Running Mice Live Longer With Degenerative Brain Disorder

Cognitive decline with aging is an increasingly important research topic. This week Science Magazine has produced a special issue on the brain and a summary article and one main articles discusses the impact on a specific neurodegenerative disease (spinocerebellar ataxia type 1) in mice.

A “mild” exercise regimen helped the mice live significantly longer. The effects lasted for a considerable time, even after stopping the exercise program. The disease studied has features in common with Alzheimer’s in that an insoluble protein that accumulates in nerves is involved. Exercise has been shown to have positive effects on Alzheimer’s disease and the research here on how exercise impacts the proteins and future exercise on a variety of growth factors produced during exercise may help in producing strategies for Alzheimer’s disease and numerous other degenerative diseases.

The accompanying summary article states:

“In addition to the benefits of exercise on brain health and cognitive function, it may promote slowing neurodegenerative disease progression. For example, exercise slowed the decline in cognitive abilities of Alzheimer’s disease patients and improved postural stability and balance in Parkinson’s disease patients.”

References:

Another Reason to Exercise Aaron D. Gitler. Science 4 November 2011: Vol. 334 no. 6056 pp. 606-607. DOI: 10.1126/science.1214714

Exercise and Genetic Rescue of SCA1 via the Transcriptional Repressor Capicua. John D. Fryer, Peng Yu et. al. Science 4 November 2011: Vol. 334 no. 6056 pp. 690-693 DOI: 10.1126/science.121267

Micro NMR (Sci Trans Med)

Miniaturization of technology continues to bring new innovations in science and technology. The very latest innovation which you probably have not seen yet is a miniature NMR. On a larger scale this is the old familiar MRI machine. The micro-NMR is coupled to a Smart Phone and used to analyze cell surface proteins. A study published this week in Science Translational Medicine showed that this micro-NMR (μNMR) device run by a smart phone could be used to analyze a series of proteins/markers (pCAM (epithelial cell adhesion molecule), MUC-1 (mucin 1, cell surface associated), HER2, EGFR (epidermal growth factor receptor), B7-H3, CK18, Ki-67, p53, and vimentin]) showed a 10% to 20% improved diagnostic accuracy over traditional cell staining and other traditional techniques.

The current study analyzed needle aspiration biopsies. The study was limited to intra-abdominal cancers. The researchers found that 4 markers: MUC-1, HER2, EGFR, and EpCAM provided high diagnostic accuracy. These 4 markers used in conjunction gave the  correct diagnoses in 48 of the 50 initial patients examined and in 20 of 20 in the next round. For biology, science and technology geeks this was a fascinating article. I’ll link below to the Editor’s summary.

As we wonder what our Smart Phones can do besides play music surf the web, and track our running mileage, we see that forward thinkers are finding new ways to use the smart phone along with creative and new ways to use current technology. And yes, genomics and proteomics have a future.

Reference:
Sci Transl Med 23 February 2011: Vol. 3, Issue 71, p. 71ra16 DOI: 10.1126/scitranslmed.3002048. Micro-NMR for Rapid Molecular Analysis of Human Tumor Samples. Haun J. et. al.

“The Case Against Lance Armstrong” is the title of an article in the January 24, 2011 issue of Sports Illustrated. The case that is made within this article is based on in large part on what a few people with gripes against Lance have said. The other “hard” evidence is based on several tests detailing a very high Testosterone:Epitestosterone ratio. Before 2005 the tests normal was considered up to 6:1 and was then lowered to 4:1. Several tests over the years, which may have been Lance’s were considerably higher than this.

According to SI “Three results stand out: a 9.0-to-1 ratio from a sample collected on June 23, 1993; a 7.6-to-1 from July 7, 1994; and a 6.5-to-1 from June 4, 1996.”

Each time the ratio was found to be high, the “B” Sample was tested and found to not confirm the preliminary test. The second test is usually a carbon isotope test that is more specific to studying the makeup of the individual’s testosterone.

