**3. Deficiency of minor mineral elements and lifespan**

#### **3.1 Boron (B)**

It occurs mostly in soil and water; dietary sources include leafy vegetables, pineapple, dry fruits, lemon, nuts, and berries and daily intake is <20 mg. It is ingested through diet and found higher quantities in hair, nails, bone whereas fat tissue being low [65]. It is absorbed into the intestine through boric acid and stored in tissues. The toxic effects of boron include DNA damage and repair and has effect on protein folding and stability. In infants, excess of boron leads to anaemia, seizures, erythema, dermatitis, cardiac problems [66–68]. Chronic exposure leads to disorders of brain, kidney, and testis (88). Boron determination utilises spectrophotometry [69], spectrofluorimetry [70], potentiometry [71], inductive coupled plasma atomic emission spectroscopy [72], and inductive coupled plasma mass spectrometry techniques [73]. Beneficial effects include reduction in sterility, osteoporosis, inflammation, coagulation, and cancer. Its application widely relays on food and medicinal sector.

#### **3.2 Fluoride (F<sup>−</sup> )**

Fluoride levels abundantly found in barley, rice, cassava, canned fruits and least in food grain, breast milk, beverages and daily intake is about 2 ppm. Fluoride levels in the environment is taken up either by food, water or inhaled by air, drugs and

**35**

**Figure 3**.

**3.4 Iron (Fe)**

*Mineral Deficiencies: A Root Cause for Reduced Longevity in Mammals*

reach the digestive tract for metabolism and distributed inside the body bone, soft tissue, milk, tooth. The factors that influence the fluoride metabolism inside the body include acid–base disorders, hormones, physical activity, cardiac rhythm, and diet. Fluorine functions as prevention of dental caries, necessary for development of bones. The mechanism of action of fluoride inside the body involves inhibition of demineralisation of enamel. A small amount may substantially contribute to health benefits that include dental caries, decreases acid production. High levels leads to alterations in cell architecture, abnormalities in hepatic and renal systems. Fluoride poisoning inside the cells diagnosed by contraction of muscle, stiffness of body, failure of respiratory and cardiac systems. The methods for removing excess of fluorine done using coagulation-precipitation, electro coagulation, adsorption etc. Excreted through faeces, urine. Deficiency diseases include dental caries, osteoporosis. Fluoride helps in remineralisation, crystallisation and Fluoroapatite formation through enhancement of tooth and improves against acid resistance thereby preventing dental caries [74]. The role of fluorine in dental caries shown in **Figure 2f**. Reports reveal that klotho/KLF4 protein is involved in secretion of saliva from salivary gland and attenuation of KLF4 pathway thereby inactivating mTOR, AMPK, cyclin D1 that leads to dental caries [75]. The signalling pathway connecting

It is abundant in seafood, iodised salt and daily intake is about 150-200 ug. It is component of thyroid hormones stored in the form of thyroglobulin and toxicity symptoms include thyrotoxicosis, goitre. Iodine is mainly absorbed through small intestine but also occurs through skin and lungs. Plasma level is 4-10 mg/dl. Iodine mainly excreted through kidney but also through skin, milk saliva and bile. Deficiency causes cretinism, goitre, and myxoedema. It is evident from existing reports that iodine uptake by thyroid cells occurs with the help of sodium iodine symporter and translocates to apical membrane fuses with thyroglobulin with the help of thyroperoxidase to form monoiododthyronine (MIT), diiodothyronine (DIT) in thyroid follicle cells. Coupling of MIT & DIT results in triiodothyronine (T3) & tetra iodothyronine (T4) which is internalised through endocytosis that releases free T3, T4 into the blood stream. Iodine deficiency leads to uptake of more thyroid-stimulating hormone (TSH) into thyroid cells for production of thyroid hormones (T3 & T4) which results in enlargement of thyroid gland to form goitre [76]. Age associated abnormality of thyroid gland is not consequence of ageing but result of thyroid autoantibodies that leads to age associated diseases [77]. The role of iodine in goitre shown in **Figure 2g.** Disturbed TSH signalling found in ageing individuals due to reduced release of TRH and less production of TSH thereby lowering the thyroid gland response to TSH with concomitant release of T3 and T4 [78] and enhances Ras activity that leads to increase of thyroid gland cell proliferation [79]. The signalling pathway connecting iodine deficiency and ageing shown in

