February 2000 Blog with Durk and Sandy

HAPPY 2000! STICK AROUND.
THE BEST OF LIFE EXTENSION IS YET TO COME!

LOOKING AHEAD-LIFE EXTENSION: 2000 AND BEYOND
The future of life extension is looking great! Keep yourself in good health so you can take advantage of some of the upcoming opportunities . . .

GLUCOWATCH

A new medical device promises a major breakthrough in practical life extension, as well as in the treatment of serious diseases such as diabetes. The device, called the GlucoWatch (Cygnus, Inc., 400 Penobscot Dr., Redwood City, CA 94063, Attn.: Russell O. Potts, Ph.D.), was described in an article in the November 17, 1999 Journal of the American Medical Association. As the name suggests, the device measures blood glucose by means of a painless, automatic, and noninvasive method while the user wears it on his/her wrist like a watch. The device is said to provide up to three readings per hour for as long as 12 hours after a single blood glucose measurement (using finger-stick blood sample) for calibration.

The device extracts glucose through the skin using an applied potential (a process known as iontophoresis) and measures the extracted sample using an electrochemical-enzymatic sensor. The electro-osmotic flow causes glucose to be transported across the skin. A single-point calibration (taken with - OUCH - a finger-stick blood sample) compensates for the variability in the amount of glucose extracted compared with blood glucose in individuals and at skin sites. The results of a study using five subjects with diabetes in twelve uses showed a mean correlation (between glucose extracted and blood glucose) coefficient of 0.89 and a mean absolute error of 13%. Full details of how the device works are contained in the JAMA article.

The potential for this device in the design of practical life extension programs is immense. A well-known hypothesis proposes that a low-glycemic-index diet (one that does not increase blood glucose excessively) is likely to have beneficial health and possibly even life-extending effects. It is well known that high blood glucose levels (even temporarily following a high-carbohydrate meal) promote glycation¹ (cross linking between sugars and proteins), obesity, and increased oxidative stress,² among other things.

LOW-GLYCEMIC-INDEX DIET BECOMES PRACTICAL
As noted in a comment on a recent review,³ a low-glycemic-index diet is very difficult to follow because of several factors, including the lack of availability of data on the glycemic indices of individual foods and of mixed meals. Also, the comment notes that "in the determination of glycemic index, there are no widely practiced standards regarding food preparation, cooking, storage . . . ." Thus, even the available data are difficult to use. The GlucoWatch virtually eliminates these problems by making it possible to painlessly follow one's blood sugar levels directly. Hence, each individual user can establish the best dietary practices for himself or herself, with data that relate blood sugar levels to diet, time of day, stress conditions, and so forth.

Furthermore, one can quickly test the effects of various dietary supplements (such as those containing various fibers, a range of doses of lipoic acid, vitamin E, chromium, ethyl alcohol, and so forth) to determine how they affect blood sugar levels. The development of better formulations to keep blood sugar levels in a desired range will accelerate. It will likely soon be possible for people to eat nearly any desired foods (even sweet desserts) without having surges in blood sugar levels (which may help to prevent obesity) and to do so without pain, fear, or guilt. And no longer will you have to use measurements made by other people, as you can do your own with the GlucoWatch and devices to follow.

DNA GENE ARRAYS FOR LIFE EXTENSION
As many of you may know, there has already been a study published using a gene array to simultaneously monitor the expression of 6,347 genes (representing, the authors estimate, 5% to 10% of the mouse genome) in gastrocnemius [calf] muscle of calorically restricted mice (76% of calories fed to controls) as compared to controls.⁴The idea was to pinpoint those genes that had their expression markedly reduced or increased by caloric restriction to focus on genes responsible for the life-extending effects of the diet on mice. Examples of their many findings were: Of those genes whose age-associated expression was changed the most (twofold or greater increase or decrease), 29% were completely prevented by caloric restriction (CR), while another 34% were partially prevented by CR. CR resulted in the induction of 51 genes (1.8-fold or larger) as compared with the age-matched control animals. CR-induced genes were involved in energy metabolism, stress response, and DNA-repair pathways. The authors suggest that some of the observed gene changes may be the basis for the metabolic shift toward increased biosynthesis and macromolecular turnover seen in CR animals. "A hormonal trigger for this shift may be an alteration in the insulin-signaling pathway through increased expression of genes that mediate insulin sensitivity, a finding that links our observations to those obtained through the genetic analysis of aging in the nematode C. elegans [see Figure 1]." This is the first of a series of publications these authors plan to make on the basis of their analysis. They have also begun collecting data for a study of gene-expression changes in muscle of Rhesus monkeys of different ages and various degrees of caloric restriction, using a human gene-array chip. Richard Weindruch, one of the researchers, stated: "Technically, there will be the concern about the human chip not working for the Rhesus monkey, which is 'only' 95-97% genetically similar to humans. We think, however, that probably won't be a problem, at least for many of the genes that may be most important, and those are the ancient, highly conserved kinds of molecules, such as heat-shock factors and the like . . . ."⁵ WOW!