While the article goes on to say that one high number (of the T:E ratio) should be a once in a blue moon occurrence, there are significant genetic factors that can come into play.  A 2008 article published in The Journal of Clinical Endocrinology & Metabolism titled “Doping Test Results Dependent on Genotype of UGT2B17, the Major Enzyme for Testosterone Glucuronidation” showed that if an individual had two alleles for the UGT2B17 gene, there was a large chance that they would not test positive for cheating even after having taken a large dose of synthetic testosterone. The estimates were that 40% of individuals could pass the ratio examination just by virtue of having two copies of this gene. On the other hand with mixed alleles (ins/del) or in the absence of  this allele there was a fair chance that the ratio would always be abnormal. Estimates were that in a normal population, up to 9-14% of people would have a false positive result and fail the test.

It seems that if you have the del/del or ins/del variations of alleles, you are going to pretty consistently fail the test. The authors suggest that this gene should be tested and the results modified based upon the genotype of the individual.

Understanding the purpose of the Testosterone:Epitestosterone ratio testing and doing at least a brief look at  factors that might affect this test, not just once but repeatedly are important when an article such as the SI one is written. This specific gene and its implication on testing is widely known and has been covered in a variety of journal articles. The Canadian Medical Journal detailed, in an editorial titled “Doping, Sport, and the Community“, the difficulties in testing for Growth Hormone abuse and Testosterone. The editorial also mentioned research I came across elsewhere which indicated that many Asians (up to 40%) had the version of this gene that would give a false negative.

So, let’s get all the evidence out. And let’s make sure the public sees all the scientific information on the validity and the problems that exist with this particular test. For another perspective on heroes in American culture, you can seek out one of George Carlin’s last specials in which he expresses his opinion on hero worship and in particular on Lance Armstrong, Tiger Woods, and Dr. Phil.

The next test is to determine if the song “Bike” by Pink Floyd was written in a drug free state. In case you can’t make them out the lyrics begin:

I’ve got a bike
You can ride it if you like
It’s got a basket
A bell that rings
And things to make it look good
I’d give it to you if I could
But I borrowed it

Available video of Pink Floyd’s Bike (blocked currently at Youtube)

and if Pink Floyd is just not your cup of tea. Here is Queen performing their song “Bicycle Race”

Podiatry Management (October, 2010) has just published an article I’ve written titled  Overuse Injuries: All The Small Things . You are just another click away from the PDF version. This is a challenging article. It introduces mechanotransduction, a theory of cellular and tissue function, which is little known in the sports medicine community. The article touches lightly on this topic and then reviews the latest literature and theory on overuse injuries to bone and tendon.

The Needle - Kenneth Snelson

The cellular level is where things start and where we will find many answers. I expect to add more details on the web site on mechanotransduction and mechanobiology for those with hardcore, deep science interest. The article is limited in size, but was longer than many published in PM Magazine. But, I didn’t even touch on the theory canalicular flow and osteocyte induction or mechanotransduction and control of stem cell development by matrix stiffness. Research in the field of mechanobiology is growing daily and the outlook is great that it will be fruitful.

Hot Peppers

Red hot chili peppers just might be good for you. An article in the current issue of “Science Signaling” (Aug 10, 2010. Vol 3, Issue 134, p ec241) summarizes two articles and gives the details.

Capsaicin, in chili peppers, is what makes them taste hot. For several years it has been used in topical creams that are used to decrease pain from a variety of causes. The biochemical means of action is via a cation channel of a receptor group called TRPV1, which allows calcium ions to enter the cell. The authors of the current article found that the TRPV1 receptors were also found in the endothelial cells of blood vessels. They studied the activity in rats and found that exposure to capsaicin resulted in  an increase in the  “amount of phosphorylated endothelial nitric oxide synthase (eNOS), protein kinase A (PKA) activity, and NO production.” They found that a 6 month long diet high in capsaicin triggerred a relaxation response in the arteries and that hypertensive rats were found to have lowered their blood pressure when they continued to have a diet high in capsaicin.

While they seem to  suggest that a diet high in capsaicin may reduce blood pressure in humans or at least that targeting the receptor TRPV1 for further research, I think a direct test for a diet hypothesis would be to take your blood pressure before and after munching on a chili pepper. I’ll bet you may see a bit of a rise, at least in the short term.

