Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging

Ames, Bruce N.; Atamna, Hani; Killilea, David W.

doi:10.1016/j.mam.2005.07.007

Cited by 100 publications

(63 citation statements)

References 120 publications

(132 reference statements)

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“…We have discussed that heme synthesis requires the cofactors iron, copper, zinc, biotin, pantothenic acid, riboflavin, and lipoic acid (13,45). Deficiencies of these in the U.S. population are very common, e.g., 25% of menstruating women ingest Ͻ50% of the recommended dietary allowance for iron.…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Atamna¹,

Boyle²

2006

Proc. Natl. Acad. Sci. U.S.A.

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272

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Amyloid-␤ peptide (A␤) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive A␤ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H 2O2) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that A␤ binding to regulatory heme in vivo is the mechanism by which A␤ causes HD. Heme binds to A␤, thus preventing A␤ aggregation by forming an A␤-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The A␤-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H 2O2. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of A␤ to heme supports a unifying mechanism by which excessive A␤ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive A␤ for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.curcumin ͉ heme deficiency ͉ mitochondria ͉ regulatory heme ͉ serotonin

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Section: Discussionmentioning

confidence: 99%

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Atamna¹,

Boyle²

2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

272

279

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“…Additionally, Ribeiro and Armelin (41) The molecular mechanisms that drive magnesium deficiencyinduced cellular senescence are not clear at this time. One possible explanation is that exposure to magnesium-deficient conditions caused an increase in steady-state oxidative stress levels, because this is common among many micronutrient deficiencies (42,43). Previous work showed that bovine endothelial cells cultured in magnesium-deficient media were more sensitive to oxidant challenge (20).…”

Section: Discussionmentioning

confidence: 99%

Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts

Killilea

Ames

2008

Proc. Natl. Acad. Sci. U.S.A.

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110

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Magnesium inadequacy affects more than half of the U.S. population and is associated with increased risk for many age-related diseases, yet the underlying mechanisms are unknown. Altered cellular physiology has been demonstrated after acute exposure to severe magnesium deficiency, but few reports have addressed the consequences of long-term exposure to moderate magnesium deficiency in human cells. Therefore, IMR-90 human fibroblasts were continuously cultured in magnesium-deficient conditions to determine the long-term effects on the cells. These fibroblasts did not demonstrate differences in cellular viability or plating efficiency but did exhibit a decreased replicative lifespan in populations cultured in magnesium-deficient compared with standard media conditions, both at ambient (20% O 2) and physiological (5% O 2) oxygen tension. The growth rates for immortalized IMR-90 fibroblasts were not affected under the same conditions. IMR-90 fibroblast populations cultured in magnesium-deficient conditions had increased senescence-associated ␤-galactosidase activity and increased p16 INK4a and p21 WAF1 protein expression compared with cultures from standard media conditions. Telomere attrition was also accelerated in cell populations from magnesium-deficient cultures. Thus, the long-term consequence of inadequate magnesium availability in human fibroblast cultures was accelerated cellular senescence, which may be a mechanism through which chronic magnesium inadequacy could promote or exacerbate agerelated disease.oxygen tension ͉ telomeres ͉ tumor suppressor M agnesium is an essential micronutrient required for an extensive range of metabolic, regulatory, and structural activities. It is predominantly obtained from diet by eating green leafy vegetables and unprocessed grains (1). The typical U.S. diet has drifted away from these food sources in favor of more refined and often nutrient-poor food options, thus magnesium inadequacy has become quite common (2). Intake estimates generated by national surveys including the National Health and Nutrition Examination Survey (NHANES) have predominantly indicated that more than half of the U.S. population has magnesium intakes below the Estimated Average Requirement (EAR), a measure of population adequacy that is 2 SD below the Recommended Daily Allowance (3). Moreover, the incidence and severity of magnesium inadequacy is even greater in at-risk groups, including children, the poor, and the elderly (4, 5).Despite growing appreciation of the prevalence of magnesium inadequacy, essentially no immediate clinical symptoms are known, due in part to the lack of robust biomarkers of magnesium status in vivo. However, there is a sizeable literature on the functional consequences linked with long-term magnesium inadequacy. Epidemiological data have associated increased risk of several agingrelated diseases with chronic magnesium inadequacy, including cardiovascular disease, hypertension, diabetes, osteoporosis, and some cancers (1, 6-8). Numerous animal studies on magnesium inadequacy...

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“…Large-scale screens are being considered for a number of model organisms to accelerate discovery of compounds with the greatest potential for extending lifespan (Bauer et al, 2004, Wang et al, 2004. One class of compounds with potentially beneficial effects on aging are the tocopherol isomers found in Vitamin E and which are found naturally in plant oils (Ames et al, 2005). Vitamin E is a mixture of several related tocopherol and tocotrienol isomers, including the α-and γ-tocopherols.…”

Section: Discussionmentioning

confidence: 99%

Comparative approaches to facilitate the discovery of prolongevity interventions: Effects of tocopherols on lifespan of three invertebrate species

Zou

Sinclair

Wilson

et al. 2007

Mechanisms of Ageing and Development

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SummaryMany compounds hold promise for pharmacologic manipulation of aging. However, such claims are difficult to investigate due to time and budget constraints. Here, we took a comparative approach, using short-lived invertebrate species, to directly test the effects of two tocopherols (vitamin E) on longevity. γ-tocopherol represents the most abundant tocopherol in the Western diet, while α-tocopherol is selectively enriched in human plasma. Both isoforms demonstrate antioxidant activity and are proposed to have anti-aging activities. We compared the effects of α-and γ-tocopherol supplementation on lifespan in three invertebrate species. γ-, but not α-, tocopherol slightly extended lifespan in nematodes, but neither significantly affected lifespan in two fly species. This study shows that a comparative approach, utilizing multiple invertebrate species, can increase the robustness of invertebrate-based pilot screens for prolongevity interventions.Pharmacological and nutritional approaches to retard aging and increase longevity have been proposed (Floyd, 2006, Joseph et al., 2005. Large-scale screens are being considered for a number of model organisms to accelerate discovery of compounds with the greatest potential for extending lifespan (Bauer et al., 2004, Wang et al., 2004. One class of compounds with potentially beneficial effects on aging are the tocopherol isomers found in Vitamin E and which are found naturally in plant oils (Ames et al., 2005). Vitamin E is a mixture of several related tocopherol and tocotrienol isomers, including the α-and γ-tocopherols. The Western diet is enriched in γ-tocopherol, but α-tocopherol is selectively retained in human plasma (Jiang et al., 2001, Tucker andTownsend, 2005). Both tocopherols are derived from fatty acids and exist within membranes, where they affect membrane fluidity and can act as antioxidants.The high antioxidant capacity of vitamin E makes it a candidate for a prolongevity therapy, since aging is correlated with increased oxidative stress in cells (Ames et al., 1993, Harman, 1 These authors contributed equally to this work. * Corresponding author: CAW: Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore MD 21224; Tel: 410-558-8566; Fax: 410-558-8323; wolkowca@grc.nia.nih.gov.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. One efficient strategy for directly examining whether these compounds have any effect on lifespan is to determine whether supplementation can affect lifespan in short-lived invertebrate species, which offer models for aging in...

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Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging

Cited by 100 publications

References 120 publications

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts

Comparative approaches to facilitate the discovery of prolongevity interventions: Effects of tocopherols on lifespan of three invertebrate species

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