AGINGSCIENCES™ – Anti-Aging Firewalls™

Previous studies have found that women who have babies naturally in their 40s or 50s tend to live significantly longer than other women. At first it seemed that epigenetic factors were at work here.  The theory was that something changes in the DNA of women who give birth late in life leading them to live longer.  However, a new study reported today indicates that brothers of women who gave birth late in life also lived longer, but their brothers’ wives did not.  “Brothers who had at least three sisters, including at least one sister who gave birth at age 45 or later, were 20 percent to 22 percent less likely to die during any year after age 50 than brothers who had no “late fertile” sisters.(ref)”  Moreover,the wives of the brothers lived normal life spans.  This suggests that familial genes were a major factor enabling women both to give birth later in life and to live longer as their brothers did, suggesting that the same genes prolong both lifespan and female fertility.

The study is based on examination of  birth and death data from two disparate historical databases, a genealogical records database at the University of Utah comprising records of 1.6 million Utah Mormons, and  a database at the University of Montreal’s Program on Demographic History Research, which has records on 400,000 people who lived in Quebec between 1608 and 1850, mainly Catholics.  The strong religious influences in both populations encouraged large families, and led to some women giving birth in their 40s and 50s. Modern birth control was rarely practiced.

The study’s main author, demographer Ken R. Smith, a professor of family and consumer studies at the University of Utah. Said “If women in your family give birth at older ages, you may well have a chance of living longer than you would otherwise.” “If you have a female relative who had children after age 45, then there appears to be some genetic benefit in your family that will enhance your longevity”.  Further, “The new thing here is what most evolutionary biologists long have argued: that survival and reproduction are intrinsically linked to one another. So the novel finding in this paper is discovering this link in humans before modern contraception.(ref)”

The answer depends on the study.  As far back as 1997, epidemiological studies suggested that moderate regular consumption of wine, red wine in particular, was associated with decreased risk of ischemic heart disease death(ref).   Then there is the often-cited 2007 study done by researchers at Wageningen University in the Netherlands of 1373 men born between 1900 and 1920(ref).  That study showed that, compared with men who did not consume alcoholic beverages, wine drinkers lived an average 3.8 years longer. Dr. Daan Kromhout, a senior author of the the study and vice president of the Health Council of The Netherlands is reported to have said “– men who drank about a half a glass of wine a day had a 40% reduction in all cause mortality and a 48% lower incidence of cardiovascular death.” 

On the other hand, it appears that women who drink just one small glass of wine a day significantly increase their risk of getting a number of cancers.  This is according to an article in the Feb 24, 2009 issue of the Journal of the National Cancer Institute reporting on a study of 1,280,296 middle-aged women conducted at the University of Oxford in the UK.  Of the women who drank, the average intake was the equivalent to a small glass of wine or 8g of alcohol. Drinking is estimated to result in 7,000 additional cancer deaths a year in the UK, 15 extra cases of cancer per 1,000 women(ref).  Rates of breast, oral, rectal, oesophageal, laryngeal and liver cancer were higher in the wine-drinking group.   “In an editorial published alongside the research, Michael Lauer and Paul Sorlie at the National Heart, Lung and Blood Institute in Maryland, US, write: ‘From the standpoint of cancer risk the message of this report could not be clearer. There is no level of alcohol consumption that can be considered safe.’” 

So what is going on here?  Is drinking a little red wine daily very good for the longevity of Dutch men but quite bad for British women?  Is there a critical health difference between drinking a half-glass and a full glass?  If Dutch men can be equated with British women, do the two studies taken together say the cardiovascular benefit of drinking the daily shot of wine exceeds the increased cancer risk?  Or should the British study be paid more attention to because of its much larger population sample?  Or perhaps the Dutch gentlemen were drinking better organic wines than cheaper stuff the English ladies were drinking.  Were the English ladies possibly imbibing wines with carcinogenic contaminants or additives?  Grapes can absorb pesticides and arsenic from the soil and wine can be contaminated by ochratoxin, or aflatoxin, all of which promote cancers.  It is enough to get me dizzy without drinking any wine at all. 

Personally, I might  drink a half-glass of red wine once or twice a month.  However, I take trans-resveratrol capsules twice daily without fail. 

Major future leaps in longevity will most likely result from developments in molecular biology and genomics.  And, on a practical level individual DNA testing will sooner or later play a major role simply because our genomes are different. 

