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Nuclear DNA Damage, Aging, and Stem Cells

Posted: March 27, 2011 at 3:58 pm

Nuclear DNA damage accumulates with age, but is it a cause of aging? This open access paper illustrates why there is a question - as for many studies, the results do not point unambiguously in one direction or another. "Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of aging. Here we tested this hypothesis in healthy individuals of different ages by examining unrepaired DNA double-strand breaks (DSBs) in hematopoietic stem/progenitor cells matured in their physiological microenvironment. ... The highest inter-individual variations for non-telomeric DNA damage were observed in middle-aged donors, [where] the individual DSB repair capacity appears to determine the extent of DNA damage accrual. However, analyzing different stem/progenitor subpopulations obtained from healthy elderly (>70 years), we observed an only modest increase in DNA damage accrual, [but] sustained DNA repair efficiencies, suggesting that healthy lifestyle may slow down the natural aging process. ... Based on these findings we conclude that age-related non-telomeric DNA damage accrual accompanies physiological stem cell aging in humans. Moreover, aging may alter the functional capacity of human stem cells to repair DSBs, thereby deteriorating an important genome protection mechanism leading to exceeding DNA damage accumulation. However, the great inter-individual variations in middle-aged individuals suggest that additional cell-intrinsic mechanisms and/or extrinsic factors contribute to the age-associated DNA damage accumulation." Meaning that nuclear DNA damage may or may not be a primary cause of aging, and may or may not be important in comparison to other factors.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049780/

Recommendation and review posted by Fredricko

Towards Stem Cell Therapy for Macular Degeneration

Posted: March 27, 2011 at 3:57 pm

Small steps: "The notion of transplanting adult stem cells to treat or even cure age-related macular degeneration has taken a significant step toward becoming a reality. ... researchers have demonstrated, for the first time, the ability to create retinal cells derived from human-induced pluripotent stem cells that mimic the eye cells that die and cause loss of sight. Age-related macular degeneration (AMD) [gradually] destroys sharp, central vision needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD progresses with death of retinal pigment epithelium (RPE), a dark color layer of cells which nourishes the visual cells in the retina. While some treatments can help slow its progression, there is no cure. The discovery of human induced pluripotent stem (hiPS) cells has opened a new avenue for the treatment of degenerative diseases, like AMD, by using a patient's own stem cells to generate tissues and cells for transplantation. For transplantation to be viable in age-related macular degeneration, researchers have to first figure out how to program the naïve hiPS cells to function and possess the characteristics of the native retinal pigment epithelium, RPE, the cells that die off and lead to AMD. ... This is the first time that hiPS-RPE cells have been produced with the characteristics and functioning of the RPE cells in the eye. That makes these cells promising candidates for retinal regeneration therapies in age-related macular degeneration."

Link: http://www.eurekalert.org/pub_releases/2011-03/gumc-sct031811.php

Recommendation and review posted by Fredricko

An Overview of the Molecular Mechanisms by Which Exercise Impacts Aging

Posted: March 27, 2011 at 3:57 pm

Exercise slows many of the degenerations of aging and - much like calorie restriction - this appears to be the result of changes in a multitude of biological processes and systems. In effect exercise adjusts the operation of your metabolism, moving it into a better configuration.

If you'd like a look under the hood, an overview of what is presently known of the biology that links exercise to improved long term health, you might read this recent open access review paper. It focuses on the heart, but the underlying mechanisms are of general interest:

It is generally accepted that regular exercise is an effective way for reducing cardiovascular morbidity and mortality. Physical inactivity and obesity are also increasingly recognized as modifiable behavioral risk factors for a wide range of chronic diseases, including cardiovascular diseases. Furthermore, epidemiologic investigations indicate that the survival rate of heart attack victims is greater in physically active persons compared to sedentary counterparts. Several large cohort studies have attempted to quantify the protective effect of physical activity on cardiovascular and all cause mortality. Nocon et al. in a meta-analysis of 33 studies with 883,372 participants reported significant risk reductions for physically active participants. All-cause mortality was reduced by 33%, and cardiovascular mortality was associated with a 35% risk reduction. Exercise capacity or cardiorespiratory fitness is inversely related to cardiovascular and all-cause mortality, even after adjustments for other confounding factors.

...

Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. ... A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.

Being sedentary appears to be just as self-sabotaging as letting yourself become obese. It will lower your odds of living in good health for as long as you might like - and that is enormously important in this age of biotechnology. Every additional year is another year of progress in the laboratories, of progress in advocacy for longevity science, of progress towards rejuvenation therapies that could arrive in time for those of us reading this today. Failing to take care of your health will shift the odds against you, and it's already the case that far too many people will die before the advent of repair technologies for the biological damage of aging. Why add to your risk becoming one of them?