References:

D. Yang, Z. Luo, S. Ma, W. T. Wong, L. Ma, J. Zhong, H. He, Z. Zhao, T. Cao, Z. Yan, D. Liu, W. J. Arendshorst, Y. Huang. M. Tepel, Z. Zhu, Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension.Cell Metab. 12, 130–141 (2010). [PubMed]

W. C. Sessa, A new way to lower blood pressure: Pass the chili peppers please! Cell Metab. 12, 109–110 (2010). [PubMed]

N. R. Gough, Spicy Diet to Reduce Hypertension. Sci. Signal. 3, ec241 (2010).

Ambling Along With 4.5 Million Year Old Flat Feet

A hominid species predating Lucy, (Australopithecus africanus) has been more fully described. Journalists have had first crack at the issue of Science in which the updated description of the species,  Ardipithecus ramidus (from 4.5 million years ago), appears. The rest of us could only see this issue late in the day.  The recently studied Ardipithecus specimens include the feet, which were clearly missing on Lucy (from 3.2 million years ago), but present among a limited set of other Australopithecus specimens. Ardipithecus was originally discovered in 1994 in Ethiopia.

The treasure trove of the day are the eleven fresh papers detailing  Ardipithecus and it’s (with a delay in publication for years) environment including botanical and other specimens found locally, the anatomy, and evolutionary conjectures all published in Science magazine. Details on excavation, locale, personnel, CT scans, three-dimensional reconstruction, dimensions and sizes of the specimens, were included in this comprehensive set of articles.

Ardipithecus was thought to live and spend time in trees, but would carefully climb rather than swing from the branches. Ardipithecus was also believed to spend time foraging for food, primarily plant based, on the ground while moving in a bipedal manner. Australopithecus was not a runner, nor is it likely with feet less well adapted  was Ardipithecus. Among other lower extremity differences between Homo erectus and Ardipithecus were flatter feet and an opposable big toe (metatarsus primus varus – actually  metatarsus primus adductus – a large angle in stance between the first and second metatarsal bones – but I’ll have to check out more photos and study the  articles in detail in Science magazine). If Ardipithecus twiddled her thumbs she could likely also twiddle her opposable big toes. Speaking of toes, one of the changes that is thought to make running possible for the later hominids was a shortening of the length of toes, in addition to an increase in arch height, and a host of other biomechanical changes.

An opposable big toe with a non-functional first ray makes for a decidedly different bipedal gait than even Lucy had. The tight grouping of the cuneiforms present in later hominids allowed the first ray to function effectively in weight transfer and propulsion rather than the little it could do as an opposable digit without stability in ground based bipedal gait. Of course a humanoid great toe does not offer much assistance in the trees. An important feature to note is that Ardipithecus did not knuckle walk, as can be determined from the wrist and hand structure, during bipedal gait, although the upper extremities were long. Nor did Ardipithecus appear to brachiate or swing through the tree branches.

Below are images of the upcoming cover of Science magazine with Ardipithecus on the cover and an image of Lucy missing her feet.

Update: Freely available articles at Science

Ardipithecus

Lucy on The Ground with no Toes

Related Articles

Movement and Exercise Spurred Evolutionary Brain Development

In The Beginning: We Were Made To Stand Upright

Walk This Way (Early Foot Prints  of Homo erectus)

Additional References:

Bonus Music: Ventures – “Walk Don’t Run” – Primitive filming (B&W)

Recent Evolution of Walk Don’t Run

Stimulating Brain Development: Evolution Of The Brain Spurred By Movement (a speculative hypothesis)

We previously mentioned the early hominid development of upright, obligatory, habitual bipedal posture mentioning the richer protein and calorie dense food which may have enabled better brain development. We’ll expand on that a bit with a “big think” and take it down a slightly different road. And we can have a bit of fun with a speculative hypothesis.

My thought (and hypothesis) is that exercise, viewed as aerobic movement, was the spur to development of a larger brain as is found in later hominids and modern humans. Tool making, enhanced socialization, all other more modern features and the larger cortex itself derive from motion, movement, and the positive effect that “exercise” has on the chemistry of the brain.

As we stop and think about what made the brain enlarge we hear those who say that bipedal movement freed up our hands. Now you can walk and juggle or do other tricks.  Another theory posits that early hominids could now carry food back to their tribe, make tools, ultimately jewelry and developed other useful talents. Whatever occurred likely was multi-factorial and not a simple single means event.