After several years of nothing much happening, individual DNA testing is slowly entering the mainstream. On the medical side, applications include diagnosis of disease susceptibilities, tissue typing for organ transplantation, prenatal genetic assessment, assessments in cardiology and oncology, and screening for infectious diseases. On the consumer side, popular applications include paternity testing and testing for HIV; such tests are sold via Internet. And of course there are niche markets such as in forensics.  The cost-effectiveness of DNA testing is rapidly improving as is the range of applications, and within a five-year period. Individual DNA testing will probably have expanded by an order or two of magnitude.  According to an article in GEN, “The Sky Could Be The Limit For DNA Testing.” 

The traditional technology for DNA testing uses a technique called PCR standing for polymerase chain reaction.  PCR is a technique used to multiply one or a few pieces of DNA in a couple of hours into millions or more copies.  It works even when the source DNA is of relatively poor quality and it has become one of the most widely used laboratory techniques in molecular biology. Plain PCR is a labor-intensive multistep process that can be done for specific screening purpose in a lab but not in an ordinary kitchen.  Some companies, Roche Molecular diagnostics in particular, have developed technological “platforms” which automate the major steps of PCR.  For example “The COBAS® AMPLICOR Analyzer is the first benchtop system to fully automate the amplification and detection steps of the Polymerase Chain Reaction (PCR) testing process on a single instrument. It combines five instruments into one (thermal cycler, automatic pipettor, incubator, washer and reader).”  A number of other platforms for DNA amplification and molecular testing are being developed.  They include microarrays, beadarrays, and electrochemical arrays and may some day displace PCR.  Their cost-effectiveness and user-friendliness continue to improve.  But so far PCR remains the main technology with Roch Molecular Diagnostics enjoying by far the biggest slice of the market. 

As time moves on and the diagnostic processes become simpler and less expensive, more and more medical labs are acquiring molecular diagnostic capabilities.  Short-term driving forces include lower cost and simpler test units, units capable of doing multiple kinds of tests, and desire for faster turnaround time than possible if the tests have to be outsources. Today, in the infectious disease and oncology areas, traditional biochemical testing still is the dominant mode, with molecular testing representing only 20%-30% of the market, but the molecular/genetic testing continues to gain market share. 

In the news and frequently reported  in this Blog, there is a steady stream of research reports linking diseases to genes and gene polymorphisms and indicating new molecular therapy targets.  There is an accelerating need for individual genetic testing if the fruits of such research are to be harvested.  A longer-term driving force for widespread adoption of individual DNA testing is the slow emergence of personalized molecular-based medicine for assessing disease susceptibilities, disease detection, disease course prognosis, and prediction of patient drug response.  I think this shift in paradigm may require 20 or more years before it is firmly in the forefront.  Clearly this paradigm shift will have a major impact on protecting the health and extending the lives of those who will benefit from it. 

Of course there are other segments of DNA analysis besides tests designed to helped individuals.  There has been enormous progress in development of automated technologies for analyzing entire genomes.  An example is Affymetrix’s microarray-based Gene Titan  system. 

Molecular laboratory testing is already a big business.  The Gen article quotes a source (Kalorama) indicating estimating the 2007 worldwide market for molecular assays to be $3.7 billion.   The market is projected to grow at an 11% annual rate, reaching $6.2 billion in 2012.  Certain segments of this market are expected to grow at much higher rates.   The highest-growth areas of DNA testing according to the GEN article are pharmacogenomics (35%), inherited disease testing (25%), oncology and infectious diseases. 

In previous postings I have compared the rate of progress in the computer field in 1956 with the rate of progress in genomics and longevity science today.  Personalized diagnostic testing today is playing a transformative role today in medicine as developments in computer memories did back then.  Both then and today, scientific and commercial developments strongly supported each other.  It will be a while before we have the analog of the PC revolution, however, when everyone does their own DNA testing in their homes using inexpensive kits.  I fully expect this to happen within 20 years or so, however.

I have mentioned the P53 tumor-suppressor gene a number of times in my Anti-Aging Firewalls treatise, for example pointing out that  “Resveratrol and curcumin activate the P53 gene in many strains of cancer cells, leading them to commit apoptosis.”  Today’s news revealed new research findings regarding normal P53 genes and mutant P53 genes found in cancers. 

