Review ArticleEffect of Antioxidants Supplementation on Aging and LongevityIzabela Sadowska-Bartosz1 and Grzegorz Bartosz1,2

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014, Article ID 404680, 17 pageshttp://dx.doi.org/10.1155/2014/404680 Practice of Advanced Human

Nutrition, 330052, SS 2014; Diana Gessner, 0747266

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Topic overview

1. Introduction: Free radical theory of aging

2. Effect of AOs on the Lifespan of Model Organism

3. How Do ‘‘AOs’’ (Do Not) Act? Possible Explanations

4. Antioxidant Supplementation in Humans: Does It Make Sense?

5. Conclusion

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“Free Radical Theory of Aging” (FRTA)

• Denham Harman, 1950s

• Biomolecules– thermodynamically unstable in an

oxygen-containing atmosphere

• formation of oxygen free radicals and other reactive oxygen species (ROS)

• basic idea of the FRTA– free radicals and other ROS damage

biomolecules

– accumulation of this damage during life• Aging and age-related diseases

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“Free Radical Theory of Aging” (FRTA)• …If FRTA is true, AO should slow down aging and

prolong lifespan…

• Pubmed: over 13300 hits for conjunction of terms “antioxidant” and “aging or ageing ”

• answer to the question is still unclear

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Free radicals and reactive oxygen species (ROS)

• free radicals: any atom, molecule, or ion with an unpaired valence electron• superoxide ( O2- )

• ROS: hydrogen peroxide (H2O2), peroxynitrite (OONO-)• important roles within the body linked to cell signaling• AO: a molecule capable of inhibiting the oxidation of other molecules.

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AO Systems in the human body

Some antioxidants studied as antiaging agents

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Aos:• radical scavengers• reducing agents

Effect of AOs on the Lifespanof Model Organism• Vitamin E– main hydrophobic AO in cell membranes and

lipoproteins

– hypothesis: prevents atherosklerosis

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Effect of AOs on the Lifespanof Model Organism• Vitamin C: ascorbic acid

• Major hydrophobic AO– Regenerates alpha tocopherol

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Effect of AOs on the Lifespanof Model Organism• Melatonin– Similiar structure to endogenous indolpropionamid

– AO function• Binds to a component of oxadtive phosphorlytation in complex I

of resperatory chain• Reduces ROS production stabilzes energy metabolism

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Effect of AOs on the Lifespanof Model Organism• Resveratrol (RSV)– Huge amounts in redwine (2 - 12 mg/l)

– Polyphenol

– Protective role in plants:• Stimulates cell defense against fungal infection and UV

irradiation

– Protective role in animals:• 1990s : the french paradoxon

• Low occurence of coronary heart desease in South Western French despite the consumption of high SFA diet

• Regular high consumption of red wine in South Western French high intake of RSV

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Effect of AOs on the Lifespanof Model Organism• RSV– Hector et al. (2012): meta-analysis to assess the effect

of RSV on survival• using data from 19 published papers, including six species• yeast, nematodes, mice, fruit flies, Mexican fruit flies, and

turquoise killifish• lifespan of the turquoise killifish was positively affected • results are less clear for flies and nematodes • variability between the studies

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Effect of AOs on the Lifespanof Model Organism• Curcumin (CUR)– Main component of the yellow extract of curcuma longa

– Bioactive polyphenol

– Active metabolite: terta-hydro-curcumin (THC)

– THC: extremly strong AO activity compared to other CUR components

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Effect of AOs on the Lifespanof Model Organism• SkQ1 – mitochondrially targeted AO

– plastoquinone-containing decyltriphenylphosphonium

– mitochondria are the main source of ROS targeted AO more effective?

– Basic idea: • synthesis of positively charged derivatives of plastoquinone and

other Aos• retained in the mitochondria due to the high negative potential

at the inner mitochondrial membrane

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Effect of AOs on the Lifespanof Model Organism• AO mixtures: KPG-7 commercially available herb

mixture– containing

• Thymus vulgaris, Rosmarinus officinalis, Curcuma longa, Foeniculum vulgare, Vitis vinifera (polyphenol), silkprotein, Taraxacum officinale, and Eleutherococcus senticosus

• include a variety of antioxidant, antitumoral, and anti-inflammatory bioactivities

• better than simple antioxidant formulas• synergism between antioxidants

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Effect of AOs on the Lifespanof Model Organism• Divergent results of studies on the supplementation of model

organisms with AO vitamins and other AOs

• AOs: life-prolonging effects on mutant model organism– deficient in antioxidant defense !

