitamin B2 (FAD) and B3 (NAD), required for the synthesis of the D3 precursor, 7-dehydrocholesterol, are also Mg dependent (see Figure 2).
Vitamin D efficacy in longevity is linked to its healthful effects on methylation and the epigenome35. Vitamin D supplementation reduces total cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride levels but not HDL-C levels36 (see section V). Vitamin D reversibly improves the gut microbiome37. D3 directly inhibits Candida hyphal morphogenesis. Candida can produce its own IDO, which redirects and alters tryptophan metabolism (ATM)38.

I. Telomeres

The link between telomere length and mortality, like HDL-C (section VI), may be U shape. Initially telomere length was reported as positively linked to longevity. However, recently this has been challenged. Long telomeres may be associated with cancers39. Telomeres shorten with age (attrition) and longevity is characterized by less telomere attrition, i.e., longer telomeres v those less long lived40. This shortening is due to loss of telomere homeostasis with cellular senescence. Mg maintains telomere homeostasis41. Anti-aging agents and conditions that delay telomere shortening include vitamin D42, dietary Mg43, calorie restriction44, and GLP-145. Telomere attrition is influenced by oxidative stress, inflammation, insulin resistance, and hyperglycemia, well controlled by GLP-146. Gilbert’s Syndrome also manifests less telomere attrition47. Regulation of telomerase and telomere homeostasis is subject to epigenetic control and DNA methylation48 (see section VIII).

I. AhR

Recently the vital role of aryl hydrocarbon receptors (AhRs) in aging49, dementia, autoimmune disease, cancer50, and ASCVD51 has been recognized. AhR activity is dependent on its ligands. Kynurenines are AhR ligands that accelerate aging and neurodegeneration, while butyrates and indoles of intestinal bacterial origin are AhR ligands that oppose this49 and promote longevity. ATM inactivates the immune response dependent function of AhR52. Not only are indoles and butyrate AhR ligands53, but subsequent AhR activation induces cytochrome CYP450 enzymes that facilitate gut absorption of indoles54. All CYP450 enzymes are Mg dependent11. Indole derivatives also stimulate butyrate-producing gram-positive bacteria54.

I. HDL-C

HDL-C has long been linked to longevity55. However, more recent studies report that the HDL-CVD relationship is U-shape, i.e., low and extremely high HDL-C levels can entail health risks56. Mechanisms underlying this non-linear relationship are presently unknown. However, one study suggests that the capacity of HDL to acquire free cholesterol during triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk57. Lipoprotein lipase (LPL) induced lipolysis removes blood triglycerides. Elevated triglycerides directly compromise the ability of HDL to clear cholesterol, as HDL-C increases above 100 mg/dL. This creates a scenario of elevated but ineffectual HDL-C in a triglyceride rich environment, hypothetically explaining the increase in CVD despite extremely high HDL-C. LPL mediated lipolysis is the rate-limiting step in the removal of triglyceride from the bloodstream58 and also regulates HDL-C. LPL is Mg dependent59. Perhaps a Mg shortfall and its consequent impact on rate limiting LPL contribute to the increase in CVD, despite high HDL-C. Might Mg deficiency compromise the efficacy of elevated HDL just as it compromises the efficacy of vitamin D3?

I. HRV

Serum HDL-C levels correlate with high frequency HRV indices60. Low total cholesterol and LDL-C were significantly associated with low frequency HRV indices61. Not surprisingly HRV is another well recognized longevity agent62.
It can predict disease well before symptoms appear63 and directly reflects vagal tone64. Anti-aging butyrate suppresses food intake via vagal signals to the brain65.
Calorie restriction also improves HRV66. The impact of HRV and calorie restriction on longevity suggest that the appetite suppressing properties of butyrogenic gut bacteria via vagal afferents may increase HRV. This has recently been reported67. Mg level is positively related to HRV, while Ca/Mg ratio is negatively related to HRV68. Vitamins D and B-12 deficiencies are associated with reduced HRV69. The active forms of both are Mg dependent.

Melatonin, Resveratrol, Vitamin C, Tryptophan, and α-Ketoglutarate

Two popular decades old anti-aging supplements are melatonin and resveratrol.
Melatonin can be sourced endogenously from the pineal gland or exogenously. Its synthesis from tryptophan is Mg dependent (see Figure 1). Melatonin opposes CVD and neurodegenerative disease with antioxidant and anti-inflammatory properties70.
Many of the healthful benefits of resveratrol are mediated by Mg dependent enzymes, e.g., protein and nucleotide kinases. This enables resveratrol to function as anti cancer, antioxidant, anti obesity, anti-dementia, anti-T2DM, and anti CVD71. Moreover, resveratrol and quercetin, proven to extend lifespan, are compounds that can also serve as AhR ligands72. Mg enhances the anti cancer property of Vitamin C via SCVT (sodium coupled vitamin C transporter)73,74. Tryptophan has recently emerged as a longevity agent75. It opposes the hyphal morphogenesis of Candida76, associated with decreased healthspan. ATM is characterized by tryptophan depletion and increased K/T ratio and is associated with cancer, dementia, autoimmune disease, and T2DM78. Alpha-ketoglutarate is another recently discovered longevity agent, prominent in the Krebs cycle. Its longevity property mimics calorie restriction via inhibition of ATP synthase79. However, Mg enhances the efficacy of calorie restriction80 and probably α-KG as well. In addition the enzymes responsible for the synthesis of α-KG and glutamine from glutamate are both Mg dependent. Any Mg deficiency may increase glutamate, an anti-aging and dementia promoting agent81.

Methylation

Methylation of certain CpG islands (cytosine paired with guanine) in the DNA epigenome promotes or not the expression of other genes. Aberrant DNA methylation predicts aging82,83,84. Aberrant methylation enhances risks for cancer, dementia, and autoimmune disease85. This promotion/suppression mechanism for the epigenome occurs through transfer of methyl groups from SAMe to DNA and proteins (see Figure 3). Aberrancy arises when this transfer is compromised. Methylation is compromised by the 677T MTHFR allele, present in most Americans86, and certain vitamin B deficiencies (see Figure 3). B9 (folate) and B12 (cobalamin), critical to both the folic acid cycle and the methionine cycle, require methylation for activation. Heterozygous 677T reduces MTHFR activity by 35%, while the homozygous state reduces MTHFR activity by 70%87. B2 and B3 are FAD (flavin adenine dinucleotide) and NAD (niacinamide adenine dinucleotide) dependent respectively. Dinucleotides contain two phosphates, incorporation of which requires two ATP-Mg++ molecules. The active form of B6 also requires phosphorylation (ATP-Mg++). Therefore, any Mg deficiency further compromises optimal DNA methylation and accelerates aging.

