The SENS Foundation, biomedical gerontologist Aubrey de Grey's umbrella organization for Strategies for Engineered Negligible Senescence research, is putting their best foot forward with a new, more functional, and attractive website:

The news section contains some updates of interest, such as this from the web team:

The new site is organized around a series of projects, which are in progress at our Research Center, in the facilities of our collaborators, or under the auspices of our Academic Initiative. Blogs and news items relating to all these projects will be added regularly, giving you an up-to-date picture of the work we do. News items from outside the Foundation, which relate to our mission, will be available here. Publications and proceedings of past conference are also available, and we'll be creating a wider media library over the coming months. ... To make use of some of the features of the new sens.org - particularly our new forums - you'll need to register an account. You can do this by clicking here, or on the Members link in the top right hand corner.

Now I must go and update a hundred or so deep links...

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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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