Fight Aging!

FIGHT AGING! NEWSLETTER
February 24th 2014

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENTS

• A Review of the Work of More of Last Year's Class of SENS Research Foundation Interns
• Heat Shock Protein Levels Predict Insulin Resistance With Aging
• Working on Methods of Generating Blood Vessel Networks in Engineered Tissue
• Did the Historical Impetus to Seek Rejuvenation Treatments Lead to As Much Good Medicine as Fraud and Nonsense?
• SENS Research Foundation February 2014 Newsletter
• Latest Headlines from Fight Aging!
  • Are All Those Memory T Cells Present in the Elderly in Fact Due to CMV Exposure?
  • Decellularization Demonstrated in Human Lungs
  • Multiplying Still-Functional Old Muscle Stem Cells to Reverse Age-Related Muscle Declines
  • More Mitochondrial DNA in Long-Lived Individuals
  • Suggesting That Mitochondrial Changes Are Consequences, Not Causes of Aging
  • More Evidence Against a Late-Life Mortality Plateau in Mammals
  • A Programmed Aging Theory Involving RNA
  • Immunotherapy Effective Against Advanced Leukemia
  • Protein Misfolding and Reversal of Age-Related Sleep Issues
  • Accelerometer Studies Show That Even Marginal Differences in Activity Have Noticeable Effects on Health

A REVIEW OF THE WORK OF MORE OF LAST YEAR'S CLASS OF SENS RESEARCH FOUNDATION INTERNS
https://www.fightaging.org/archives/2014/02/a-review-of-the-work-of-more-of-last-years-class-of-sens-research-foundation-interns.php

Young researchers intern each year at the SENS Research Foundation, doing their part to help advance the state of the art closer towards working rejuvenation treatments. The Foundation exists not just to coordinate and fund cutting edge research today, but also to help build the research community of tomorrow. Completing clinical deployment of the first generation of applied rejuvenation biotechnologies will be a big job, something that ideally will see the growth of a research community to rival the stem cell and cancer institutions in size, funding, and enthusiasm. Among today's life science undergraduates and graduates are those who will be leading laboratories two decades from now, creating therapies to reverse some of the causes of aging. But they haven't yet chosen that path, or made the necessary connections, or decided that they find the molecular biology of aging to be an exciting field, wide open for ambitious newcomers to make a mark.

If you look back in the Fight Aging! archives you'll find a few posts covering the SENS Research Foundation publications on their intern program:

• A Spotlight on SENS Research Foundation Interns
• Reviewing the Work of More of the SENS Research Foundation 2013 Interns
• Another Spotlight on SENS Research Foundation Interns

This is another post in the series, looking at the more of the work accomplished by last year's class. A number of articles have been published over the last month by the Foundation, and here they are:

Search begins for non-toxic enzymatic solution to macular degeneration: 2013 intern Anuj Kudva

Age-related macular degeneration (AMD) is a major cause of sight loss in the elderly. There are multiple risk factors that can result in the onset of AMD, but it is believed that the pathogenesis of AMD is due to dysfunctional retinal pigment epithelium (RPE) cells. It is believed that the buildup of a lipofuscin molecule called A2E within RPE lysosomes hinders the metabolic behavior of RPE cells and hence causes the AMD pathogenesis. Fortunately, a recent study has provided evidence that peroxidase enzymes can metabolize A2E within lysosomes. Unfortunately 10% of the cells died as a result of the enzymatic reaction.

The goal of my research team is to identify a peroxidase enzyme that can degrade the buildup of A2E with limited toxic side effects. My project focused on developing an assay to assess the cytotoxicity of possible peroxidase enzyme treatments. We decided to measure apoptosis as a readout of cytotoxicity. I tested a number of DNA damaging agents to establish a positive control for apoptosis. With a positive control established, I began Western blot analysis of the lysate from cells treated with or without a candidate peroxidase enzyme called SENS20. I found that SENS20 has no toxic effects at concentrations up to 100 ug. Once the team overcomes a few remaining technical issues, the assay will be ready for routine use. The apoptosis assay paves the way for more conclusive cytotoxicity studies in the future.

Generation of thymus ex vivo - SRF and WFIRM intern Daniel Bullock

The thymus is an essential component of the immune system, which configures T-cells to meet novel threats. Unlike most organs, the thymus reaches its maximum size and functionality around the onset of puberty after which it atrophies, leading to a decline in the immune system's ability to respond to new threats. If it were possible to prolong the viability of the thymus, or even revitalize it later in life, we might be able to bolster the body's defences against threats such as viruses, autoimmune diseases, and even cancer.

Our goal was to develop a method for growing a transplantable thymus, using donor thymus cells to colonize a scaffold containing an extracellular matrix, the mesh of tissue components found between cells. This entailed a number of intermediary steps, including harvesting thymic tissue from porcine donors, the decellularization of those tissues (i.e. reducing the tissue to an extracellular matrix), the harvesting of epithelial cells from murine donors, and finally the culturing of potential donor thymus tissue. Although these procedures have been successfully implemented in the past for a number of other organs and tissues, the precise protocols are only partly applicable for work with the thymus. Thus, a new protocol needed to be developed and optimized.

I performed a number of quantitative assessments to measure the optimization of the decellularization process and growth of thymic epithelial cell populations in vitro. Additionally, I also characterized the microphysical and biological features of the newly decellularized material. Our initial results have been promising and, as my internship was coming to a close, the lab was preparing to begin transplantation experiments in a live mouse model.

