AGINGSCIENCES™ – Anti-Aging Firewalls™

A reported study about free radicals is radical in its conclusions.  The study was based on disabling five genes in mutant Caenorhabditis elegans worms.  The study’s authors suggest that damage due to free radicals may not be a cause of aging but rather is a consequence of aging and suggest instead that the aging process may originate in the mitochondria.  See my discussion on the Mitochondrial DNA mutation theory of aging.  It would seriously upset the anti-aging establishment’s applecart if oxidative damage turned out to be only a symptom.  However, I hesitate to accept such a broad conclusion given the preponderance of evidence that exposure to strong oxidative stress, such as massive doses of radiation, generates the overt symptoms of aging.  Most likely we are dealing with a chicken-and-egg causative process here where it is both the case that oxidative damage contributes to aging and that aging contributes to oxidative damage.  And the mitochondria play an important role in mediating the aging process.  See the previous blog post as well.

Stress may increase the rate of progression of the most malignant form of melanoma, according to a report on a study conducted in New Zeeland of 1600 people diagnosed with that disease.  Small wonder given what we know about stress and how stress-generated cortisol suppresses the functioning of the immune system. Of course, some of the stress may come from the diagnosis itself.  This study  points again to the importance of the substances in the anti-aging firewalls that encourage regular sleep and mental calm like l-theanine and melatonin as well as a relaxed mental attitude that takes any problems in stride.

I have been quite skeptical of futuristic claims about how nanotechnology will enable immortality.  Specifically, the idea of intelligent nanorobots swimming around freely in my bloodstream diagnosing diseases and repairing cells seems too far off in the future for me to be concerned about it. I have focused more on the growing stream of here-and-now longevity-related discoveries based on genetics and molecular biology. 

Nontheless, an item came to my attention today that leads me to question the severity of my skepticism about the potential contribution of nanotechnology to life extension.  A research study reported in December 2008 indicates that nano-scale substrate surface topography (micro characteristics of the surface on which a cell culture is grown) can significantly affect stem cell differentiation.  The study looked at human mesenchymal stem cells (hMSC) that can differentiate into a variety of cell types including chondrocytes, osteoblasts,  myocytes, and adipocytes.  It was discovered that when the surface consisted of relatively small nanotubes, hMSC adhered to the tubes without noticeable differentiation.  Somewhat larger diameter nanotubes (≈70- to 100-nm diameter)  “elicited a dramatic stem cell elongation (≈10-fold increased), which induced cytoskeletal stress and selective differentiation into osteoblast-like cells.”  The result is relevant to the 14^th theory of aging treated in my Anti-Aging Firewalls treatise which is Decline in adult stem cell differentiation.  The challenge with age is how to assure a continuing high rate of differentiation of adult stem cells to replace depleted body cells without incurring risk of cancer.   The new research result suggests that surface geometry can be an important consideration related to stem cell differentiation, and that control of nanosurface characteristics may prove to be helpful to elicit differentiation.  Another small piece of research in the 2,500,000 piece puzzle that will define aging.

One of the areas of research I track carefully is that related to the Telomere shortening theory of aging.  You will recall that telomeres are like shoestring caps, inert sequences of DNA at the end of chromosomes.   Telomeres provide stability that protects DNA in the chromosomes against getting mixed up in the process of cell reproduction.  Telomeres get shorter as cells divide, and when they get too short a cell can get into big trouble and create trouble for its neighbors – like cancer.  Telomerase is an enzyme that pastes telomere ends back on again, and one theory for life extension is to cause cells to express telomerase so that the telomeres don’t get too short.  You can read about that in my treatise here.  A report appeared yesterday on a Swedish study of changes in telomere lengths in 959 individuals who had contributed blood samples at 9- to 11-year intervals.  The study revealed several interesting findings. 

·         Telomere shortening with age varies significantly between individuals

·         Telomere length at a certain age may not be as good a predictor of future lifespan as previously thought.

·         In general, the rate of telomere shortening appears to depend on the telomeres’ original length.  People starting out with the longest telomeres experienced the fastest rate of telomere shortening and vice versa. 

·         In some individuals, the telomeres measured actually got longer with time. In roughly a third of the subjects, the telomeres actually lengthened over the study period.

