In recent years a number of studies have shown a correlation between high levels of psychological stress and shorter telomeres. For example, we have this from 2004:

The UCSF-led team determined that chronic stress, and the perception of life stress, each had a significant impact on three biological factors - the length of telomeres, the activity of telomerase, and levels of oxidative stress - in immune system cells known as peripheral blood mononucleocytes, in healthy premenopausal women.

A greater weight of work over a much longer period of time links chronic psychological stress with poor health in general, and there is also reason to believe that shorter telomeres correlate well to poor health and greater risk of age-related disease. So does psychological stress over time cause what amounts to somewhat accelerated aging? This is plausible, but still unclear. While the research quoted above fairly clearly suggests that psychological stress leads to a less robust, more damaged immune system, with all that this implies for health and aging, the role of telomeres in the biochemical and cellular damage that accumulates with aging is not yet firmly established. They may be a root cause of age-related degeneration, or they may be a secondary marker of other processes, such as mitochondrial damage. Further, note that studies have generally looked at telomere length in only a limited population or subset of the body's different cell types.

But the data on stress and telomere length continues to arrive. At some point a firm conclusion will emerge. Here, for example, is a more recent study:

Telomere length is a measure of biological aging because telomeres shorten progressively with each cell division. Shorter telomere lengths have been linked to a variety of aging-related medical conditions including cardiovascular disease and cancer.

Stress and trauma, such as childhood abuse and neglect, are risk factors for several medical and psychiatric illnesses, and stress is known to promote cellular aging. So, Audrey Tyrka and her colleagues from Butler Hospital and Brown University examined the DNA of healthy adults who had a history of childhood maltreatment and found they had shorter telomeres than those who did not experience child maltreatment.

Dr. Tyrka explained that the findings "suggest the possibility that early developmental experiences may have profound effects on biology that can influence cellular mechanisms at a very basic level and even lead to accelerated aging."

All of which still hinges on the role of telomeres in aging, and whether telomere length in any specific cell type is a good biomarker of aging - questions that remain in need of solid answers.

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The Longer Life Foundation is an example of one of the conservative funding sources in aging research; it is similar to the Ellison Medical Foundation in choices of which research to fund and the public face of the organization. Nothing that will rock the boat, in other words, or appear to be advocating near-future longevity engineering in humans. This describes much of the funding landscape, sadly, which is how the Glenn Foundation can look like a force for change by comparison, simply by talking about extending the healthy human life span in the context of funding mainstream aging research.

From the Longer Life Foundation website:

The Foundation, a not-for-profit organization, funds research that has immediate and practical applications for health promotion and for the assessment of longevity trends. ... The Foundation will study the scientific and social factors that help predict longevity and wellness in selected populations, domestically and internationally. ... Findings will be published for the benefit of the entire medical community, to help improve human health and longevity. ... The Longer Life’s mission is to study factors that assist in predicting mortality and morbidity of selected populations and to research methods to promote improvements in longevity and health by analyzing the effects of changes in medicine and advances in public health practices.

A recent university press article gives an idea as to the sort of research funded by the Foundation:

Over the last 10 years, the foundation has awarded more than $2 million to [Washington University]. This most recent group of grants provides a total of $279,000, and each grant award totals between $26,000 and $75,000.

Grant renewals were awarded to John O. Holloszy, MD, professor of medicine, and Luigi Fontana, MD, PhD, research associate professor of medicine, for the "Longer Life Foundation Longevity Research Program," a project comparing key functions in people who practice calorie restriction with the same bodily functions in normal weight individuals and in endurance athletes.

Also receiving a second year of funding was Shin-ichiro Imai, MD, PhD, associate professor of developmental biology and of medicine, for a project entitled "Diagnostic and Therapeutic Applications of a Novel Plasma Metabolite, Nicotinamide Mononucleotide (NMN), for Age-Associated Metabolic Complications in Humans." Another renewal went to Ravi Rasalingam, MD, assistant professor of medicine, for the project "Novel Methods for Detection of Coronary Artery Disease in Diabetic Patients," which is looking at the feasibility of using of sound waves to detect blocked blood vessels as a screening tool for people with diabetes who are at risk for coronary heart disease.