Stem cell-based therapy for the treatment of inflammatory bowel disease (IBD) - SRF intern John Moon

Inflammatory bowel disease is characterized by intestinal inflammation, which causes severe damage to the tissue of the intestinal lining. The precise cause of IBD remains uncertain. However, evidence suggests that dysregulation of the immune system plays a role in the autoimmune response that leads to the inflammation that characterizes IBD.

Mesenchymal stromal cells (or MSCs) are cells which differentiate into multiple tissue types and have been shown to reduce local inflammation, decrease the immune response, and counteract the signals released to recruit immune cells to the site of inflammation. It was therefore hypothesized that MSCs may be an effective therapy for IBD. However, clinical trials have demonstrated that MSC infusions were only effective in 30% of IBD patients. Furthermore, animal model studies have demonstrated that the limited tendency of MSCs to graft to the intestine may have been the limiting factor.

Previous work by the Almeida-Porada lab indicates that endothelial progenitor cells home promptly to the intestine. Therefore, my summer project sought to explore whether a cell-based therapy using a combination of both MSCs and endothelial cells (EC) would be an effective treatment for IBD.

Therefore, I isolated and characterized mesenchymal stromal cells and endothelial cells from human umbilical cord tissue. Then, I utilized flow cytometry and immunofluorescent double-staining to characterize these cells, and show that our cells are expressing molecules necessary for homing and immunomodulation. These results also lay the groundwork for future experiments to evaluate the effectiveness of cord tissue-derived MSC and EC cell therapy.

HEAT SHOCK PROTEIN LEVELS PREDICT INSULIN RESISTANCE WITH AGING
https://www.fightaging.org/archives/2014/02/heat-shock-protein-levels-predict-insulin-resistance-with-aging.php

Heat shock proteins such as HSP70 are a component of the cellular response to stress: they are generated in greater amounts when a cell is exposed to heat, toxins, starvation, and so forth. They have numerous important roles, but the roles of interest here involve protein quality control, activities that include ensuring that protein machinery folds correctly and misfolded proteins are quickly disposed of before they can cause harm. Misfolded and otherwise broken proteins are a form of damage, and the better the maintenance the less damage there is to impact cells and the organism to which those cells belong.

Heat shock protein activity is thus a noteworthy part of the hormetic response to mild levels of stress, something that contributes to the long-term benefits of calorie restriction, exercise, mild irradiation, and so forth. All of these things spur cells to undertake greater maintenance activities for a period of time, which results in a net benefit. If trying to create a therapy based on mimicking generalized increased levels of hormesis, then boosting levels of heat shock proteins might be a starting point. The mainstream research community hasn't headed in that direction yet with anywhere near the enthusiasm demonstrated for calorie restriction mimetics, however.

Here is an interesting primate study that shows HSP70 levels to predict growth in insulin resistance years later. Given that excess fat tissue and lack of exercise are just as involved as aging in rising insulin resistance in we humans, that raises a number of questions as what is going on here:

Muscle Heat Shock Protein 70 Predicts Insulin Resistance With Aging

Heat shock protein 70 (HSP70) protects cells from accumulating damaged proteins and age-related functional decline. We studied plasma and skeletal muscle (SkM) HSP70 levels in adult vervet monkeys (life span ≈ 25 years) at baseline and after 4 years (≈10 human years). Insulin, glucose, homeostasis model assessment scores, triglycerides, high-density lipoprotein and total plasma cholesterol, body weight, body mass index, and waist circumference were measured repeatedly, with change over time estimated by individual regression slopes.

Low baseline SkM HSP70 was a proximal marker for developing insulin resistance and was seen in monkeys whose insulin and homeostasis model assessment increased more rapidly over time. Changes in SkM HSP70 inversely correlated with insulin and homeostasis model assessment trajectories such that a positive change in SkM level was beneficial. The strength of the relationship between changes in SkM HSP70 and insulin remained unchanged after adjustment for all covariates. Younger monkeys drove these relationships, with HSP70 alone being predictive of insulin changes with aging.

Results from aged humans confirmed this positive association of plasma HSP70 and insulin. In conclusion, higher levels of SkM HSP70 protect against insulin resistance development during healthy aging.

One possible explanation is that this measure, by focusing on a repair and maintenance marker, is a filter for the proportion of insulin resistance caused by low-level biological damage over time, rather than by lifestyle choices. Another possible explanation is that higher levels of HSP70 associate with more physical activity, and in turn with all of the benefits that this brings. So the study could be demonstrating an inverse measure of variations in vervet indolence, which then translates over time to different health trajectories. It would be interesting to see a similar primate study of artificially increased levels of HSP70 - an expensive proposition in a world in which mouse studies can cost millions, and would therefore have to be driven by something more concrete than mere interest.

WORKING ON METHODS OF GENERATING BLOOD VESSEL NETWORKS IN ENGINEERED TISSUE
https://www.fightaging.org/archives/2014/02/working-on-methods-of-generating-blood-vessel-networks-in-engineered-tissue.php

Perhaps the greatest technical challenge in tissue engineering is the matter of blood vessels. The cells in any tissue larger than a sliver must be supported by a network of capillaries and larger blood vessels, and putting those in place isn't a simple undertaking. This is one of the principal reasons why decellularization is such an attractive option for engineering organs and large tissue sections: the decellularized donor organ provides a scaffolding of blood vessel networks and other structures, along with chemical cues necessary to guide the right cells to the right places.

