Fight Aging!

FIGHT AGING! NEWSLETTER
June 30th 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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CONTENTS

• The SENS View on Cell Loss in Aging and How To Reverse It
• American Federation for Aging Research 2013 Annual Report
• A Reminder that Mitochondrial Biochemistry is Complex
• Methuselah Foundation Interviews Robert Langer on the Topic of Tissue Engineering Research
• An Article on the Immortality Project
• Latest Headlines from Fight Aging!
  • A Novel Form of Cancer Immunotherapy
  • Working on the Next Generation of Prototype Artificial Vision
  • The SENS Approach to Mitochondrial Damage in Aging
  • Speculative Calorie Restriction Research in Nematodes
  • A Review of Immunotherapy for Alzheimer's Disease
  • Drug Discovery in Search of Ways to Boost Autophagy
  • A Lower Mortality Rate for Vegetarians
  • Improving the Infrastructure for Therapeutic Transfer of T Cells
  • Longevity Correlates with Childbirth at Later Ages
  • Fasting May Be a Useful Addition to Many Medical Procedures

THE SENS VIEW ON CELL LOSS IN AGING AND HOW TO REVERSE IT
https://www.fightaging.org/archives/2014/06/the-sens-view-on-cell-loss-in-aging-and-how-to-reverse-it.php

Jason Hope is one of the more generous philanthropists to have funded projects in rejuvenation biotechnology carried by under the auspices of the SENS Research Foundation. His funds went towards making a start on breaking down glucosepane cross-links in old tissues, thereby removing its contribution to loss of skin elasticity, arterial stiffening, and other forms of degeneration caused when sugar compounds link proteins together in ways that hamper tissue function. This buildup of cross-links is an important aspect of numerous age-related medical conditions, but in principal it and its effects are reversible - if the glucosepane can just be safely removed.

The challenge here is twofold: firstly that there are few tools in the biotechnology toolkit for working with glucosepane and similar compounds, and secondly that the people involved in most ventures in medical research are not going to break new ground by building tools when there are a thousand other potentially profitable things they could be doing for which the tools already exist. Unfortunately those other profitable activities don't fix the glucosepane problem. This is where the network of researchers, advocates, and philanthropists connected to the SENS Research Foundation really shines: acting together they can find this sort of blockage in research where a comparatively small effort can push a field over the hump and make it much more attractive for development.

In any case, Jason Hope isn't just interested in glucosepane. In recent months he's published a series of articles that covers more of the SENS portfolio of research projects. Aging is a phenomenon caused by a number of fundamental processes, and all of them will have to be addressed in some meaningful way in order to achieve rejuvenation of the old and indefinite postponement of all age-related disease. If any one of the contributing causes of aging were removed as if by magic tomorrow, then the others would still kill us on roughly the same time frame of a normal present day human life span.

In the article quoted below, Hope looks at one of the areas of SENS that I feel needs less help than the others. Numerous different types of important cells are damaged or lost over the course of aging, such as stem cells and long-lived nerve cells, and these must be replaced or repaired to restore function. Fortunately there is an enormously active medical research and development community focused on the manipulation and use of stem cells so as to do just this. These researchers just need to be steered into focusing a little more on aging in the context of their work, but even this is not a huge challenge: all of the most profitable potential applications of cell-based regenerative medicine involve the treatment of age-related conditions. The stem cell community is thus already forced into the position of needing to figure out how to overcome the effects of aging on stem cells - and eventually on cells in general - in order to reliably treat the majority of their potential patients.

This is of course not to say that everything is rosy, and that there are no lagging areas that need attention, but the situation is far better than is presently the case for most of the rest of the technologies that need to be produced to form a near future comprehensive toolkit of rejuvenation treatments. One area in which the SENS Research Foundation is intervening to accelerate progress is that of thymic regeneration, restoring an old thymus to its youthful structure and function and thus boost immune system activity. This is something that does not attract as much attention as it might from the broader research community perhaps because it is natural for the thymus to atrophy quite early in life, and there is a strong - and frankly rather silly - bias in much of the medical establishment against anything that might be perceived as enhancement.

