**3.1 The reservatrol material**

564 Selected Topics in DNA Repair

1. Specifically Uncaria spp. are an important historical medicine having been used for

2. When carefully studied, alkaloids were not the main class of bioactive agents, but rather the water soluble carboxy alkyl esters (CAEs) which were only found extracted by

3. Quinic acid containing analogs such as quinic acid esters (QAEs) were identified as the

4. The mode of action of CAEs/QAEs is via stimulating uptake of tryptophan and nicotinamide (Pero et al 2009b, Pero and Lund 2011). There are no other DNA repair

5. It became apparent that if a DNA repair enhancer had other non-competitive metabolic

6. Given that bioactive quinic acid analogs (e.g QAEs) were first discovered in Cat's Claw bark in the 1990's, the bulk of our knowledge that dietary supplements can enhance DNA repair and provide anti-aging properties comes from this plant species (Reviewed in Pero 2010b). There is little doubt that the most extensive documentation of a DNA repair enhancer leading to treatment of anti-aging effects comes from quinic acid analogs and extracts isolated from Uncaria spp. For example, there are voluminous data published establishing Uncaria products can induce (a) DNA repair and anti-aging effects, (b) immune function enhancement, (c) anti-oxidation and (d) neurological

7. Based on this historical data, and combined with our background knowledge of the process of excision DNA repair involving at least 5 enzymes each having separate regulatory functional components, it has been fortunate to determine that there exists for many DNA repair enzymes a non-competitive metabolism allowing for a cooperative DNA repair effect that can be synergistic or at least additive. For example, when known DNA repair modulating ingredients were combined to synergize DNA repair, if competing metabolic events were eliminated from these mixtures then metabolic synergism was observed as evidenced by accounting for rehydration properties; i.e thirst quenching, (Pero and Garret 2010) as well as enhanced DNA repair

8. After reviewing the Background and Historical Development Sections presented above, it is safe to conclude there have been many milestones achieved documenting the successful development of a dietary supplement that optimally can enhance DNA repair and reduce aging effects from chronic diseases. The learning curve is presented within these 8 points of development, ending up with a synergized combination of the dietary supplements including: resveratrol material, carotenoid material, nicotinamide material, zinc source material, and quinic acid material that is present in proportions effective, in combination, to improve resistance to DNA damage, enhance DNA repair capacity, and stimulate immune function in a human subject to whom the composition is administered as a daily dosage. Any product not encompassing these points of

**Prevalence of DNA repair deficiencies in the general population.** There are now more than 130 DNA repair - regulated genes identified that also can influence individual susceptibility to DNA damage, and as a consequence, the incidence of human diseases. The number has increased dramatically in the last 20 years, and no doubt will continue to

centuries to treat inflammation and other age-related diseases.

modes of action then they would be synergistic to each other.

enhancing substances having this mode of action.

(Pero 2000; Sheng et al 1998, Pero and Lund 2011).

development is by definition an inferior product development.

bioactive agents.

effects (Pero 2010b).

water, which explains why indigenous Indians found them useful.

The known molecular mechanisms of resveratrol are described herein. The main effects of resveratrol are to regulate cell cycle events that favor growth arrest allowing DNA repair enhancement before cells die from DNA damage blockage of cell replication (Valenzano et al 2006; Gatz et al 2008; Feng et al 2002; Whyte et al 2007). There are changes in both gene and protein expression, such as the up-regulation of p53 and p21 and the down-regulation of cyclin A, chk1, CDC27, and Eg5 (a mitotic motor protein). Resveratrol also alters the intracellular Smad signaling of the TGF-β pathway. Finally, dietary restriction, the beststudied life-extension treatment, causes overexpression of SIRT 1 (Cohen et al. Science 2004), and since these effects are not additive to resveratrol, they suggest that a similar molecular mechanism to dietary restriction.
