Fight Aging! Newsletter, July 28th 2014

July 28th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • Delivering Stem Cells to Improve the Response to Exercise
  • Involvement of the Extracellular Matrix in Age-Related Memory Loss in Mice
  • More Researchers are Calling for Efforts to Treat Aging
  • An Interview with Thiel Fellow Thomas Hunt
  • Correlations in Dysfunction Abound in Aging
  • Latest Headlines from Fight Aging!
    • Larger Animals and Cancer Rates
    • Acquired Inheritance in Response to Starvation
    • Mechanisms Linking Peridontitis and Atherosclerosis
    • Telomere Length is Complicated
    • Speculating on a Viral Cause of Parkinson's Disease
    • More Physically Aged People Have a Lower Life Expectancy
    • Immune Surveillance of Mitochondrial DNA Deletions?
    • Advocacy for Longevity Science Can Take Many Forms
    • Stemness of Central Memory T Cells
    • Restoring Function in Spinal Cord Injury


There are countless potential ways to use stem cells to improve health. These are still the very early stages of stem cell medicine, when looking at the long term. Researchers have barely scratched the surface of what could be accomplish once patient-matched stem cells of any arbitrary type can be reliably and rapidly generated to order. To give just a few examples that are already possible: deliver vast numbers of immune cells into the body to attack cancer, a specific pathogen, or simply to boost immune function in the elderly; deliver neural stem cells to improve plasticity in the brain; repairing worn joints and heart tissue with stem cells that alter signaling in tissues to instruct native cells to get back to work. But there is much, much more than this presently under investigation in the laboratory.

A great deal of present work on stem cells focuses on muscle and the various types of stem cell that support it. These stem cells are better understood than others, and the techniques for working with them are more robust and reliable. In addition, muscle tissue is easier to work with in animal models in comparison to internal organ tissue. All of this translates to a lower cost of research in money and time, and greater ease in raising funds and producing results. Details matter. On the topic of muscles and stem cells I noticed this report of an interesting application of stem cell infusions today:

Stem cells aid muscle repair and strengthening after resistance exercise

Mesenchymal stem cells (MSCs) occur naturally in the body and may differentiate into several different cell types. They form part of the stroma, the connective tissue that supports organs and other tissues. MSCs also excrete growth factors and, according to the new study, stimulate muscle precursor cells, called satellite cells, to expand inside the tissue and contribute to repair following injury. Once present and activated, satellite cells actually fuse to the damaged muscle fibers and form new fibers to reconstruct the muscle and enhance strength.

By injecting MSCs into mouse leg muscles prior to several bouts of eccentric exercise (similar to the lengthening contractions performed during resistance training in humans that result in mild muscle damage), researchers were able to increase the rate of repair and enhance the growth and strength of those muscles in the exercising mice. "We have an interest in understanding how muscle responds to exercise, and which cellular components contribute to the increase in repair and growth with exercise. But the primary goal of our lab really is to have some understanding of how we can rejuvenate the aged muscle to prevent the physical disability that occurs with age, and to increase quality of life in general as well. Satellite cells are a primary target for the rejuvenation of aged muscle, since activation becomes increasingly impaired and recovery from injury is delayed over the lifespan. MSC transplantation may provide a viable solution to reawaken the aged satellite cell."

Satellite cells themselves will likely never be used therapeutically to enhance repair or strength in young or aged muscle "because they cause an immune response and rejection within the tissue." But MSCs are "immunoprivileged," meaning that they can be transplanted from one individual to another without sparking an immune response.

I think that last prediction about the use of satellite cells will be quickly proven wrong. The trajectory of research is clearly toward the ability to generate large numbers of any type of cell as needed from a sample of a patient's skin or similar. So why not satellite cells? The only good reason that immediately springs to mind is that it may turn out to be more efficient or effective to use patient-matched mesenchymal stem cells instead. Either way, ultimately the transfer of stem cells itself will most likely vanish for the majority of therapeutic applications, to be replaced with direct programming of existing in situ cell populations. Stem cell medicine is a bridge technology in this sense, though one likely to last decades.

Here is another thought for the day: how long before athletes are engaging in the use of stem cell treatments to build muscle? I would not be entirely surprised to find haphazard attempts at this taking place in today's medical tourism industry, but I suspect we are still some years away from more reliably effective treatments if enhancement of youthful muscle is the end goal.


All of the myriad conditions of degenerative aging stem from comparatively simple roots: a small number of different types of cellular and molecular damage that accumulate over the decades. From there secondary forms of dysfunction spin off into spirals of cause and effect, becoming ever more complex and challenging to interpret at each new turn. It is just the same as rust in a complex metal framework: a simple root cause, but thousands of ways in which the rust can progress to cause the structure to finally collapse.