SENS Research Foundation Investigates Cell Loss

In many tissues, the body tries to replace lost cells quickly with specialized, tissue-specific stem cells. Exercise can stimulate the division of specialized stem cells in muscle tissue, for example. This works well in young bodies but over time, the degenerative process of aging makes older stem cells less effective at repairing damaged cells. Additionally, some tissues are not equipped with such specialized stem cells: in such tissues, the cells a person has in early adulthood are all he or she has to last a lifetime.

This is especially significant when long-lived tissue, like that in the brain, heart and muscles begins to lose cells and the ability to function well. Decreased cell count and poor function in the brain causes neuron loss that contributes to cognitive decline, dementia, and loss of muscle coordination. Diminished cell count causes skeletal muscles to weaken and fail to respond to exercise. Cell loss in heart tissues results in poor cardiovascular function associated with old age and invites a host of cardiac conditions.

Nowhere, perhaps, is cell loss more devastating than in the thymus. The thymus is a pyramid-shaped organ in the chest, located between the breastbone and the heart. Before birth, throughout childhood and into puberty, the thymus is instrumental in the production and maintenance of a specific type of white blood cell that protects the body from viruses and other threats. This white blood cell, known as T-lymphocytes or T cells, is essential to human immunity. It circulates around the body, searching for cellular abnormalities and infections.

The thymus begins to shrink after puberty, and its functional tissue is slowly replaced with fat. The organ slows T-cell production as it shrinks. This leaves the aging person increasingly vulnerable to infectious diseases, including influenza and pneumonia. Engineering a youthful thymus, therefore, would help restore a youth immune system.

SENS Research Foundation funding is helping Dr. John Jackson's lab at the Wake Forest University Institute for Regenerative Medicine investigate the potential to engineer a new thymus gland to restore a youthful and vital immune function. SENS Research Foundation continues to work towards reversing the detrimental effects of aging that cause widespread and unnecessary debilitation and misery among the older population. Their advances in preventing cell loss in vital organs can vastly improve the lives of the aging population that now inhabits planet earth.

AMERICAN FEDERATION FOR AGING RESEARCH 2013 ANNUAL REPORT
https://www.fightaging.org/archives/2014/06/american-federation-for-aging-research-2013-annual-report.php

The American Federation for Aging Research (AFAR) has been around for a while, and best represents the gently-gently approach to moving forward towards greater human longevity. They speak to an audience of researchers who are largely disinterested in working to extend healthy life, an attitude typical of the silent majority in the field, with an eye to moving more of them into the so far smaller category of researchers who support and actively engage in efforts to modestly extend life. This sort of work is typified by initiatives aimed at the development of age-slowing drugs, such as calorie restriction mimetics or compounds that influence mTOR.

From my point of view this approach to longevity science is a slow boat to nowhere, highly unlikely to produce any end result of great utility to old people: slowing aging just a little bit is of very limited use when you are already old. Folk such as myself who support progress towards SENS-like rejuvenation treatments based on repair of the underlying causes of aging have to remember that we are still the upstart minority, however. Despite tremendous growth in support for SENS inside and outside the scientific community over the past decade, it is still the case that work on drug development to slightly slow aging through altering the operation of metabolism receives far, far more funding and attention. In turn work on merely studying aging, with no attempt or interest in doing anything to treat aging as a medical condition, receives yet again far greater funding and attention than does drug development aimed at modestly slowing aging. The times are changing, but this is the present picture.

In the charitable viewpoint, organizations such as AFAR are putting a great deal of effort into raising the waters for longevity science. They are helping to create an environment in which it is easier for more ambitious scientific goals - such as the development rejuvenation therapies in the SENS model - to find support. The principals at AFAR certainly do their part to collaborate with more ambitious organizations such as the SENS Research Foundation. A counterpoint to this is that if we all sat around and adopted the gently-gently approach of advocating small, incremental advances, then going for small incremental advances would be the outside, extreme position in the exchange of ideas. Then nothing would happen, as the middle conservative position would be to do just about nothing. Too many decades have been spent doing next to nothing to treat aging, even in the presence of numerous promising biotechnologies that can be brought to bear on the challenge.