Recommendation and review posted by Fredricko

The Unreliability of Many Studies of Rodent Longevity

Posted: March 27, 2011 at 3:57 pm

As noted in this paper, many researchers still fail to control for calorie intake in their studies - and thus their experimental results are largely worthless, given the impact of even mild calorie restriction on the life spans of laboratory animals: "Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed. Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic. Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds. Though still widely cited, studies showing life span extension using short-lived or 'enfeebled' rodents have not been shown to predict longevity effects in long-lived animals. We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. ... These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21424790

Recommendation and review posted by Fredricko

A Popular Science Article on Autophagy and Longevity

Posted: March 27, 2011 at 3:57 pm

From Science News: "the cells of organisms from yeast to humans regularly engage in self-cannibalism. Cells chew on bits of their cytoplasm - the jellylike substance that fills their bellies - and dine on their own internal organs ... It may sound macabre, but gorging on one's own innards, a process called autophagy, is a means of self-preservation, cleansing and stress management. ... A munch here gets rid of garbage that might otherwise clog the system. A nibble there rids cells of malfunctioning parts. One chomp disposes of invading microbes. In lean times, all that stands between a cell and starvation may be the ability to bite off and recycle bits of itself. And in the last decade or so it has become clear that self-eating can also make the difference between health and disease. ... Starvation inhibits an important biological signaling system, known as the mTOR pathway - named for a key protein involved in regulating cell growth and survival, cell movement and protein production. The inhibition of mTOR sets off a cascade of reactions inside the cell that end in autophagy and may be crucial to prolonging cell life and ultimately fending off cancer. A drug that inhibits mTOR, called rapamycin, has been shown to extend life span in mice. It and calorie restriction are [amongst a handful of] methods proven to prolong longevity, suggesting both may work through autophagy to make cells live longer."

Link: http://www.sciencenews.org/view/feature/id/70887/title/Dining_In

Recommendation and review posted by Fredricko

From the SENS Foundation: 2010 Research Report and SENS5 News

Posted: March 27, 2011 at 3:57 pm

The SENS Foundation will be hosting the SENS5 conference in Cambridge, England at the end of August. Registration is open, and this note arrived in my in-box today:

I am writing to inform you that June 15th is the deadline for discounted registration and abstract submission for the fifth Strategies for Engineered Negligible Senescence (SENS) conference ... The conference program features 33 confirmed speakers so far, all of them world leaders in their field. As with previous SENS conferences, the emphasis of this meeting is on "applied gerontology" - the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to the physical and mental robustness of young adults.

I notice that Caleb Finch will be giving the SENS Lecture, entitled "Regenerative medicine for aging: a new paradigm worth trying" - now there's an example of progress in winning over the mainstream of aging research to the SENS approach of repair rather than slowing down aging. In this context, "regenerative medicine" means SENS; SENS Foundation founder Aubrey de Grey uses the term more expansively than the general public and media, who use it only in reference to stem cell therapies.

The SENS Foundation also recently issued a research report (in PDF format) for the first ten months of last year, with a year end report to follow. You should find it interesting to see funding amounts listed for the varying strands of SENS research, as well as insight into exactly what the researchers are up to at present:

I'm delighted to be able to share with you our research report, prepared for the first 10 months of 2010, by Tanya Jones (our Director of Research Operations), working with our researchers and my CSO Team. I thought it would be of interest to our supporters, and serve as a precursor to our 2010 Year End Report, which is currently under production as part of our finalizing our 2010 accounts.

...

SENS Foundation conducts intramural research in its Research Center in Mountain View, California. The primary focus of our intramural work is LysoSENS - investigating novel lysosomal hydrolases against intracellular aggregates that impair cell function - and we recently produced a detailed and comprehensive LysoSENS planning document in collaboration with our extramural project at Rice University.

We have also arranged for research in the MitoSENS strand - obviating mitochondrial DNA deletions - to be conducted at the Research Center, following the negotiation of a transfer agreement with Dr Corral-Debrinski covering materials produced, and used in, previous successful work by her group. Dr Matthew "Oki" O'Connor joined us in September to initiate this project.

The relative amounts devoted to each project clearly illustrate that the Foundation's primary focus at this time is the LysoSENS project, and I can guess at some of the strategic reasoning there. Much money and many connections with industry might be gained through success in the LysoSENS platform. Not just aging, but many diseases could be effectively treated in their late stages through progress in bioremediation of this sort, and that means that big pharma and big biotech would be very interested in licensing agreements - which in turn would assist the Foundation in greatly expanding its purview and influence.

It is, however, frustrating to see far less funding devoted to MitoSENS, the project aimed at removing the contribution of mitochondrial DNA damage to aging. Everyone has an opinion, and mine (for what it's worth, which isn't all that much in this case, and nor should it be) is that mitochondrial repair would make a better primary focus. Irrespective of the methodology chosen, it seems clear that the research community as a whole is frustratingly close to something that will work to completely reverse mitochondrial damage, whether it is through allotopic expression as advocated by the SENS Foundation or periodic whole-body replacement of mitochondrial DNA as demonstrated in mice some years ago.

Yet the funds going towards mitochondrial repair - both here and generally - are in no way proportionate to the degree to which the research community believes mitochondrial DNA damage to be a cause of aging and longevity.

The advice I give myself on this issue is the same as I'll give to anyone else in the same position: if you believe that too little funding is devoted to any given research goal, then get out there and do something about it. Earn money and donate it, and persuade others to do the same. After all, that's exactly what Aubrey de Grey did in order to arrive at his present position: helping to direct a Foundation of his own creation where enthusiastic people are now writing annual reports on their progress towards engineering the end of aging.

Recommendation and review posted by Fredricko


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