A Wisdom for Improving Our QOL: Activating the Anti-cancer/Anti-aging gene FOXO

Since I retired from an international cancer research institute in Melbourne a few years ago, I have learned a lot of things which could help us improve our own quality of life (QOL), not just curing cancers. Among them the most worth to note is the wisdom from honey bees and a tiny nematode called C. elegans, which we gained during my voluntary work in Hamburg, Baltimore and Melbourne.

The very essence is to activate a ubiquitous (universal) specific gene called "FOXO" encoding a unique transcription factor that controls our QOL, by safe natural products such as propolis from beehives and a polyphenol called trans-resveratrol (R3) from red grapes. This is the common basis to both "apitherapy" and "grape cure" of a variety of formidable diseases or disorders such as cancers, NF (neuro-fibromatosis), obesity, arthritis, asthma, AIDS, Alzheimer's (AD), Huntington's (HD) and a part of autism, which would significantly shorten our life span without any proper treatment.

The first FOXO gene was discovered in a chromosomal locus mutated in cancer patients, and its dysfunction was later found to cause cancers. Thus, it is a tumor suppressor gene. However, it turned out that FOXO controls not only the growth of cells, but also a variety of other cellular functions. Perhaps among its most interesting physiological roles is its positive contribution to our longevity. In 1981, the FOXO gene was discovered in a tiny transparent nematode called C. elegans as a "dauer" (endurance) gene called Daf-16, and in 1993 the FOXO/Daf-16 is found by Cynthia Kenyon and her colleagues to be essential for the longevity of this worm. Since then, the FOXO joined a so-called "anti-aging" (longevity) gene family.

Cynthia wants to live to be 150 years old, if she's young and engaged in life, and to realize such a dream, she actually founded with a few friends of hers in Boston a new drug company called "Elixir "(meaning fountain of youth) in Cambridge/Boston, developing a series of anti-aging drugs.
http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2005/05/29/CMGD8CH62P1.DTL

The next burning questions were: i) How does this gene control both cell growth and longevity (Which genes are the targets of this transcription factor) ? and 2) Which proteins control the FOXO protein, and how?

The FOXO signaling pathways
A gene called Hsp16 encoding a heat-shock protein of 16 kDa was among the first identified targets of FOXO. Both FOXO and Hsp16 are required for the longevity in nematode, and for suppressing tumor growth in mammals. Another target of FOXO is p27 gene encoding a CDK inhibitor of 27 kDa which is responsible for arresting the cell cycle at G1 phase to block the DNA replication in mammals. Monitoring the expression of these FOXO target genes, scientists discovered at least three different signaling pathways which control the function of FOXO proteins.

The first pathway involves RAS, insulin receptor (IR, Tyr-kinase), and the kinase AKT. AKT phosphorylates FOXO and inactivates this transcription factor by translocating from nucleus to cytoplasm. Thus, RAS or insulin stimulates tumor growth and shortens our life span through the AKT-FOXO interaction.

Another pathway involves two kinases, LKB-1 and AMP-activated kinase (AMPK). LKB-1 activates AMPK and in turn AMPK activates FOXO. Both LKB-1 and AMPK are activated when calorie restriction (CR) takes place and intracellular glucose level drops significantly (by 30% or more). In other words, CR would slow-down cancer growth and prolong our life span.

A third pathway involves an NAD-dependent histone deacetylase (HDAC) called SIRT which activates the inactive (acetylated) FOXO. During last several years David Sinclairs' group at Harvard Medical School demonstrated that the life span of both yeasts and mammals can be prolonged upon the activation of SIRT by a few compounds, and recently founded a new drug company called "Sirtris" in Boston area, to develop a set of new drugs that prolong our life span or improve our QOL by overcoming metabolic disorders such as diabetes and obesity. Why?

Natural products that activate FOXO
In 1916, shortly after her mother died of cancer, Johanna Brandt (born in 1876 ) in South Africa realized that she also got a stomach cancer. Since then she started trying to cure her own cancer, first by fast alone, following the "Fast Cure" (1911) by Upton Sinclair, which did not work well on her cancer, and then in combination of fast and red grapes which eventually caused the complete regression of cancer of her own and several others' over 9 years. A few years thereafter Johanna moved to the United States, and opened a local clinic called "Harmony Clinic", and in 1928 she published a small book "The Grape Cure", describing how to conquer cancer naturally. Since then many scientists tried to find what in red grapes could cure cancers...