I. Magnesium

Mg deficiency has been directly linked to aging88. However, the general consensus seems to be that Mg deficiency triggers altered Ca homeostasis. Ca:Mg is rarely mentioned.

A. Ca:Mg

The calcium sensing receptor (CaSR) is a Mg dependent G protein coupled receptor activated by Ca++ or Mg++89,90. Most of the focus between Mg and vitamin D pertains to the criticality of Mg in the synthesis of the sunshine vitamin. But vitamin D improves the absorption of not only Ca but also Mg, although to a lesser extent91. The active forms of Ca and Mg are their cations (Ca++, Mg++). Both bind to the CaSR and excess Ca++ can competitively inhibit Mg++. In the Western diet Ca outweighs Mg. According to NHANES (National Health and Nutrition Examination Surveys) the mean dietary intake of Ca:Mg for Americans has escalated from 2.6 in 1977 to over 3.0 since 2000. Between 1977 and 2012, US Ca intake increased at a rate 2—2.5 times that of Mg92. In1989 Jean Durlach, founder of the International Society for Development of Research on Magnesium, reported that 2.0 was the proper target ratio (circulating cation concentrations in mM). An elevated Ca:Mg ratio is characteristic of cancer, autoimmune disease93 and ASCVD94 and this ratio should be maintained between 1.7 and 2.892. The Oriental diet is typically low in Ca, while the Occidental diet is typically low in Mg95. This Ca:Mg imbalance is often overlooked, because a) Mg is not usually included in any lab chemistry panel, b) lower limit on the “normal” range may be too low, c) serum Mg (bound and free) does not reflect Mg++. The median intake of Mg is insufficient to fully exploit the healthful benefits of vitamin D, especially for CVD and colon cancer.96. This suggests that the lower limit of “normal” lab serum Mg++ values (.75-.95 mM), determined by extensive sampling from this large “healthy” population (50% are deficient), is too low. Several studies have suggested .85 mM, as a lower limit97,98. Yet lab range values for serum Mg++ in healthy controls remain unchanged, despite repeated alerts over the past two dozen years99,100,101. Another study of 91 participants found that a detailed diet questionnaire predicted suboptimal Mg status in 100%, yet lab testing confirmed this in only 76%102. Might this also challenge the validity of .75 mM as a lower limit? This gray zone between .75 and .85 may correspond to low intra-erythrocytic Mg when serum Mg is within normal limits. Initially termed normomagnesemia Mg deficiency5, it is now known as chronic latent Mg deficit. This has been demonstrated for migraines and PMS5.
Calculation of serum Mg++ in “healthy” individuals with normal renal function, with midrange serum albumin, and without medications can most likely be determined from serum Mg (bound and unbound). If one compares the normal ranges for serum Mg and Ca with the normal ranges for ionized Mg and Ca, they align exactly, but only if Mg++ and Ca++ represent 70% and 50% of total serum levels respectively. When the midpoints of the ranges for the ionized forms (Ca++ = 1.2 mM, Mg++ = .6 mM) is determined, the Ca:Mg is 2.0, very much in line with Durlach’s recommendation.
This means that if the lower limit of normal for serum Mg were to be raised to .85 mM (2.0 mg/dL), then to maintain this recommended ratio the lower limit of normal for serum Ca should be raised to ~2.4 mM (9.5 mg/dL). This increase in the lower limit of normal Ca in addition to Mg seems appropriate. According to the NIH, data from NHANES 2009-2010 indicated that 42% of Americans did not meet their Estimated Average Requirements for Ca as recommended by the Institute of Medicine103. The prevalence of Ca deficiency is even greater in low and middle income countries104.

A. Magnesium and Covid-19

Ca:Mg > 5.0 is strongly associated with Covid-19 mortality105. Mg levels directly correlate with Covid-19 disease for risk of hospitalization, length of stay, mortality, and long Covid106. Ca:Mg might even further refine this link with severity. Among individuals less than 65 y with Ca:Mg > 2.6, reducing the ratio to around 2.3 downregulated the TMPRSS2 gene. Decreasing Ca:Mg improved methylation and ameliorated or prevented Covid-19107. Aberrant methylation is not only a biomarker for Covid-19 but also for long Covid108. This suggests that those with the 677T MTHFR variant allele (half of Americans) are at greater risk, as has been reported109.
In summary, the dozen or so longevity agents evaluated in this review appear to be linked to Mg, either directly in the synthesis of the agent or indirectly along the relevant metabolic pathway. Although the magnitude of their impact in any individual is complex and impossible to quantitate, their limited presence in those on a Western diet or lifestyle is difficult to deny. Additional longevity agents may yet be discovered, expanding options in our quest for longevity. Figure 4 illustrates their interlinkage.