In any case, here is a pointer to the latest AFAR annual report, which is available as a PDF. Make your own mind up after taking a look at the pitch. You might also look over a separate publication from late last year on the topic of the Longevity Dividend, which is a flagship initiative of political advocacy that aims to steer much more US government funding into the sorts of research programs mentioned above.

American Federation for Aging Research 2013 Annual Report and Financials

This year, the American Federation for Aging Research strengthened and supported the field of aging research through a range of public programs and publications to engage investigators, industry leaders, and consumers with the latest biomedical research that will enable us all to live healthier, longer. Understanding the biology of aging is key to unlocking the etiology of the chronic diseases of old age. This outcome promises many medical and economic benefits to society and individuals alike.

Yet, for far too long, aging research has been separated from chronic disease research. But a promising shift in the scientific community's approach began taking shape in 2013: amid newfound attention to aging research, the interdisciplinary commitment to understanding the relationship between aging and age-related diseases, known as geroscience, has emerged. In the past 10 years, geroscience has yielded discoveries that once might have sounded unimaginable. Today, this growing scientific approach has profound implications for medicine and healthy aging. One of the most significant is the ability to modify the aging process in laboratory animals through a variety of interventions, including caloric restriction, pharmaceuticals, and genetic manipulation.

Scientists now believe they will soon be able to delay or even prevent the diseases of old age in humans. Indeed, for many years, geroscientific research by AFAR-affiliated investigators nationwide has been providing increasing evidence that studying aging and chronic disease together yields mutually beneficial results.

A REMINDER THAT MITOCHONDRIAL BIOCHEMISTRY IS COMPLEX
https://www.fightaging.org/archives/2014/06/a-reminder-that-mitochondrial-biochemistry-is-complex.php

Cells are very dynamic entities. They don't sit still, and they and their components are constantly in a state of flux. A cell is a sack of things that can be listed, understood and counted, sure, but at any given moment in time numerous parts are being dismantled and new parts created from raw materials. Levels of proteins ebb and flow as they are formed and destroyed.

All of this dynamism places an interesting spin on attempts to understand and then repair aspects of aging that depend on malfunctioning cellular components. Within cells there exist a range of important structures called organelles, some of which number in the hundreds or thousands, such as mitochondria. These are themselves very dynamic entities, busy with the process of dividing, fusing, and exchanging proteins between one another. Damage in mitochondria is not a static thing, as those damaged proteins can be shared around, and damaged and undamaged mitochondria can fuse to create an organelle that works. The only forms of damage that can last are those that provide some survival advantage to a mitochondrion, such as the ability to evade cellular quality control mechanisms, or wherein the particular form of damage can overwhelm undamaged variants.

Most interesting of all cells can even pass around mitochondria, which is a great way for potentially harmful forms of persistent or replicating damage to spread and thus have a greater detrimental effect than would otherwise be the case. The present view of mitochondria in aging is that there are indeed forms of damage to mitochondrial DNA that cause dysfunction in mitochondrial function that is both harmful and leads to the spread of damaged mitochondria because they evade quality control mechanisms. Thus the damaged forms can divide and multiply to take over a cell - and if exported elsewhere they will take over that cell as well. This doesn't actually appear to happen to more than a small fraction of cells over a human life span, but that small fraction is enough to cause great harm to tissues, blood vessels, and more.

The research linked below is another reminder that mitochondrial biochemistry is complicated, delving further into how mitochondrial pass around between cells. In this case it definitely looks like a vector by which bad mitochondria of the sort we care about could spread more than they otherwise would. Any approach to repairing mitochondria in aged tissue must thus be sufficiently comprehensive to ensure that all these tricks have no effect: it cannot matter how dynamic or widely traveled a mitochondrion is, the treatment must either repair it along with all of its peers or destroy it, leaving none of the damage behind to spread once more.

Getting Rid of Old Mitochondria

It's broadly assumed that cells degrade and recycle their own old or damaged organelles, but [researchers] have discovered that some neurons transfer unwanted mitochondria - the tiny power plants inside cells - to supporting glial cells called astrocytes for disposal. The [findings] suggest some basic biology may need revising, but they also have potential implications for improving the understanding and treatment of many neurodegenerative and metabolic disorders.