Treating the consequences of aging has been difficult for the medical research community because they have traditionally started their investigations at the final and most complicated end point, which is to say full-blown age-related disease. From there researchers try to work backwards towards progressively earlier causes. The first points at which they find ways to intervene are the closest proximate causes, which tend to be complex dysregulations of metabolism or cell state. Treatments involve the use of drugs to produce alterations in protein levels or epigenetic changes which in turn change the operation of cells or metabolism - but since everything in cellular biology influences everything else this is hard to get right, and it is also hard to produce benefits without significant side-effects. Also, since this is a matter of targeting proximate causes rather than root causes, the root cause of the problem continues chewing away underneath it all, making any solution temporary and fragile at best.

This is the present state of medicine. In the future, we would like to see a growth in targeting of root causes in aging and age-related disease, as exemplified by the SENS research program that I'm sure you're all at least passingly familiar with by now. A change of this nature in research and development will produce a sweeping improvement in the quality and capabilities of clinical medicine. This is very much a work in progress, however, and still in the earliest stages. The overwhelming majority of medical research continues to focus on end states and proximate causes rather than root causes, and is consequently the hard path to limited benefits.

Occasionally there are moments of luck in the present process, however, where it turns out that a pocket of comparative simplicity in the progression of degeneration from root cause to end state extends a fair way along the chain of consequences. This recently published research suggests that this might be the case for age-related memory loss in mammals. This is an aspect of cognitive decline that I would not have guessed had any simple points of intervention. The nature of the changes involved is also surprising, as it lies outside cells, not inside:

Rigid connections: Molecular basis of age-related memory loss explained

Brain cells undergo chemical and structural changes, when information is written into our memory or recalled afterwards. Particularly, the number and the strength of connections between nerve cells, the so-called synapses, changes. To investigate why learning becomes more difficult even during healthy ageing, the scientists looked at the molecular composition of brain connections in healthy mice of 20 to 100 weeks of age. This corresponds to a period from puberty until retirement in humans. "Amazingly, there was only one group of four proteins of the so-called extracellular matrix which increased strongly with age. The rest stayed more or less the same."

The extracellular matrix is a mesh right at the connections between brain cells. A healthy amount of these proteins ensures a balance between stability and flexibility of synapses and is vital for learning and memory. "An increase of these proteins with age makes the connections between brain cells more rigid which lowers their ability to adapt to new situations. Learning gets difficult, memory slows down."

Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wildtype mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90 and 100 weeks of age.

Extracellular matrix proteins were the only group of proteins that showed a robust and progressive upregulation over time. This was confirmed by immunoblotting and histochemical analysis, indicating that the increased levels of hippocampal extracellular matrix may limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission.

Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance at old age.

Note that the paper is open access, and the full PDF version is available.


The aging research community of today is a far cry from that of fifteen years ago. At that time, it was pretty close to career suicide to openly talk about aging as a medical condition amenable to treatment, or tackling the causes of aging to extend healthy life. Few people could get away with it, and those that were attempting to improve the field and open up the doors to clinical applications were largely doing so quietly in order to preserve their work. That sorry state of affairs had persisted for decades by that point, slowing down progress: scientists were not encouraging the view that treating aging was possible, archly conservative funding institutions made it clear there were no resources for that work, and there was no public pressure to see results because the public remained largely ignorant of the possibilities. It was a self-reinforcing deadlock, one that exists in many areas of potential improvement in technology, but here it was been particularly damaging because the cost of aging is so high: a hundred thousand lives lost every day, and countless more suffering from age-related diseases.

The sea change in aging research that has taken place between the turn of the century and today didn't happen by accident. It was the result of hard work and persistence on the part of numerous organizations and outspoken advocates within and without the scientific community. A number of those advocates, most notably Aubrey de Grey, were so horrified by the state of affairs in the aging community that they became scientists in order to try to set matters to rights. Many of us here have supported some of the organizations that helped to bring this all about, such as the Methuselah Foundation and SENS Research Foundation.

The results of all this work have been taking form over the past few years in the mainstream aging research community: plans and intent for the next decade of research strategy are becoming clear, and many more researchers are standing up to declare that treating aging is the way to go. Of course there are as many specific approaches as there are research groups, and nowhere near as many scientists as I'd like are jumping on the SENS bandwagon, but in many ways the most important change is that the voices of the community are now coming around to persuade the public and funding institutions that we should treat aging as the medical condition it is, and do something about it. At that point may the best approach win.

Here is an example that is much closer to the Longevity Dividend approach of modestly slowing aging than the SENS vision for rejuvenation through repair of the cellular damage that causes aging, but again it is progress to have this sort of open, public declaration of intent by noted researchers. It is a sign that we advocates will see a growing number of allies when it comes to convincing the remaining majority of the public that treating aging and extending healthy life is plausible, possible, and desirable.