A. Therapeutic Interventions

The first step in addressing a potential Mg shortage is to assess Ca:Mg. If greater than 2.6, then efforts must be directed to lowering oral intake of Ca. Otherwise, increasing oral Mg will lower PTH and suppress Mg absorption. Administering a variety of Mg chelates, e.g., glycinate, maleate, taurate, threonate, also enhances absorption. Bowel tolerance should be the limiting factor and should be approached slowly. Mg citrate is especially noted for its laxative side effect. Combining oral intake of Mg with vitamin D is also helpful.
Mg bioavailability is increased by concomitant intake of the active form of vitamin B, pyridoxal phosphate (PLP)110. PLP, but not pyridoxine, appears to form a complex with Mg and hence may enhance the transport or accumulation of Mg in cells111. However, several old and recent articles have challenged this beneficial effect of B6 on Mg absorption112,113, but both employed Magne, which is 300 mg Mg and 30 mg pyridoxine. Another article claimed that B6 enhances erythrocytic Mg but only at high doses and that high doses risk peripheral neuropathy. This study also used Magne114.
Even the NIH in its Aug 2023 update on B6 failed to acknowledge the efficacy differential between pyridoxine and PLP. Furthermore, taking P5P concomitantly with Mg can potentially double110 or triple111 the absorption of Mg. Not only does PLP enhance cellular uptake of Mg but Mg enhances that of PLP115. B6 as pyridoxine, the inactive form and the most common form in B supplements, competitively inhibits P5P, the active form, and can cause peripheral neuropathy116. B2 as FAD is a Mg dependent and required cofactor for the synthesis of PLP. This means that if B2 is deficient without PLP supplementation, then B6 supplementation as pyridoxine can cause symptoms of B6 deficiency. Synthesis of PLP is also Mg dependent.
Not surprisingly B vitamins are linked to longevity117. Of the eight, five require Mg to attain activated status. B2 as FAD, B3 as NAD, and B6 as pyridoxal phosphate require phosphorylation. B9 and B12 require methylation. All phosphorylation and methylation reactions require Mg. All five of these B vitamins are critical to methylation (see Figure 3). The value of a prebiotic, e.g., sauerkraut, kimchi, D-mannose, probiotic, e.g., yogurt, and postbiotic, e.g., butyrate, in the quest for a better gut microbiome and healthful longevity cannot be underestimated. Fecal microbiota transplantation has shown significant efficacy in treating cancer118, autoimmune disease119, and dementia120. This suggests that it is never too late to upgrade your gut microbiome in any therapeutic approach to disease, much less any preventative one (see Figure 4).

Conclusions

Bile acids and HDL-C are longevity agents that necessitate hepatic metabolism by magnesium dependent CYP450 enzymes. Production of indoles by gut bacteria also require magnesium dependent CYP450 enzymes. Syntheses of the active forms of vitamins D,B2,B3,B6,B9, and B12 are magnesium dependent. These activated B vitamins and Mg++ are all required cofactors in the remethylation (folate) and transmethylation (methionine) cycles, critical to the epigenome. Any shortfall in Mg status will weaken methylation and exacerbate the significant health problems associated with the MTHFR 677T variant allele, present in the majority of Americans (see Figure 3). Aberrant methylation compromises the immune response to SARS CoV2 and increases risk for long Covid. Magnesium potentiates the healthful benefits of the gut microbiome. It actively suppresses obesity and T2DM. The longevity properties of Mg are highly dependent on Ca:Mg, rarely mentioned in contrarian reviews on the benefits of vitamin D or Mg supplementation. Health problems related to normomagnesemia Mg deficiency, e.g., migraines and premenstrual syndrome, challenge the validity of the accepted lower limit for serum Mg. Although the discussed biochemistry and physiology are generally accepted, convincing clinical data supporting the underappreciated role of Mg in longevity awaits.