Reproducing these intricacies in sufficient detail from scratch is currently beyond the capabilities of the scientific community, but people are working on it. Over the next decade, we should expect to see increasingly sophisticated, competing efforts to produce complex scaffolds and structure in tissue engineering. More importantly there will be efforts to make this a reliable and low-cost process - scalable infrastructure is the more important part of the equation here. This is all taking place right now and has been for years; progress is being made, as this is a comparatively well-funded field.

3-D printing technologies show a great deal of promise for tissue engineering, as there is already a large and mature industry devoted to modeling and printing detailed structures in various materials. Companies such as Organovo have made inroads in this area over the past decade, but there is a great deal of work yet to accomplish. These are still the early days for tissue printing. To pick an example of the present state of the art, this recent article looks at one research group and their approach to generating blood vessel networks in bioprinted tissues. As it notes, the near term goal is not tissues for transplantation, but to obtain a result that is sufficiently close to the real thing for use in drug and toxicity testing:

An essential step toward printing living tissues

A new bioprinting method [creates] intricately patterned, three-dimensional tissue constructs with multiple types of cells and tiny blood vessels. The work represents a major step toward a longstanding goal of tissue engineers: creating human tissue constructs realistic enough to test drug safety and effectiveness. To print 3D tissue constructs with a predefined pattern, the researchers needed functional inks with useful biological properties, so they developed several "bio-inks" - tissue-friendly inks containing key ingredients of living tissues. One ink contained extracellular matrix, the biological material that knits cells into tissues. A second ink contained both extracellular matrix and living cells.

To create blood vessels, they developed a third ink with an unusual property: it melts as it cools, rather than as it warms. This allowed the scientists to first print an interconnected network of filaments, then melt them by chilling the material and suction the liquid out to create a network of hollow tubes, or vessels.

[The] team then road-tested the method to assess its power and versatility. They printed 3D tissue constructs with a variety of architectures, culminating in an intricately patterned construct containing blood vessels and three different types of cells - a structure approaching the complexity of solid tissues. Moreover, when they injected human endothelial cells into the vascular network, those cells regrew the blood-vessel lining. Keeping cells alive and growing in the tissue construct represents an important step toward printing human tissues. "Ideally, we want biology to do as much of the job of as possible."

DID THE HISTORICAL IMPETUS TO SEEK REJUVENATION TREATMENTS LEAD TO AS MUCH GOOD MEDICINE AS FRAUD AND NONSENSE?
https://www.fightaging.org/archives/2014/02/did-the-historical-impetus-to-seek-rejuvenation-treatments-lead-to-as-much-good-medicine-as-fraud-and-nonsense.php

One of the ways in which people dismiss modern, legitimate research aimed at extending healthy human life is to decry it as just more of the same fraud, wishful thinking, and lies that have accompanied the desire for restored youth throughout history. It is certainly true that there is a lot of fraud and misrepresentation out there: the largest megaphones in the matter of aging and longevity are wielded by supplement sellers and the like. These are people with no incentive to be truthful and accurate, and who suffer few if any repercussions for stretching facts and scientific findings to breaking point, and it shows. The public spends billions on what is in essence fairy dust and fairy tales, while largely shunning the realistic research programs that might actually achieve extension of life. Never let it be said that we live in a sane world.

Is it really the case that nothing besides fraud and lies emerged from the desire for longevity all the way up until the point at which it became possible to actually start to do something about degenerative aging? That point in the development of biotechnology was arguably only reached perhaps thirty years ago at most, and meaningful initiatives - such as SENS research - only began in the last decade or so. The life sciences as practiced under the modern understanding of the scientific method have a history of several centuries of good, organized work, however.

A point argued in the paper quoted below is that the urge to longevity, while not generating actual means of rejuvenation, given that the technologies and knowledge needed to work usefully towards that goal did not exist until very recently, nonetheless led to the production of useful and even important advances in medicine.

The unexpected outcomes of anti-aging, rejuvenation and life extension studies: an origin of modern therapies

The search for life-extending interventions has been often perceived as a purely academic pursuit, or as an unorthodox medical enterprise, with little or no practical outcome. Yet, in fact, these studies, explicitly aiming to prolong human life, often constituted a formidable, though hardly ever acknowledged, motivation for biomedical research and discovery.

At least several modern biomedical fields have directly originated from rejuvenation and life extension research: 1) Hormone Replacement Therapy was born in Charles-Edouard Brown-Séquard's rejuvenation experiments with animal gland extracts (1889). 2) Probiotic diets originated in Elie Metchnikoff's conception of radically prolonged "orthobiosis" (c. 1900). 3) The development of clinical endocrinology owed much to Eugen Steinach's "endocrine rejuvenation" operations (c. 1910s-1920s). 4) Tissue transplantations in humans (allografts and xenografts) were first widely performed in Serge Voronoff's "rejuvenation by grafting" experiments (c. 1910s-1920s). 5) Tissue engineering was pioneered during Alexis Carrel's work on cell and tissue immortalization (c. 1900-1920). 6) Cell therapy (and particularly human embryonic cell therapy) was first widely conducted by Paul Niehans for the purposes of rejuvenation as early as the 1930s.

Thus, the pursuit of life extension and rejuvenation has constituted an inseparable and crucial element in the history of biomedicine. Notably, the common principle of these studies was the proactive maintenance of stable, long-term homeostasis of the entire organism.

The goals haven't changed: what has changed is that we can now outline in detail exactly how to achieve the goal of indefinite homeostasis for a complex organism, based on repair of the damage that causes change and degeneration.