First, how cruciferous vegetables work to defeat cancer 

It has long been bandied about in alternative health circles that cruciferous vegetables like cabbage, watercress and broccoli tend to be cancer-preventative.  But why this was so remained a mystery.  A recent research report lends light on this mystery, indicating what might be the main biomolecular mechanism involved.  These foods contain phenethyl isothiocyante (PEITC), a natural phytochemical.   P53’s usual job is to stop a defective cell, one with DNA damage or expressing oncogenes, from dividing and possibly force the cell to kill itself. However, in many cancers the P53 gene is mutated and does not do that job.  Instead, the mutated P53 allows the cancer to develop and spread.  The reported research indicates that PEITC has a capability to selectively deplete mutant p53 leading to restoration of the wild type (normal) p53.  In effect the P53 checkpoints against the cancer are restored by the PEITC phytosubstance.  The press release concludes “This novel finding suggests that the PEITC and other compounds in the isothiocyante family could play important role in both cancer prevention and treatment of human cancers with mutant p53.” 

Second, certain efforts to protect cancer-fighting P53 can backfire and also protect mutant cancer-promoting P53 

News on a research report in the in the current issue of the journal Genes and Development points out a danger of trying to restore P53 function in a patient’s tumor without knowing what kind of P53 is involved, wild type or mutant.  If the P53 is wild type, restoring its function could help zap the tumor.  If mutant P53 is involved, however, the result could be the tumor thriving and spreading.  “The importance of this study cannot be overemphasized,” the researchers concluded. Drugs that try to protect normal p53 by inhibiting the p53-degrading protein Mdm2 also would protect mutant p53 “with dire consequences.”   

Taken together, the two studies point out the high relevance of phytochemicals like PEITC for P53 treatments of cancers – because they act differentially against mutated P53 and promote the restoration of wild-type P53.  They can tell the difference between the bad guys and the good guys.  P53 activation that can’t tell the difference is potentially dangerous.

Another cross-species pathway has been discovered that allows interventions to lengthen life in primitive organisms, C. elegans nematode worms in this case.  The pathway is related to the hypoxic response, how cells respond to protect themselves when there is insufficient oxygen.  It turns out that if the hypoxic response can be turned on when normal oxygen is present, nematodes live significantly longer.  A recent research report indicates that this was experimentally accomplished by breeding nematodes that could not produce the protein VHL-1which destroys another protein called HIF which keeps the hypoxic response turned off when oxygen is present.  Also, it appears that the cells in such long-lived nematodes are relatively free of lipofuscin and toxic age-related protein aggregations such as seen in Alzheimer’s, Huntington’s and other age-related diseases(ref).  So, as is the case for dietary restriction the increase appears to be not only in lifespan but also in healthspan.  The hypoxic response pathway is different than that which is involved in calorie restriction.  “VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin/IGF-1-like signaling.”  As of yet, however, just how HIF works downstream to extend longevity is still unclear.  The hypoxic response appears to operate in higher animals as well, including humans.  However, Dr. Matt Kaeberlein, University of Washington assistant professor of pathology and the senior author on the study is reported to caution that “mutation of VHL-1 is associated with a variety of tumors, and any therapies targeted toward activation of HIF would most likely need to be specific for cells that are not rapidly dividing, such as brain cells or muscle cells.”  It is too early to know if a practical human anti-aging intervention can be tied to the hypoxic response but the possibility is intriguing.

The conventional wisdom has been that cell division in heart muscle cells (cardiomyocytes) stops at or shortly after birth and that the cardiomyocytes of an 80 year-old are the same ones he started out with.  The technology of radioactive carbon-dating has been recently applied to study this issue and shows that this conventional wisdom is wrong.  Heart muscle cells are slowly but constantly renewing throughout life. 

Radioactive carbon-dating has long been used as the primary technology for establishing the age of archeological artifacts.  A recent study applied radioactive carbon-dating based on carbon-14, generated by nuclear bomb tests during the Cold War to analyzing the issue of heart muscle renewal.  The study looked at the integration of carbon-14 into human cardiomyocyte DNA to establish the age of cardiomyocytes. Nuclear bombs were tested above-ground between 1955 and 1963.  So, looking at the carbon-14 content in cardiomyocyte DNA from people born before 1955 it is possible to tell how many are original and the rate of cardiomycyte renewal..  “We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span.”  So, when someone reaches the age of 50, about 55% of his or her heart muscle cells date back to birth and the rest are newer(ref). 

