Longevity

Fine-Tuning Your Longevity Genes

By Bryant Villeponteau, Ph.D.

Introduction

The 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 significantly slowed by fine tuning your longevity genes. Indeed, scientific research carried out in the last 20 years has shown that lifespan can be readily modulated 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:

1. Aging is linked to altered expression in more than a hundred genes;
2. We employed artificial intelligence algorithms combined with animal longevity assays to screen for wide-spectrum herbal extracts that extend lifespan;
3. We succeeded in greatly extending 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?

Fig. 1: Aging causes an exponential increase in the annual mortality rate.

The actual declines in function with age occur at the cell, organ, and systemic levels, but the impacts of this decline can differ with the individual’s genes and environment. The net result of aging 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 from validated 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’s hypothesis, aging is indirectly caused 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’s 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’s and William’s evolutionary theories of aging are still widely believed 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 directly tested in Drosophila melanogaster by Michael Rose (UCI Professor and cofounder of Genescient). If the Evolution Theory of Aging is correct, Dr. Rose 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 indeed long lived compared to wild type flies. As Genescient’s 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.

Fig. 2: Breeding Drosophila for late reproduction leads to much longer lived flies. The result is as predicted by the Evolution Theory of Aging.

Studying gene expression in the wild type and Methuselah flies, Genescient has shown that several hundred genes have an altered 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 antiaging 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. We also tried a few combination nutraceuticals, but again were not able to extend lifespan significantly.

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 “antiaging”, 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 studies demonstrating stem cell activation ^1-4 and inhibition of mTOR ⁵. The mTOR inhibition has extended mouse mean lifespan by 33% ⁶. 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.

In looking for the best herb in the Indian Ayurvedic medicinal tradition, I soon focused on the potent anti-diabetic herb, Pterocarpus marsupium. Crude extracts of Pterocarpus marsupium (Indian keno tree) bark naturally have high concentrations of pterostilbene (one of three resveratrol analogs in Pterocarpus) and have been used as a traditional herbal treatment for diabetes in India for thousands of years ⁷. More recent studies in animals show potent anti-diabetic activity ^8-9. Published studies have also shown that pterostilbene is a potent anticancer compound. For example, pterostilbene 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 also reported 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 used in the Western herbal tradition. In this case, Pine Bark Proanthocyanidins stand out as the best wide-spectrum herbal extracts in Western herbal medicine.? 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 1980’s.? Most of the research and commercial success with proanthocyanidins has?involved 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 of proanthocyanidins is the hypothesis that they are responsible for the “French Paradox”, wherein the French tend to have much reduced 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 possible cardiovascular effects, Oligo-Proanthocyanidins (OPCs as attached units of proanthocyanidins are called) are known to have many other health benefits ¹⁰.? For example, OPCs stabilize collagen and elastin, which are two essential proteins in connective tissues including 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 caused by pollution, toxins, and cigarette smoke.? These diverse health benefits make Pine Bark proanthocyanidins another perfect candidate to combine with wide-spectrum herbal extracts of 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 a uncommon amino acid found preferentially in green tea.? Theanine is an analog of glutamine and glutamate and can cross the blood-brain barrier as a potential neuroprotective agent ^11-12. Among its psychoactive properties, theanine is reported to reduce mental stress ¹³ and improved cognition ^14-15 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 original formula Stem Cell 100, because of its positive effects on adult stem cells and have added additional herbs over time.

Drosophila Longevity Studies Using Treatment with Stem Cell 100

The current Stem Cell 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 Stem Cell 100 (cages T1 to T3) and three cages that were untreated controls (cages C1 to C3). Each cage started with 500 fruit flies including 250 males and 250 females. In this experiment mean lifespan increase by an average of 69%. 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.

Fig. 3: Lifespan Survival Curve of Stem Cell 100 Treated and Control Female Flies

The 3 cages of 500 flies each for Control or Treated Flies were averaged as flies died each day with the standard deviation between cages given by the error bars. The differences between Control and Treated flies are highly significant (P < 0.001).

The longest living fruit fly receiving Stem Cell 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 aberration. 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). The 77% increase in maximum lifespan by Stem Cell 100 outperforms every lifespan enhancing treatment ever tested in flies – including experiments using genetic modification and dietary restriction. Indeed, the maximum lifespan (oldest 5%) for females treated with Stem Cell 100 is about 82 days, which is close to the 85 day maximum lifespan of the highly selected female Methuselah flies.

Fig. 4: Lifespan of last 5% survivors using Stem Cell 100 treated and control flies

Pilot Field Trial on Human Volunteers

A small clinical field trial using Stem Cell 100 for a period of four months was carried out with healthy volunteers that had cholesterol and blood pressure readings in the normal range. Cholesterol tests and blood pressure monitoring were performed before and after treatment with StemCell 100 to see if the treatment changed cholesterol or blood pressure profiles. In the lab testing, liver function and blood chemistry were the same before and after treatment for all participants, but there was a non-significant trend toward reductions in total cholesterol, LDL, and triglycerides with the herbal treatment. These trends would likely have been significant if a larger sample size were used.