Iron (non-heme) abundantly found in cereals, pulses, fruits, vegetables whereas heme is from poultry, fish and daily requirement is about 10-15 mg. Iron present in the form of heme transports oxygen, involved in electron transport chain, required for phagocytosis in form of peroxidase. Iron is absorbed in stomach and duodenum low pH, vitamin C enhances its absorption whereas phytate and oxalate interfere its absorption. Enterocytes absorb iron through metal transporter 1 protein and

*DOI: http://dx.doi.org/10.5772/intechopen.94276*

fluoride deficiency and ageing shown in **Figure 3**.

**3.3 Iodide (I−**

**)**

#### *Mineral Deficiencies: A Root Cause for Reduced Longevity in Mammals DOI: http://dx.doi.org/10.5772/intechopen.94276*

reach the digestive tract for metabolism and distributed inside the body bone, soft tissue, milk, tooth. The factors that influence the fluoride metabolism inside the body include acid–base disorders, hormones, physical activity, cardiac rhythm, and diet. Fluorine functions as prevention of dental caries, necessary for development of bones. The mechanism of action of fluoride inside the body involves inhibition of demineralisation of enamel. A small amount may substantially contribute to health benefits that include dental caries, decreases acid production. High levels leads to alterations in cell architecture, abnormalities in hepatic and renal systems. Fluoride poisoning inside the cells diagnosed by contraction of muscle, stiffness of body, failure of respiratory and cardiac systems. The methods for removing excess of fluorine done using coagulation-precipitation, electro coagulation, adsorption etc. Excreted through faeces, urine. Deficiency diseases include dental caries, osteoporosis. Fluoride helps in remineralisation, crystallisation and Fluoroapatite formation through enhancement of tooth and improves against acid resistance thereby preventing dental caries [74]. The role of fluorine in dental caries shown in **Figure 2f**. Reports reveal that klotho/KLF4 protein is involved in secretion of saliva from salivary gland and attenuation of KLF4 pathway thereby inactivating mTOR, AMPK, cyclin D1 that leads to dental caries [75]. The signalling pathway connecting fluoride deficiency and ageing shown in **Figure 3**.

#### **3.3 Iodide (I− )**

*Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*

magnesium deficiency and ageing shown in **Figure 3**.

muscle fitness comparable to younger ones [63] whereas NAD+

**3. Deficiency of minor mineral elements and lifespan**

and ageing shown in **Figure 3**.

on food and medicinal sector.

**)**

**3.2 Fluoride (F<sup>−</sup>**

**3.1 Boron (B)**

an antioxidant responsive protein plays a role in protection of cells from oxidative stress and essential for optimal activity inside the cell [52]. The role of magnesium in neuro degeneration shown in **Figure 2d.** Dysregulated Nrf-2 activity in neurodegenerative diseases linked to ageing [53, 54]. The signalling pathway connecting

2.5 Sulphur (S): Egg white, chicken, fish, beef are major sources of sulphur. Daily intake is 14 mg for healthy adult and distributed in nails, hair, and skin. Sulphur plays a role as antioxidant, anti-inflammation, metal transport, free radical scavenging, protein stabilisation, xenobiotic detoxification, metabolism of lipids. Sulphur resides inside the body in organic form as methionine, cysteine, and cysteine functions as part of vitamins such as thiamine, biotin, and coenzyme A and excreted through oxidised form as taurine and cholic acid. Deficiency diseases are almost unknown. Although reports revealed that, sulphur containing amino acids in the form of methionine and cysteine forms creatinine, carnitine and coenzyme. Sulphur in the form of methylsulfonylmethane (MSM) acts to prevent muscle pains and joint pains through reduction of pro-inflammatory cytokines (NFkB, IL-1, IL-6, IL-8, TNF-α) [55–57] and decreased infiltration of immune cells by reducing inflamed synovial membrane [58, 59]. The role of sulphur in muscle pains and joint pains shown in **Figure 2e**. An essential for muscle functioning and deficiency leads to muscle impairment and aged phenotype. Aged muscle has altered Redox signalling [60–62] and exercised individuals in their lifetime had preserved enough

reverse these effects. Strenuous exercise result in muscle damage [64] and dysregulated redox response within the muscle increase in transient ROS/RNS. This clearly explains redox mechanisms operate with ageing and contraction of skeletal muscle can activate a number of transcription factors thereby affecting gene expression of specific cellular pathways. The signalling pathway connecting sulphur deficiency