Strategy proposed for preventing diseases of aging

Medicine focuses almost entirely on fighting chronic diseases in a piecemeal fashion as symptoms develop. Instead, more efforts should be directed to promoting interventions that have the potential to prevent multiple chronic diseases and extend healthy lifespans. Researchers say that by treating the metabolic and molecular causes of human aging, it may be possible to help people stay healthy into their 70s and 80s. A trio of aging experts calls for moving forward with preclinical and clinical strategies that have been shown to delay aging in animals. In addition to promoting a healthy diet and regular exercise, these strategies include slowing the metabolic and molecular causes of human aging, such as the incremental accumulation of cellular damage that occurs over time.

The researchers, at Washington University School of Medicine in St. Louis, Brescia University in Italy, the Buck Institute for Aging and Research and the Longevity Institute at the University of Southern California, write that economic incentives in biomedical research and health care reward treating disease more than promoting good health. "You don't have to be a mathematician or an economist to understand that our current health care approach is not sustainable. As targeting diseases has helped people live longer, they are spending more years being sick with multiple disorders related to aging, and that's expensive."

It's been difficult to capitalize on research advances to stall aging in people. Most clinicians don't realize how much already is understood about the molecular mechanisms of aging and their link to chronic diseases. And scientists don't understand precisely how the drugs that affect aging pathways work. The time is right for moving forward with preclinical and clinical trials of the most promising findings from animal studies. But challenges abound. The most important change is in mindset. Economic incentives in biomedical research and health care reward treating diseases more than promoting good health. "But public money must be invested in extending healthy lifespan by slowing aging. Otherwise, we will founder in a demographic crisis of increased disability and escalating health care costs."


One part of the mission of the SENS Research Foundation is to help build the next generation of motivated biogerontologists, scientists who see aging and longevity research as a cutting edge field in which there is a tremendous opportunity for both professional growth and the ability to save lives and improve health. These are the presently young people who will be at the height of their careers twenty years from now, leading varied research groups to complete the first comprehensive rejuvenation toolkit and demonstrating robust reversal of aging in mice. These dedicated researchers of the future won't spring forth from nothing, however, in just the same way as widespread support and funding for the defeat of age-related disease won't arrive fully formed from out of the void. It requires a lot of work and planning to nurture a new field of science, and hence we see the existence of funding for programs such as the Summer Scholars, intended to bring together exceptional life science students and given them the opportunity to join the growing SENS research network.

Long-term and short-term, it is networking that makes the world go round. A lot of this is hidden from the outside; funding and progress just seems to happen of its own accord if you read press releases and newspapers. But behind every printed story lie years of connections, relationships, persuasion, and networking between researchers, funding sources, and advocates. Nothing happens that is not a part of a web of connections.

The SENS Research Foundation has its headquarters in the Bay Area, California, and is very much a part of the highly connected communities of aging research, technology talent, and venture capital that exist in that part of the world. There are several world-class institutes focused on the biology of aging in the Bay Area alone, and more in Southern California. The SENS principals move in the same network that links Google Ventures, the aging researchers being hired for the California Life Company initiative, Peter Thiel's initiatives in advocacy and philanthropy, biotech-focused venture firms, and a collection of further eclectic, intelligent, and motivated individuals who believe in the ability of technological progress to change the world for the better. Building new forms of medicine to treat aging, and the SENS engineering approach of damage repair in particular, has always played well with the technology crowd. Many of the early supporters of SENS are technology industry people: entrepreneurs, software developers, hardware designers.

So one consequence of this highly networked environment is that you will see numerous eclectic, intelligent, and motivated individuals involved with the SENS Research Foundation as the years roll by. That has included a number of very young and highly talented folk who started serious research careers in their early teens and went on to become Thiel Fellows, such as Laura Deming and more recently Thomas Hunt:

The Youngest Thiel Finalist: SRF's Thomas Hunt

At just 15, Thomas Hunt became the youngest 20Under20 Finalist selected by Peter Thiel's Foundation to compete for a $100,000 Fellowship and the chance at two years of freedom to pursue his dreams. But Thomas's entire story is even more amazing. He's been conducting research here at SENS Research Foundation in Mountain View since the age of 13.
Before I joined SRF, I started out as a curious and active member of the Do-It-Yourself (DIY) bio community. As a young teen, I got involved with BioCurious in its earliest days to help build the BioCurious lab. I also participated in other organizations like the Health Extension Salon and Thiel Fellowship Under20 Summits before applying for a 20Under20 Fellowship this past year.

Currently I volunteer at SRF four days a week. I spend my time conducting research to understand a poorly understood pathway that plays a key role in cancer cell immortality called alternative lengthening of telomeres, or ALT. I keep current with new developments in my field by reading scientific papers at the cutting edge of ALT work, and I am currently in charge of studying POT1, a protein that could negatively affect ALT activity. I am also performing experiments on cancer cells to test for ALT activity.

When I'm not at SRF, I've designed my own home schooling curriculum, where I get to choose which subjects I want to study. I take local college classes that I feel will assist me in my research goals, like chemistry and public speaking. I love telling people about the latest discoveries in science, and have spoken at The University of California, Santa Cruz (UCSC) about genetic modification.