New grants this year went to Marco Colonna, MD, professor of pathology and immunology and of medicine, for the project "Does Caloric Restriction Slow Aging of the Human Immune System?"

There are a good few years of research results to suggest that calorie restriction does indeed slow the age-related degeneration of the human immune system. As you might have gathered from the list of awards above, Washington University is one of the research centers most involved in modern calorie restriction research. It is one of the host universities for the CALERIE study program, for example.

CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) is a trial currently underway in the U.S. to study the effects of prolonged calorie restriction on healthy human subjects. The CALERIE study is being carried out at the Pennington Biomedical Research Center (Baton Rouge, Louisiana), the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (Boston, Massachusetts) and the Washington University School of Medicine (St. Louis, Missouri).

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You might recall the accidental discovery of unusually potent regeneration in MRL mice by Ellen Heber-Katz's team some years ago:

Our laboratory has determined that the MRL mouse strain is unique in its capacity for regenerative wound healing, as shown by the closure of ear punches with normal tissue architecture and cartilage replacement reminiscent of amphibian regeneration as opposed to scarring.

One line of research into regenerative medicine is based on understanding and then recreating in mammals the regenerative powers of lower animals like the salamander or zebrafish. The existence of MRL mice, a laboratory breed originally created for quite different reasons, provides hope that the required genetic or other alterations to mammalian biochemistry are not in fact insurmountably large or complex. Some researchers believe that mammals retain much of the salamander's regenerative capabilities encoded within their genome, and that it is currently only unused or inaccessible rather than completely lost.

But onwards: my eye was caught today by an update from Heber-Katz's laboratory, in which the regenerative capacity of MRL mice is matched up to a single genetic deletion:

A quest that began over a decade ago with a chance observation has reached a milestone: the identification of a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice long thought to have been lost through evolution and reserved for creatures like flatworms, sponges, and some species of salamander.

...

Snyder found that p21, a cell cycle regulator, was consistently inactive in cells from the MRL mouse ear. P21 expression is tightly controlled by the tumor suppressor p53, another regulator of cell division and a known factor in many forms of cancer. The ultimate experiment was to show that a mouse lacking p21 would demonstrate a regenerative response similar to that seen in the MRL mouse. And this indeed was the case. As it turned out, p21 knockout mice had already been created, were readily available, and widely used in many studies. What had not been noted was that these mice could heal their ears.

Those of you so inclined might want to take a look at the paper; not open access, I'm afraid. But what does this mean for the future of mammals that regenerate like salamanders? It is hard to say at this stage, although one could speculate on the similarities between full regeneration in amphibians, cancerous growth in adults, and embryonic development. The gene p21 is fairly central to a range of mechanisms, and it is probably important that one of those mechanisms is cancer suppression; if adult tissue is undertaking controlled regrowth that bears many things in common with cancer, the normal cancer suppression mechanisms might interfere in that process. While mice lacking p21 are basically fairly normal (which is surprising, all things considered) there is every reason to expect wide-ranging and unpredictable side-effects to turn up on closer inspection:

A decline in adult stem cell function occurs during aging, likely contributing to the decline in organ homeostasis and regeneration with age. An emerging field in aging research is to analyze molecular pathways limiting adult stem cell function in response to macromolecular damage accumulation during aging. Current data suggest that the p21 cell cycle inhibitor has a dual role in stem cell aging: On one hand, p21 protects adult stem cells from acute genotoxic stress by preventing inappropriate cycling of acutely damaged stem cells. On the other hand, p21 activation impairs stem cell function and survival of aging telomere dysfunctional mice indicating that p21 checkpoint function is disadvantageous in the context of chronic and persistent damage, which accumulates during aging.

Still, learn by doing should be the mantra of modern biotechnology. The determination of a single gene of interest in this matter will lead researchers to investigate a narrow range of potential underlying mechanisms in order to explain why the MRL mice heal as they do. Those mechanisms can then be manipulated directly, one by one, to establish a better picture as to what exactly is going on here.