These results suggests to me that telomere shortening is a complex process involving a balance of shortening due to cell division, lengthening due to telomerase expression and perhaps cell replacement due to differentiation of stem cells.  And these in turn are affected by many lifestyle and dietary factors.  The new findings also lead to optimism in that they suggests that strategies to keep telomeres from shortening or for making them longer may in fact work.  Readers of the Anti-Aging Firewalls treatise know that I take the supplement astragaloside IV for this purpose as well as pursue other strategies like stress minimization, taking antioxidants, etc.

Powerful behind-the-scenes engines are increasing the scientific knowledge base related to longevity at an ever-increasing pace. For example, the following bulleted items are drawn from articles in the February 1, 2009 issue of GEN: Genetic Engineering and Biotechnology News, a biotechnology industry trade magazine.

One set of engines is to be found in the field of drug discovery.

• Research in RNAi (RNA interference) mechanisms, drugs and therapies, approaches that interfere with the role of RNA, the complement of DNA in the cell cycle. RNAi therapies work through selectively silencing genes, effectively interfering with entire gene-activation pathways, and are under development for a number of diseases. This research is forwarding our knowledge of cell cycle and gene activation path basics and the roles of micro RNAs in the human genome – key issues insofar as longevity is concerned.

• Epigenomics is of increasing importance as a research tool – the area that goes beyond genetics to look at what is going in the cell nucleus the DNA and RNA to determine characteristics of organisms and explain the vast complexity of what is going on in the biological world. Genes are located on chromosomes with large sequences of DNA separating them. Once this was called “junk DNA” and ignored, but we now know that junk contains secrets essential for life. Not only is there important information and variations in the genes and their variations (polymorphisms) but also in the rest of the DNA, and also in the RNA. Decoding the human genome was just the tip if the iceberg. Much of this basic research is also driven by the quest for drug discovery, looking for ways to interfere with cancer proliferation for example. Meanwhile, this research is starting to tell us more about how we are put together at the most basic level and what might help us live longer.

Another set of engines accelerating the rate of knowledge discovery is rapid and relentless underlying improvements in the tools for genetic and biotechnology research and engineering, the tools that make the above kinds of life-science research possible. There is constant improvement in capacity along with cost decrease of gene microarray chips, chips that allow simultaneous screening for hundreds or thousands of genes. There seems to be a version of Moore’s Law operating here. Moore’s Law says the capacity, power and cost-effectiveness of microprocessors doubles every 12-18 months, and that law that has consistently operated during the last 30 years. The same nature of increase in cost effectiveness is also true for gene sequencers. I can imagine going into Wallgreens or CVS, paying $14.99, spitting on a chip and getting back a printed and on-line profile checking 1500 of my genes for susceptibility to diseases. This could happen in 10 years, perhaps less. But there are many other improvements in bioresearch technology going on right now as well. For example:

· A new bioreactor design allows for the 3-D cultivation of cells, important to mimic the 3-D conditions in actual organisms.

· New molecular visualization technologies are allowing mapping of vascular cell surfaces in normal and pathological organs, mapping the locations of proteins and identifying key chemical biomarkers.

· New technologies are now available for visualizing signal transduction pathways and protein-protein interactions within a single cell, transcending the limits of Western Blotting, a traditional laboratory workhorse technique. Of course, the central issue for the more advanced theories of aging is further understanding critical cell signaling pathways.

Every month, GEN reports on developments similar to the above, so this is just a small sampler of the engines powering our increasing understanding of longevity.

News items constantly appear that attribute longevity to all kinds of causal factors.  Broccoli, cumquat  and Acai berry diet, anybody?  Here is one factor that can stir up the hornet’s nest. A recent research study indicates that polygamist men live on average seven years longer than their monogamist counterparts.  The study is based on population statistics, looking at men aged over 60.  Carefully adjusting for socioeconomic differences, men from 140 countries that practice polygamy to varying degrees live on average 12% longer than men from 49 mostly monogamous nations(also see ref).  Why this difference in male longevity exists is not clear.  One possibility is subtle pheromonal communications with younger women that enliven older men, another is the challenge multiple wives pose requiring constant physical and mental activity, another yet is evolutionary advantage to those who have many grandchildren to take care of, another-yet is simply eating better due to having more cooks.  As of this moment pending further research, I do not dare to suggest adding another wife as part of my anti-aging firewalls for men.