Aging is a global phenomenon, the spiraling consequences of underlying damage that accumulate in every organ and biological system of the body concurrently. Becoming damaged is a matter of wear and tear; it is a side-effect of the operation of metabolism. Over most of life and for most people at a given age environmental factors make up the largest difference in the pace of aging from individual to individual: who takes care of their health; who becomes fat; who fails to exercise; and so forth. When compared with the differences caused by advances in medical technology, this is small change, however - not something to spend too much time worrying about. Live a sensibly healthy life, and where you do have time and energy for doing more, focus on helping to create new forms of medicine that can break us out of the old traditional length of life, adding decades to healthy life span while preventing and curing the diseases of old age.

Given that aging is a global process, it is comparatively easy to identify correlations between specific forms of dysfunction. If you are further along in failing health in one way, then the odds are very good that the same is true of all every other measure of aging as well. Chronic diseases of aging, and the general loss of function and health that precede them, tend to come in clusters. Everything is failing at once, and then in the end it is just a roll of the dice as to which fatal event happens first. One day people will look back on the ugly realities of aging as we look back on the ugly realities of infectious disease in past centuries. How did they bear it? Why was there any acceptance at all of such widespread death and suffering? Why didn't they try harder to build the medical and other technologies needed to escape that state of affairs?

While you ponder that, here are a few recent examples of correlations in aging and longevity:

Association of exceptional parental longevity and physical function in aging

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited.

The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance and gait speed. Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.

Slow walking speed and memory complaints can predict dementia

"As a young researcher, I examined hundreds of patients and noticed that if an older person was walking slowly, there was a good chance that his cognitive tests were also abnormal. This gave me the idea that perhaps we could use this simple clinical sign - how fast someone walks - to predict who would develop dementia."

[Researchers] reported on the prevalence of motoric cognitive risk syndrome (MCR) among 26,802 adults without dementia or disability aged 60 years and older enrolled in 22 studies in 17 countries. A significant number of adults - 9.7 percent - met the criteria for MCR (i.e., abnormally slow gait and cognitive complaints). While the syndrome was equally common in men and women, highly educated people were less likely to test positive for MCR compared with less-educated individuals. A slow gait is a walking speed slower than about one meter per second, which is about 2.2 miles per hour (m.p.h.). Less than 0.6 meters per second (or 1.3 m.p.h.) is "clearly abnormal."

To test whether MCR predicts future dementia, the researchers focused on four of the 22 studies that tested a total of 4,812 people for MCR and then evaluated them annually over an average follow-up period of 12 years to see which ones developed dementia. Those who met the criteria for MCR were nearly twice as likely to develop dementia over the following 12 years compared with people who did not.

Association of Hearing Impairment and Mortality in Older Adults

Hearing impairment (HI) is highly prevalent in older adults and is associated with social isolation, depression, and risk of dementia. Whether HI is associated with broader downstream outcomes is unclear. We undertook this study to determine whether audiometric HI is associated with mortality in older adults.

Prospective observational data from 1,958 adults ≥70 years of age from the Health, Aging, and Body Composition Study were analyzed using Cox proportional hazards regression. Participants were followed for 8 years after audiometric examination. Mortality was adjudicated by obtaining death certificates. Of the 1,146 participants with HI, 492 (42.9%) died compared with 255 (31.4%) of the 812 with normal hearing. After adjustment for demographics and cardiovascular risk factors, HI was associated with a 20% increased mortality risk compared with normal hearing. Confirmatory analyses treating HI as a continuous predictor yielded similar results, demonstrating a nonlinear increase in mortality risk with increasing HI.


Monday, July 21, 2014

Larger animals have more cells in their bodies, and cancer occurs when one cell suffers the right combination of mutations to run amok, so why is it that animals such as whales do not have higher cancer rates? Here researchers propose a partial answer to that question:

Larger species do not have higher cancer rates than smaller species, an observation known as Peto's paradox, named after the eminent Oxford cancer epidemiologist Sir Richard Peto who first remarked on the phenomenon in the 1970s. "Cancer is caused by errors occurring in cells as they divide, so bigger animals with more cells ought to suffer more from cancer. Put simply, the blue whale should not exist."

Now a study of the genomes of 38 mammal species, ranging in size from the mouse to the blue whale, has resulted in a partial explanation for the paradox - larger animals are just better at eliminating cancer-causing viruses from their DNA. A team of [scientists] analysed the genomes for DNA sequences of endogenous retroviruses (ERVs), which are viruses that are able to integrate their DNA within the DNA of the human chromosomes. The researchers found that there was an inverse relationship between the number of endogenous retroviruses - "relics" of viral infections over many millions of years of evolution - and the overall size of the species in question.