In 1997, almost seven decades later, the very secret of "Grape Cure" was finally unveiled at molecular level. John Pezzuto 's group in Chicago found that the major anti-cancer ingredient in red grape skin (or red wines) is a polyphenol called "resveratrol" (trans R3).

http://en.wikipedia.org/wiki/Resveratrol

How could trans R3 cure cancers? First of all, in stomach it is converted by hydroxylation to "Piceatanol" (trans R4) which directly inhibits a Tyr-kinase called SYK. SYK is required for the activation of an oncogenic kinase called PI-3 kinase that eventually activates the kinases AKT and PAK1. Because AKT inactivates the tumor suppressor FOXO, trans R3 or R4 could activates FOXO. Later it was also found that trans R3/R4 up-regulates another tumor suppressor called "PTEN", an antagonist of PI-3 kinase, and eventually inactivates both AKT and PAK1.

More recently, David Sinclair's group and others discovered that trans R3/R4 activates two enzymes. One is SIRT, and the other LKB-1. Since both enzymes eventually activates FOXO, trans R3/R4 could activates this tumor suppressor through the above three or four pathways. In addition, our recent study on nematode has revealed that like AKT, PAK1 is also responsible for the inactivation of FOXO. Thus, R3/R4-rich red grapes or propolis such as "Bio 30" (CAPE-based NZ propolis extract) and ARC-based Brazilian green propolis extract (GPE), that activate FOXO, by either blocking the oncogenic/aging PAK1 pathways or activating SIRT and LKB-1, would be potentially useful not only for the treatment of cancers, but also many other diseases or disorders leading to the shortening of our life.

Besides, CR (calorie restriction) or fast activates the anti-aging FOXO by activating both AMPK and SIRT. Thus, it wouldn't be a big surprise for us to learn that since the publication of her 1928 book, Johanna Brandt continued enjoying a very healthy life over four decades (although she did not manage to break the world record of human longevity, 122 years by a French lady, 1875-1997!) with CR and red grapes or red wines.

Diabetes (type 2)
There are two types of diabetes. Type 1 is caused by insulin-deficiency, whereas type 2 is caused by several other disorders such as dysfunction of either IR (insulin receptor) or its down-stream targets such as PI-3 kinase, the glucose transporter GLUT-4 or AMPK. In all cases, the GLUT-4 that transports glucose from blood stream into cells fails to work efficiently. As a consequence, sugar (glucose) level in blood stream goes up abnormally. For normally both PI-3 kinase and AMPK activate GLUT-4 to stimulate the glucose transport.

Interestingly, trans R3/R4 or CR alone turned out to be useful for the treatment of diabetes (type 2), because each eventually activates the GLUT-4 by activating AMPK. In addition, bitter melon from China or Okinawa (a southern island of Japan) was recently found to activate AMPK, thereby activating both GLUT-4 and FOXO. Furthermore, 25 years ago, Dolores Takemoto's group at Kansas State University showed that an extract of this melon blocks the chemical-induction of cancers (lymphomas) in mice. Although its anti-cancer ingredients still remain to be identified, it is likely that the activation of AMPK-FOXO signal pathway might be responsible for its anti-cancer effect at least in part, in addition to its immune boosting activity. People there cook routinely this unique melon for their everyday meals. This might explain why the mean life span of Okinawa people is the longest in the world so far.

Obesity
High-Calorie Diet (HCD) causes the obesity (excess fat accumulation) and shortens our life span. Opposite to CR (calorie restriction), HCD inactivates both SIRT and AMPK, and eventually leads to the inactivation of both GLUT-4 and FOXO. Consequently, HCD (obese) mice suffer from diabetic symptom (due to a poor insulin sensitivity), would be more susceptible to cancers, and can survive significantly shorter time period. Interestingly, however, in 2006 David Sinclair's group at Harvard and "SIRTRIS" found that trans R3 can reverse the HCD effect on mice by activating both SIRT and AMPK, and increase their insulin sensitivity, lower the blood sugar level, and reduce the fat accumulation. Since the bioavailability of trans R3 is rather poor, this company is currently developing a much more potent derivative of trans R3 called "SIRT1720" to conduct its clinical trials for diabetes (type 2) and perhaps obesity as well.

http://www.medpagetoday.com/PrimaryCare/DietNutrition/tb/7527

Capsiate for a gold medal at Beijing Olympic
In 1989 a Japanese group led by Susumu Yazawa at Kyoto University selected a unique non-pungent cultivar from a pungent pepper called CH-19 from Thailand. This sweet cultivar called "CH-19 Sweet" contains a capsaicin derivative called capsiate. In capsiate, the amide bond of capsaicin is replaced by an ester bond. Like capsaicin, capsiate also serves as an anti-cancer ingredient. Furthermore, capsiate was recently found to boost the endurance swimming capacity of mice by stimulating their lipid metabolism (a great news for long-distance swimmers or marathoners to win the Beijing Olympic races!).

Actually in Japan capsiate has been widely used to lose the body weight or an extra fat by stimulating the resting lipid metabolism (oxidation). Thus, capsiate appears to be potentially useful not only for cancer therapy but also for preventing the obesity.

http://www.ajinomoto.com/about/press/g2007_07_12.html

To be continued