Chinese Herbal Medicine

Random damage to your mitochondrial DNA is a bad, bad thing in the long term - or so present theory has it. It happens all the time in your cells, however, as a natural consequence of the mitochondria doing their intended job of turning food into ATP, the universal fuel source used by your cells. The standard issue process by which food becomes ATP is called oxidative phosphorylation (OXPHOS); it generates damaging free radicals as a side-effect of its operation. Those free radicals won't get far before running into some other molecule and reacting with it, changing or damaging it in the process.

OXPHOS requires several key portions of your mitochondrial DNA to be intact and undamaged - or rather it requires the proteins that are created from those DNA blueprints. Now, if the needed portion of mitochondrial DNA is altered or destroyed by free radicals churned out by the OXPHOS process - well, no more OXPHOS for that mitochondrion. No more free radicals, either, and that's a more serious problem:

• Sufficient free radical damage to mitochondrial DNA shuts down OXPHOS within that mitochondrion, as the necessary proteins can no longer be produced. The mitochondrion switches over to using a less efficient method of producing power, one that doesn't produce free radicals, but has to run at a much higher rate to produce the same level of ATP.

• Mitochondria, like most cellular components, are recycled on a regular basis. Components called lysosomes are directed around the cell in response to various signals, engulfing and breaking down damaged or worn components. After the herd has been culled, surviving mitochondria within a cell divide and replicate, much like bacteria, to make up the numbers - this is called clonal expansion.

• The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it's old, leaky, inefficient and needs to be replaced with a shiny new power plant.

• BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.

• One DNA-damaged, non-OXPHOS mitochondrion will eventually take over the entire mitochondrial population of a cell in this way. At that point, the trouble really gets started.

These cells entirely populated with damaged mitochondria start churning out large quantities of free radicals - through another, more forceful mechanism - into the body at large. That's a path to age-related degeneration and fatal conditions like atherosclerosis. The free radical theory of aging is based upon the harm done to tissues, structures and processes by these damaging biochemicals.

So how does this all get started again? Free radical damage to mitochondrial DNA? Possibly. There has been some debate of late as to how plausible this is as a mechanism, based on mutation rates, examinations of mitochondrial function in mice with many damage-induced point mutations in mitochondrial DNA, and so forth. With that in mind, I noted with interest a recent Nature Genetics paper:

What causes mitochondrial DNA deletions in human cells?

Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are likely to have a central role in the aging of postmitotic tissues. Understanding the mechanism of the formation and subsequent clonal expansion of these mtDNA deletions is an essential first step in trying to prevent their occurrence. We review the previous literature and recent results from our own laboratories, and conclude that mtDNA deletions are most likely to occur during repair of damaged mtDNA rather than during replication. This conclusion has important implications for prevention of mtDNA disease and, potentially, for our understanding of the aging process.

Deletion mutations are much more damaging than point mutations, and can result in a sequence of many genes being snipped out and lost. Thus a greater likelihood of losing one of the genes vital to OXPHOS. This paper presents an interesting nuance to the source of deletions - serious damage created as a result of errors in the processes that repair minor damage due to OXPHOS free radicals. Irony abounds throughout the mitochondrial free radical theory of aging.

To switch gears a little, I should note that the beauty of the Strategies for Engineered Negligible Senescence (SENS) approach to the mitochondrial free radical theory of aging is that it doesn't require medical engineers to understand why the damage happens. If we can successfully move genes that express the proteins vital to OXPHOS into the cellular nucleus, it then doesn't matter what happens to the mitochondrial DNA, OXPHOS will keep on working.

Similarly for wholesale replacement strategies - we don't need to know how the damage occurred to know that protofecting fresh, undamaged mitochondrial DNA into every cell will fix things for a while. "A while" being at least 30 years, given how long it takes the problem to become damaging to health.

Research is good - there is no such thing as useless knowledge, and every additional level of detail helps those building new therapies. But never feel as though there isn't enough to go on with already when it comes to engineering the repair of aging. Researchers know more than enough to be underway, and it's a tragedy that the field of aging repair - real rejuvenation medicine - is far less funded than present understanding merits.

Future Current provides a valuable service by transcribing and making available the proceedings of meetings on transhumanist topics, such as healthy life extension and the ultimate defeat of degenerative aging. Two recent posts cover talks by Ronald Bailey and Anders Sandberg, given at the 2007 IEET event entitled Securing the Longevity Dividend. They are well worth your time as a reminder of the way in which the policy-focused world thinks.

Policy Scenarios for the Longevity Dividend

Here we have a very important driving factor, that is the belief that it is possible to extend life, which is not that widespread. People are in general very interested in life extension, but they don’t quite believe in it. I think this is very much the same situation as cloning before Dolly. I remember myself two weeks before the cloning of the sheep Dolly actually saying in a public forum, “Oh, cloning of mammals is years away.” It’s good to know that I’m a conservative guy that is sometimes wrong about the future. Life extension might come unexpectedly, and that’s not necessarily just a good thing, because some people might panic. On the other hand, if people don’t believe it’s possible, they won’t fund it.