In other words, the bigger the animal, the fewer the number of viral relics found in its genome. The mouse for instance has 3,331 endogenous retroviruses, humans have 1,085 and whales have just 55 viral relics. This is seen as important for Peto's paradox on cancer rates because these retroviruses can jump around within the genome and in doing so trigger those kinds of cancer that are linked with viral infections, such as the T-cell leukaemia. Showing that larger species of animals have fewer ERVs in their genomes indicates that these kinds of viruses must be harmful, otherwise there would be no need to remove them. "Logically we think this is linked to the increased risk of ERV-based cancer-causing mutations and how mammals have evolved to combat this risk. So when we look at the pattern of ERV distribution across mammals it's like looking at the 'footprint' cancer has left on our evolution."

Monday, July 21, 2014

In recent years researchers have discovered that the metabolic response to calorie restriction can extend into following generations, passed along via epigenetic and other mechanisms. The metabolism of descendant individuals is altered from the norm even when they never experience calorie restriction themselves. Data on this effect is harder to establish for humans in comparison to short-lived laboratory species, but it does exist:

Evidence from human famines and animal studies suggests that starvation can affect the health of descendants of famished individuals. Starving women who gave birth during the famine had children who were unusually susceptible to obesity and other metabolic disorders, as were their grandchildren. Controlled animal experiments have found similar results, including a study in rats demonstrating that chronic high-fat diets in fathers result in obesity in their female offspring. But how such an acquired trait might be transmitted from one generation to the next has not been clear.

[Researchers] starved roundworms for six days and then examined their cells for molecular changes. The starved roundworms, but not controls, were found to have generated a specific set of small RNAs. (Small RNAs are involved in various aspects of gene expression but do not code for proteins.) The small RNAs persisted for at least three generations, even though the worms were fed normal diets. The researchers also found that these small RNAs target genes with roles in nutrition.

Since these small RNAs are produced only in response to starvation, they had to have been passed from one generation to another. "We know from other studies that small RNAs can be transported from cell to cell around the body. So, it's conceivable that the starvation-induced small RNAs found their way into the worms' germ cells - that is, their sperm or eggs. When the worms reproduced, the small RNAs could have been transmitted generationally in the cell body of the germ cells, independent of the DNA."

The study also found that the progeny of the starved worms had a longer life span than the progeny of the controls. "We have not shown that the starvation-induced small RNAs were responsible for the increased longevity - it's just a correlation. But it's possible that these small RNAs provided a means for the worms to control the expression of relevant genes in later generations."

Tuesday, July 22, 2014

Chronic infection and inflammation of the gums, peridontitis, is associated with increased risk of atherosclerosis, a clogging of the arteries. This is because inflammation spreads beyond the mouth, and the process of inflammation in artery walls over the long term contributes to the production of plaques of dead cells and metabolic waste. Here researchers look into the details of this link between the two conditions:

Chronic oral infection with the periodontal disease pathogen, Porphyromonas gingivalis, not only causes local inflammation of the gums leading to tooth loss but also is associated with an increased risk of atherosclerosis. Like other gram-negative bacteria, P. gingivalis has an outer layer that consists of sugars and lipids. The mammalian immune system has evolved to recognize parts of this bacterial coating, which then triggers a multi-pronged immune reaction. As part of the "arms race" between pathogens and their hosts, several types of gram-negative bacteria, including P. gingivalis, employ strategies by which they alter their outer coats to avoid the host immune defense.

[The researchers] focused on the role of a specific lipid expressed on the outer surface of P. gingivalis, called lipid A, which is known to interact with a key regulator of the host's immune system called TLR4. P. gingivalis can produce a number of different lipid A versions, and the researchers wanted to clarify how these modify the immune response and contribute to the ability of the pathogen to survive and cause inflammation - both locally, resulting in oral bone loss, and systemically, in distant blood vessels.

They constructed genetically modified strains of P. gingivalis with two distinct lipid A versions. The resulting bacteria produced either lipid A that activated TLR4 (called "agonist") or lipid A that interacted with TLR4 but blocked activation ("antagonist"). Utilizing these strains, they demonstrate that P. gingivalis production of antagonist lipid A renders the pathogen resistant to host bacterial killing responses. This facilitates bacterial survival in macrophages, specific immune cells that normally not only gobble up the bacteria but also "digest" and kill them.

When the researchers infected atherosclerosis-prone mice with the P. gingivalis TLR4 antagonist strain, they found that this exacerbates inflammation in the blood vessels and promotes atherosclerosis. In contrast, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A variations, which demonstrates that there are distinct mechanisms for induction of local versus systemic inflammation.

Tuesday, July 22, 2014

Telomeres are lengths of repeated short DNA sequences that cap the ends of chromosomes. The process of cell division shortens telomeres, and they form a part of the cell division counter that gives most somatic cells an expiration date after which they cease dividing. Telomeres are lengthened by the activity of the enzyme telomerase, which is more active in some cells than others - such as in stem cells, which need long telomeres so that they can divide to produce fresh new long-telomere somatic cells to keep tissues healthy and well-maintained.