– did not affect the lifespan of healthy wild type animals!

• Pallauf et al. 2012: Effect of vitamin C on the lifespan of several multicellular model organisms (Caenorhabditis elegans, Drosophila melanogaster, mice, rats, and guinea pigs) – No consistent picture of data

– some studies demonstrating prolongation of lifespans others showing no effect

• AOs can also decrease lifespan!

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How Do ‘‘AOs’’ (Do Not) Act? Possible Explanations

• administered antioxidants may be not fully taken up especially when added to complex media

• methods of delivery – use of liposomes loaded with water-soluble substances:

• resulted in successful oral delivery of chemicals into the intestines of C. elegans• oral administration of hydrophilic antioxidants (ascorbic acid, N-acetyl-cysteine, reduced

glutathione, and thioproline prolonged the lifespan of the nematodes• conventional method of delivery showed no longevity effects

• difficult to estimate the amount of ingested food in many model organisms

• life-prolonging effect of antioxidants may be limited to a “therapeutic window”– differences in the uptake rate and metabolism in various organisms

• relevance of using model organisms if we want to understand human aging

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How Do ‘‘AOs’’ (Do Not) Act? Possible Explanations:• indirect functions of Aos:

– Induction of AO – systems on the level of gene regulation

– Interference in signaling cascades

• Examples:– RSV activates SIRT1 the deacetylase activity of human sirtuin 1 (SIRT1)

– sirtuin proteins : regulate epigenetic gene silencing

– SIRT1: functions as an NAD+-dependent histone and nonhistone protein deacetylase in several cellular processes• energy metabolism, stress responses, inflammation

– RSV inhibits SIRT3• can mimic calorie restriction/dietary restriction (DR) effects

– DR with adequate nutrition:• the only nongenetic and the most consistent nonpharmacological intervention that

extends lifespan in model organisms from yeast to mammals

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Antioxidant Supplementation in Humans:Does It Make Sense?• The Mediterranean diet (MeDi)– heart-healthy eating plan that

– emphasizes fruits, vegetables, whole grains, beans, nuts,seeds, healthy fats

– red wine consumption rich in antioxidants like RSV

– The Mediterranean lifestyle: worked intensively and survived with very few seasonal foods

– MeDi is associated with lowmortality (higher longevity) and reduced risk of developing chronic diseases

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Antioxidant Supplementation in Humans:Does It Make Sense?• Okinawa (Japan), Sardinia (Italy),Loma Linda (California),

Ikaria (Greece), and Nicoya (CostaRica)– very high prevalence of octogenarians

– Common lifestyle of those populations:• high levels of daily physical activity (e.g., gardening and walking)• positive attitude• Diet: high consumption of fruit, wild plants and vegetable,low

consumption of meat products similato the MeDi• MeDi lower

• mortality rates • speed of disease progression

• prospective cohort study of 1410 older adults• higher adherence to MeDi did not lower the risk for incident

dementia

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Antioxidant Supplementation in Humans:Does It Make Sense?• Bacalini et al. (2013): potential impact of so-called

“epigenetic diet” on age-related diseases– highlighting the involvement of epigenetic modifications

• DNA methylation• microRNA

• Epi geneticmodifications may delay the aging process

• impact diverse health benefits– by activating numerous intracellular pathways.

• One leading theory :• bioactive phytochemicals • Epigallocatechin gallate, RSV, and CUR play significant roles as epigenetic

modifiers

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Take home message• Only in some cases considerable prolongation of lifespan was

obtained and in organisms which are evolutionarily quite distant from mammals

• AO cannot be expected to prolong significantly the lifespan, especially of mammals, which does not support the FRTA

• AO supplements – do not possess preventive effects

– may be harmful with unwanted consequences to our health, especially in well nourished populations

• the optimal source of AO seems to come from our diet, not from AO supplements in pills or tablets

• even more, beta-carotene, vitamin A, and vitamin E may increase mortality– Large studies support these findings (ATBC-study ; CARET – study)