Figure 1. The nematode C. elegans in reproductive embrace.

Another gene-array study was recently reported⁶ that detected changes in gene expression that took place in prostate cancer cells as they progressed from androgen-dependent to androgen-independent. The study found, for example, that insulin-like growth-factor-binding protein 2 and HSP27, a heat-shock protein, were the most consistently overexpressed in the hormone-refractory tumor cells. Studies like this will have a major impact on how cancer is treated.

FUTURE STUDIES USING GENE ARRAYS
DNA gene-array technology has just become available, of course, and the implications for health and life extension are immense. Using this new technology, for example, studies could determine changes in gene expression using methyl-donor dietary supplements. Methylation is a major biological method of regulating gene expression, with methylation generally silencing genes. It is thought that some early cancers may involve hypomethylation,⁷ a deficiency in methylation. It is possible that this could be prevented by increasing consumption of methyl donors such as choline and betaine, along with necessary cofactors such as folic acid and vitamin B12. This can be tested using the new technology.

Other gene-array studies could locate major changes in gene expression that arise from exercise compared to nonactivity, possibly leading to the development of a dietary supplement that can be demonstrated to provide at least some of the benefits of exercise. Researchers could look at gene expression in obese versus lean subjects, testing potential weight-loss formulations for their ability to make obese subjects express genes more like lean subjects.

The ability of DNA gene arrays to analyze and make sense of data is dependent upon silicon technology, and silicon technology is doubling such abilities every 18 months! New medicines, medical devices, and longer life span are about to explode into the marketplace, along with the inevitable authoritarian discussions by supposed ethicists (more ethical than you and me) about inequality in the receipt of information and medical care. For example, should you be allowed to buy this new medical technology with your own money or should government "experts" decide how you can spend your own money? Should anybody be allowed to increase his or her own life span when there are starving people in Africa? These are not silly questions. They will be asked with the utmost seriousness by people who do not think you own your own life and who are willing to use the guns of the government to manipulate your life or even to take it in the pursuit of their own agenda.

GENE-CONTROLLING MAMMALIAN LIFE SPAN IDENTIFIED
In the meantime, using a different method (not a gene array), a group of scientists has identified a gene, p66^shc, that induced stress resistance and increased life span by 30% in mice in which the gene was mutated to decrease its function or ablated to eliminate it.⁸ The scientists studied the role of p66^shc in stress responses by measuring the extent of its tyrosine phosphorylation when mouse-embryo fibroblasts were treated with ultraviolet light, hydrogen peroxide, or epidermal growth factor. Ablation of the gene increased resistance of the fibroblasts to hydrogen peroxide to less than 30% cell death.

The cells that survived this stress maintained their proliferative potential. Similar results were obtained with ultraviolet treatment. In the wild-type (normal gene) fibroblasts, about 80% and 40% of the cells survived after one and two days of treatment, whereas in the cells with ablated p66^shc, the cytotoxic effect of UV was negligible. The authors suggest that p66^shc is a critical component of the apoptotic (programmed cell death) response to oxidative damage, whereas it has no effect on the arrest of cell proliferation induced by DNA damage.

Clearly, we are fast approaching a time when human gene therapy will be able to deliver longer life span and improvements in mental and physical function, as well as (but not merely for) the treatment of disease. This will have bewildering results for many whose philosophies require stability and maintenance of the biological status quo of both humans and the world in which we live. For example, widespread genetic modification could scramble the identity of racial groups, since each is by definition a group that shares certain genetically determined phenotypic traits. The increasing use of genetic modification of plant and animal life (including the upcoming cloning of "extinct" species such as mammoths) will destroy the idea of a single environmental ideal (e.g., the parochial snapshot that exists at exactly this moment) that must be protected from change at all cost.