References

  1. Fiorentini D, Cappadone C, Farruggia G, Prata C. Magnesium: Biochemistry, Nutrition, Detection, and Social Impact of Diseases Linked to Its Deficiency. Nutrients. 2021 Mar 30;13(4):1136. [CrossRef]
  2. Workinger JL, Doyle RP, Bortz J. Challenges in the Diagnosis of Magnesium Status. Nutrients. 2018 Sep 1;10(9):1202. [CrossRef]
  3. Dominguez LJ, Veronese N, Barbagallo M. Magnesium and the Hallmarks of Aging. Nutrients. 2024; 16(4):496. [CrossRef]
  4. Killilea DW, Maier JA. A connection between magnesium deficiency and aging: new insights from cellular studies. Magnes Res. 2008 Jun;21(2):77-82. Available online: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2790427/.
  5. Mansmann, H.C. (1993) Consider Magnesium Homeostasis: II: Staging of Magnesium Deficiencies. Pediatric Allergy, Immunology and Pulmonology, 7, 211-215. [CrossRef]
  6. Jin L, Shi L, Huang W. The role of bile acids in human aging. Med Rev (2021). 2024 Mar 7;4(2):154-157. [CrossRef]
  7. Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne). 2023 Jul 25;14:1169624. [CrossRef]
  8. Chavda VP, Balar PC, Vaghela DA, Dodiya P. Unlocking longevity with GLP-1: A key to turn back the clock? Maturitas. 2024 Aug;186:108028. [CrossRef]
  9. Wei Peng , Rui Zhou , Ze-Fang Sun , Jia-Wei Long , Yong-Qiang Gong. Novel Insights into the Roles and Mechanisms of GLP-1 Receptor Agonists against Aging-Related Diseases. Aging and disease. 2022, 13(2): 468-490. [CrossRef]
  10. Huang LY, Liu CH, Chen FY, Kuo CH, Pitrone P, Liu JS. Aging Affects Insulin Resistance, Insulin Secretion, and Glucose Effectiveness in Subjects with Normal Blood Glucose and Body Weight. Diagnostics (Basel). 2023 Jun 24;13(13):2158. [CrossRef]
  11. Mansmann, H.C. (1994). Consider magnesium homeostasis: III: cytochrome P450 enzymes and drug toxicity. Applied Immunohistochemistry & Molecular Morphology, 8, 7-28. [CrossRef]
  12. Fuchs, C.D., Trauner, M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 19, 432–450 (2022). [CrossRef]
  13. Wise JL, Cummings BP. The 7-α-dehydroxylation pathway: An integral component of gut bacterial bile acid metabolism and potential therapeutic target. Front Microbiol. 2023 Jan 9;13:1093420. [CrossRef]
  14. Vico-Oton, E., Volet, C., Jacquemin, N. et al. Strain-dependent induction of primary bile acid 7-dehydroxylation by cholic acid. BMC Microbiol 24, 286 (2024). [CrossRef]
  15. Ji S, Pan Y, Zhu L, Tan J, Tang S, Yang Q, Zhang Z, Lou D, Wang B. A novel 7α-hydroxysteroid dehydrogenase: Magnesium ion significantly enhances its activity and thermostability. Int J Biol Macromol. 2021 Apr 30;177:111-118. [CrossRef]
  16. Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert’s syndrome and the risk of death: a population-based cohort study. J Gastroenterol Hepatol. 2013 Oct;28(10):1643-7. [CrossRef]
  17. Wagner KH, Khoei NS, Hana CA, Doberer D, Marculescu R, Bulmer AC, Hörmann-Wallner M, Mölzer C. Oxidative Stress and Related Biomarkers in Gilbert’s Syndrome: A Secondary Analysis of Two Case-Control Studies. Antioxidants (Basel). 2021 Sep 15;10(9):1474. [CrossRef]
  18. Matoba N, Une M, Hoshita T. Identification of unconjugated bile acids in human bile. J Lipid Res. 1986 Nov;27(11):1154-62. [CrossRef]
  19. Li XJ, Fang C, Zhao RH, Zou L, Miao H, Zhao YY. Bile acid metabolism in health and ageing-related diseases. Biochem Pharmacol. 2024 Jul;225:116313. [CrossRef]
  20. Oxenkrug G, Navrotska V. Extension of life span by down-regulation of enzymes catalyzing tryptophan conversion into kynurenine: Possible implications for mechanisms of aging. Exp Biol Med (Maywood). 2023 Apr;248(7):573-577. [CrossRef]
  21. Gribble, F.M., Reimann, F. Metabolic Messengers: glucagon-like peptide 1. Nat Metab 3, 142–148 (2021). [CrossRef]
  22. Chaudhary, P., Kathuria, D., Suri, S., Bahndral, A., & Kanthi Naveen, A. (2023). Probiotics- its functions and influence on the ageing process: A comprehensive review. Food Bioscience. [CrossRef]
  23. Mahboobi S, Ghasvarian M, Ghaem H, Alipour H, Alipour S, Eftekhari MH. Effects of probiotic and magnesium co-supplementation on mood, cognition, intestinal barrier function and inflammation in individuals with obesity and depressed mood: A randomized, double-blind placebo-controlled clinical trial. Front Nutr. 2022 Sep 28;9:1018357. [CrossRef]
  24. Seefeldt, J.M., Homilius, C., Hansen, J., Lassen, T.R., Jespersen, N.R., Jensen, R.V., et al. (2024). Short-Chain Fatty Acid Butyrate Is an Inotropic Agent With Vasorelaxant and Cardioprotective Properties. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 13. [CrossRef]
  25. Yu Z, Han J, Chen H, Wang Y, Zhou L, Wang M, et al. Oral Supplementation With Butyrate Improves Myocardial Ischemia/Reperfusion Injury via a Gut-Brain Neural Circuit. Front Cardiovasc Med. 2021 Sep 23;8:718674. [CrossRef]
  26. Su S, Li X, Yang X, Li Y, Chen X, Sun S, Jia S. Histone acetylation/deacetylation in Candida albicans and their potential as antifungal targets. Future Microbiol. 2020 Jul;15:1075-1090. [CrossRef]
  27. Alseksek RK, Ramadan WS, Saleh E, El-Awady R. The Role of HDACs in the Response of Cancer Cells to Cellular Stress and the Potential for Therapeutic Intervention. Int J Mol Sci. 2022 Jul 24;23(15):8141. [CrossRef]
  28. Yu, R., Cao, X., Sun, L. et al. Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism. Nat Commun12, 1981 (2021). [CrossRef]
  29. Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020 Jan 31;11:25. [CrossRef]
  30. Sasaki H, Hayashi K, Imamura M, Hirota Y, Hosoki H, Nitta L, et al. Combined resistant dextrin and low-dose Mg oxide administration increases short-chain fatty acid and lactic acid production by gut microbiota. J Nutr Biochem. 2023 Oct;120:109420. [CrossRef]