In keeping with Darwinian principles, it is incorrect to say that the environment created changes. We need to look to see what environmental features were taken advantage of by those best prepared to do so. Mutations are random, selection is purposeful, and geared towards the survival of those most fit for the environment. There are a variety of phenotypes present at any time, and those exhibiting desirable and helpful characteristics do survive and pass on those useful genes.

Mammalian brains produce BDNF (brain derived neurotrophic factor) which assists in neural plasticity and in the creation of new neural cross links. Humans today moving at high rates of oxygen uptake show that at up to 60% of maximum VO2, several things come into play. The first is an increase in Cerebral Blood Flow (CBF). The CBF increases as does the production of  BDNF and other compounds that among other effects stimulate brain growth and development. These other compounds include IGF-1 (insulin growth factor 1), VEGF (vascular endothelial growth factor), and FGF (fibroblast growth factor).

Bathing the brain in this enhanced biochemical “miracle grow” mix, likely would have resulted in superior neural growth and response for those who were best able to respond to this physical and neurological environment.  This seems to have been a contributing factor in the maximal development of the early hominid brain, and continued down through the hominid line.

Those most able to respond to the biochemical results of their activity of  motion, movement, and gathering would have become the smartest of the lot and been most likely to survive . They would be better suited for survival and more able to pass on their genes.  Bipedal movement in hominids was first to be short in duration. Lasting for only a limited distance and allowed for limited scavenging.  Ultimately it resulted in habitual and obligate bipedalism of longer duration, and finally in walking and then, later, running.

There have been debates over the energetics of bipedal motion versus brachiation and advantages over older forms of quadripedal locomotion. But with the thought that nothing gets wasted, if the energetics don’t balance perfectly it is probable that the energy itself that may not have been optimally efficient for walking, certainly was put to excellent use in the development, enhancement, and gradual evolution of the hominid and ultimately modern human brain.

Bipedal walking allowed the former tree apes a  better and more easily sustained motion. This  over the course of time, possibly led to persistence hunting, or at the least an expanded range for gathering, foraging, and then much later hunting. And the migration out of Africa was another sustained effort and may have stimulated brain development.

Sensory stimuli, socialization, diet, and many factors went into brain evolution and development. Then, as now, it is likely that the sustained efforts of moving increased focus, attention, and concentration. Creating mental maps of where they had been, and how to return home gave their small brains a work out. And speculating a bit, ultimately mental maps led to many other things and perhaps even primitive games of hide and seek.  Later came blind folded chess and google maps.

Many facets of evolutionary thought are interesting and valuable. Socialization and network theory, the role of sensory stimulation all are explorable, viable theories and played a major role in evolution. Here we’ve brought into play another facet of hominid evolution not previously described. The energetics and resultant neurochemical (and other changes) as a result of  motion, movement and exercise is a contributing and driving force for brain development and evolution. Put this in the context of the fact that everything moves and there is nothing entirely still in the universe, we have another small factor to consider about our world and how we and it have evolved.

So it seems we weren’t just born to walk or run. We were born to think, develop and evolve. In fact, we’ve evolved to evolve. And evolution continues today. If your thoughts stop with barefoot running, and you think our evolution stopped then, you’ve got a lot more thinking and catching up to do. Exercise and movement are good for what ails you, and assisted in the development of today’s modern human brain.

(Outline presented at American Podiatric Medical Association Annual Scientific Seminar. August 1, 2009. Toronto, Canada)

Many people have played the facebook game “What’s Your Real Age”. My guess that those who played it wanted to feel they were younger than their biological age. Telomere length seems to be the real way to determine actual “biological age”. These are the real “biological clocks”. Telomeres are repetitive sequences at the ends of chromosomes that shorten with age and also shorten in certain metabolic and disease states. They are sometimes called the protective “caps” on the ends of chromosomes. Because of the manner in which chromosomes are replicated during cellular division, a bit of the telomere is not copied with each subsequent cellular generation resulting in a gradual shortening of the telomere restriction fragment (TRF) length.