When researchers measure telomere length in some specific group of cells, they are taking a snapshot of the blurred results of numerous processes in many cells, such as telomerase activity and pace of cell replacement by stem cells, that are themselves affected by near every aspect of health and environment. The most common measure of average telomere length in white blood cells is very dynamic, for example, rising and falling based on day to day health, even though over a lifetime it tends to decrease. But simple measures of average length tend not to capture these effects well, and the precise details of how a telomere length snapshot is taken make the difference between a result that is meaningless, and has no correlation to health, and a result that does tend to correlate with age, health, and future life expectancy.

So we have results like this one in which researchers run a rigorous study and find no correlation whatsoever between telomere length and mortality risk. You can compare that with animal studies that used a variety of techniques for telomere measurement and number crunching, such as proportion of very short telomeres versus average length, that do show good correlations with life expectancy and health. The sum of all this seems to me that rushing out to have your telomere length measured by one of the new services started in recent years is premature:

Human chromosomes are capped by protective ends called telomeres. These ends are shortened during renewal of tissue and eventually become critically short, causing cells to become senescent or die. It is widely believed that lifestyle features such as smoking, obesity, physical inactivity, and possibly alcohol intake enhance shortening of telomeres. However, strong evidence to support such an interpretation is hard to find. We therefore tested whether these lifestyle factors are associated with telomere length change in 4,576 healthy individuals from the general population.

Individuals had relative telomere length measured twice with a 10-year interval, and were then followed for mortality and morbidity for a further 10 years after the second measurement. We found change in telomere length to be more dynamic than previously believed, as we observed both shortening (in 56%) and lengthening (in 44%) among participants. Contrary to previous beliefs, we found telomere length change to be unaffected by lifestyle factors. Instead, we found the strongest association between past telomere length and age with change in telomere length over 10 years. Also, we found no association between change in telomere length and risk of all-cause mortality, cancer, chronic obstructive lung disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease.

Wednesday, July 23, 2014

Parkinson's disease is characterized by the progressive loss of a small population of dopamine-generating neurons in the brain. This loss happens to everyone, but progresses much faster and further in Parkinson's sufferers, for reasons that are still not fully understood. Here is a speculative paper in which researchers suggest that there are viral and autoimmune mechanisms at work:

Current concepts regarding the pathogenesis of Parkinson's disease support a model whereby environmental factors conspire with a permissive genetic background to initiate the disease. The identity of the responsible environmental trigger has remained elusive. There is incontrovertible evidence that aggregation of the neuronal protein alpha-synuclein is central to disease pathogenesis.

A novel hypothesis of Parkinson's pathogenesis implicates a pathogen acting in the olfactory mucosa and gastrointestinal tract as the inciting agent. In this point-of-view article, we hypothesize that α-synuclein aggregation in Parkinson's disease is an Epstein-Barr virus (EBV)-induced autoimmune phenomenon. Specifically, we have shown evidence for molecular mimicry between the C-terminal region of α-synuclein and a repeat region in the latent membrane protein 1 encoded by EBV.

We hypothesize that, in genetically-susceptible individuals, anti-EBV latent membrane protein antibodies targeting the critical repeat region cross react with the homologous epitope on α-synuclein and induce its oligomerization. We contend that axon terminals in the lamina propria of the gut are among the initial targets, with subsequent spread of pathology to the central nervous system. While at this time, we can only provide evidence from the literature and preliminary findings from our own laboratory, we hope that our hypothesis will stimulate the development of tractable experimental systems that can be exploited to test it. Further support for an EBV-induced immune pathogenesis for Parkinson's disease could have profound therapeutic implications.

Wednesday, July 23, 2014

Aging is no more than damage at the level of cells and tissues and the evolved reactions of biological systems to that damage, not all of them helpful. The pace of damage accumulation is largely determined by lifestyle and environmental factors such as burden of infectious disease and available medical technology over most of a human life span. Only in very old age do common genetic differences rise in importance. Thus if you find that someone at a given chronological age is more frail and is suffering from more evident age-related conditions than their peers, you would expect them to have a shorter remaining life expectancy, since they are more damaged. That is the way it works:

We analyze life expectancy in Medicare beneficiaries by number of chronic conditions [in a] retrospective cohort study using single-decrement period life tables. [The subjects are] Medicare fee-for-service beneficiaries (N=1,372,272) aged 67 and older as of January 1, 2008.

Our primary outcome measure is life expectancy. We categorize study subjects by sex, race, selected chronic conditions (heart disease, cancer, chronic obstructive pulmonary disease, stroke, and Alzheimer disease), and number of comorbid conditions. Comorbidity was measured as a count of conditions collected by Chronic Conditions Warehouse and the Charlson Comorbidity Index.

Life expectancy decreases with each additional chronic condition. A 67-year-old individual with no chronic conditions will live on average 22.6 additional years. A 67-year-old individual with 5 chronic conditions and ≥10 chronic conditions will live 7.7 fewer years and 17.6 fewer years, respectively. The average marginal decline in life expectancy is 1.8 years with each additional chronic condition - ranging from 0.4 fewer years with the first condition to 2.6 fewer years with the sixth condition. These results are consistent by sex and race. We observe differences in life expectancy by selected conditions at 67, but these differences diminish with age and increasing numbers of comorbid conditions.