"It does call into question the conventional assumption that cells necessarily degrade their own organelles. We don't yet know how generalized this process is throughout the brain, but our work suggests it's probably widespread. The discovery of a standard process for transfer of trash from neuron to glia will most likely be very important to understanding age-related declines in function of the brain and neurodegenerative or metabolic disorders. We expect the impact to be significant in other areas of biomedicine as well."

Transcellular degradation of axonal mitochondria

Mitochondria are organelles that perform many essential functions, including providing the energy to cells. Cells remove damaged mitochondria through a process called mitophagy. Mitophagy is considered a subset of a process called autophagy, by which damaged organelles are enwrapped and delivered to lysosomes for degradation. Implicit in the categorization of mitophagy as a subset of autophagy, which means "self-eating," is the assumption that a cell degrades its own mitochondria. However, we show here that in a location called the optic nerve head, large numbers of mitochondria are shed from neurons to be degraded by the lysosomes of adjoining glial cells. This finding calls into question the assumption that a cell necessarily degrades its own organelles.

METHUSELAH FOUNDATION INTERVIEWS ROBERT LANGER ON THE TOPIC OF TISSUE ENGINEERING RESEARCH
https://www.fightaging.org/archives/2014/06/methuselah-foundation-interviews-robert-langer-on-the-topic-of-tissue-engineering-research.php

The Methuselah Foundation is publishing a series of interviews in recent weeks related to their activities in support of the research community. The overall purpose of the Foundation is to accelerate progress towards the defeat of aging, but since spinning off the Strategies for Engineered Negligible Senescence (SENS) research initiatives into the SENS Research Foundation, the Methuselah Foundation staff have focused most of their efforts on tissue engineering, with a side-helping of numerous other projects related to aging research and biotechnology. The Foundation was one of the early investors in the bioprinting venture Organovo, for example, and has some influence behind the scenes in the regenerative medicine research community thanks to the New Organ initiative.

Here is an interview with Robert Langer, one of the luminaries of the field of tissue engineering. Some things are always true in the sciences, one being that there is never enough funding for any given research to progress at the best possible pace. There is always work for advocates and fundraisers, and the delivery of more funding can make a real difference. This is just as true in comparatively wealthy fields such as tissue engineering as it is for their poorer cousins such as biogerontology. Researchers who work on aging and longevity would be ecstatic with the level of attention and funding enjoyed by the stem cell research community, and the chance to experience resource issues at that higher level, but in the end every lab does less than its researchers would like to achieve. Most people don't value medical research in the slightest, and that fact is reflected by the vanishingly narrow slice of total economic activity that is devoted to building better treatments and healthier lives.

On Taking Risks and Thinking Big

MF: In your mind, what is the most promising work going on these days in tissue engineering?

Langer: I think there's a lot of it - everything from IPS cells to stem cells to new materials. There's a lot of very good basic and applied work going on. People are trying to understand and design bioreactors, factors that affect cell growth, new kinds of biomaterials, decellularized constructs. There are all kinds of animal and clinical trials going on. And then in each particular area, I think there's been exciting work - skin, lung, eyes, kidneys, pancreas, vocal cords, spinal cords, etc. There's just a tremendous amount of good work being done.

MF: You've founded and been involved with a lot of biotech companies. What have been the biggest challenges to success, especially in the U.S.?

Langer: The key is raising money, because it's just so incredibly expensive. I think they estimate now that it costs well over a billion dollars to create a new drug. So raising money is crucial. You also have to have mitigation strategies for things that don't work out. You don't get that many shots on goal. Doing good science and having good intellectual property are the foundation, but anything in the medical area is a very, very expensive proposition. It's not like the internet.

MF: Are you happy with the amount of funding that tissue engineering is receiving?

Langer: No, I think it needs a lot more. To me that's a huge issue.

MF: How do we change that situation?

Langer: Well, it's very hard. For example, I think what you're doing with New Organ is great, but you're doing it on the back end, and the problem is that we need more funding on the front end. Government grants are really the key, and it's very hard to get them.

