Fine-Tuning Your Longevity Genesthe nearly universal human desire to preserve youth can often motivate people to make major lifestyle changes or try the latest wonder supplement. But is it really possible to slow the rate of aging with current knowledge and technology? I argue herein that aging can be slowed dramatically by fine-tuning your longevity genes. Indeed, scientific research carried out in the last 20 years has shown that lifespan can be modulated readily by a variety of genetic or dietary strategies. In this article, I describe our efforts at Genescient LLC in Irvine, CA to develop strategies to delay aging and age-related disease. Genescient's primary business focus is on the development of pharmaceuticals for age-related diseases, but in conjunction with its spinoff firm Life Code LLC, it has provided testing services for the development of nutraceuticals based on its unique genomics platform. Our findings can be summarized as follows: Aging is linked to altered expression in more than a hundred genes; We employed artificial intelligence algorithms combined with animal longevity assays to screen for wide-spectrum herbal extracts that extend lifespan; We succeeded in doubling animal lifespan using a novel class of nutrigenomic supplements that modulate genes involved in both aging and age-related disease. What Are the Main Effects of Aging? Aging causes an exponential increase in the annual mortality rate. The actual decline in function with age occur at the cell organ, and systemic levels, but the impacts of this decline can differ with the individual genes and environment. The net result of aging in an animal population is a progressive increase in all-cause mortality and morbidity. In the case of humans, all-cause mortality is known to double every eight years after sexual maturity until it reaches an annual mortality rate plateau of about 50%over 105 years of age. All grafted data under 110 years are from the Social security administration Death Master file while data on 110 to 119 year olds are validated from human super-centenarians from the website www. grg. org. Why Do We Age? All life forms on earth have evolved through natural selection, which selects the best genotype for fitness in a particular ecological niche. In 1952 The british Nobel zoologist Peter Medawar proposed that aging is the simple result of the failure of natural selection to maintain fitness in older animals with declining fertility. As fertility wanes, then the chances to correct inappropriate gene expression via natural selection also decline, generating the aging phenotype. Thus, according to Medawar hypothesis, aging is caused indirectly by the declining forces of natural selection to select the best fitness genes for the aged animal as reproductive capacity declines. In 1957 George Williams further developed Medawar evolutionary theory of aging by introducing the concept of antagonistic pleiotropy, wherein a gene may promote fitness in young fertile animals (and thus be selected for) but become a liability late in life leading to a subsequent decline in fitness. Modern versions of Medawar and William evolutionary theories of aging are believed still widely today by most experts in aging science, as the theory fits well with the immense body of literature showing that natural selection is responsible for virtually all of the phenotypes present in the diverse species observed in Nature. Evolution appears to evolve a life history for each species that is best adapted to its ecological niche. Besides its sound theoretical basis in the well-known mechanisms of natural selection, the Evolution Theory of Aging has also been tested directly in Drosophila melanogaster by Michael Rose (UCI Professor and cofounder of Genescient. If the Evolution Theory of Aging Is rose correct, Dr predicted that he should be able to select populations of long-lived animals by simply selecting for reproductive longevity. To carry out his longevity experiment, Dr. Rose started with 5 lines of wild type Drosophila flies and selected for reproductive longevity over a 27-year period. Dr. Rose finally obtained robust Methuselah flies with a demonstrated lifespan of some 3 to 4 times that found in the non-selected control lines, while retaining fertility and sexual vitality. Genescient has carried out several independent experiments to verify that these Methuselah flies are lived indeed long compared to wild type flies. As Genescient VP of R&d I carefully monitored the most recent comparative lifespan experiment done in 2010 (Fig. 2). The Methuselah flies (O populations) far outlive their unselected wild type fly B populations. The selected Methuselah O flies have some 3 or 4 times longer mean lifespan than the non-selected wild type B flies (Fig. 2). This selection experiment is a dramatic verification that evolution modulates the aging process. Studying gene expression in the wild type and Methuselah flies, Genescient has shown that several hundred genes have altered an expression in the Methuselah flies. In late 2010, Genescient sequenced the DNA