**4. Discussion**

The family of dietary supplements proposed herein; e.g. Nutra-Reservatrol, ReservaQuin, AIO, or carotenoids/nicotinamide/zinc combinations (Pero and Garret 2010, Pero and Lund 2011, Sheng et al 1998) are break through products embedded in the science of synergism, often hypothesized, rarely if ever accomplished. Listed below are 6 ingredients all known to be useful in enhancing DNA repair by independent molecular mechanisms, because their interaction with the DNA repair process results in non-competitive molecular metabolism; i.e. they regulate different pathways essential to mediate successful repair of genetic lesions. In order to achieve synergism of DNA repair, it is necessary to combine at least two of this family of dietary supplements to achieve a synergistic mixture development. This fact in turn provides a great diversity to product development by providing 6 ingredients to choose from and still achieve an increased blend of efficacy for any desired clinical indication. For example, nicotinamide supplies the energy source, zinc helps bind a repair enzyme to the damaged are in DNA, carotenoids help scavenger radicals that in turn damage the DNA in the first place, resveratrol modulates growth arrest and cell survival, DMAE (deanol, dimethylaminoethanol) dietary supplement reduces the harmful health effects of neurological stress, and by increasing critical nutrient uptake such as tryptophan and nicotinamide with quinic acid analogs. The scientific basis for further substantiation can be found in Sections 3.1 to 3.6 of this review.

Most anti-aging products have at least one of the following mechanisms of action that address: Inflammation, Immunity, DNA repair, Nutrition, or Oxidative stress. However, rarely do anti-aging products have most of these known modes of action present and shown to occur by simply avoiding metabolic competition the DNA repair ingredients. The logic in this case is that synergism is hypothesized to come from co-varying lifestyle factors all being simultaneously metabolically regulated by the same dehydration/rehydration properties being induced by non-competitive metabolism of a family of DNA repair enhancing dietary supplements (data in Pero 2000, Pero and Garret 2010, Pero and Lund 2011, ). They are listed below together with optimal dose ranges:


Enhancing DNA Repair by Combining only Dietary Supplement

established (Pero et al 2009a; 2009b; Pero et al 2011).

dehydration/rehyration imbalances.

**5. References** 

1994

Ingredients that do not Metabolically Compete in Order to Achieve Synergism 569

then there must also be produced large amounts of tryptophan and nicotinamide which becomes immediately available for human absorption and the benefits thereof. In fact this proved to be the case and a direct benefit to stimulation of human DNA repair was

Finally the common thread tying this particular dietary supplement development together is the common predominant role of life style factors. First there was the composition itself. Although the DNA repair enhancing ingredients have been studied many times before never in high dose combination with each other. When they were the included DNA repair ingredients they also possessed thirst quenching abilities, never before observed to be associated with DNA repair. This observation was accounted for by the fact that nonmetabolic competition between the DNA repair enhancing ingredients could be observed because thirst quenching (i.e. rehydration) was observed whereas as single agents none was. Second, lifestyle factors are key to generation of oxidative stress, aging, and dehydration in turn is the dominant cause behind weight generated ill health, because weight gain also covaries with the lifestyle changes associated with the obese. Weight regulates essentially all aspects of a disease-free life via nutrition and metabolism balances/imbalances via

Thirdly, DNA repair enhancers have also been shown in human studies to be regulated by life style factors that are in turn associated to obesity and lifespan (Banne et al 2004, Pero et al 1985,Pero et al 2000,) and as cited therein for life syle fluctutions and DNA repair capacity) These facts have allowed the development of a proprietary "Wellness Test" that is sensitive to individual fluctuations in life style factors because it can estimate daily changes in urinary nicotinamide and trypotphan and compare them with serum thiol status (Pero 2008). Now success or failure of dietary supplements like Nutra-Reservatrol can be monitored by this functional test to deliver even more accurate health care monitoring.

Althaus, FR, Hofferer L, Kleczkowska, HE, Malanga M, Naegeli H, Panzeter PL, Realini CA.

Banne, A, Amiri, A, Pero, RW. Reduced Level of Serum Thiols in Patients with a Diagnosis

Bernofsky. C. Physiology aspects of pyridine nucleotide regulation in mammals. Mol. Cell.