  31. Nogal A, Valdes AM, Menni C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes. 2021 Jan-Dec;13(1):1-24. [CrossRef]
  32. Menni, C., Zierer, J., Pallister, T. et al. Omega-3 fatty acids correlate with gut microbiome diversity and production of N-carbamylglutamate in middle aged and elderly women. Sci Rep 7, 11079 (2017). [CrossRef]
  33. Fantini C, Corinaldesi C, Lenzi A, Migliaccio S, Crescioli C. Vitamin D as a Shield against Aging. Int J Mol Sci. 2023 Feb 25;24(5):4546. [CrossRef]
  34. Rude RK, Adams JS, Ryzen E, Endres DB, Niimi H, Horst RL, Haddad JG Jr, Singer FR. Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab. 1985 Nov;61(5):933-40. [CrossRef]
  35. Ong LTC, Booth DR, Parnell GP. Vitamin D and its Effects on DNA Methylation in Development, Aging, and Disease. Mol Nutr Food Res. 2020 Dec;64(23):e2000437. [CrossRef]
  36. Daniel T Dibaba, Effect of vitamin D supplementation on serum lipid profiles: a systematic review and meta-analysis, Nutrition Reviews, Volume 77, Issue 12, December 2019, Pages 890–902. [CrossRef]
  37. Thomas, R.L., Jiang, L., Adams, J.S. et al. Vitamin D metabolites and the gut microbiome in older men. Nat Commun 11, 5997 (2020). [CrossRef]
  38. Kherad Z, Yazdanpanah S, Saadat F, Pakshir K, Zomorodian K. Vitamin D3: A promising antifungal and antibiofilm agent against Candida species. Curr Med Mycol. 2023 Jun;9(2):17-22. Available online: https://pubmed.ncbi.nlm.nih.gov/38375518/.
  39. DeBoy EA, Tassia MG, Schratz KE, Yan SM, Cosner ZL, McNally EJ, Gable DL, Xiang Z, Lombard DB, Antonarakis ES, Gocke CD, McCoy RC, Armanios M. Familial Clonal Hematopoiesis in a Long Telomere Syndrome. N Engl J Med. 2023 Jun 29;388(26):2422-2433. [CrossRef]
  40. Ye Q, Apsley AT, Etzel L, Hastings WJ, Kozlosky JT, Walker C, et al. Telomere length and chronological age across the human lifespan: A systematic review and meta-analysis of 414 study samples including 743,019 individuals. Ageing Res Rev. 2023 Sep;90:102031. [CrossRef]
  41. Maguire D, Neytchev O, Talwar D, McMillan D, Shiels PG. Telomere Homeostasis: Interplay with Magnesium. Int J Mol Sci. 2018 Jan 5;19(1):157. [CrossRef]
  42. Richards JB, Valdes AM, Gardner JP, Paximadas D, Kimura M, Nessa A, et al., Swaminathan R, Spector TD, Aviv A. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr. 2007 Nov;86(5):1420-5. [CrossRef]
  43. Hu L, Bai Y, Hu G, Zhang Y, Han X, Li J. Association of Dietary Magnesium Intake With Leukocyte Telomere Length in United States Middle-Aged and Elderly Adults. Front Nutr. 2022 May 19;9:840804. [CrossRef]
  44. Hastings WJ, Ye Q, Wolf SE, Ryan CP, Das SK, Huffman KM, Kobor MS, Kraus WE, MacIsaac JL, Martin CK, Racette SB, Redman LM, Belsky DW, Shalev I. Effect of long-term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis. Aging Cell. 2024 Jun;23(6):e14149. [CrossRef]
  45. Ridout KK, Syed SA, Kao HT, Porton B, Rozenboym AV, Tang J, et al. Relationships Between Telomere Length, Plasma Glucagon-like Peptide 1, and Insulin in Early-Life Stress-Exposed Nonhuman Primates. Biol Psychiatry Glob Open Sci. 2021 Aug 3;2(1):54-60. [CrossRef]
  46. Wang J, Dong X, Cao L, Sun Y, Qiu Y, Zhang Y, Cao R, Covasa M, Zhong L. Association between telomere length and diabetes mellitus: A meta-analysis. J Int Med Res. 2016 Dec;44(6):1156-1173. [CrossRef]
  47. Tosevska A, Moelzer C, Wallner M, Janosec M, Schwarz U, Kern C, et al. Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert’s Syndrome. Sci Rep. 2016 Mar 1;6:22300. [CrossRef]
  48. Dogan F, Forsyth NR. Telomerase Regulation: A Role for Epigenetics. Cancers (Basel). 2021 Mar 10;13(6):1213. [CrossRef]
  49. Ojo ES, Tischkau SA. The Role of AhR in the Hallmarks of Brain Aging: Friend and Foe. Cells. 2021 Oct 13;10(10):2729. [CrossRef]
  50. Wang Z, Snyder M, Kenison JE, Yang K, Lara B, Lydell E, et al. How the AhR Became Important in Cancer: The Role of Chronically Active AhR in Cancer Aggression. Int J Mol Sci. 2020 Dec 31;22(1):387. [CrossRef]
  51. Zhu K, Meng Q, Zhang Z, Yi T, He Y, Zheng J, Lei W. Aryl hydrocarbon receptor pathway: Role, regulation and intervention in atherosclerosis therapy (Review). Mol Med Rep. 2019 Dec;20(6):4763-4773. [CrossRef]
  52. Seo, SK., Kwon, B. Immune regulation through tryptophan metabolism.Exp Mol Med 55, 1371–1379 (2023). [CrossRef]
  53. Marinelli, L., Martin-Gallausiaux, C., Bourhis, JM. et al. Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci Rep 9, 643 (2019). [CrossRef]
  54. Li X, Zhang B, Hu Y, Zhao Y. New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases. Front Pharmacol. 2021 Dec 13;12:769501. [CrossRef]
  55. Rahilly-Tierney C, Sesso HD, Michael Gaziano J, Djoussé L. High-density lipoprotein and mortality before age 90 in male physicians. Circ Cardiovasc Qual Outcomes. 2012 May;5(3):381-6. [CrossRef]
  56. Franczyk B, Rysz J, Ławiński J, Rysz-Górzyńska M, Gluba-Brzózka A. Is a High HDL-Cholesterol Level Always Beneficial? Biomedicines. 2021; 9(9):1083. [CrossRef]
  57. Feng M, Darabi M, Tubeuf E, Canicio A, Lhomme M, Frisdal E, et al. Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease. Eur J Prev Cardiol. 2020 Oct;27(15):1606-1616. [CrossRef]
  58. Basu D, Goldberg IJ. Regulation of lipoprotein lipase-mediated lipolysis of triglycerides. Curr Opin Lipidol. 2020 Jun;31(3):154-160. [CrossRef]
  59. Mathew AA, Panonnummal R. ‘Magnesium’-the master cation-as a drug-possibilities and evidences. Biometals. 2021 Oct;34(5):955-986. [CrossRef]