Telomeres Shorten With Age

A recent study showed that people who perform more leisure time physical activity have longer telomeres. Another recent study, with an admitted low subject number, demonstrated that eating processed meat  such as sliced bologna would also slice down the size of your telomeres. This study, published in the American Journal of Clinical Nutrition did not find other expected dietary associations.

The Cardiovascular Health Study (2007) found inverse correlations (shortened telomeres) between TRF length and fasting glucose level, fasting insulin level, systolic and diastolic blood pressure, carotid intima-media thickness, interleukin-6, high BMI, overweight (in men).

Some studies including one with “voluntary running” in mice showed the production of telomere protective compounds with the “voluntary” running. On a side note,  I’ll have to look closer at this study. If we can can get mice to  voluntarily participate in a “fitness” program, maybe we can figure out the secret to get more people to do so. Perhaps cheese is the answer.

Aubert and Lansdorp (2008) published an excellent review of  the biology of telomeres and aging. They noted that Barbara McClintock, in her 1983 Nobel acceptance speech pointed out the significance of cellular response to stress and dangers. “In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell, monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events, and responding to them, often by restructuring the genome. We know about the components of genomes that could be made available for such restructuring. We know nothing, however, about how the cell senses danger and instigates responses to it that often are truly remarkable.”

Short Telomeres Trigger Cellular Defences

The shortened telomeres are likely sending more “damage” signals to the cells which lead to a number of biochemical pathways which degrade the contents of the cell. Studies on cellular senescence, apoptosis, and research on genomics is leading us to a better understanding, but we have a long ways to go. The complexity never ends, but it continues to unwind. And you can almost hear the tick tock of the biological clock. Your best means of slowing up the ticking are life habit changes: exercise regularly, maintain healthy body weight, don’t smoke and eat a healthy diet.
What’s my age again? – Blink 182

What's My Age Again?

References:

Lynn F. Cherkas, PhD; Janice L. Hunkin, BSc; Bernet S. Kato, PhD; J. Brent Richards, MD; Jeffrey P. Gardner, PhD; Gabriela L. Surdulescu, MSc; Masayuki Kimura, MD, PhD; Xiaobin Lu, MD; Tim D. Spector, MD, FRCP; Abraham Aviv, MD. Arch Intern Med. 2008;168(2):154-158.

Annette L. Fitzpatrick1, Richard A. Kronmal2, Jeffrey P. Gardner3, Bruce M. Psaty1,4, Nancy S. Jenny5, Russell P. Tracy5,6, Jeremy Walston7, Masyuki Kimura3 and Abraham Aviv . Leukocyte Telomere Length and Cardiovascular Disease in the Cardiovascular Health Study. American Journal of Epidemiology 2007 165(1):14-21; doi:10.1093/aje/kwj346.

J. A Nettleton, A. Diez-Roux, N. S Jenny, A. L Fitzpatrick, and D. R Jacobs Jr. Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA). Am. J. Clinical Nutrition, November 1, 2008; 88(5): 1405 – 1412

Liza S.M. Wong, Hisko Oeseburg, Rudolf A. de Boer, Wiek H. van Gilst, Dirk J. van Veldhuisen and Pim van der Harst.. Telomere biology in cardiovascular disease: the TERC–/– mouse as a model for heart failure and ageing. Cardiovascular Research 2009 81(2):244-252; doi:10.1093/cvr/cvn337

Aubert, G. and P. M. Lansdorp (2008). “Telomeres and Aging.” Physiol. Rev. 88(2): 557-579.

The Bare Outline of Bipedal Beginnings

Humans are the only primate habitual, obligate, bipedal on the planet. And not only can we walk, but we can launch ourselves completely off the ground and run. It is important to note that running is a one legged exercise. Only one limb is in contact with the ground at any time. This has implications for both energetics, efficiency, and the type of injuries that we end up with in the present.

How did we get here? The middle part of the story is that there seems to be a relationship between tree apes and those of us who ended up on the ground. Our structure is homologous, yet different in many respects. In becoming the first runners the fossil and bone evidence seems to be that we first stood upright before our skull and brain enlarged. Australopithecus has a small skull, yet seems built for bipedal movement.  Some feel that Australopithecus could not run, and that it’s bipedal locomotion was a shuffling gait. Remnants of the apes remained, particularly the long upper limbs and curved fingers. Changes occurred in the feet. The great (first) toe and first metatarsal moved closer to the rest of the toes and was no longer opposable like the thumb. The limbs functioned better nearly straight. The pelvis changed and the spine changed to allow for limb connections. The knees could extend fully and lock.  The spine changed both with curves to better position the center of gravity and to allow for the new way in which the skull was oriented to allow for an upright head with eyes looking forward.