Computer-assisted brain fitness seems to be one of the in-vogue topics when it comes to longevity.  There is a genre of “brain fitness software” that is designed to exercise and maintain the memory and mental agility of older folks.  An example is Nintendo’s Brain Age Game.  I don’t think use of such software is necessary and strongly suspect that using computers day-to-day for multi-faceted intellectual work can achieve the same objectives.   Some of the toughest puzzles I face personally involve diagnosing and fixing mysterious hardware and software bugs that keep cropping up in the 9 computers I maintain. This is possibly a counterpart for me of a rat having to find its way through a complex maze to get the cheese. 

There is evidence that searching on Google provides great brain exercise.  A recent news item reports on a study that looks at brain activity of people who search on the web using Google.  The study was done at the Semel Institute for Neuroscience and Human Behavior at UCLA and used MRI techniques to monitor brain activity.  The benefits of computer searching go beyond what can be achieved by reading a book.  “The bottom line is, when older people read a simulated book page, we see areas of the brain activated that you’d expect, the visual cortex, and areas that control language and reading,” he said. “When they search on the Internet, they use the same areas, but there was much greater activation particularly in the front part, which controls decision-making and complex reasoning. But it was only for the people who had previous experience with the Internet.”  — “Members of the technologically advanced group had more than twice the neural activation than their less experienced counterparts while searching online.”  Apparently, like for other forms of exercise, systematic mental exercise leads to the most benefits.

From a personal viewpoint this is great news. I average well over 100 on-line searches a day using  Google and in specialized science databases as part of my research on Anti-Aging Firewalls.  And I do this day after day.  Try and get your arms around longevity research and I can personally guarantee you will get ample mental exercise.

I have buried myself in the biomolecular/genetics/medical research literature during the last week, driving myself somewhat nuts in the process.  My original objective was to research what is known now relating to autoimmune diseases and possible molecular therapies for them.  I also wanted to see what insight I could get as to the impacts of some of the central supplements in my anti-Aging firewalls Treatise on people with autoimmune diseases, scleroderma and SLE (Lupus) in particular.  I found my research veering off in all kinds of unexpected directions.  I don’t have all the answers I was looking for but learned several other things in the process.  As usual I capture relevant references, articles and abstracts, on my hard drive as I encounter them and carefully read and try to digest them for new information.  I separate these materials into categories including Gene Activation, Cancer-Related, Nf-Kappa-B, Sirtuins, Stem-Cell Related, Apoptosis, Cell-cycle Basics, Ink4a/P16, P53, Neurogenesis, Telomerase-Related, Supplements, Auto-Immune Diseases, etc.  This time I could not stay on one track and I found myself adding references to each of these categories, often pursuing scientific byways that led nowhere or that that folded back on each other.  Starting with autoimmune diseases I found the expression of NF-kappaB is profoundly implicated in them as is apoptosis.  Turning to NF-kappaB and apoptosis, I was led into the world of cancer research, cell cycle basics and the apoptotic protein factors like P53, INK4a, and bcl-family proteins.  These n turn are wrapped up with telomerase activation, sirtuins, stem cell proliferation and neurogenesis.  And all of these relate to the suggestions I have made in the Anti-Aging Firewalls.  The bad news is that there is an incredibly complex maze out there that is for the most part still unexplored.  The good news is that there is a unity in the underlying science.  It seems, for example, that the same biochemical factors that determine life and death of stem cells apply more or less equally to cancer cells. Research in autoimmune diseases, cancers, stem cells, epigenetics and longevity powerfully support each other.  Comprehending this maze is painfully slow, but it is likely that answers for some things will also provide answers for lots of other important things.  Decoding what makes for longevity is not different than decoding what makes for life itself.  When I get impatient with my progress I have to remember that and remain humble in front of the task. — Vince

Going through my research archives I came across this item from a few months back based on a study performed on Wistar rats exposed to microwave radiation.  “Conclusion: We demonstrated two important findings; that mobile phones caused oxidative damage biochemically by increasing the levels of MDA, carbonyl groups, XO activity and decreasing CAT activity; and that treatment with the melatonin significantly prevented oxidative damage in the brain.”  My comment is that most rats don’t know enough to take melatonin but some of us humans do.

