Juvenon Health Journal volume 7 number 9 september 2008
By Benjamin V. Treadwell, Ph.D.
The more data scientists generate about what makes us grow old, the clearer one thing becomes: aging is complicated. The complexities encompass a wide range of factors, not the least of which may be how our genetic information is arranged and regulated.Slight variations in gene composition are what make us unique. No two people, (even identical twins) are identical. Yet, family members of long-lived humans seem to have a greater chance of living longer, too. So, what’s the genetic connection? Researchers in Hawaii recently demonstrated a strong association between long life and a variation in the structure of a specific human gene. But the groundwork was laid by lower life forms.Studying Worms
Realizing the technical challenges – long lifespan, expense, legal issues, etc. – associated with human studies, scientists turned to worms, flies and yeast as models for human aging. Similar to man and other mammals, these organisms have a metabolic pathway that is regulated by insulin signals. Studying them revealed a connection between the insulin-regulated pathway, a specific gene and how long an individual organism lives.Let’s start with worms. One of the most studied genes associated with longevity is present in the nematode C. elegans. It is known as DAF-16 (D for dauer, the German word for endurance), which is a regulator of the insulin pathway in this organism. Research showed that mutations in this gene had profound effects on C. elegans’ metabolism, resulting in extended lifespan.Further research found counterparts of DAF-16 in the fruit fly and humans. In the fly, D. melanogaster, there is a single related gene known as dFOXO. Humans have at least four homologous genes, FOXO1, FOXO3, FOXO4 and FOXO6. As with DAF-16 in C. elegans, the FOXO, or forkhead (from spike-like structures, produced under the control of this gene, on the head of the developing fruit fly) transcription factor genes, are all involved in regulating the insulin pathway.Hawaii 615
How could isolating the longevity-related genetic mutation in C. elegans and identifying the human genetic counterparts of DAF-16 help to answer some of the questions about how and why we age? By providing the foundation for the study of humans who live a long time, in the neighborhood of 100 years, and whether they have a unique mutation in any of the DAF-16 counterparts, the five FOXO genes. Researchers in Hawaii were aware of a human longitudinal study carried out there, which commenced in 1965 and was designed to study cardiovascular disease in Japanese-American men (both parents were Japanese), living in the state. The investigators proposed selecting participants to examine the genetic profile of the five FOXO genes.In brief, they divided the study participants into two groups: “controls,” 402 men whose mean age at death was 77.9 years, and “cases,” 213 men who lived to age 95 or older. The investigators drew blood from the subjects in each group, extracting and examining genetic material, the DNA.SNP In FOXO3A
Focusing on the five genes suspected of being associated with longevity, the researchers looked for variations in the sequence of the four nucleotide building blocks (A, G, T, C). In four of the five genes, there was virtually no difference in a single nucleotide change, or polymorphism (SNP, single nucleotide polymorphism) between the controls and the cases. In other words, the frequency in gene structural variation in these four genes was about the same for the average-lived (controls) and long-lived (cases) men.One gene, FOXO3A, however, contained an SNP that was much more prevalent in the cases than the controls. Furthermore, the long-lived men, carrying this SNP, also seemed to have a much higher quality of life. They were more mentally alert and had lower incidences of cancer, heart disease and stroke. In other words, a single change in the sequence of the gene-building blocks in FOXO3A seemed to correlate with improved health and longer life.FOXO3A And You
At this point, you may be thinking, “If I’m not born with this gene SNP, so much for longevity.” Not exactly. Short of genetic manipulation, which may be on the horizon, there seem to be ways to improve the function of the FOXO3A gene. For example, there is evidence that a healthy lifestyle (exercise, proper nutrition) and certain plant-derived nutrients make the gene more efficient, even without the SNP associated with longer life.
In fact, a recent report described the activation of this gene in human cells in culture with the major polyphenolic compound contained in green tea extract, EGCG. There are other nutrients, too, that may facilitate the multiple, health-beneficial activities associated with FOXO3A, including resveratrol and N-acetylcysteine.
FOXO3A From Here
The research in Hawaii may help us more fully appreciate other events involved in human aging. For example, the FOXO3A gene carries the template for the construction of a protein (transcriptional factor) that, in turn, has been shown to activate a number of genes involved in maintaining cellular health.
Under conditions of stress, including oxidant stress, FOXO3A can help neutralize cell-damaging free radicals associated with the insulin-signaling pathway. The gene also appears to be involved in cellular house-cleaning (autophagy) and this, too, helps reduce cellular stress. (See Juvenon Health Journal Volume 7, No. 8 Healthier Aging: Clues From The Youthful Liver of an Aging Mouse.)
At present, it is not known how a specific SNP in the FOXO3A gene confers longevity. A reasonable guess might be that it alters the gene structure, in a way, to make it more efficient in regulating cellular metabolism, especially those metabolic pathways influenced by, or under the control of, insulin signaling.
More work is needed to fully understand the process. But the results of the Hawaiian study, as well as research in progress, can help investigators gain traction toward the overall goal of improving the quantity as well as the quality of life.
A group of investigators from a number of Pacific institutions recently published, “FOXO3A genotype is strongly associated with human longevity,” in the Proceedings of the National Academy of Sciences (PNAS). They reported on their findings regarding a specific genetic variation of FOXO3A.
This gene was investigated as a possible link to human aging based on previous work with lower forms of life (worm and fly), which identified a gene that, when mutated, seemed to confer longer life on the organism. The longevity-associated gene is involved in the regulation of insulin signaling pathways. Known as DAF-16 in the worm C. elegans, it is the counterpart of the human gene, FOXO3A, also associated with metabolic pathways regulated by insulin signals.
The investigators hypothesized a correlation between a similar mutation in the human FOXO3A gene and longevity in humans. They set out to test their theory by examining the frequency of a mutation in FOXO3A in a population of Japanese-American men living in Hawaii.
The subjects were divided into two pools, those who died before the age of 81, mean age 79 years (402 subjects), and those who lived 95 years or longer (213 subjects). Genetic material (DNA) was extracted from the blood cells of both groups and the FOXO3A gene was examined for specific genetic variation (mutations known as SNP).
The results of the gene analysis established a strong association between a specific SNP and longevity. This would seem to indicate that, like the worm and fly genes, the FOXO3A gene is, at least partially, responsible for longer life.
This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.
Dr. Treadwell answers your questions about Juvenon™ Cellular Health Supplement
question: A friend claims many people don’t even digest vitamins and that chewing up vitamins or using liquid vitamins is the only way to have effective delivery. This is his claim but I know of no data to back it. What is the most effective way to take Juvenon and the other Century Club supplements? – D
answer: Some people may find that taking vitamins in liquid form is more effective than tablet form. However, in general, tablets dissolve readily and should be absorbed as well, or almost as well, as a liquid. I suggest taking the tablets with water or juice. If you find it difficult to swallow a tablet, try taking it with a thicker drink, like V-8 juice, or a food like yogurt.
As to the most effective way/time to take the various Juvenon supplements, here’s what I recommend:
– Juvenon Cellular Health Supplement. Take one tablet at breakfast and a second at lunch.
– New Juvenon Resveratrol Supplement. Take one capsule at breakfast.
– Juvenon Multivitamin, Q-Veratrol, Calcium Magnesium, and Omega-3.
Take one tablet of each at breakfast and a second at dinner.
Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor and member of Juvenon’s Scientific Advisory Board.