of the wild type and Methuselah flies and again found that more than a hundred genes appear to be altered in the long-lived Methuselah flies. These experimental results are fully consistent with the Evolution Theory of Aging, which predicts that aging leads to poorly functioning organisms as natural selection for optimal gene function wanes with age. In summary, we age because of the declining force of natural selection in adult life, which leads to unfit gene expression with age. Developing Nutraceuticals That Can Extend Mean and Maximum Lifespan If there are hundreds of genes that function poorly as we age, then one possible anti-aging strategy is to utilize wide-spectrum nutraceuticals to modify gene expression to a state consistent with greater longevity. Note that the ideal gene expression pattern is not identical to youthful gene expression as some of the youthful gene expression is inconsistent with longevity (e g. genes promoting rapid growth that can lead to cancer. To develop potential wide-spectrum antiaging nutraceuticals, Genescient initially set out to identify nutraceutical compounds that would target as many of the complementary longevity pathways as possible and thereby extend Drosophila lifespan. Unfortunately, none of the single compound nutraceuticals tested appeared to significantly extend fly lifespan in our longevity screens. The typically poor longevity effects of single compounds argue against the use of drug-like therapeutics directed to a single target for longevity treatments. At this point, I decided to test mixtures of medicinal herbal extracts, as these have had a long history of success in Chinese and Indian traditional medicine and are known to have a wide spectrum of positive effects in humans. To affect as many longevity genes as possible I focused on complementary herbal extracts that have antioxidant, anti-inflammatory, and metabolic potential (known factors in driving aging) along with a positive effect on longevity genes and a proven history of use in traditional herbal medicine to treat a wide spectrum of diseases. In selecting a group of herbal extracts, I did not take the traditional route of choosing an existing herbal mixture or the normal scientific route of choosing a mix of herbal extracts that target a particular disease or target. While there are many claims that a particular herbal extract is oeanti-aging I found that these claims were too anecdotal to be believed. The screen for herbal extracts I used was novel in several ways. First, I tried to identify the best wide-spectrum herb in Chinese, Indian, or Western medicine based on its long term traditional use and data indicating that the herbal extract can target multiple longevity genes identified by Genescient or by other research groups. In Chinese traditional medicine, Astragalus membranaceus (Huang Qi) appeared to be the best Chinese herb because of its many traditional uses and recent studies demonstrating stem cell activation and inhibition of mtor. The mtor inhibition has extended mouse mean lifespan by 33%.%In traditional Chinese medicine astragalus is considered a true tonic that can strengthen debilitated patients and increase resistance to disease in general. Modern herbal treatments with Astragalus membranaceus root (often in concert with other herbs) are partly based on clinical trials showing benefits in strengthening immune function during viral (e g. chronic hepatitis) or bacterial infection or in those individuals undergoing dialysis for kidney failure. Clinical trials at the US National Cancer Institute and other world centers have indicated that Astragalus can strengthen immunity and improve survival in some individuals with cancer. In western herbal medicine Astragalus root is used to enhance immunity and to help in wound healing. Astragalus compounds have also been shown to stimulate stem cells, promote peripheral nerve regeneration in rats, and inhibit mtor (a major longevity gene shown by extensive government studies to extend lifespan in mice). In looking for the best herb in the Indian Ayurvedic medicinal tradition, I soon focused on the potent antidiabetic herb, Pterocarpus marsupium. Crude extracts of Pterocarpus marsupium (Indian keno tree) bark naturally have high concentrations of pterostilbene (more than 4%by weight and extraction can get this level much higher) and have been used as a traditional herbal treatment for diabetes in India for thousands of years. More recent studies in animals show potent antidiabetic activity. Published studies have shown also that pterostilbene is a potent anticancer compound. For example, pterostilbene, an analog of resveratrol has dose-dependent anticancer activity in five cancer cell lines. As expected, pterostilbene is known to affect most or all of the longevity genes targeted by resveratrol, but has far greater stability and efficacy. As an herbal medicine, Pterocarpus marsupium is popular in India for its diverse health benefits. Besides diabetes, the herb is reported also to cure a wide spectrum of ailments like skin