You can kill house flies by hitting them with a four-pound hammer.  Often you will miss so you have to keep smashing to get a single fly.  The collateral damage to the inside of your home can be very serious, worse than having a fly around. If you own a china shop, killing flies this way could put you out of business.  A similar situation exists with two of the three mainline approaches to treating many cancers – radiation therapy and chemotherapy.  These decades-old “hammer” approaches use brute force to kill cancer cells, namely by poisoning cancer cells via chemotherapy or destroying their internal structures via intense X-radiation.  The collateral damage to normal cells may take years off a person’s expected lifetime.  If you have a compromised immune system, killing a cancer this way could put you out of business.   Historically, for many cancers there were no alternative approaches.  Now there are “adjunctive therapies” available, new drugs and ones just coming out of the pipeline that work smarter taking advantage of new knowledge such as angiogenesis inhibitors and cancer cell telomerase inhibitors.  But the brute force approaches of surgery, radiation oncology and chemotherapy still rule the roost in most cancer treatment centers.

A growing number of researchers in centers pursuing molecular biology approaches to cancer treatment, such as at the University of Michigan, the University of Pittsburgh and Duke University, are pursuing the vision that these “hammer” approaches can eventually be supplanted by biochemical and stem-cell approaches that are non-invasive and do not inflict collateral damage on healthy tissues. 

First, I need comment that the best approach to defense against having cancers is to not have them develop in the first place.  This can be facilitated by creating conditions in the body where cancers don’t develop or are nipped in the bud by your immune system.  Cells are constantly mutating, occasionally into precancerous forms.  Does your body’s biochemical signaling system identify any precancerous cells and signal the immune system to go after them or force these deviant cells to kill themselves (apoptosis)?  If so, you may never experience an overt cancer.   See the Section on cancer in my anti-aging firewalls treatise and the associated cancer firewall discussion for ways to help ward off cancers.   

Here is a small sample of some of the research on less brute-force cancer therapies:

One new avenue of cancer treatment research is based on a recent discovery that there are cancer stem cells for many kinds of cancers which fuel the proliferation of regular cancer cells of the same kind.  Research teams at the University of Michigan are studying cancer stem cells in many different types of cancer – including adrenal, breast, colon, head and neck, leukemia, lung, melanoma, myeloma, pancreatic, prostate and thyroid cancers.  The idea is to discover genetics-based and bio-molecular therapies which go after and kill the cancer stem cells, turning off the source of new cancer cells. “New therapies designed to target stem cells could eliminate cancer without the risks and side effects of current treatments that also destroy healthy cells in the body. Destroying cancer stem cells in the original tumor could reduce the risk of deadly metastasis, where malignant cells move from the primary tumor to other places in the body. Finally, by killing the cells driving the tumor’s growth, treatments targeted at cancer stem cells could eliminate recurrences of the disease.”     At the University of Pittsburgh Cancer Institute, research is being pursued on the combination of two different biotherapies for patients with inoperable melanoma, the most serious and potentially deadly form of skin cancer. A combination of two biotherapies that stimulate the immune system to fight cancer was found to be promising in terms of anti-tumor effectiveness and tolerable in terms of toxicity. The therapies are high-dose interferon alfa-2b, a standard treatment for metastatic skin cancer, and tremelimumab, an antibody thought to instigate the body’s immune system to attack tumors.  These were reported to be combined for the first time in a phase 2 clinical trial and larger trials are planned.  The main cure for melonama now is surgery and some cases of melanoma are inoperable and death sentences.  At Duke University, another team has gone after a biomolecular approach to treatment of a rare and therapy-resistant type of melanoma that originates in the eye and spreads to other organs.  The researchers think that interferon gamma, an immune system protein together with decitabine, which can turn on certain genes in cancer cells, might work together to induce these kinds of melanoma cells to die.  If their hopes work out, the result could be a therapy for an otherwise untreatable and possibly fatal condition. Many brain cancers , glioblastoma in particular, are sure-fire killers with the best available therapies able to add only a few months to a patient’s life.  Researchers at Duke University have suggested that glioma stem cells, brain cancer stem cells, promote angiogenesis (blood vessel growth) in brain tumors, and that targeting these cells may be good approach to treating gliomas. 

Also, curcumin, a very important substance in the anti-cancer firewall, has been shown to act powerfully against glioblastoma cells.   (Research references can be found by searching in Pubmed using the terms glioblastoma and curcumin).  In fact, curcumin acts powerfully against several cancer types, as does resveratrol and certain other phyto-substances in the anti-cancer firewall. 

I have mentioned just a few of many current research developments that in time will likely replace most uses of radiation and chemotherapy for treatment of cancers. They are all examples of seeking to replace the hammer approach with safe uses of smart molecules.