It occurs mostly in soil and water; dietary sources include leafy vegetables, pineapple, dry fruits, lemon, nuts, and berries and daily intake is <20 mg. It is ingested through diet and found higher quantities in hair, nails, bone whereas fat tissue being low [65]. It is absorbed into the intestine through boric acid and stored in tissues. The toxic effects of boron include DNA damage and repair and has effect on protein folding and stability. In infants, excess of boron leads to anaemia, seizures, erythema, dermatitis, cardiac problems [66–68]. Chronic exposure leads to disorders of brain, kidney, and testis (88). Boron determination utilises spectrophotometry [69], spectrofluorimetry [70], potentiometry [71], inductive coupled plasma atomic emission spectroscopy [72], and inductive coupled plasma mass spectrometry techniques [73]. Beneficial effects include reduction in sterility, osteoporosis, inflammation, coagulation, and cancer. Its application widely relays

Fluoride levels abundantly found in barley, rice, cassava, canned fruits and least in food grain, breast milk, beverages and daily intake is about 2 ppm. Fluoride levels in the environment is taken up either by food, water or inhaled by air, drugs and

treatment [28]

**34**

It is abundant in seafood, iodised salt and daily intake is about 150-200 ug. It is component of thyroid hormones stored in the form of thyroglobulin and toxicity symptoms include thyrotoxicosis, goitre. Iodine is mainly absorbed through small intestine but also occurs through skin and lungs. Plasma level is 4-10 mg/dl. Iodine mainly excreted through kidney but also through skin, milk saliva and bile. Deficiency causes cretinism, goitre, and myxoedema. It is evident from existing reports that iodine uptake by thyroid cells occurs with the help of sodium iodine symporter and translocates to apical membrane fuses with thyroglobulin with the help of thyroperoxidase to form monoiododthyronine (MIT), diiodothyronine (DIT) in thyroid follicle cells. Coupling of MIT & DIT results in triiodothyronine (T3) & tetra iodothyronine (T4) which is internalised through endocytosis that releases free T3, T4 into the blood stream. Iodine deficiency leads to uptake of more thyroid-stimulating hormone (TSH) into thyroid cells for production of thyroid hormones (T3 & T4) which results in enlargement of thyroid gland to form goitre [76]. Age associated abnormality of thyroid gland is not consequence of ageing but result of thyroid autoantibodies that leads to age associated diseases [77]. The role of iodine in goitre shown in **Figure 2g.** Disturbed TSH signalling found in ageing individuals due to reduced release of TRH and less production of TSH thereby lowering the thyroid gland response to TSH with concomitant release of T3 and T4 [78] and enhances Ras activity that leads to increase of thyroid gland cell proliferation [79]. The signalling pathway connecting iodine deficiency and ageing shown in **Figure 3**.

#### **3.4 Iron (Fe)**

Iron (non-heme) abundantly found in cereals, pulses, fruits, vegetables whereas heme is from poultry, fish and daily requirement is about 10-15 mg. Iron present in the form of heme transports oxygen, involved in electron transport chain, required for phagocytosis in form of peroxidase. Iron is absorbed in stomach and duodenum low pH, vitamin C enhances its absorption whereas phytate and oxalate interfere its absorption. Enterocytes absorb iron through metal transporter 1 protein and