The study is interested in that it opens the possibility for interventions that greatly accelerate the rate of renewal of heart muscle cells.  Such could be useful for treating a number of cardiac pathologies and for helping extend the working lifetimes of hearts.

It has been pointed out to me that this Blog and my Anti-Aging Firewalls treatise sites are now experiencing enough Internet traffic that I could generate revenue by accepting advertisements such as for proprietary dietary supplements, health cures, anti-aging treatments, anti-wrinkle creams, etc.  While the money would be nice, I will continue to follow a non-commercial model such as that of a professional scientific journal.  There are several reasons for this.  First of all, many advertisements seen on other longevity-related sites make me uncomfortable.  They claim anti-aging results based on science that is shaky at best or nonexistent at worst.  They go against the messages I am trying to deliver.  Services that automatically place advertisements on my site would not give me the option of filtering these out.  Second, I don’t like the idea that any one substance or approach is the central key to longevity today based on the state of science as it is.  And third, I want it to be crystal clear to my readers that my commitment is to the science of longevity and that I will not beholden to any commercial interest.  I think many longevity-related articles appearing on commercial sites are very good.  But I am in this game for the long run and do not want to go in a commercial direction at this point.  So, no advertising.

Longevity research keeps showing up in unexpected places.  The US Army is pursuing research related to the third theory of aging in my Anti-Aging firewalls treatise, Mitochondrial Damage. They have an anti-aging research program called “Optimized Human Performance: Mitochondrial Energetics” The stated objective of the program is “Develop metabolic supplements to optimize adenosine triphosphate production in eukaryotes.”  Of course, optimizing adenosine triphosphate production in humans is one of the prime objectives of the supplements in the firewall for this theory of aging.  But the Army is out to see how the job can best be done. The project involves screening libraries of compounds for their effects “that increase mitochondrial copy number and/or the efficiency of mitochondrial oxidative phosphorylation.”  One intended outcome of the project is to identify supplements which would allow older experienced soldiers to have the same physical and mental performance capabilities as a 20 year-old. This could allow for later retirement of experienced soldiers and significantly increase the human resource capability of the army.

Whatever else you may think about Henry Ford, I think you will agree he knew what he wanted and in large part got it.  I spent most of yesterday with cousins in Greenfield Village, a large historical theme park founded by Henry Ford in 1929, the year I was born.   Greenfield Village, part of a Ford historical complex in Dearborn Michigan, presents the lifestyle and technology of the mid-industrial era 1880 – 1920.  The artifacts are authentic and are presented in original or replica buildings of the times.    What I saw set me off thinking about technology, including the technology of life extension. 

Greenfield Village has numerous buildings full of the massive machines of the mid-industrial era – giant piston steam engines, a massive Edison-designed DC power generator used for the first commercial electricity production in New York City.  Massive machines weighing tens of tons, giant foundation castings, 20-foot flywheels, 12-foot pistons, giant belts and man-eating gears seemed to be everywhere.  Many of the machines are fully installed and still can be run. 

My revelation came while I was marveling at a 160-ton locomotive built in 1908, one with 12 foot steel wheels that easily weighed 5 or 10 tons each.  I had tarried and my relatives had wandered on so I pulled out my cell phone to call them.  In doing so it came to me that my 1.2 ounce cell phone was vastly more complex and powerful in its own way than the locomotive which was relatively simple despite its massive scale.  Besides having millions transistors on its processor chip, my phone has sophisticated software and personal information that weighs nothing. 

So what happened in technology between1908 and 2009?   One obvious thing is that things have gotten lighter and smaller all along – from the locomotive to the automobile to the cell phone.  Second, they became more personal.   The locomotive served large communities. It could connect you with relatives in another city in a few days.  Henry Ford’s vision was that every family would have an automobile.  It could connect you with relatives in the same city in minutes or hours.  And it is now getting to where everybody has their own cell phone. It can connect you with anyone who wants to be connected with just about anywhere in seconds.  Third, as weight has gone down exponentially, precision and intellectual content has shot up in the same way.  The mechanical tolerances in the engine of a modern car are a hundred times more precise than they were when the locomotive was built.  And the cell phone is only possible because of high-technology chip design and manufacturing which allows packing tens or hundreds of millions of elements on a half-inch chip.  The precision is a thousand times finer than that found in a car engine.  This in turn was only possible because of computers that used earlier-generation chips and software, etc.  