It's only unexpected if we advocates haven't done our jobs - and the same goes for any alleged panic ("oh no, we don't have to suffer and die quite so soon..."). It seems to me that healthy life extension is a good deal more challenging than mammalian cloning, to the point at which it will take a very large and well supported research community to make real progress. It's more in line with cancer or regenerative medicine in that respect. No-one is going to be surprised by the advent of working rejuvenation therapies, for all the same reasons that no-one will be surprised by the development of cures for a broad range of cancers, or tissue engineered replacement organs.

The Political Economy of the Longevity Dividend

I would like to conclude that I think it is easily the case that these kinds of treatments are very likely to be affordable. The pro-mortalists fail to understand the effort to extend healthy human lifespan is a perfect flourishing of our uniquely human nature. The future generations will look back at the beginning of the 21st century with astonishment that some very well meaning and intelligent people actually wanted to stop biomedical research just to protect their cramped and limited vision of human nature. Those future generations will look back, I predict, and thank us for making their world of longer, healthier lives possible. To end, let me quote Sirtris Pharmaceuticals co-founder David Sinclair who said, "I would be disappointed if we were all born one generation too early." Me too.

For more information on the ongoing Longevity Dividend initiative that was the focus of this IEET event, you might look back in the Fight Aging! archives:

• Pitching Healthy Life Extension as the "Longevity Dividend"
• Criticizing the Longevity Dividend
• The Longevity Dividend: A Call for Endorsements

Utilizing a technique that combines low temperature measurements and theoretical calculations, Hebrew University of Jerusalem scientists and others have revealed for the first time the electronic structure of single DNA molecules.

The knowledge of the electronic properties of DNA is an important issue in many scientific areas from biochemistry to nanotechnology -- for example in the study of DNA damage by ultraviolet radiation that may cause the generation of free radicals and genetic mutations. In those cases, DNA repair occurs spontaneously via an electronic charge transfer along the DNA helix that restores the damaged molecular bonds.

In nano-bioelectronics, which is the advanced research field devoted to the study of biological molecules (to produce electrical nanocircuits, for example), it has been suggested that DNA, or its derivatives, may become used as possible conducting molecular wires in the realization of molecular computing networks which are smaller and more efficient than those produced today with silicon technology.

The knowledge that has been acquired in this project, say the researchers, may also be relevant for current attempts to develop new sophisticated, reliable, faster and cheaper ways to decode the sequence of human DNA.

The research, published in the prestigious journal Nature Materials, is a result of an international collaboration. The research was conducted by Errez Shapir and coordinated by Dr. Danny Porath at the Department of Physical Chemistry and Center for Nanoscience and Nanotechnology at the Hebrew University and by Dr. Rosa Di Felice at the S3 Center of INFM-CNR in Modena, Italy. Also collaborating in the project were Prof. Alexander Kotlyar at Tel Aviv University, who synthesized the molecules, the CINECA supercomputing center in Italy, and Prof. Gianaurelio Cuniberti at the University of Regensburg, Germany.

In their work, the researchers were able to decode the electronic structure of DNA and to understand how the electrons distribute into the various parts of the double helix, a result that has been pursued by scientists for many years, but was previously hindered by technical problems.

The success of this project was finally achieved thanks to collaboration between experimental and theoretical scientists who worked with long and homogeneous DNA molecules at minus 195 degrees Celsius, using a scanning tunneling microscope (STM) to measure the current that passes across a molecule deposited on a gold substrate. Then, by means of theoretical calculations based on the solution of quantum equations, the electronic structure of DNA corresponding to the measured current has been obtained. These results also suggest an identification of the parts of the double helix that contribute to the charge flow along the molecule.

http://www.huji.ac.il/

A chronic autoimmune disease, rheumatoid arthritis (RA) is characterized by persistent inflammation of the synovial membrane and progressive joint destruction.

Beyond loss of mobility, sufferers face a high risk of heart failure. An inflammatory cytokine known for contributing to the development of RA, tumor necrosis factor a (TNFa) has also been implicated in cardiovascular disorders. Inhibition of TNFa has opened promising new treatment options for RA patients. Anti-TNF drugs such as infliximab, etanercept, and adalimumab have been shown to not only diminish signs and symptoms of the disease, but also prevent joint damage. However, in cardiac trials, TNFa inhibitors have shown no more positive effects on heart failure risk -- and sometimes less -- than placebo.