gets metabolised (heme) through heme oxygenase-1 [80, 81]. Inhibitors of iron absorption includes phytic acid [82], polyphenols [83], and calcium [84] whereas ascorbic acid is enhancer [85]. Iron is transported inside the body through circulating proteins namely transferrin, lactoferrin, ferritin, heme proteins [86]. Iron regulation inside the cells occurs by 2 mechanisms one is by binding of iron responsive elements (IRE) [87] to iron responsive proteins (IRP) and other by Hepcidin. Gene mutations of transferrin receptor 2, haemochromatosis, haemochromatosis type 2, hepcidin antimicrobial peptide (HAMP) [88] for impaired expression had observed. Iron storage inside the body is by ferritin [89] in liver, spleen, bone marrow [90]. Bodily iron is mostly excreted in form of blood through menstrual release and other forms includes skin and gastro intestinal tract [91] but not through urine. Iron deficiency results in depletion of iron and primary cause is low bioavailability of iron. It also occurs through pregnancy, menstruation, and pathologic conditions [92, 93]. Anaemia is the sign of iron deficiency [94]. Iron deficiency overcome by improvement in iron uptake and bioavailability, supplementation of iron with food and its fortification. Deficiency diseases include hypochromic microcytic anaemia. Reports evidence that iron (Fe+ 2) is absorbed by duodenal cells and binds with apoferritin to form ferritin which then binds to heme carrier protein (HCP) to form ferroportion (FPN). Ferroprotein is either stored in liver or transported in the blood, combines with transferrin in blood and reach erythrocytes that then binds to transferrin receptor and internalised into the cell and gets dissociated with the help of divalent metal carrier transporter 1 and performs functions such as erythropoiesis, cell metabolism, myoglobin production in muscles. Heme combines with myoglobin to form haemoglobin [59]. Recent reports reveal that PR domain zinc finger protein 8 (PRDM8) gene had a role in premature ageing of haematopoietic cells through DNA methylation that leads from aplastic anaemia (AA) patients independent of telomere attrition a haemoglobin disorder [95]. The role of iron in haemoglobin synthesis shown in **Figure 2h.** Reports also state that anaemia resulting from erythropoiesis of haematopoietic ageing of intrinsic altered microenvironment had upregulated IL-6, TGF-β signalling [96]. The signalling pathway connecting iron deficiency and ageing shown in **Figure 3**.

#### **3.5 Molybdenum (Mo)**

The daily intake of molybdenum was 75-250 ug and toxicity characterised by gout and joint pains. Molybdenum is present as cofactor for nitrate reductase, Xanthine oxidase and sulphite oxidase enzymes. Molybdenum cofactor biosynthesis occurs in steps formation of precursor Z from GTP, synthesis of molybbdeoprotein from precursor Z, addition of adenyl group to molybdoprotein and its insertion [97]. Molybdenum uptake inside the cells occurs with the help of ATP binding cassette transporters [98]. Molybdenum deficiency results in improper functioning of enzymes responsible for specific metabolic pathways in which they were involved and leads to metabolic diseases such as Xanthinuria, Hyperuricemia, and neurodegeneration. Deficiency diseases are almost unknown but some reports reveal its deficiency leads to chrons disease.

### **3.6 Sodium (Na)**

Abundantly found in common salt and other sources include leafy vegetables, milk, eggs, and nuts and daily intake is about 5-10 g. Absorbed as sodium ions and circulates inside the body in plasma and plasma levels were 135-145 mEq/L. It is cheif extra cellular cation regulates acid–base balance and involved in osmotic pressure. It is involved in activation & transmission of nerve impulse, absorption of biomolecules

**37**

**4. Conclusion**

*Mineral Deficiencies: A Root Cause for Reduced Longevity in Mammals*

pathway connecting sodium deficiency and ageing shown in **Figure 3**.

necting zinc deficiency and ageing shown in **Figure 3**.

Minerals play an important role in daily life ranging from nuts to leafy vegetables. Minerals mainly function as cofactors along with enzymes to show their metabolic effect. Minerals form holoenzymes in metabolism of biomolecules and help in cellular vital process for cell survival. In their absence, the show some deficient metabolic effects and required in small amounts to function effectively. Intake