Thursday, July 24, 2014

Regular readers will know that mitochondrial DNA damage is thought to be an important contributing cause of aging. It can lead to dysfunctional mitochondria that overtake cells and turn them into exporters of damaging reactive compounds, harming both surrounding tissues and important proteins that circulate widely in the body.

This is a fascinating paper that suggests the immune system has evolved to detect the presence of mitochondrial DNA deletions and destroy the cells that harbor those damaged mitochondria. Assuming this holds up there are several ways one could interpret this mechanism: firstly that mitochondrial DNA damage is less important than thought because there are more processes controlling it; or secondly that it is more important because it will lead to increased inflammation and immune system activation, which is a serious issue in later life; and either way thirdly that the age-related decline of the immune system should be considered more important because here is yet another fundamental aspect of aging that it influences.

Mutations in mitochondrial (mt) DNA accumulate with age and can result in the generation of neopeptides. Immune surveillance of such neopeptides may allow suboptimal mitochondria to be eliminated, thereby avoiding mt-related diseases, but may also contribute to autoimmunity in susceptible individuals. To date, the direct recognition of neo-mtpeptides by the adaptive immune system has not been demonstrated.

In this study we used bioinformatics approaches to predict major histocompatibility complex binding of neopeptides identified from known deletions in mtDNA. Six such peptides were confirmed experimentally to bind to HLA-A*02. Pre-existing human CD4+ and CD8+ T cells from healthy donors were shown to recognize and respond to these neopeptides. One remarkably promiscuous immunodominant peptide (P9) could be presented by diverse MHC molecules to CD4+ and/or CD8+ T cells from 75% of the healthy donors tested.

The common soil microbe, Bacillus pumilus, encodes a 9-mer that differs by one amino acid from P9. Similarly, the ATP synthase F0 subunit 6 from normal human mitochondria encodes a 9-mer with a single amino acid difference from P9 with 89% homology to P9. T cells expanded from human peripheral blood mononuclear cells using the B. pumilus or self-mt peptide bound to P9/HLA-A2 tetramers, arguing for cross-reactivity between T cells with specificity for self and foreign homologs of the altered mt peptide.

These findings provide proof of principal that the immune system can recognize peptides arising from spontaneous somatic mutations and that such responses might be primed by foreign peptides and/or be cross-reactive with self.

Looking back in the Fight Aging! archives, I see a paper from a couple of years ago in which researchers link inflammation in aging with mitochondrial damage, but via the mechanism of reactive oxygen species production. That seems worth another look in light of the above recent research.

Thursday, July 24, 2014

Advocacy for the cause of longevity science doesn't have to mean writing or getting up in front of people to give presentations. There are many ways in which you can go about changing the way in which the rest of the world thinks about aging, so as to grow support for rejuvenation research. Here, for example, delivery of the message is via a simple game about achieving actuarial escape velocity, the point past which advances in medical science add more than one year of additional future life expectancy for each year that passes, thus enabling indefinite healthy life spans.

At the moment the present approach to medicine produces a gain of one year every decade in life expectancy at 60, so there is a great deal of work yet to accomplish. That work will only happen rapidly enough to benefit most of those reading this today in an environment of widespread public understanding and support, but that doesn't exist yet either. Hence the need for advocacy:

The premise of LEV: The Game is the same as the aim of those of us who wish to extend our lives without end. One's character is challenged with living for as long as possible and attaining longevity escape velocity by reversing the damage of senescence at a faster rate than it accumulates. Every year in the game, the character receives an allotment of energy points with which to purchase power-ups, such as stem-cell therapies, applications of nano-medicine, cybernetic enhancements, or simple increments of diet and exercise. Each power-up can either increase the remaining expected lifespan, increase the rate at which energy points accumulate (called "productivity" in the game), or reduce the character's rate of bodily decay. The player needs to achieve a delicate balancing of these power-ups to avoid expiring before he/she accumulates enough energy points to purchase the next life-extending advance.

Our ability to achieve indefinite life extension personally will depend on the amount of resources and support from the general public invested in the overcoming of age-related bodily damage. Most people, unfortunately, continue to either be resigned to the inevitability of death, or to argue against the desirability of indefinite longevity due to extremely basic misconceptions. Even apart from the absurdly false boredom argument, overpopulation argument, and "playing God" argument, there is a more basic fallacy - the Tithonus error, which posits that becoming chronologically older necessarily means becoming biologically more decrepit. Yet the only way indefinite longevity could be achieved would be for people to remain biologically young, so that their susceptibility to deadly diseases does not increase beyond that of people in their twenties today. How could longevity advocates get the general public to understand this? Convincing people through arguments alone may often fail, simply because the Dragon-Tyrant of death is so ubiquitous and so overwhelming that many people will grasp at any straw, no matter how flimsy, to avoid being confronted with the grave injustice of their current predicament.