I have mixed feelings about holding up hormone replacement therapy (HRT) and probiotics as exemplars here, given their abuse at the hands of the "anti-aging" marketplace and similar unhelpful entities. But we should remember that HRT is a useful treatment for a narrow range of comparatively rare medical conditions that can cause considerable suffering. Similarly for probiotics. But neither seem particularly beneficial or useful as a general palliative treatment for aging, based upon the research consensus. In comparison to SENS-style targeted applications of cutting-edge molecular biology aimed at very narrowly defined forms of cellular damage, HRT and probiotics might as well be lumped together in the technology pyramid at the same level as apes banging rocks together. Though of course you won't get that message from the people in the "anti-aging" industry trying to sell you on their treatments.

SENS RESEARCH FOUNDATION FEBRUARY 2014 NEWSLETTER
https://www.fightaging.org/archives/2014/02/sens-research-foundation-february-2014-newsletter.php

Here is a copy of a recent arrival in my in-box from the SENS Research Foundation, currently the world's most important research organization when it comes to work on the foundations of near-future rejuvenation biotechnologies, ways to repair the known forms of cellular and molecular damage that cause degenerative aging. The section on mitochondrial damage repair is well worth reading:

Full Series of SRF Education Coursework Videos Now Online

SRF asked world-renowned researchers to participate in a series of lecture videos explaining how regenerative medicine can help treat and prevent the diseases of aging. We are happy to announce that the 10-part series of videos is now complete and available on the SRF website.

Learn more about stem cells, tissue engineering, cancer mitigation strategies and regenerative medicine from such luminaries as Dr. Daniel Kraft, Dr. Alan Russell, Dr. Judith Campisi, and Dr. Michael West on our Video Lecture Course
page.

Supporter Profile: Jason Hope

1) How did you become interested in SENS Research Foundation's work?

It really started for me once I read the book "The Singularity Is Near" by Ray Kurzweil. It made me realize that we advanced technology so fast that we really left ourselves behind. I spent some time researching technology in the health industry and came across Dr. Aubrey de Grey. I quickly realized his unique engineering approach to fighting the diseases of aging was exactly what we needed to finally solve some of today's biggest killers and drivers of healthcare costs, including heart disease, stroke, and cancer.

2) Why do you think it is important for people to support SENS Research Foundation?

Although hundreds of billions of dollars have been poured into biotech and healthcare research over the past several decades, not much has changed about how we approach solving our biggest health problems. The wars on heart disease and cancer are far from over and little progress has been made against these diseases. SENS gives us a new approach that stands to alleviate a significant amount of human suffering in the near future. SRF's cutting edge research is going to really move us forward. It's going to give us and our loved ones the ability to live longer, healthier lives and the more people that get involved, the faster this becomes a reality.

Question Of The Month #1: How To Manage Mutant Mitochondria?

SRF is pleased to present a new monthly column. Expert science writer Michael Rae will answer one question from our inbox each month. Please send your questions to foundation@sens.org and your question may be featured.

Q: Dr. De Grey says in his Mitochondrial Mutations in Aging video that there are three principal ways to solve the problem of eliminating mitochondria with mutated DNA, but what seems to me the most straightforward method is not discussed. Why not simply selectively target the mutated mitochondria (since we can clearly identify them) and tag them for mitochondrial autophagy (by inducing damage, etc.) and thus selectively destroy the mutated organelles?

A: In principle, your proposal would be a great solution, but the key would be to find a way to selectively target mutant mitochondria, and there are no known ways of doing so at present. First, while it's true that we can identify such damaged mitochondria, we can only do so in cells isolated from the body and stained with various dyes, or heated up to break down the DNA into smaller chunks that are then analyzed -- not while those cells and tissues are still present and carrying out their function inside a person's living body.

As yet, there is no known signal put out by mitochondria harboring large deletions (the main class of mutations that accumulate in aging cells) that we could use for the purpose you describe. That's all the more true since such mitochondria are minimally metabolically active and can no longer produce their own proteins.

Second, there's good reason to think that the endogenous way of tagging defective mitochondria for destruction in the lysosome actually drives the problem! You can read the details in Ending Aging, but under a model Dr. de Grey nicknamed "Survival of the Slowest," cells identify old, damaged, but non-mutant mitochondria by the damage they accumulate in their membranes from the free radicals that they are constantly producing. By contrast, mitochondria bearing these deletion mutations avoid destruction because they no longer have the ability to produce key proteins in their energy-producing machinery. Without these proteins, the main mechanism of energy production in mitochondria shuts down - and along with it, free radical generation ceases. In the absence of the constant bombardment of free radicals, these mutant mitochondria no longer suffer damage to their membranes, and as a result, they they evade the normal mechanism that would target them for destruction. Mutated mitochondrial DNA then accumulates, as only non-mutant mitochondria are consumed.

Once the first mitochondrion in a cell suffers a deletion mutation, this process appears to lead very rapidly to the elimination of all of the non-mutant mitochondria in the cell, leaving behind a cell completely taken over by mutants. We never find cells in a state of transition between all-healthy and all-mutant mitochondria.

Any system that therefore aims to prevent the expansion of mutation-bearing mitochondria would have to cull deletion-bearing mitochondria faster than the normal processes of mitophagy already apparently culls healthy ones. This system would have to be thorough enough - and durable enough - to prevent the selective "clonal expansion" from happening indefinitely, under the full range of metabolic states of the cell. Next, we'd have to ensure that this dual culling would not somehow harm the cell: this doesn't seem likely, since the mutant mitochondria are by their nature harmful, but it would have to be tested.