  60. Balikai FA, Javali SB, Shindhe VM, Deshpande N, Benni JM, Shetty DP, et al. Correlation of serum HDL level with HRV indices using multiple linear regression analysis in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2022 Aug;190:109988. [CrossRef]
  61. Lin, S., Lee, I.H., Tsai, H.C., Chi, M.H., Chang, W.H., Chen, P.S., Chen, K., & Yang, Y. (2019). The association between plasma cholesterol and the effect of tryptophan depletion on heart rate variability. The Kaohsiung Journal of Medical Sciences, 35, 440—445. [CrossRef]
  62. Hernández-Vicente A, Hernando D, Santos-Lozano A, Rodríguez-Romo G, Vicente-Rodríguez G, Pueyo E, et al. Heart Rate Variability and Exceptional Longevity. Front Physiol. 2020 Sep 17;11:566399. [CrossRef]
  63. Jarczok MN, Weimer K, Braun C, Williams DP, Thayer JF, Gündel HO, Balint EM. Heart rate variability in the prediction of mortality: A systematic review and meta-analysis of healthy and patient populations. Neurosci Biobehav Rev. 2022 Dec;143:104907. [CrossRef]
  64. Gidron Y, Deschepper R, De Couck M, Thayer JF, Velkeniers B. The Vagus Nerve Can Predict and Possibly Modulate Non-Communicable Chronic Diseases: Introducing a Neuroimmunological Paradigm to Public Health. J Clin Med. 2018 Oct 19;7(10):371. [CrossRef]
  65. Goswami C, Iwasaki Y, Yada T. Short-chain fatty acids suppress food intake by activating vagal afferent neurons. J Nutr Biochem. 2018 Jul;57:130-135. [CrossRef]
  66. 66 Nicoll R, Henein MY. Caloric Restriction and Its Effect on Blood Pressure, Heart Rate Variability and Arterial Stiffness and Dilatation: A Review of the Evidence. Int J Mol Sci. 2018 Mar 7;19(3):751. [CrossRef]
  67. Tsubokawa M, Nishimura M, Mikami T, Ishida M, Hisada T, Tamada Y. Association of Gut Microbial Genera with Heart Rate Variability in the General Japanese Population: The Iwaki Cross-Sectional Research Study. Metabolites. 2022 Aug 7;12(8):730. [CrossRef]
  68. Kim YH, Jung KI, Song CH. Effects of serum calcium and magnesium on heart rate variability in adult women. Biol Trace Elem Res. 2012 Dec;150(1-3):116-22. [CrossRef]
  69. Lopresti AL. Association between Micronutrients and Heart Rate Variability: A Review of Human Studies. Adv Nutr. 2020 May 1;11(3):559-575. [CrossRef]
  70. Martín Giménez VM, de Las Heras N, Lahera V, Tresguerres JAF, Reiter RJ, Manucha W. Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases. Front Aging Neurosci. 2022 Jun 3;14:888292. [CrossRef]
  71. Meng X, Zhou J, Zhao CN, Gan RY, Li HB. Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review. Foods. 2020 Mar 14;9(3):340. [CrossRef]
  72. Abudahab S, Price ET, Dozmorov MG, Deshpande LS, McClay JL. The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process. J Nutr Health Aging. 2023;27(4):291-300. [CrossRef]
  73. Roa FJ, Peña E, Gatica M, Escobar-Acuña K, Saavedra P, Maldonado M, Cuevas ME, Moraga-Cid G, Rivas CI, Muñoz-Montesino C. Therapeutic Use of Vitamin C in Cancer: Physiological Considerations. Front Pharmacol. 2020 Mar 3;11:211. [CrossRef]
  74. Cho S, Chae JS, Shin H, Shin Y, Kim Y, Kil EJ, Byun HS, Cho SH, Park S, Lee S, Yeom CH. Enhanced Anticancer Effect of Adding Magnesium to Vitamin C Therapy: Inhibition of Hormetic Response by SVCT-2 Activation. Transl Oncol. 2020 Feb;13(2):401-409. [CrossRef]
  75. Dang, H., Castro-Portuguez, R., Espejo, L. et al. On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging. Nat Commun 14, 8338 (2023). [CrossRef]
  76. Bozza, S, Fallarino, F, Pitzurra, L, Zelante, T, Montagnoli, C, Bellocchio, S, et al.; A Crucial Role for Tryptophan Catabolism at the Host/Candida albicans Interface. J Immunol 1 March 2005; 174 (5): 2910–2918. [CrossRef]
  77. Chambers, PW, Hyphae and Healthspan: Hypothesis. ResearchGate June (2024). [CrossRef]
  78. Xue C, Li G, Zheng Q, Gu X, Shi Q, Su Y, et al. Tryptophan metabolism in health and disease. Cell Metab. 2023 Aug 8;35(8):1304-1326. [CrossRef]
  79. Naeini SH, Mavaddatiyan L, Kalkhoran ZR, Taherkhani S, Talkhabi M. Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives. Exp Gerontol. 2023 May;175:112154. [CrossRef]
  80. Abraham KJ, Chan JN, Salvi JS, Ho B, Hall A, Vidya E, Guo R, Killackey SA, Liu N, Lee JE, Brown GW, Mekhail K. Intersection of calorie restriction and magnesium in the suppression of genome-destabilizing RNA-DNA hybrids. Nucleic Acids Res. 2016 Oct 14;44(18):8870-8884. [CrossRef]
  81. Cox MF, Hascup ER, Bartke A, Hascup KN. Friend or Foe? Defining the Role of Glutamate in Aging and Alzheimer’s Disease. Front Aging. 2022 Jun 16;3:929474. [CrossRef]
  82. Seale, K., Horvath, S., Teschendorff, A. et al. Making sense of the ageing methylome. Nat Rev Genet 23, 585–605 (2022)2). [CrossRef]
  83. Salameh Y, Bejaoui Y, El Hajj N. DNA Methylation Biomarkers in Aging and Age-Related Diseases. Front Genet. 2020 Mar 10;11:171. [CrossRef]
  84. Horvath, S., Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19, 371–384 (2018). [CrossRef]
  85. Milicic L, Porter T, Vacher M, Laws SM. Utility of DNA Methylation as a Biomarker in Aging and Alzheimer’s Disease. J Alzheimers Dis Rep. 2023 May 31;7(1):475-503. [CrossRef]
  86. MTHFR Gene Variant and Folic Acid Facts. Available online: https://www.cdc.gov/folic-acid/data-research/mthfr/index.
  87. Moll S and Varga E, Homocysteine and MTHFRMutations, Circulation 132(1). [CrossRef]
  88. Barbagallo M, Veronese N, Dominguez LJ. Magnesium in Aging, Health and Diseases. Nutrients. 2021; 13(2):463. [CrossRef]
  89. Zhang C, Zhang T, Zou J, Miller CL, Gorkhali R, Yang JY, et al. Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist. Sci Adv. 2016 May 27;2(5):e1600241. [CrossRef]
  90. Ferrè S, Hoenderop JG, Bindels RJ. Sensing mechanisms involved in Ca2+ and Mg2+ homeostasis. Kidney Int. 2012 Dec;82(11):1157-66. [CrossRef]