Does TNFa inhibition prevent heart failure in RA patients -- or promote it? That's the critical question Dr. Joachim Listing and a team of specialists with the German Rheumatism Research Centre in Berlin set out to answer. Featured in the March 2008 issue of Arthritis & Rheumatism ( http://www.interscience.wiley.com/journal/arthritis), their study indicates that anti-TNF therapy does a patient's heart more good than harm, when it successfully reduces the inflammatory toll of RA.

To clearly assess the role of TNFa inhibitors in heart failure risk, the researchers analyzed a 3-year span of disease activity and cardiovascular incidents in 4,248 RA patients enrolled in an ongoing Germany-wide study of biologic therapy. At the time of enrollment, 2,757 of the subjects had started treatment with an anti-TNF drug -- infliximab, etanercept, or adalimumab -- and 1,491 had started a new disease-modifying antirheumatic drug (DMARD). Within the study period, several hundred of the patients were also treated with glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), or COX-2 inhibitors. Over 78 percent of the patients were women. The mean age at baseline was 53.7 years for the anti-TNF group and 56 years for the DMARD controls.

Recorded at baseline and regular intervals through the 60-month follow-up, data on every patient included C-reactive protein level, duration of morning stiffness, and the number of tender and swollen joints, based on the 28-joint count Disease Activity Score (DAS). Cardiovascular events, whether acute or congestive, were also noted. Researchers used Cox proportional hazards models to investigate the impact of disease-related and treatment-specific risk factors on the development or worsening of heart failure.

At baseline, RA patients in the anti-TNF group had significantly more active disease, more physical limitations, and more heart problems than patients in the control group. Not surprisingly, the incidence rates of heart failure were significantly higher -- more than double -- for patients with a cardiovascular condition at the start of treatment than for those in good heart health. After adjusting for age, sex, body mass index, and prevalence of cardiovascular events, an increased risk of heart failure was found in patients with low functional capacity and high disease activity. Notably, a 2-point increase in the DAS28 score resulted in a 1.8-fold increase in heart failure risk.

When adjusting for functional capacity and disease activity at follow-up, along with the standard risk factors, the contribution of anti-TNF therapy to heart failure risk was insignificant. The small residual risk was balanced by the treatment's effectiveness in reducing inflammation, ultimately protecting the heart and other vital organs in addition to the joints. In contrast, COX-2 inhibitors and glucocorticoids, which tend to promote elevated blood pressure and insulin resistance, were associated with an increased risk of heart disease and heart attack.

Confirming the grave risk of heart failure for patients with severe rheumatoid arthritis, especially those with highly active disease, this study also sheds light on the benefits of treatment with TNFa inhibitors to the heart and whole body. "Our data suggests that controlling the inflammatory activity of RA not only leads to better outcome of the rheumatic disorder, but also contributes to a reduction of cardiovascular risk," Dr. Listing notes. He calls attention to the need for more research to weigh the positive effects of glucocorticoids, such as cellular proliferation, against their harmful effects to the cardiovascular system. Finally, he urges caution in prescribing any drug that may be hazardous to the heart of a vulnerable patient. "Screening for cardiac risk factors and effective treatment of both the rheumatic disorder and the cardiac disease are essential," Dr. Listing stresses.

http://www.wiley.com/wiley-blackwell

The U.S. Food and Drug Administration approved Nexium (esomeprazole magnesium) for short-term use in children ages 1-11 years for the treatment of gastroesophageal reflux disease (GERD).

The agency approved Nexium in two forms, a delayed-release capsule and liquid form. Nexium is approved in 10 milligrams (mg) or 20 mg daily for children 1-11 years old compared to 20 mg or 40 mg recommended for pediatric patients 12 to 17 years of age.

"This approval provides important information for appropriate dosing for children ages 1-11 years with GERD," said Julie Beitz, M.D., director of the FDA's Office of Drug Evaluation III in the Center for Drug Evaluation and Research. "Children prescribed this drug should be monitored by their physicians for any adverse drug reactions."

Nexium is part of a class of drugs known as proton pump inhibitors (PPIs). PPIs decrease the amount of acid produced in the stomach and help heal erosions in the lining of the esophagus known as erosive esophagitis.

FDA approved the use of Nexium in patients 1 to 11 years for short-term treatment of GERD based upon the extrapolation of data from previous study results in adults to the pediatric population, as well as safety and pharmacokinetic studies performed in pediatric patients. In one study, 109 patients 1-11 in age, diagnosed with GERD, were treated with Nexium once-a-day for up to eight weeks to evaluate its safety and tolerability. Most of these patients demonstrated healing of their esophageal erosions after eight weeks of treatment.

The most common adverse reactions in children treated with Nexium were headache, diarrhea, abdominal pain, nausea, gas, constipation, dry mouth and sleepiness. The safety and efficacy of Nexium has not been established in children less than one year of age.

http://www.fda.gov/