But a game gives a fresh, different, and engaging way to see and experience what indefinite longevity would truly entail. Anyone playing LEV: The Game would quickly see that becoming increasingly frail is no way to increase life expectancy. Your character will die if he/she experiences sufficient biological decay. You will be able to see a graph of the character's remaining life expectancy and the rate at which decay is expected to proceed during the years they have left. If you apply the most effective combinations of power-ups, you will also see the life-expectancy curve shift upward - sometimes slightly, at other times by massive jumps. The latter situation reflects what can happen once humans begin to undergo periodic rejuvenation therapies to remove age-related damage, as posited in Dr. Aubrey de Grey's SENS approach.

Furthermore, LEV: The Game encourages its players to engage in paradigm-shifting thinking about their own future trajectories. Instead of planning for gradual debilitation and eventual death, as most people do today when projecting their careers, retirements, finances, and family lives, a strikingly different mindset can take hold - the quest for perpetual maintenance and a return to youthfulness that may be possible at any chronological age, with sufficient technological advances and vigilance regarding one's health.

Friday, July 25, 2014

This research suggests that some aspects of re-engineering an age-damaged immune system to restore its performance may be easier than expected. It is also supportive of work on immune cell transplant therapies as cancer treatments that has taken place over the past few years, as well as a range of other existing and potential immune therapies:

Researchers have proven for the first time that specific individual cells of the immune system, termed central memory T cells, have all the essential characteristics of adult tissue stem cells. Such cells are capable of perpetuating themselves indefinitely as well as generating diverse offspring that can reconstitute "tissue" function. These findings indicate that it should be possible to fully restore specific immunity to pathogens in patients with a compromised immune system by substitution of small numbers of central memory T cells.

The researchers first established that a high potential for expansion and differentiation in a defined subpopulation, called "central memory T cells," does not depend exclusively on any special source such as bone marrow, lymph nodes, or spleen. This supported but did not yet prove the idea that certain central memory T cells are, effectively, adult stem cells. Further experiments, using and comparing both memory T cells and so-called naive T cells - that is, mature immune cells that have not yet encountered their antigen - enabled the scientists to home in on stem-cell-like characteristics and eliminate other possible explanations.

Step by step, the results strengthened the case that the persistence of immune memory depends on the "stemness" of the subpopulation of T cells termed central memory T cells: Individual central memory T cells proved to be "multipotent," meaning that they can generate diverse types of offspring to fight an infection and to remember the antagonist. Further, these individual T cells self-renew into secondary memory T cells that are, again, multipotent at the single-cell level. And finally, individual descendants of secondary memory T cells are capable of fully restoring the capacity for a normal immune response.

One implication is that future immune-based therapies for cancers and other diseases might get effective results from adoptive transfer of small numbers of individual T cells. "In principle, one individual T cell can be enough to transfer effective and long-lasting protective immunity for a defined pathogen or tumor antigen to a patient. These results are extremely exciting and come at a time when immunotherapy is moving into the mainstream as a treatment for cancer and other diseases. The results provide strong experimental support for the concept that the efficacy and durability of T cell immunotherapy for infections and cancer may be improved by utilizing specific T cell subsets."

Friday, July 25, 2014

Researchers are making progress on a variety of ways to encourage nerve regrowth in mammals where it normally doesn't occur, such as in the aftermath of spinal injuries:

A therapy combining salmon fibrin injections into the spinal cord and injections of a gene inhibitor into the brain restored voluntary motor function impaired by spinal cord injury. In a study on rodents, [researchers] achieved this breakthrough by turning back the developmental clock in a molecular pathway critical to the formation of corticospinal tract nerve connections and providing a scaffold so that neuronal axons at the injury site could grow and link up again.

Axons flourish after the deletion of an enzyme called PTEN, which controls a molecular pathway regulating cell growth. PTEN activity is low during early development, allowing cell proliferation. PTEN subsequently turns on, inhibiting this pathway and precluding any ability to regenerate. Salmon fibrin injected into rats with spinal cord injury filled cavities at the injury site, giving axons a framework in which to reconnect and facilitate recovery. Fibrin is a stringy, insoluble protein produced by the blood clotting process and is used as a surgical glue.

In their study, [the researchers] treated rodents with impaired hand movement due to spinal cord injury with a combination of salmon fibrin and a PTEN inhibitor called AAVshPTEN. A separate group of rodents got only AAVshPTEN. The researchers saw that rats receiving the inhibitor alone did not exhibit improved motor function, whereas those given AAVshPTEN and salmon fibrin recovered forelimb use involving reaching and grasping. "The data suggest that the combination of PTEN deletion and salmon fibrin injection into the lesion can significantly enhance motor skills by enabling regenerative growth of corticospinal tract axons."


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