I can see at least two ways that a system used to identify mutation-bearing mitochondria and send them to the lysosome for disposal might be subverted over time. First, the system might require us to insert new genes into the mitochondria (to express a marker under conditions where the activity of certain components of the citric acid cycle were very high, for instance). But since the whole problem is that such genes can be mutated, it's likely that many mutation-bearing mitochondria (again, particularly the most important class, which bear large deletions) would have mutations that inactivate these very genes. Secondly, the signal tag itself could be degraded or damaged while the mutation-bearing mitochondrion is awaiting disposal.

The advantage of the approaches that we favor is that they bypass the need for the mitochondria to behave in any particular way (such as to express any particular protein or produce any particular metabolite), and make the presence or absence of deletions in the mitochondrial DNA irrelevant to the body. Because we will engineer an alternative means of getting the mitochondria's energy-producing machinery the proteins it needs to function normally (whether by putting backup copies in the nucleus, or by delivering the needed RNAs directly into the mitochondria), the mitochondria will function normally whether they have deletions or not. This means that deletion-bearing mitochondria (a) can keep producing energy in the cell, (b) don't cause the cell to produce the toxins that they normally do, and thus avoid poisoning the rest of the body, and (c) will once again be subject the standard mechanism of clearing damaged mitochondria out of the cell thereby effecting what you propose by a circuitous route.

REMINDER: SRF Summer Scholars Program Applications Due March 3

The search for undergraduates to participate in the 2014 SRF Summer Scholars Program continues. If you are a qualifying student (click here for eligibility guidelines), make sure to submit your application before the deadline of 12 AM PST on March 3, 2014.

If you know an undergrad who might be interested in participating, make sure and alert them to this paid opportunity to join researchers at several distinguished institutions, including SENS Research Foundation's own Research Center, to tackle the diseases of aging.

Again, the application period ends at 12 AM PST on March 3, 2014. No applications will be accepted after the deadline.To learn more, visit http://sens.org/2014-summer-scholars.

New SENS6 Video Content: Translational Research Challenges and More

New video presentations from the SENS6: Reimagine Aging Conference are now available. In addition to Dr. George Church's keynote address outlining the latest advances in genomics and -ome technology, you can now also view Richard Barker's presentation on the challenges facing translational research, Dr. Brian O'Nuallain's talk on the therapeutic and diagnostic potential of innate and vaccine-generated antibodies, and others here on our SENS6: Reimagine Aging Conference Videos page.

Do you like what you see here? Then donate to help support the work of the SENS Research Foundation. You can look at the organization's annual reports to see where your funds will go, which is largely to specific research projects needed to develop means of rejuvenation. Life science and biotechnology research is becoming cheaper with every passing year, and even small sums make a big difference by enabling incremental new projects that move us all closer to the day on which actual, working rejuvenation treatments come into being. There are precious few opportunities for people like you and I to make such a large difference to the future of health and longevity - so seize this one.

LATEST HEADLINES FROM FIGHT AGING!

ARE ALL THOSE MEMORY T CELLS PRESENT IN THE ELDERLY IN FACT DUE TO CMV EXPOSURE?
Monday, February 17, 2014
https://www.fightaging.org/archives/2014/02/are-all-those-memory-t-cells-present-in-the-elderly-in-fact-due-to-cmv-exposure.php

The failing immune system of the elderly is characterized by a greatly increased number of memory T cells, and too few naive T cells capable of taking on new threats. One explanation for why this is the case is exposure to cytomegalovirus (CMV), a ubiquitous herpesvirus that the immune system cannot clear. Ever more T cells become uselessly devoted to fighting it until the immune system can no longer do its job. There are research results from human studies to support this view. It isn't the only reason that the immune system fails, but it may be one of the more important ones.

These researchers see a different picture when working in mice, however. To their eyes memory T cells are expanding in number with age due to some other process, something yet to be fully understood. CMV may prove to be a red herring yet, or this may turn out to be a significant difference between the immunology of mice and people:

The number of memory phenotype CD8 T cells increases dramatically with aging in both humans and mice. However, the mechanism for this is unknown. The prevailing hypothesis is that memory T cells accumulate with aging as a result of lifelong antigenic stimulation. However, data supporting this supposition are lacking.

In this study, we demonstrate that central memory CD8 T cells, which represent a large majority of memory CD8 T cells in aged mice, are not memory cells that develop in response to antigenic stimulation but are virtual memory cells that develop without antigenic stimulation. In addition to phenotypic evidence, we show that accumulation of central memory CD8 T cells is independent of CD4 T cells, CCR5, and CXCR3, all of which are known to be essential for [antigen]-driven development of central memory CD8 T cells. Thus, this study reveals a novel mechanism for aging-related changes in CD8 T cells.

The direct short-cut approach here is to destroy all these memory cells, and let the immune system repopulate with fresh new cells, perhaps helping it along with an infusion of cells generated from the patient's own stem cells. It doesn't matter how memory cells come to use up the allotted space for immune cells so long as they can reliably be singled out and cleared away.

DECELLULARIZATION DEMONSTRATED IN HUMAN LUNGS
Monday, February 17, 2014
https://www.fightaging.org/archives/2014/02/decellularization-demonstrated-in-human-lungs.php

The lung is a very complex organ, and that complexity is one reason why the tissue engineering of lungs is lagging behind that of other, less complex organs. It will be a while yet before any organ can be reliably grown from the starting point of a patient's own cells - though groups like the New Organ initiative hope to speed the arrival of that goal.