Following the development of upright posture, we had two free hands that could be used to carry tools, hunting implements, or food. We could move about fairly efficiently on the ground. We could range far in order to find food. Chimps and apes do not have a wide hunting range to gather food. As we ranged about, we found non-plant sources of protein. This enhanced the development of those built to use the protein, and allowed for eventually the development of a larger brain. This in turn led to the development of the genus homo, including Homo Erectus and later Homo Habilis.

The control of fire, and the use of fire for cooking made for easy to digest protein sources and richer, more calorie dense food. Some feel that the socialization that may have arisen around the ritual of cooking and meals helped enriched humans both culturally and socially. No food fights or no food!

As we developed more and more complex, those with larger brains, and skulls to hold them needed to be born through a larger pelvis. Eventually the pelvis enlarged in two different ways, Neandertal in width and our branch of hominids in an anterior – posterior direction.

Shortly we’ll take a look at the first runners. These first runners had larger gluteal muscles, a longer Achilles tendon, and even developed a bit of an arch along with toes that were all in line. Our knees could lock out. We already could look straight ahead and move on two limbs. As we became obligate bipeds we could no longer climb trees as well as those that came earlier.  I expect to have more details with recommended readings and references on my main web site. And of course, follow up here. To quote Charles Darwin in The Origin of Species: “To treat this subject at all properly, a long catalogue of dry facts should be given; but these I shall reserve for my future work.”

Science Magazine 323 Feb 27, 2009

Science magazine has just published an article on the oldest footprints found which correspond to modern day human biomechanical function. These footprints are about 1.5 Million years old and appear to belong to homo erectus, a species which predated homo sapiens.

The great toe was in similar alignment to modern day humans. An arch was present. Heel strike occurred at initial contact, weight transfer progressed forward with apparent foot function in the midfoot (midtarsal joint) proceeding in a modern manner. Weight bearing then went to the central metatarsals, (seemingly bearing more than the first metatarsal) followed by push off at the big toe.

The foot prints appear to show someone slowed to a near stop (or starting from a stop) and then picking up speed. To my eye, with an initial angle of gait being first high on the left, than on the right (about 24-26 degrees), followed by a narrow angle of gait (about 1 degree) as speed picked up, it looked as though the pre-human hominid was looking to the left, and then to the right. He likely would have been able to cross some of our streets, at least those with traffic bearing to the right side of the road. And in fact he may have avoided getting run over by a bovine, which blotted out part of one of his foot prints.

Bipedalism, walking on two limbs, was an important evolutionary step. Bipedalism is thought to have been present for about 6 million years.  It is energy efficient. It allows free hands to carry things, make tools, build things that are more complex than bird’s nests and beaver’s dams. It frees the hands  for hunting and fishing. Ultimately, it led to holding hands while walking. It led to artistic undertaking such as cave paintings, fashioning musical instruments, fingering the holes of a flute or playing chords and notes on strings. But, it also led some to throw stones at others. But that is another story.

The energy saved may have led to enhanced brain function. The energetics of bipedal walking, determined on an individual basis (some calculations have been done on chimpanzees) show a significant reduction in energy cost for walking in a bipedal manner. Some theorists believe that upright walking, and even running came before the larger skull and brain size.  That may very well have been true, based on these and other findings. There are many interesting adaptations and changes that occurred over the years. Some of the differences that occurred evolutionarily that are important to human bipedalism and are of significant, walking and running energetics include altered f0rm and function of the calf muscle, Achilles tendon, and the gluteal muscles. But, we can’t judge all of that from the footprints alone.

Science 323, 1197 (2009);  Early Hominin Foot Morphology Based on 1.5-Million-Year-Old Footprints from Ileret, Kenya. Matthew R. Bennett, et. al.

Science Now “Early Humans Toed The Line”

Music + Video: “Walk This Way”

Music + Video: “Walk The Line”