Böhm F, Haley J, Truscott TG, Schalch W. Cellular bound beta-carotene quenches singlet oxygen in man. J Photochem Photobiol *B*, vol. 21(2-3), 219-221, 1993. Brunori M, and Rotilio G Biochemistry of oxygen radical species. Methods in Enzymology

Cheuvront S.N, Ely BR, Kenefick, RW, Sawka MN. Biological variation and diagnostic accuracy of dehydration assessment markers. Am J. Clin. Nutr 92(3): 565-573, 2010 Chiricolo M, Musa AR, Monti D, Zannotti M, Franceschi C. Enhanced DNA repair in

Cohen HY, Miller C, Kevin J. Bitterman KJ, Wall NR, Hekking B, Benedikt Kessler B, Howitz

lymphocytes of Down syndrome patients: the influence of zinc supplementation.

KT, Gorospe M, de Cabo R, Sinclair DA. Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase Science 305 (5682): 390–392, 2004

of Active Disease. J Anti Aging Med 6(4): 325-32, 2004

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Mutation Res. 295(3):105-111, 1993

105: 22-35, 1984

A Histone shuttling by poly ADP-ribosylation. Mol. Cell. Biochem. 138(1-2):53-59,



Weight regulates essentially all aspects of a disease-free life via nutrition and metabolism balances/imbalances that can be estimated reproducibly by assessment of dehydration (Cheuvront et al 2010). Primary causes of everyday ill health from weight gain are bodily fluctuations in water balance (hydration) (Manz 2007). Moreover, it is a very large market since 27% of American adults have metabolic syndrome (i.e. disturbances in hydration), while 85% of overweight people do (Ford et al 2004, Grundy et al 2005). Your lifestyle demands you to react to your environment, and metabolic hydration is the gage of how successful you have managed health risk from exposure to these factors.

Lifestyle factors are key to generation of oxidative stress, aging, and dehydration in turn is the dominant cause behind weight generated ill health, because weight gain also co-varies with the lifestyle changes associated with the obese. Examples are narcotics (smoking, alcohol consumption, drugs, binge over-eating), diet (fats, proteins, carbohydrates, fiber, vitamins, minerals) exercise, weight gain, sleep (psychotropic stress). Hence, treating dehydration with re-hydration, and anti-DNA damaging agent metabolism also optimizes a first good line of defense against age-associated diseases in general.

There is another important link between essential amino acid metabolism and DNA repair capacity. It is based on the discovery of a previously unappreciated metabolic connection between naturally occurring hippuric acid and quinic acid. Hippuric acid is not found in plant material nor is it metabolized by higher plants (Reviewed in Pero 2010b). Hippuric acid is known to be catabolically synthesized from benzene-type aromatic compounds usually believed to be originating from environmental exposures, or from the cyclic sugar type-compound quinic acid. Quinic acid is ubiquitous especially in healthy foodstuffs which in turn can lead to aromatic plant biosynthesis *via* the microbial shikimate pathway existing in the human gastrointestinal tract. Consequently, Pero (2010a) reasoned that if the urinary level of hippuric acid co-varied and increased in proportion with urinary quinic acid levels as they in fact did, then it follows then that the primary levels of these metabolites (i.e hippuric and quinic acids) are coming from the diet and not environmental exposures. Hence, because the GI tract was primarily responsible for this metabolism and not the liver, then there must also be produced large amounts of tryptophan and nicotinamide which becomes immediately available for human absorption and the benefits thereof. In fact this proved to be the case and a direct benefit to stimulation of human DNA repair was established (Pero et al 2009a; 2009b; Pero et al 2011).

Finally the common thread tying this particular dietary supplement development together is the common predominant role of life style factors. First there was the composition itself. Although the DNA repair enhancing ingredients have been studied many times before never in high dose combination with each other. When they were the included DNA repair ingredients they also possessed thirst quenching abilities, never before observed to be associated with DNA repair. This observation was accounted for by the fact that nonmetabolic competition between the DNA repair enhancing ingredients could be observed because thirst quenching (i.e. rehydration) was observed whereas as single agents none was. Second, lifestyle factors are key to generation of oxidative stress, aging, and dehydration in turn is the dominant cause behind weight generated ill health, because weight gain also covaries with the lifestyle changes associated with the obese. Weight regulates essentially all aspects of a disease-free life via nutrition and metabolism balances/imbalances via dehydration/rehyration imbalances.

Thirdly, DNA repair enhancers have also been shown in human studies to be regulated by life style factors that are in turn associated to obesity and lifespan (Banne et al 2004, Pero et al 1985,Pero et al 2000,) and as cited therein for life syle fluctutions and DNA repair capacity) These facts have allowed the development of a proprietary "Wellness Test" that is sensitive to individual fluctuations in life style factors because it can estimate daily changes in urinary nicotinamide and trypotphan and compare them with serum thiol status (Pero 2008). Now success or failure of dietary supplements like Nutra-Reservatrol can be monitored by this functional test to deliver even more accurate health care monitoring.