diseases, fractures, bruises, constipation, hemorrhages, and rheumatoid arthritis. These diverse health benefits of Pterocarpus marsupium make it a clear favorite to include in a preventive herbal cocktail along with Astragalus. Having selected two of the biggest stars in the traditional herbal medicines of China and India I looked for an effective herb with wide-spectrum health effects from the Western herbal tradition. In this case, pine bark proanthocyanidins stand out as the best wide-spectrum herbal extracts in the Western herbal medicine tradition. Proanthocyanidins are polymer chains of flavonoids (flavan-3-ols) that were discovered by Jacques Masquelier in 1948 and have been a major therapeutic supplement in Europe since the 1980s. Most of the research and commercial success with proanthocyanidins has come from extracts of a French maritime pine bark called Pycnogenol (65 to 75%proanthocyanidins) and various grape seed extracts (80-90%proanthocyanidins. One interesting claim of health benefits from proanthocyanidins is the hypothesis that they are responsible for the oefrench Paradox, wherein The french tend to have reduced much rates of cardiovascular disease compared to other Western countries on a high-fat diet because of their high intake of red wine made with grapes. Besides their cardiovascular effects, Oligo-Proanthocyanidins (OPCS as attached units of proanthocyanidins are called) are known to have many other health benefits. For example, OPCS stabilize collagen and elastin, which are two essential proteins in connective tissues from blood vessels, muscles, and skin. OPCS are reported to reduce genetic mutations so they have some anticancer benefits. OPCS have also been shown in clinical trials to promote blood flow and endothelial nitric oxide while reducing edema, capillary fragility, and damage from pollution, toxins, and cigarette smoke. These diverse health benefits make Pine Bark proanthocyanidins another perfect candidate to combine with wide-spectrum herbal extracts from Astragalus membranaceus and Pterocarpus marsupium bark. To round out the above herbs, I wanted an herbal compound that provided neural protection in the brain. L-theanine (also known as gamma-glutamylethylamide, or 5-N-ethyl-glutamine) is an uncommon amino acid found preferentially in green tea. Theanine is an analog of glutamine and glutamate and can cross the blood-brain barrier to directly affect the brain. Among its psychoactive properties, theanine is reported to reduce mental stress and improved cognition and mood via its binding to the GABA brain receptors in the parasympathetic nervous system. Thus, theanine appears to increase the overall level of the brain inhibitory transmitter GABA and is reported to promote alpha wave production in the brain. Theanine also increases brain dopamine concentrations and has significant affinities for the AMPA and NMDA receptors. The NMDA receptors help control memory and synaptic plasticity. Theanine may also have positive effects on serotonin levels to promote restful Sleep in rats, theanine is neuroprotective. All of these neuroprotective properties of L-theanine make it a strong complementary addition to the three essential core herbs of the herbal mix. We named the final 4-herb mix Stemcell 100 because of its positive effects on adult stem cells and have filed a patent application on this wide-spectrum nutraceutical. Drosophila Longevity Studies Using Treatment with Stemcell 100 The current Stemcell 100 herbal blend has gone through extensive longevity testing with Drosophila fruit flies. The Drosophila longevity study (see Figs 3 and 4 below) included three cages of fruit flies that were treated with Stemcell 100 (T1 to T3) and three cages that were untreated controls (C1 to C3). Each cage started with 500 fruit flies including 250 males and 250 females. The experiment showed that mean lifespan more than doubled with a 123%increase. That would be like the average human living to 167 years of age! While fruit flies are not people, they are more like us than you might think. Drosophila has a heart and circulatory system, and the most common cause of death is heart failure. Like humans and other mammals (e g. mice), it is quite difficult to increase their lifespan significantly. The doubling of mean lifespan by Stemcell 100 outperforms every lifespan enhancing treatment ever tested in flies including experiments using genetic modification and dietary restriction. The longest living fruit fly receiving Stemcell 100 lived 89 days compared to the longest living untreated control which lived 48 days. That is an increase in maximum lifespan of 85%which is the equivalent of a person living to be 191 years old! It is possible that the single longest living fruit fly lived longer for other reasons such as genetic mutation; however, there were many others that lived almost as long so it was not just an abberation ababerration. For example, the oldest 5%of the treated fruit flies lived 77%longer than the oldest 5%of the control group (see Fig. 4 below

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