The biggest surprise was the relatively large increases in HDL (good cholesterol) in all test subjects including those individuals who were taking statins. The mean HDL was 58 mg/dL before treatment (range of 44 to 73 mg/dL) and was a mean of 72 mg/dL after treatment (range of 58 to 82 mg/dL). Treatment with Stem Cell 100 thus increased HDL by a mean of 13 mg/dL (SD = 1.29 and P = 0.006) or 22% increase in the treated volunteers. Although this was not a placebo controlled trial, this mean HDL increase is much larger than any expected placebo effect and is likely to be significant despite the lack of a placebo control.

We also checked most volunteers before and after Stem Cell 100 treatment for changes in blood pressure. While some individuals were concurrently taking antihypertensive drugs, all volunteers initially tested in the normal range for both systolic (mean = 122 mm Hg with a range of 102 to 133) and diastolic (mean = 79 mm Hg with a range of 70 – 88) blood pressure. After 4 weeks on Stem Cell 100, systolic levels fell to a mean of 112 mm Hg (range of 99 to 121 mg Hg) and diastolic blood pressure fell to a mean of 69.5 mm Hg (range of 61 to 78 mm Hg). These data translate into a highly significant mean systolic loss of 9.5 mm Hg (P < 0.0003), while diastolic blood pressure had a mean loss trend of 12 mm Hg (P = 0.092). If the sample size were larger, we believe that diastolic blood pressure would also have dropped significantly.

Finally, a few trial volunteers also tested their blood glucose levels before and after Stem Cell 100 treatment. All of these volunteers had blood glucose levels in the normal range before treatment and saw a fasting blood glucose drop after treatment. However, these blood glucose results must still be considered anecdotal because of small sample size.

Higher levels of HDL cholesterol, reduced blood pressure, and reduced fasting blood glucose are all independent indicators of longevity, so these preliminary results suggest that the Stem Cell 100 may reduce all-cause mortality in humans as is the case for Drosophila. Note however that the changes in cholesterol, blood pressure, and blood glucose described here are for individuals within the normal range of these indicators. Stem Cell 100 was not designed as a clinical treatment for abnormal levels of cholesterol, blood pressure, or blood glucose. Abnormal levels of these three markers can lead to serious disease endpoints and should be referred to your medical doctor for treatment, rather than attempts to self medicate.

Since this clinical field trial gave such unexpectedly favorable results, we wish to verify these data via a double-blind, placebo-controlled clinical trial using Stem Cell 100 and these indicators. Of course, proper clinical trials are expensive, so sufficient funding will have to be secured before such clinical trials can be started. If you are planning a clinical trial with any of these blood markers or age related-disease endpoints, Stem Cell 100 might be a good adjunct to other therapies that are to be tested.

Conclusion

Genescient used genomic studies in Drosophila to determine that aging is modulated by over a hundred genes. We then used animal longevity assays to screen for nutrigenomic supplements that extend lifespan. We succeeded in greatly extending both mean and maximum lifespans in Drosophila using a novel class of wide-spectrum herbal supplements that modulate genes involved in both aging and age-related disease. The dramatic elongation of both mean and maximum lifespans by Stem Cell 100 outperforms every lifespan enhancing treatment ever tested in Drosophila – including experiments using genetic modification and dietary restriction. With this successful demonstration of the power of Genescient’s genomic R & D system, Genescient’s proprietary genomic techniques can now be applied to developing wide-spectrum drug combinations for the age-related diseases.

To market Stem Cell 100, Genescient entered a joint venture with Centagen Inc. (the creator of the Stem Cell 100 formulation) to found Life Code LLC. Genescient and Centagen have spent two years in extensive animal and human testing to demonstrate the effectiveness of the herbal formulation in Stem Cell 100. The dosage and quality of the individual components emerged as critical factors in providing safety and efficacy. With Scientific evidence showing it works, Stem Cell 100 is now available commercially online.

While the four herbal extracts in Stem Cell 100 have tremendous synergistic properties when properly manufactured in our optimized patent-pending formulation, each of the four herbal extracts in Stem Cell 100 taken separately has strong scientific support and a long history in alternative or traditional medicine for promoting animal and human health. For example, the individual components of Stem Cell 100 help support:

1. Adult stem cell rejuvenation ^1-4.
2. A healthy cardiovascular system ^16-19.
3. Healthy blood glucose levels for those already in the normal range ⁸, ^20-23.
4. Healthy blood pressure levels for those already in the normal range ^24-25.
5. Healthy cholesterol levels for those already in the normal range ²⁰, ^26-27.
6. Younger looking skin ^28-34.
7. Better learning and focus ¹⁵, ^35-39.
8. More endurance with vigorous exercise ^40-44.
9. A healthy immune system ^40-41, ^45-48.
10. Healthy breasts, colon, pancreas, and prostate ^49-55.

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