Khamilia Bedelbaeva, Andrew Snyder, Dmitri Gourevitch, Lise Clark, Xiang-Ming Zhang, John Leferovich, James M. Cheverud, Paul Lieberman, & Ellen Heber-Katz (2010). Lack of p21 expression links cell cycle control and appendage regeneration in mice PNAS : 10.1073/pnas.1000830107

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Amidst the preprint list of the Rejuvenation Research journal, I see an interesting paper I'd somehow missed: life span can be extended in old mice by transplant of a young thymus.

Noninvasive Neonatal Thymus Graft into the Axillary Cavity Extends the Lifespan of Old Mice:

Neonatal thymus grafts exert a rejuvenating action on various immunological and nonimmunological functions found altered in old mice. Commonly, half of a thymus is grafted under the kidney capsule. The invasiveness of the surgical procedure and the use of limited thymus tissue may explain why precedent survival kinetics remain unaffected.

In this trial, we grafted two neonatal thymi into the axillary cavity of old mice, thus reducing the invasiveness of the intervention and increasing the amount of grafted neonatal tissue. Using a Piantanelli parametric model of survivorship, we found a significant change in mortality rate between the two groups (thymus graft and controls).

You might recall that the degeneration of the thymus over time - a process known as involution - is one of the limits placed upon your immune system. The thymus is the source of T cells, the workers of the active immune system. Considered within the framework of a normal life span, the thymus spins up early, churns out your population of T cells while you are a child, and then largely shuts down once you reach adulthood. You are left with what is essentially a fixed population of immune cells to see you through the rest of your life. Which is a simplification of a more complex set of processes, but close enough for our purposes here.

The degenerating effectiveness of an aging immune system results in large part from the limited T cell population: it runs out of T cells that are not already assigned to specific tasks. Over the years, exposure to persistent but usually harmless viruses like cytomegalovirus (CMV) chews up your quota of T cells, leaving too few to effectively defend against new threats, destroy senescent cells, or destroy cancerous cells before they can form a tumor. So you suffer, and the degenerations of aging are accelerated.

One possible way to deal with this problem and restore the immune system to a more youthful capacity is to destroy the clutter. Use targeted therapies of the type under development by cancer researchers to kill off the T cells that are dedicated to fight CMV, and then repopulate your immune system via stem cell medicine. Or, more radically, completely destroy and then recreate your immune system, wiping the slate clean. This second method has already been achieved in early trials for autoimmune diseases.

But another approach is to simply boost the number of immune cells circulating in the body. I've discussed rejuvenation of the thymus through tissue engineering or other techniques in the past - essentially gearing it up to generate more T cells than would normally be the case. Transplantation of young thymus tissue, as the researchers in the paper quoted above have demonstrated, is one way of validating this approach. The immune system is so critical to resisting various forms of progressive cellular and other biochemical damage in the body that it is not unreasonable to expect at least some enhanced longevity to result from its restoration.

Basso, A., Malavolta, M., Piacenza, F., Santarelli, L., Marcellini, F., Papa, R., & Mocchegiani, E. (2009). Noninvasive Neonatal Thymus Graft into the Axillary Cavity Extends the Lifespan of Old Mice Rejuvenation Research DOI: 10.1089/rej.2009.0936

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Via FuturePundit, I see that a recent open access paper outlines the results of applied cancer research over the past four decades.

Declining Death Rates Reflect Progress against Cancer

The success of the "war on cancer" initiated in 1971 continues to be debated, with trends in cancer mortality variably presented as evidence of progress or failure. We examined temporal trends in death rates from all-cancer and the 19 most common cancers in the United States from 1970-2006. ... Progress in reducing cancer death rates is evident whether measured against baseline rates in 1970 or in 1990. The downturn in cancer death rates since 1990 result mostly from reductions in tobacco use, increased screening allowing early detection of several cancers, and modest to large improvements in treatment for specific cancers. Continued and increased investment in cancer prevention and control, access to high quality health care, and research could accelerate this progress.