Genetic modification will increase human inequality (i.e., diversity) by permitting humans to increase their genetic choices beyond those made available by evolutionary processes. People who have a low tolerance for differences in others may be in for a shock. Of course, there is always Prozac^® . . . .

References

See, for example, Paul and Bailey, - Glycation of Collagen: The Basis of its Central Role in the Late Complications of Ageing and Diabetes,- Int. J. Biochem. Cell Biol. 28(12):1297-1310 (1996).
See, for example, VERIS Research Summary, May 1998.
Saltzman, - The Low Glycemic Index Diet: Not Yet Ready for Prime Time- (comment), Nutrition Reviews 57(9):1999; Morris and Zemel, - Glycemic Index, Cardiovascular Disease, and Obesity,- same journal, same issue.
Lee, Klopp, Weindruch, Prolla, - Gene Expression Profile of Aging, and Its Retardation by Caloric Restriction,- Science 285(5432), 1999.
Quoted from an interview with Weindruch and Prolla in the November 1999 Life Extension (publication of the Life Extension Foundation, 1-800-841-LIFE).
Bubendorf et al., - Hormone Therapy Failure in Human Prostate Cancer: Analysis by Complementary DNA and Tissue Microarrays,- J. Natl. Cancer Inst. 91(20):1758-1764 (1999).
See, for example, Chen et al., - DNA Hypomethylation Leads to Elevated Mutation Rates,- Nature 395:89-93 (1998).
Migliaccio et al., - The p66^shc Adaptor Protein Controls Oxidative Stress Response and Life Span in Mammals,- Nature 402:309-313 (1999).

LOOKING AHEAD - A FEW HIGHLIGHTS

What specific events might be coming up in the near future? We consulted our crystal ball, which revealed to us a few examples . . . .

In 2004, a Nobel Prize-winning physiologist writes a best-selling book called What It Means to Be Human, which concludes that being human means, in the 21st century, being able to choose for yourself what it means to be human.

The Nobel Prize for Physiology or Medicine and the Nobel Peace Prize for 2008 are won by the same scientists, who discover the genes that control irrational violent behavior and the signal-transduction pathways that regulate them. This knowledge, plus discoveries on the genetic and biochemical bases of the pygmy chimpanzees' use of sex as a remedy for interpersonal conflict, leads to a new drug called "Make Love Not War" (a true aphrodisiac, not just a performance enhancer) that creates an immense controversy as its use results in a tremendous decline in the interest of young people in war and politics and creates a huge illicit subculture.

In 2012, the first person to run a three-minute mile loses his or her Olympic gold medal when post-race DNA tests reveal that he/she has racehorse mitochondrial DNA.

By 2048, The Sharper Image is selling universe lamps, which are small globes each containing a real universe of some 100,000,000,000 galaxies, each of which contains about 100,000,000,000 stars. Each universe lamp has an estimated lifetime of at least one trillion years. With no on-off switch (since they are always on), each lamp comes with a decorative cover so it won't keep you awake at night. The universe lamp is guaranteed by The Sharper Image to contain at least one friendly, intelligent, humanoid species. For an additional charge of only 10 grams of gold, you get a miniature radio telescope and a CD-ROM that teaches you First Contact Protocol. Great for kids from 9 to 290!

Oh dear, the crystal ball has dimmed (or maybe it is just asking for another payment). Its final message as it fades out is: "Reality is likely to be a lot more amazing. . . ."

A BIOMAKER FOR MORTALITY YOU CAN EASILY AND CHEAPLY MEASURE

You don't have to be visibly falling apart and about to keel over to have an increased risk of death. So it's nice to have some biomarkers you can easily detect to sound an alarm if your risk is increased. One such useful marker has been reported in a recent paper:¹ a slow return of heart rate to normal after exercise can predict an increased risk of mortality.

The authors note that the increase in heart rate that accompanies exercise is due in part to a reduction in the tone of the vagus nerve and that recovery of heart rate to normal immediately after exercise is a function of vagal reactivation. A generalized decrease in vagal activity is reported to be a known risk factor for death; hence, the authors hypothesized that a delayed fall in heart rate after exercise might point to a higher risk of mortality.