I have mentioned Moore’s Law in an earlier posting, the Law states that every two years the number of transistors on a processor chip will double keeping essentially the same price point. And, led by Intel, the industry has kept that pace for nearly 40 years. This represents an intellectual accumulation of knowledge, an exponential increase in cost effectiveness.  If the same were true of the locomotive you could probably buy one for a dime by now – shipping not included. Intellectual content and technology, unlike industrial-era technology, feeds on itself.  

How do these trends apply to the technology of life extension?  First, consider scale.  Chip manufacturing technology is now getting to be precise below the 90 nanometer size range. Proteins on the other hand are typically 3 to 10 nanometers long and their interaction sites can be much smaller.  So it appears that gene activation and other biomolecular events take place at a size scale an order of magnitude or more smaller than the dimensions involved in current chip manufacturing.  So the shrinking size trend is continuing.  Second, effective life extension interventions will be extremely personal – they will take place inside us and will eventually act in person-specific manners.  Third, longevity is a field of intellectual content absolutely built on the shoulders of the computer and microprocessor revolution.  We would be nowhere near where we are today with respect to our state of longevity knowledge without computers, automated gene sequencers, gene and protein chips, etc..  And, like information-age technology, longevity technology is feeds on itself and expands exponentially. 

In a previous post I proposed Giuliano’s Law for longevity technology, suggesting that it behaves like Moore’s Law. That is: Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period.  That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period.  Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population.  

With regard to the title quote by Henry Ford, I think I can live healthily and productively to the age of at least 235.  And I think his quote which proved correct for him in the industrial revolution will also work for me in the longevity revolution.  Henry Ford wanted people to have cars.  I want the availability of great longevity to be there for everybody who wants it.  One final Henry Ford quote is: “Anyone who stops learning is old, whether at twenty or eighty. Anyone who keeps learning stays young. The greatest thing in life is to keep your mind young.”

A number of proteins in the body play dual roles with respect to longevity – negative roles in some circumstances and good roles under other circumstances.  I mention three substances in this regard: VEGF, telomerase and P16(Ink4a).

–         VEGF stands for vascular endothelial growth factor, a family of growth factors , signaling proteins that play predominant roles in angiogenesis, the proliferation of new blood vessels.    When the angiogenesis facilitates the viability and expansion of a cancer tumor, the result can be very bad for longevity.  Also, VEGF defeats an important avenue the body uses to defend itself against cancer by causing dendritic cells to not work properly.  Bad stuff! Under such circumstances the best thing to do is inhibit VEGF.  On the other hand, when the body is repairing an injury, promotion of VEGF could be good, in fact required for healing to take place. VEGF is important for maintaining glomerular and other capillary integrity(ref), for example.  A component of VEGF plays an important role in the survival of hematopoietic progenitor cells(ref), cells necessary for renewal of blood and other cells and longevity.  Good stuff!

–         Telomerase is a substance I have already discussed extensively, the substance that serves to enlongate the telomere caps at the end of chromosomes and therefore forestall replicative cell senescence.  Some longevity researchers have thought that telomerase activation could be a golden key to enabling life extension since cell senescence may be at the heart of many kinds of diseases including cancers as well as age-related organ degeneration.  Good stuff!  But wait.  Telomerase expression is turned on in most cancer cells, allowing them to replicate indefinitely and be immortal.  So, most research on telomerase today is focused on finding substances that turn its expression off as a way of making cancer cells mortal again(ref)(ref).  Bad stuff!

–         P16(INK4a) is also a substance I have discussed in my Anti-Aging Firewalls treatise.  On the one hand its increasing concentration with age provides a strengthening defense against cancers.  It works by driving cells into senescence through cell cycle arrest as an alternative to them possibly becoming malignant.  Good stuff!  On the other hand, it “induces an age-dependent decline in islet regenerative potential” and reduces the ability of stem cells to proliferate.  Bad stuff!  As I have said before, P16/Ink4a works together with the three other genes to articulate a process of simultaneously protecting against cancers and shutting down adult stem cell function and regenerative capacity in aging tissues.  Good stuff and bad stuff botIh!

These three Dr. Jekyll and Mr. Hyde proteins illustrate a key point with regard to longevity research: many pathways which promote healthy cell proliferation and organ renewal also promote cancer expression.  Likewise, pathways important for inhibiting cancer proliferation also generally inhibit cell and organ renewal.  The key issue is how to achieve the renewal affects without triggering or promoting cancers.