  91. Hardwick LL, Jones MR, Brautbar N, Lee DB. Magnesium absorption: mechanisms and the influence of vitamin D, calcium and phosphate. J Nutr. 1991 Jan;121(1):13-23. [CrossRef]
  92. Rosanoff, A., Dai, Q. and Shapses, S.A. (2016) Essential Nutrient Interactions: Does Low or Suboptimal Magnesium Status Interact with Vitamin D and/or Calcium Status? Advances in Nutrition, 7, 25-43. [CrossRef]
  93. Ashique S, Kumar S, Hussain A, Mishra N, Garg A, Gowda BHJ, et al. A narrative review on the role of magnesium in immune regulation, inflammation, infectious diseases, and cancer. J Health Popul Nutr. 2023 Jul 27;42(1):74. [CrossRef]
  94. Yang Z, Zhang Y, Gao J, Yang Q, Qu H, Shi J. Association between dietary magnesium and 10-year risk of a first hard atherosclerotic cardiovascular disease event. Am J Med Sci. 2024 May 26:S0002-9629(24)01261-8. [CrossRef]
  95. Du K, Zheng X, Ma ZT, Lv JY, Jiang WJ, Liu MY. Association of Circulating Magnesium Levels in Patients With Alzheimer’s Disease From 1991 to 2021: A Systematic Review and Meta-Analysis. Front Aging Neurosci. 2022 Jan 10;13:799824. [CrossRef]
  96. Deng, X., Song, Y., Manson, J.E. et al. Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Med 11, 187 (2013). [CrossRef]
  97. Costello R.B., Elin R.J., Rosanoff A., Wallace T.C., Guerrero-Romero F., Hruby A., Lutsey P.L., Nielsen F.H., Rodriguez-Moran M., Song Y., et al. Perspective: The Case for an Evidence-Based Reference Interval for Serum Magnesium: The Time Has Come. Adv. Nutr. 2016;7:977–993. [CrossRef]
  98. Razzaque MS. Magnesium: Are We Consuming Enough? Nutrients. 2018; 10(12):1863. [CrossRef]
  99. Elin, R.J. Assessment of magnesium status for diagnosis and therapy. Magnes Res. 2010 Dec;23(4):S194-8. [CrossRef]
  100. Micke, O., Vormann, J., Kraus, A. and Kisters, K. (2021) Serum Magnesium: Time for a Standardized and Evidence-Based Reference Range. Magnetic Resonance, 34, 84-89. Available online: https://www.magnesium-ges.de/Micke_et_al._2021.pdf.
  101. Rosanoff A, West C, Elin RJ, Micke O, Baniasadi S, Barbagallo M, et al. MaGNet Global Magnesium Project (MaGNet). Recommendation on an updated standardization of serum magnesium reference ranges. Eur J Nutr. 2022 Oct;61(7):3697-3706. [CrossRef]
  102. Weiss D, Brunk DK, Goodman DA. Scottsdale Magnesium Study: Absorption, Cellular Uptake, and Clinical Effectiveness of a Timed-Release Magnesium Supplement in a Standard Adult Clinical Population. J Am Coll Nutr. 2018 May-Jun;37(4):316-327. [CrossRef]
  103. Hoy MK, Goldman JD. Calcium intake of the U.S. population: What We Eat in America, NHANES 2009-2010. 2014 Sep. Available online: https://www.ncbi.nlm.nih.gov/books/NBK589560/.
  104. Shlisky J, Mandlik R, Askari S, Abrams S, Belizan JM, Bourassa MW, Cormick G, Driller-Colangelo A, Gomes F, Khadilkar A, Owino V, Pettifor JM, Rana ZH, Roth DE, Weaver C. Calcium deficiency worldwide: prevalence of inadequate intakes and associated health outcomes. Ann N Y Acad Sci. 2022 Jun;1512(1):10-28. [CrossRef]
  105. Guerrero-Romero F, Mercado M, Rodriguez-Moran M, et al. Magnesium-to-Calcium Ratio and Mortality from COVID-19. Nutrients. 2022 Apr;14(9):1686. [CrossRef]
  106. La Carrubba A, Veronese N, Di Bella G, Cusumano C, Di Prazza A, Ciriminna S, et al. Prognostic Value of Magnesium in COVID-19: Findings from the COMEPA Study. Nutrients. 2023 Feb 6;15(4):830. [CrossRef]
  107. Fan L, Zhu X, Zheng Y, Zhang W, Seidner DL, Ness R, Murff HJ, Yu C, Huang X, Shrubsole MJ, Hou L, Dai Q. Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2). Nutrition. 2021 Sep;89:111340. [CrossRef]
  108. Balnis J, Madrid A, Drake LA, Vancavage R, Tiwari A, Patel VJ, et al. Blood DNA methylation in post-acute sequelae of COVID-19 (PASC): a prospective cohort study. EBioMedicine. 2024 Aug;106:105251. [CrossRef]
  109. Ponti G, Pastorino L, Manfredini M, Ozben T, Oliva G, Kaleci S, Iannella R, Tomasi A. COVID-19 spreading across world correlates with C677T allele of the smethylenetetrahydrofolate reductase (MTHFR) gene prevalence. J Clin Lab Anal. 2021 Jul;35(7):e23798. [CrossRef]
  110. Abraham, G.E.; Schwartz, U.D.; Lubran, M.M. Effect of vitamin B-6 on plasma and red blood cell magnesium levels in premenopausal women. Ann. Clin. Lab. Sci. 1981, 11, 333–336. Available online: https://pubmed.ncbi.nlm.nih.gov/7271227/.
  111. Boylan, L.M.; Spallholz, J.E. In vitro evidence for a relationship between magnesium and vitamin B-6. Magnes. Res. 1990, 3, 79–85. Available online: https://pubmed.ncbi.nlm.nih.gov/2133627/.
  112. Noah, L., Pickering, G., Dubray, C., Mazur, A., Hitier, S., & Pouteau, E. (2020). Effect of vitamin B6 supplementation, in combination with magnesium, on severe stress and magnesium status: Secondary analysis from an RCT. Proceedings of the Nutrition Society, 79(OCE2), E491. [CrossRef]
  113. Pouteau E, Kabir-Ahmadi M, Noah L, Mazur A, Dye L, Hellhammer J, Pickering G, Dubray C. Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial. PLoS ONE 2018 Dec 18;13(12):e0208454. [CrossRef]
  114. Eisinger J, Dagorn J. Vitamin B6 and magnesium. Magnesium. 1986;5(1):27-32. Available online: https://pubmed.ncbi.nlm.nih.gov/3959594/.
  115. Planells E, Lerma A, Sánchez-Morito N, Aranda P, LLopis J. Effect of magnesium deficiency on vitamin B2 and B6 status in the rat. J Am Coll Nutr. 1997 Aug;16(4):352-6. [CrossRef]
  116. Vrolijk MF, Opperhuizen A, Jansen EHJM, Hageman GJ, Bast A, Haenen GRMM. The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Toxicol In Vitro. 2017 Oct;44:206-212. [CrossRef]
  117. Mikkelsen K, Apostolopoulos V. B Vitamins and Ageing. Subcell Biochem. 2018;90:451-470. [CrossRef]