There is a technology to bridge the gap between the donor transplants of today and the organs grown to order of tomorrow, however: it is decellularization. A donor organ can be stripped of its cells, leaving only the structure of the extracellular matrix. When new cells are introduced, such as those derived from a recipient's stem cells, they are guided by the scaffold and chemical cues of the extracellular matrix to reassemble the correct tissues. The end result is an organ that will match the patient with little to no threat of immune of rejection. It will even possible to use organs from pigs or other similarly sized animals to create a source of decellularized tissues for transplantation.

A few years ago researchers demonstrated the ability to create and transplant decellularized rat lungs. Here this popular science article notes that decellularization in human lungs has reached the proof of concept stage. It is interesting to see that researchers are far more ready to put timelines for development on the table than they were in past years:

For the first time, scientists have created human lungs in a lab -- an exciting step forward in regenerative medicine, but an advance that likely won't help patients for many years. "It's so darn cool," said Joan Nichols, a researcher at the University of Texas Medical Branch. "It's been science fiction and we're moving into science fact."

The researchers started with lungs from two children who'd died from trauma, most likely a car accident. Their lungs were too damaged to be used for transplantation, but they did have some healthy tissue. They took one of the lungs and stripped away nearly everything, leaving a scaffolding of collagen and elastin.

The scientists then took cells from the other lung and put them on the scaffolding. They immersed the structure in a large chamber filled with a liquid "resembling Kool-Aid" which provided nutrients for the cells to grow. After about four weeks, an engineered human lung emerged. Repeating the process, they created another lung from two other children who'd died.

The lab-made lungs look very much like the real thing, just pinker, softer and less dense. Nichols said she thinks it will be another 12 years or so until they'll be ready to try using these lungs for transplants. "My students will be doing the work when I'm old and retired and can't hold a pipette anymore." Before researchers experiment on humans, they'll try out lab-made lungs on pigs.

MULTIPLYING STILL-FUNCTIONAL OLD MUSCLE STEM CELLS TO REVERSE AGE-RELATED MUSCLE DECLINES
Tuesday, February 18, 2014
https://www.fightaging.org/archives/2014/02/multiplying-still-functional-old-muscle-stem-cells-to-reverse-age-related-muscle-declines.php

Researchers here demonstrate a way to restore old muscle stem cell populations to youthful levels of activity and tissue maintenance, and show that it produces benefits in old mice:

The researchers found that many muscle stem cells isolated from mice that were 2 years old, equivalent to about 80 years of human life, exhibited elevated levels of activity in a biological cascade called the p38 MAP kinase pathway. This pathway impedes the proliferation of the stem cells and encourages them to instead become non-stem, muscle progenitor cells. As a result, although many of the old stem cells divide in a dish, the resulting colonies are very small and do not contain many stem cells.

Using a drug to block this p38 MAP kinase pathway in old stem cells (while also growing them on a specialized matrix called hydrogel) allowed them to divide rapidly in the laboratory and make a large number of potent new stem cells that can robustly repair muscle damage. "Aging is a stochastic but cumulative process. We've now shown that muscle stem cells progressively lose their stem cell function during aging. This treatment does not turn the clock back on dysfunctional stem cells in the aged population. Rather, it stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew."

The researchers found that, when transplanted back into the animal, the treated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair. "We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice. Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all."

MORE MITOCHONDRIAL DNA IN LONG-LIVED INDIVIDUALS
Tuesday, February 18, 2014
https://www.fightaging.org/archives/2014/02/more-mitochondrial-dna-in-long-lived-individuals.php

A herd of mitochondria exist in every cell, each with their own copies of mitochondrial DNA. Mitochondria replicate like bacteria, and mitochondrial dynamics are complex and reactive. So counting mitochondria, such as by measuring levels of mitochondrial DNA, doesn't necessarily tell us anything about cause and effect. If we see this measure declining with aging, but not in long-lived individuals, that really only says that we might want to look more closely at the role of mitochondria in aging. Long-lived individuals are long-lived precisely because they have less damage and fewer age-related changes in their biochemistry:

Mitochondrial DNA (mtDNA) content plays an important role in energy production and sustaining normal physiological function. A decline in the mtDNA content and subsequent dysfunction cause various senile diseases, with decreasing mtDNA content observed in the elderly individuals with age-related diseases. In contrast, the oldest old individuals, for example, centenarians, have a delayed or reduced prevalence of these diseases, suggesting centenarians may have a different pattern of the mtDNA content, enabling them to keep normal mitochondrial functions to help delay or escape senile diseases.

To test this hypothesis, a total of 961 subjects, consisting of 424 longevity subjects and 537 younger control subjects from Hainan and Sichuan provinces of China, were recruited for this study. The mtDNA content was found to be inversely associated with age among the age of group 40-70 years. Surprisingly, no reduction of mtDNA content was observed in nonagenarians and centenarians; instead, these oldest old showed a significant increase than the elderly people aged between 50 and 70 years. The results suggest the higher mtDNA content may convey a beneficial effect to the longevity of people through assuring sufficient energy supply.