The researchers tested their hypothesis by measuring the recovery of heart rate after exercise, which was defined as the decrease in heart rate from peak exercise to one minute after the cessation of exercise. (After reaching peak workload, all patients spent at least two minutes in a cool-down period during treadmill testing at a speed of 2.4 km (1.5 mi) per hour at a grade of 2.5%.) The authors defined an abnormally slow recovery as a reduction of 12 beats per minute or less from the heart rate at peak exercise. They followed for six years 2,428 consecutive adults they saw at the Cleveland Clinic Foundation who had no history of heart failure, coronary revascularization, or heart pacemakers. The subjects had a mean age of 57 + 12 years, with 63% men.

They found that 26% of the patients had abnormally low values for heart-rate recovery. Over the six years, 213 deaths from all causes occurred. Of those who died, the majority (56%) had an abnormally low value. A low value for recovery of heart rate was strongly predictive of death, with a relative risk, after adjusting for various factors, of 2.0, which was independent of workload, the presence or absence of heart perfusion defects (as measured at the start of the study by thallium scintigraphy), and changes in heart rate during exercise. Not surprisingly, there was a strong association between a decreasing exercise capacity and an abnormal value for heart-rate recovery in both men and women.

All you need to keep track of your heart recovery rate is a heart-rate sports watch or similar device that you can buy for $30 and up, depending upon how fancy you want it.

References

Cole et al, "Heart-Rate Recovery Immediately After Exercise As a Predictor of Mortality," New Engl. J. Med. 341(18):1351-1357 (1999).

FOLIC ACID MAY REDUCE THE RISK OF CERTAIN CANCERS

Just as the FDA has resigned itself to having to allow a folic acid claim for the reduction of the risk of neural-tube-defect births (or, more precisely, has picked itself up after having been dragged kicking and screaming by both public and Congressional pressure to its new position), it had better get ready for the next folic acid claim: that folic acid may reduce the risk of some cancers.

A recent review¹ describes some evidence that folic acid may be protective for people at risk of developing colorectal, pancreatic, and breast cancer, especially for male smokers at risk for pancreatic cancer and for women regularly consuming moderate amounts of alcohol at risk for breast cancer. Folic acid is a key component in DNA replication and repair and DNA methylation, which are plausible mechanisms to account for its cancer-protective effects.

The greatest amount of evidence relating folate to cancer risk is in the case of colorectal cancer. The majority of the 20 published epidemiologic studies indicate that dietary folate intake is inversely associated with the risk of developing colorectal neoplasms in a dose-dependent fashion, reports the review. Very convincing evidence came from a prospective study involving 88,756 female nurses in the U.S. (the Nurses Health Study), which reported a 75% reduction in colorectal cancer risk in women using multivitamin supplements containing 400 mcg or more of folic acid for 15 years or more, compared with those not taking folic acid, after correcting for known confounding factors such as vitamins A, C, D, and E, and calcium. Animal studies and small, human, randomized intervention studies also support the protective effect of folate supplementation against colorectal cancer.

Women consuming at least 15 grams a day of alcohol were reported (using data from the Nurses Health Study) to have a 24% increased risk of breast cancer, compared to women consuming no alcohol. Alcohol has an adverse effect on folate transport and metabolism, so the study authors looked at the association between total folate intake and breast-cancer risk by levels of alcohol consumption. Among women consuming at least 15 grams a day of alcohol, there was a significant dose-dependent inverse association between total folate intake and breast-cancer risk. In this cohort, it was reported that total folate intake of at least 600 mcg per day was associated with a 45% reduction in breast-cancer risk, compared with 150-299 mcg per day. The protective effect of folate on breast-cancer risk was not evident for women consuming less than 15 grams a day of alcohol.

A case-control study conducted as part of the ATBC (Alpha-Tocopherol Beta-Carotene) Cancer Prevention Study, looking at 29,133 Finnish men over 7-10 years, reported that serum folate concentrations were inversely related to the risk of pancreatic cancer. Baseline serum levels in the highest percentile (over 4.45 ng/ml were associated with a 55% reduction in risk, compared to those at the lowest level of 3.33 ng/ml or less. (A similar inverse dose-response relationship was reported for vitamin B6.) This is especially good news, since pancreatic cancer is rapidly deadly, with current approved treatments not very effective.

References

Young-In Kim, "Folate and Cancer Prevention: A New Medical Application of Folate Beyond Hyperhomocysteinemia and Neural Tube Defects," Nutrition Reviews 57(10):314-321 (1999).