  118. Stoff R, Wolf Y, Boursi B. Fecal Microbiota Transplantation as a Cancer Therapeutic. Cancer J. 2023 Mar-Apr 01;29(2):102-108. [CrossRef]
  119. Liu X, Liu M, Zhao M, Li P, Gao C, Fan X, Cai G, Lu Q, Chen X. Fecal microbiota transplantation for the management of autoimmune diseases: Potential mechanisms and challenges. J Autoimmun. 2023 Dec;141:103109. [CrossRef]
  120. Wang, H., Yang, F., Zhang, S. et al. Genetic and environmental factors in Alzheimer’s and Parkinson’s diseases and promising therapeutic intervention via fecal microbiota transplantation. npj Parkinsons Dis. 7, 70 (2021). [CrossRef]
  121. Matsuoka, H. (2005) Aldosterone and Magnesium. Clinical Calcium, 15, 187-191. Available online: https://pubmed.ncbi.nlm.nih.gov/15692156/.
  122. Piuri G, Zocchi M, Della Porta M, Ficara V, Manoni M, Zuccotti GV, Pinotti L, Maier JA, Cazzola R. Magnesium in Obesity, Metabolic Syndrome, and Type 2 Diabetes. Nutrients. 2021 Jan 22;13(2):320. [CrossRef]
  123. Dan J, Yang J, Liu Y, Xiao A, Liu L. Roles for Histone Acetylation in Regulation of Telomere Elongation and Two-cell State in Mouse ES Cells. J Cell Physiol. 2015 Oct;230(10):2337-44. [CrossRef]
  124. Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res. 2014 Jan;55(1):13-31. [CrossRef]
  125. Chen J, Zhao KN, Chen C. The role of CYP3A4 in the biotransformation of bile acids and therapeutic implication for cholestasis. Ann Transl Med. 2014 Jan;2(1):7. [CrossRef]
  126. Pikuleva, I.A. Cholesterol-metabolizing cytochromes P450: implications for cholesterol lowering. Expert Opin Drug Metab Toxicol. 2008 Nov;4(11):1403-14. [CrossRef]
  127. Li X, Zhang B, Hu Y, Zhao Y. New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases. Front Pharmacol. 2021 Dec 13;12:769501. [CrossRef]
  128. Pludowski P, Holick MF, Pilz S, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmunity Reviews. 2013 Aug;12(10):976-989. [CrossRef]
  129. Laborde S, Mosley E, Thayer JF. Heart Rate Variability and Cardiac Vagal Tone in Psychophysiological Research—Recommendations for Experiment Planning, Data Analysis, and Data Reporting. Front Psychol. 2017 Feb 20;8:213. [CrossRef]
  130. Shanmukha KD, Paluvai H, Lomada SK, Gokara M, Kalangi SK. Histone deacetylase (HDACs) inhibitors: Clinical applications. Prog Mol Biol Transl Sci. 2023;198:119-152. [CrossRef]
  131. Banik D, Moufarrij S, Villagra A. Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy. International Journal of Molecular Sciences. 2019; 20(9):2241. [CrossRef]
  132. Guha, S., Jagadeesan, Y., Pandey, M.M., Mittal, A., & Chitkara, D. (2024). Targeting the epigenome with advanced delivery strategies for epigenetic modulators. Bioengineering & Translational Medicine. [CrossRef]
  133. Zhang S, Kiarasi F. Therapeutic effects of resveratrol on epigenetic mechanisms in age-related diseases: A comprehensive review. Phytother Res. 2024 May;38(5):2347-2360. [CrossRef]
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Figure 1. AhR=aryl hydrocarbon receptor, LC=long Covid, FMT=fecal microbiota transplantation, K/T=kynurenine to tryptophan, T2DM=type 2 diabetes, GLP=glucagon like peptide, red arrows, boxes => unfavorable, green arrows, boxes => favorable.
Figure 1. AhR=aryl hydrocarbon receptor, LC=long Covid, FMT=fecal microbiota transplantation, K/T=kynurenine to tryptophan, T2DM=type 2 diabetes, GLP=glucagon like peptide, red arrows, boxes => unfavorable, green arrows, boxes => favorable.
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Figure 2. This sterol biosynthetic pathway for cholecalciferol decreases with age and is further challenged by Mg deficiency. Intensity of red arrows indicates the impact of Mg deficiency. DHC=dehydrocholesterol, PTH=parathormone, VDBP=vitamin D binding protein, D3=cholecalciferol.
Figure 2. This sterol biosynthetic pathway for cholecalciferol decreases with age and is further challenged by Mg deficiency. Intensity of red arrows indicates the impact of Mg deficiency. DHC=dehydrocholesterol, PTH=parathormone, VDBP=vitamin D binding protein, D3=cholecalciferol.
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Figure 3. Methylation is the primary promoter/suppressor mechanism for the epigenome. Pink boxes are molecules, green boxes are required cofactors, and red boxes are critical enzymes. MTHFR=methylenetetrahydrofolate reductase, THF=tetrahydrofolare, SAMe=S-adenosyl methionine, SAH=S-adenosyl homocysteine, Hcy=homocysteine.
Figure 3. Methylation is the primary promoter/suppressor mechanism for the epigenome. Pink boxes are molecules, green boxes are required cofactors, and red boxes are critical enzymes. MTHFR=methylenetetrahydrofolate reductase, THF=tetrahydrofolare, SAMe=S-adenosyl methionine, SAH=S-adenosyl homocysteine, Hcy=homocysteine.
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Figure 4. All blue boxes are directly associated with longevity. Green boxes are Mg++ dependent. Red boxes are anti-longevity. Green arrows promote and red arrows inhibit. PUFAs=polyunsaturated fatty acids, HDAC=histone deacetylase, GLP=glucagon like peptide, CYP=cytochrome P, AhR=aryl hydrocarbon receptor, HRV=heart rate variability, HDL-C= high density lipoprotein cholesterol, LP=lipoprotein.
Figure 4. All blue boxes are directly associated with longevity. Green boxes are Mg++ dependent. Red boxes are anti-longevity. Green arrows promote and red arrows inhibit. PUFAs=polyunsaturated fatty acids, HDAC=histone deacetylase, GLP=glucagon like peptide, CYP=cytochrome P, AhR=aryl hydrocarbon receptor, HRV=heart rate variability, HDL-C= high density lipoprotein cholesterol, LP=lipoprotein.
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