SUGGESTING THAT MITOCHONDRIAL CHANGES ARE CONSEQUENCES, NOT CAUSES OF AGING
Wednesday, February 19, 2014
https://www.fightaging.org/archives/2014/02/suggesting-that-mitochondrial-changes-are-consequences-not-causes-of-aging.php

It is thought that mitochondrial DNA damage - and consequent mitochondrial dysfunction - is a contributing cause of aging. There is plenty of evidence to support that view, but it still lacks the sort of conclusive proof needed to sink all arguments, such as engineering longer life for laboratory animals through mitochondrial DNA repair, something that will soon be possible. Here, researchers look at specific forms of age-related mitochondrial change in nematodes and suggest that they are consequences, not causes of aging:

Mitochondrial dysfunction is a hallmark of skeletal muscle degeneration during aging. One mechanism through which mitochondrial dysfunction can be caused is through changes in mitochondrial morphology. To determine the role of mitochondrial morphology changes in age-dependent mitochondrial dysfunction, we studied mitochondrial morphology in body wall muscles of the nematode C. elegans.

We found that in this tissue, animals display a tubular mitochondrial network, which fragments with increasing age. This fragmentation is accompanied by a decrease in mitochondrial volume. Mitochondrial fragmentation and volume loss occur faster under conditions that shorten lifespan and occur slower under conditions that increase lifespan. However, neither mitochondrial morphology nor mitochondrial volume of five- and seven-day old wild-type animals can be used to predict individual lifespan.

Our results indicate that while mitochondria in body wall muscles undergo age-dependent fragmentation and a loss in volume, these changes are not the cause of aging but rather a consequence of the aging process.

MORE EVIDENCE AGAINST A LATE-LIFE MORTALITY PLATEAU IN MAMMALS
Wednesday, February 19, 2014
https://www.fightaging.org/archives/2014/02/more-evidence-against-a-late-life-mortality-plateau-in-mammals.php

At the high level aging is defined as an increase in mortality rate with time due to intrinsic causes. By this definition some species become "immortal" in old age: their mortality rates grow to become high but then cease to rise further in the final stage of life. The best data for this effect has been gathered in flies, and a lot of theorizing has taken place on what this might mean for the evolution of aging.

Finding this same effect in humans is a more challenging undertaking, as the data for human aging in extreme old age is sparse. The number crunching to date has leaned strongly towards there being no slowing of the increase in mortality rate over time in humans, and certainly no late life mortality plateau of the sort that occurs in flies. Here is a recent publication on this topic:

The growing number of persons living beyond age 80 underscores the need for accurate measurement of mortality at advanced ages and understanding the old-age mortality trajectories. It is believed that exponential growth of mortality with age (Gompertz law) is followed by a period of deceleration, with slower rates of mortality increase at older ages. This pattern of mortality deceleration is traditionally described by the logistic (Kannisto) model, which is considered as an alternative to the Gompertz model.

Mortality deceleration was observed for many invertebrate species, but the evidence for mammals is controversial. We compared the performance (goodness-of-fit) of two competing models - the Gompertz model and the logistic (Kannisto) model using data for three mammalian species: 22 birth cohorts of U.S. men and women, eight cohorts of laboratory mice, and 10 cohorts of laboratory rats. For all three mammalian species, the Gompertz model fits mortality data significantly better than the "mortality deceleration" Kannisto model (according to the Akaike's information criterion as the goodness-of-fit measure). These results suggest that mortality deceleration at advanced ages is not a universal phenomenon, and survival of mammalian species follows the Gompertz law up to very old ages.

A PROGRAMMED AGING THEORY INVOLVING RNA
Thursday, February 20, 2014
https://www.fightaging.org/archives/2014/02/a-programmed-aging-theory-involving-rna.php

These researchers put forward a theory of programmed aging that is based on the interactions between RNA populations and the genome. At present the mainstream view is that aging is not programmed, but rather a matter of stochastic accumulation of damage and the reactions to that damage - therefore developing methods of repair is the best way to prevent and reverse aging. No view in a developing field is ever shared universally of course:

Aging individuals can no longer maintain homeostasis in response to physiologic and environmental changes as easily as they once could. Through the years, copious hypotheses have been proposed to explain the mechanisms of aging. These hypotheses include two main types: one is an orderly, genetically programmed event that is the consequence of differentiation, growth, and maturation; the other is a stochastic event resulting from accumulation of random errors. However, each type of hypothesis cannot independently explain aging.

We propose the RNA population model as a genetic theory of aging. The new model can also be applied to differentiation and tumorigenesis and could explain the biological significance of non-coding DNA, RNA, and repetitive sequence DNA.

The RNA population in a cell is comprised of all of its transcriptional RNAs. The RNAs produced from a single transcription site (including multiple genes) make up an RNA subpopulation that forms a local network via RNA repetitive sequence complementation. Interactions between DNA and RNA in the local network disturb the tight packing of chromatin and maintain gene activation. In contrast, RNA fragments that destroy the RNA network or that disturb the interaction between DNA and the network RNA inhibit gene transcription. Gene transcription resulting from the interaction between DNA and the RNA network produces an RNA population that, in turn, affects gene transcription via changing chromatin packing in cell division. Gene transcription can be altered by changes in the interactions between the RNA population and DNA. Such changes are the foundation of aging and differentiation. If the interaction between the RNA population and DNA runs a cyclical course, it would result in immortal cells.

IMMUNOTHERAPY EFFECTIVE AGAINST ADVANCED LEUKEMIA
Thursday, February 20, 2014
https://www.fightaging.org/archives/2014/02/immunotherapy-effective-against-advanced-leukemia.php

The next generation of cancer treatments will be targeted approaches that destroy only cancer cells, with few or no side-effects. Given the results of the past decade of work, it looks likely that a majority of these treatments will be immune therapies, in which a patient's immune cells are engineered or trained to identify and attack the cancer. Clinical trials for a few such therapies are ongoing, mixed in with established treatment options. This is an example one of the more effective applications to date:

The largest clinical study ever conducted to date of patients with advanced leukemia found that 88 percent achieved complete remissions after being treated with genetically modified versions of their own immune cells. "These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies. Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer."