Zinc mostly found in meat, cabbage, dates, mushrooms etc. and daily intake is 10-15 mg. Exposure of zinc is mainly by three ways inhalation, dermal exposure, oral exposure [105] and excess zinc shows symptoms such as abdominal pain, nausea, anaemia, gastrointestinal effects. Zinc plays an essential role as structural, catalytic, mild deficiency causes oligospermia, hyperammonemia [106]. Zinc is absorbed in duodenum phytate inhibits absorption whereas amino acids enhances its absorption. Oral uptake of zinc absorbs through small intestine and distributed in serum by binding to albumin, α-microglobulin, and transferrin [107]. Zinc homeostasis occurs mainly with the help of transport proteins namely Zinc importer (ZIP) and zinc transporter (ZnT) [108] which then binds to metallothionin, and sequester to other cell organelle. Beneficial aspects of zinc were antioxidant [109], antidepressant, antidiabetic [110], delayed wound healing, and anticancer [111]. Toxic effects of zinc observed when it crosses more than 100-300 mg/day typical symptoms include reduction of HDL and cholesterol levels, vomiting, lethargy, and fatigue. Serum zinc levels is about 100 mg/dl. Excretion of zinc occurs mainly by kidney, skin, and intestine. The role of zinc as immune protector well studied as anti-inflammatory and performs its action through reducing intracellular ROS by activating superoxide dismutase (SOD), NADPH oxidoreductase (NOX), metallothionin (MT) thereby suppressing inflammatory pathway (NFkB) and reduces it [112]. The role of zinc in immunity shown in **Figure 2j**. Zinc deficiency induces oxidative stress activates transcription factors NFkB, AP 1 through NFkB signalling in ageing process [113, 114]. The signalling pathway con-

and aldosterone. High levels were observed in cushions disease and low levels were observed in addisons disease. Excreted from kidney in the form of sodium chloride through urine or as phosphate and other routes is by sweat. Deficiency diseases are almost unknown but reports reveal that higher risk of cardiovascular disease with low sodium intake [99]. Sodium inside the cells were present as sodium channels as (sodium-potassium ATPase, sodium-proton antiporter) the role of sodium in heart function is mostly presented by stimuation of aldosterone which enhaces its influx into the cell and activates inositol 1,4,5 tri phosphate (IP3) [100, 101]. Activated IP3 releases stored calcium from endoplasmic reticulum and makes excitation coupled to contraction for effective heart function [102]. The role of sodium in heart function shown in **Figure 2i**. SIRT1, mTORC1 regulate cell balance between cell growth and survival. Activation of SIRT1 along with PGC-1α, AMPK and inhibition of mTORC1 along with Akt act to prolong cell longevity and retard cardiac ageing. Autophagy underlies the activation of SIRT1/PGC-1 α/AMPK and inhibition of Akt/mTORC1 responsible for cardiac ageing. Chronic heart failure involves deficient autophagy phenomenon through hyperactivation of Akt/mTORC1 and suppression of SIRT1/ PGC-1 α/AMPK pathway that finally leads to cardiac ageing [103, 104]. The signalling

*DOI: http://dx.doi.org/10.5772/intechopen.94276*

**3.7 Zinc (Zn)**

#### *Mineral Deficiencies: A Root Cause for Reduced Longevity in Mammals DOI: http://dx.doi.org/10.5772/intechopen.94276*

and aldosterone. High levels were observed in cushions disease and low levels were observed in addisons disease. Excreted from kidney in the form of sodium chloride through urine or as phosphate and other routes is by sweat. Deficiency diseases are almost unknown but reports reveal that higher risk of cardiovascular disease with low sodium intake [99]. Sodium inside the cells were present as sodium channels as (sodium-potassium ATPase, sodium-proton antiporter) the role of sodium in heart function is mostly presented by stimuation of aldosterone which enhaces its influx into the cell and activates inositol 1,4,5 tri phosphate (IP3) [100, 101]. Activated IP3 releases stored calcium from endoplasmic reticulum and makes excitation coupled to contraction for effective heart function [102]. The role of sodium in heart function shown in **Figure 2i**. SIRT1, mTORC1 regulate cell balance between cell growth and survival. Activation of SIRT1 along with PGC-1α, AMPK and inhibition of mTORC1 along with Akt act to prolong cell longevity and retard cardiac ageing. Autophagy underlies the activation of SIRT1/PGC-1 α/AMPK and inhibition of Akt/mTORC1 responsible for cardiac ageing. Chronic heart failure involves deficient autophagy phenomenon through hyperactivation of Akt/mTORC1 and suppression of SIRT1/ PGC-1 α/AMPK pathway that finally leads to cardiac ageing [103, 104]. The signalling pathway connecting sodium deficiency and ageing shown in **Figure 3**.