LOOKING AT YOUR HEAD - HAIR, HAIR, EVERYWHERE

A new report in Nature¹ tells an incredible story, that hair follicles are an immune-privileged site and can, therefore, be induced to grow in an incompatible host. In fact, in the study, hair follicles from one author (male) were implanted into a genetically unrelated and immunologically incompatible female recipient, another of the authors. All the implant sites healed rapidly and lacked any overt inflammatory reaction; each site of dermal-sheath implantation produced new follicles and fibers 3 to 5 weeks after the graft. The follicles were taken from the head and implanted onto the inner forearm; the resulting hairs from the implants were not fine, unpigmented vellus hairs that grow from the inner arm, but were larger and thicker, mostly pigmented, and were said to grow in variable directions. The authors propose that this might be a new treatment for hair loss.

It might indeed. But it might also lead to very entertaining (or, to some, appalling) new hair "styles." Young people, rather than dying their hair, might have selected implants to give them multicolored heads of hair. Even beyond that, if hair follicles are indeed immune-privileged sites, then even interspecies hair transplants might be possible and desired by the more adventurous. Imagine a head of silky mink fur! Or how about an entire "coat" of mink fur?

References

Reynolds et al., "Trans-Gender Induction of Hair Follicles," Nature 402:33-34 (1999).

IS CONJUGATED LINOLEIC ACID AN ANTIOXIDANT?

There is a lot of interest in conjugated linoleic acid (CLA) because of its reported array of potentially beneficial effects, which include protective effects against atherosclerosis and carcinogenesis, changes in fat partitioning (body composition; specifically, increases in lean body mass and decreases in body fat), as well as increasing bone mass and normalizing diabetes in experimental animal models. In biological systems, CLA is incorporated into phospholipids, which are the major structural components of cell membranes.

The anticancer effects of CLA can be dramatic. For instance, in one study using severely combined immunodeficient mice, feeding 1% CLA in the diet inhibited local tumor growth of human breast adenocarcinoma cells inoculated subcutaneously, and it completely prevented the spread of breast cancer cells to lungs, peripheral blood vessels, and bone marrow, in contrast to controls.

At first, the effects of CLA were hypothesized to be the result, at least in part, of CLA's being an antioxidant, but it may be that CLA is a pro-oxidant, at least as reported in two prior papers^1,2 and a new paper.³ The new paper reports that CLA-containing phospholipids increased oxygen consumption with increasing concentration up to 5 mol%, which is the concentration that had been previously shown to result in the greatest beneficial effects on mammary-cancer prevention in lab animals. CLA-containing phospholipids in cell membranes also increased the oxygen permeability. The authors located the enhanced oxygen-diffusion-concentration product in the region of the CLA conjugated double bonds in the membranes and suggest that "[t]he combined effects of perturbing membrane structure and increasing oxygen diffusion-concentration products by double-bond conjugation imply that CLA molecules probably increase the biomolecular collision frequency of oxygen, and/or reactive oxygen species, with target molecules, thereby accelerating the oxygen consumption." They add that they do not know whether this effect contributes to the observed beneficial effects or anticancer effects of CLA.

We suspect that the chemical actions of CLA serve as a specific signal that induces upregulation of antioxidant protective mechanisms and that this may account for its anticancer and antiatherosclerosis effects. It has been established that oxidants and their scavenging by antioxidants may selectively regulate certain signal-transduction pathways, the study of which is a new cutting edge in basic biomedical research.⁴ CLA may be a regulator of gene expression. We look forward to more research on this intriguing possibility.

References

van den Berg et al., "Reinvestigation of the Antioxidant Properties of Conjugated Linoleic Acid," Lipids 30:599-605 (1995).
Chen et al., "Reassessment of the Antioxidant Properties of Conjugated Linoleic Acid," J. Am. Oil Chem. Soc. 73:749-753 (1997).
Yin et al., "Effects of Conjugated Linoleic Acid on Oxygen Diffusion-Concentration Product and Depletion in Membranes by Using Electron Spin-Label Oximetry," Lipids 34(10):1017-1023 (1999).
A new journal in this field is Antioxidants & Redox Signaling, published by Mary Ann Liebert, Inc., 2 Madison Ave., Larchmont, NY 10538-1962, (914)834-3100.