Adult B cell acute lymphoblastic leukemia (B-ALL), a type of blood cancer that develops in B cells, is difficult to treat because the majority of patients relapse. Patients with relapsed B-ALL have few treatment options; only 30 percent respond to salvage chemotherapy. Without a successful bone marrow transplant, few have any hope of long-term survival.

In the current study, 16 patients with relapsed B-ALL were given an infusion of their own genetically modified immune cells, called T cells. The cells were "reeducated" to recognize and destroy cancer cells that contain the protein CD19. While the overall complete response rate for all patients was 88 percent, even those with detectable disease prior to treatment had a complete response rate of 78 percent, far exceeding the complete response rate of salvage chemotherapy alone.

In the current study, seven of the 16 patients (44 percent) were able to successfully undergo bone marrow transplantation - the standard of care and the only curative option for B-ALL patients - following treatment. Three patients were ineligible due to failure to achieve a complete remission, three were ineligible due to preexisting medical conditions, two declined, and one is still being evaluated for a potential bone marrow transplant. Historically, only 5 percent of patients with relapsed B-ALL have been able to transition to bone marrow transplantation.

PROTEIN MISFOLDING AND REVERSAL OF AGE-RELATED SLEEP ISSUES
Friday, February 21, 2014
https://www.fightaging.org/archives/2014/02/protein-misfolding-and-reversal-of-age-related-sleep-issues.php

An interesting relationship between cellular maintenance machinery and age-related issues with sleep is uncovered and partially reversed by researchers here - though I would like to see more work on this topic before going along with their interpretation as to what is happening under the hood:

[Scientists] have been studying the molecular mechanisms underpinning sleep. Now they report that the pathways of aging and sleep intersect at the circuitry of a cellular stress response pathway, and that by tinkering with those connections, it may be possible to alter sleep patterns in the aged for the better - at least in fruit flies.

Increasing age is well known to disrupt sleep patterns in all sorts of ways. Aging is associated with increasing levels of protein unfolding, a hallmark of cellular stress called the "unfolded protein response." Protein misfolding is also a characteristic of several age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and as it turns out, also associated with sleep deprivation. [The researchers] wanted to know if rescuing proper protein folding behavior might counter some of the detrimental sleep patterns in elderly individuals.

They found that aged flies took longer to recover from sleep deprivation, slept less overall, and had their sleep more frequently interrupted compared to younger control animals. However, adding a molecule that promotes proper protein folding - a molecular "chaperone" called PBA - mitigated many of those effects, effectively giving the flies a more youthful sleep pattern. PBA (sodium 4-phenylbutyrate) is a compound currently used to treat such protein-misfolding-based diseases as Parkinson's and cystic fibrosis. Molecular analysis of sleep-deprived and PBA-treated flies suggested that PBA acts through the unfolded protein response.

The team also asked the converse question: Can protein misfolding induce altered sleep patterns in young animals. Another drug, tunicamycin, induces protein misfolding and stress, and when the team fed it to young flies, their sleep patterns shifted towards those of aged flies, with less sleep overall, more interrupted sleep at night, and longer recovery from sleep deprivation.

ACCELEROMETER STUDIES SHOW THAT EVEN MARGINAL DIFFERENCES IN ACTIVITY HAVE NOTICEABLE EFFECTS ON HEALTH
Friday, February 21, 2014
https://www.fightaging.org/archives/2014/02/accelerometer-studies-show-that-even-marginal-differences-in-activity-have-noticeable-effects-on-health.php

Wearable accelerometers are a comparatively new development in studies of the effects of exercise and activity on health. One of the outcomes is better evidence to suggest that even activities that don't rise to the level of what most people would consider exercise do in fact make a difference - standing versus sitting, for example:

If you're 60 and older, every additional hour a day you spend sitting is linked to a 50 percent greater risk of being disabled - regardless of how much moderate exercise you get, The study is the first to show sedentary behavior is its own risk factor for disability, separate from lack of moderate vigorous physical activity. In fact, sedentary behavior is almost as strong a risk factor for disability as lack of moderate exercise. If there are two 65-year-old women, one sedentary for 12 hours a day and another sedentary for 13 hours a day, the second one is 50 percent more likely to be disabled, the study found.

The study focused on a sample of 2,286 adults aged 60 and older from the National Health and Nutrition Examination Survey. It compared people in similar health with the same amount of moderate vigorous activity. Moderate activity is walking briskly, as if you are late to an appointment.

The participants wore accelerometers from 2002 to 2005 to measure their sedentary time and moderate vigorous physical activity. The accelerometer monitoring is significant because it is objective. The older and heavier people are, the more they tend to overestimate their physical activity. Previous research indicated a relationship between sedentary behavior and disability but it was based on self-reports and, thus, couldn't be verified.

Because the study examines data at one point in time, it doesn't definitively determine sedentary behavior causes disability. "It draws attention to the fact that this is a potential problem." Studies with animals have shown immobility is a separate risk factor for negative effects on health. "This is the first piece of objective evidence that corroborates the animal data."

This is the way things usually go: causality is determined in animal studies, where you can set a parameter and see what happens, but human studies largely only produce statistical correlations. Where those correlations match up with data generated in animal studies, that is good evidence to suggest that the same causality is at work in humans.