That there is debate over the effectiveness of funding for cancer research is somewhat a function of slow and steady progress rather than sudden leaps in technology both inspiring and obvious in their magnificence - which will always be the case, people being people. On the other hand, that cancer research is so dominated by government funding has no doubt led to great inefficiency and much borderline or useless work that should not have taken place; everything touched by government funding eventually turns into a low-motivation jobs program and sinkhole for graft, no matter how urgent the cause.

The dry conclusion of the paper is a conservative projection of present trends into the future, something which we should instinctively doubt given the nature of the era. Accelerating change is everywhere: any field connected in some way to computing power is rushing forward, ever faster with each passing year. Biotechnology and its application to medicine is no exception, and the next generation of cancer therapies, based on targeted nanoparticles and identification of cancer biochemistry, will be very much more effective than presently widely available medical technologies.

The existence of a technology platform that can be used to efficiently and safely kill very specific cell types reduces cancer to just another information problem in biotechnology: what do the cells you want killed look like? How is their chemistry different from that of other cells? What is the specific molecular marker I am looking for here? These questions are dead center in the fast lane of life science. The therapies based upon this technology will be as far beyond chemotherapy as chemotherapy is beyond no treatment at all.

Jemal, A., Ward, E., & Thun, M. (2010). Declining Death Rates Reflect Progress against Cancer PLoS ONE, 5 (3) DOI: 10.1371/journal.pone.0009584

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To follow on from a recent post on medical tourism for stem cell therapies, I though I'd note the pace of development in Asia. The medical industry in countries like India, Malaysia, Vietnam, and so forth is in many ways more energetic than in the West. It is certainly less burdened by regulation, and that makes all the difference in the long run. For so long as it costs less to achieve the same goals, the level of growth will be greater, and that difference will compound year after year. Heavy regulation and socialist command and control systems such as those that shackle medicine in the US will always ensure that a region becomes backwards and poor in the fullness of time. It will be overtaken by competing regions, and the bulk of new investment will go elsewhere.

We can see aspects of this process happening now in the field of stem cell research. The real action in terms of foundational growth and application of new science is taking place outside America and Western Europe. Absent large changes in the tenor and breadth of medical regulation in the US, the future of your health will be found in Asia, because that will be where the safe, reliable, low cost therapies exist.

A couple of articles I noticed recently are illustrative of the infrastructural development taking place in that region of the world:

Miracles of Science in Regenerative Medicine

The Manipal Institute of Regenerative Medicine (MIRM), a new initiative of Manipal University, has been created to transform stem cell science into reality by bringing together a group of outstanding scientists and providing them with an exceptional research environment. India is identified as one of the forerunners in stem cell research and MIRM is the first academic Institute in India to impart focused training in stem cell biology.

ISSL to invest Rs 50 cr to set up stem cell speciality hospitals in metros

International Stemcell Services Limited (ISSL) which is engaged in stem cell clinical application and banking services is planning an investment to the tune of Rs 50 crore. The funds will be utilized to establish dedicated stem cell speciality hospitals in major cities and open up Departments of Regenerative Medicine in existing hospitals. The company would chip in a portion of the funds from its internal accruals and the remaining will be raised through financial institutions. Presently, ISSL has a opened a facility at the St Theresa’s Hospital, Bangalore which is equipped with a Philips endura C-arm for transplantation of stem cells. Its Mumbai centre is a class 10,000 cGMP facility, which caters to the western parts of the country.

Pahang going ahead with stem cell research hub

The Pahang government [in Malaysia] will proceed with plans to set up a stem cell research hub despite questions being raised on the effectiveness of stem cell treatment, Mentri Besar Datuk Seri Adnan Yaakob said. Adnan said the state government was aware of questions being raised both here and abroad over the authenticity of claims that stem cells could be used to cure a number of ailments. He said some quarters felt that more research should be carried out to determine if the treatment actually worked but he noted that many individuals claimed that their condition had improved following such treatment.

This sort of thing will continue, and the pace will pick up.

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