MF: The philanthropic sector seems to be underfunding these areas as well, and has been for some time.

Langer: I think that's probably fair. I would agree with that.

MF: Why do you think that is? For example, when I look at the Giving Pledge signers list - 100 plus billionaires committing 50% or more of their net worth toward charity - it's hard to find many of them who are allocating funds toward tissue engineering or regenerative medicine.

Langer: I think people do things on a fairly disease-specific basis. Cancer and heart disease are still the number one killers, and people usually support things they've seen close relatives die from.

It is worth noting that Langer is very much a part of the governmental medical research edifice, and thus this is where his biases lie when thinking about large-scale strategic funding of his field. Even in the US public funds probably make up only a third or so of all research funding in the life sciences, however. Government funds are much more easily measured and thus much more frequently discussed by the media than is the case for private for-profit and philanthropic funding efforts, but they are not the whole story.

From what I've seen over the years if you want to see radical change in research, it will always come from philanthropy. Even those programs viewed as being largely governmental receive a great deal of support from philanthropists, who donate to fill the gaps where more adventurous work must be undertaken. The controlling institutions of public funding for medical research are very, very risk averse and resources are usually only available for the most incremental and certain late stages of the research process. All of the early, more speculative work is funded by other sources.

AN ARTICLE ON THE IMMORTALITY PROJECT
https://www.fightaging.org/archives/2014/06/an-article-on-the-immortality-project.php

The Immortality Project has been around for a couple of years, a modestly sized fund for academics that intends to make awards spanning everything from the hard life sciences to philosophy and theology. The central theme is in fact immortality, in any of its varying meanings, though it is pretty clear that the driving impulse here is religious rather than scientific. In that it is perhaps an unwelcome echo of an earlier age, something you'd expect to see undertaken by contemporaries of Isaac Newton, those with only one foot set into the Age of Enlightenment, and for all the wrong reasons.

I'm still of the mind that this project is something of a poisoned chalice. It does fund actual science, such as investigations into the biology of hydra with an eye to determining whether physical immortality exists in the natural world. There are few species such as hydra where the possibility of agelessness exists, but it isn't completely straightforward to pin that down to whether it is in fact the case or just looks a lot like it for a few years. It isn't as though you can wait for an indefinite period of time to check, and few scientists even study this question in the first place. Funding is better than no funding. But this funding comes from an organization that is about to embark on paying theologians to generate more nonsense about angels on the head of a pin, and other, similarly futile undertakings from ethicists that have absolutely nothing to do with advancing actual, concrete, actionable human knowledge. The organization will be trying to paint a picture with all of this, mixing up rigorous science with religious and secular fictions, and that certainly rubs me the wrong way.

Still, money has no provenance, and knowledge gained is knowledge gained. But I am concerned about the long-term effects of this sort of project. I noticed an article on this topic today:

Living Forever, the Right Way

But if mankind can become immortal - and, granted, that's a big "if" - what will it mean? What would a world filled with people who never age look like? Will immortality damage the environment and deepen the class divide? Is the immortal life even a life worth living?

One of the philosophers looking for answers to some of these tough questions is John Martin Fischer, a UC Riverside professor best know for his work on free will and determinism. He is leading the Immortality Project, an ambitious and first-of-its-kind endeavor fueled by a $5 million grant from the John Templeton Foundation. The project will eventually involve dozens of scientists, philosophers, and theologians.

While not yet fully scaled, the project's biological sciences component, which will look to the natural world for clues on how to extend human life, is well underway. Last June, Fischer and a panel of judges announced ten winners of the Immortality Project's $250,000 research grants (the philosophical and theological grants will be awarded this June). One winner was Dr. Daniel Martínez, a world-leading expert on the hydra, a multicellular fresh water organism. Some sub-species of hydra are capable of regenerating themselves - "almost as if they were immortal," Fischer says - while others cannot. Martínez is trying to figure out why. "He's doing this with an eye to figuring possible ways that this could apply to human longevity and possibly human immortality," Fischer says.

There is also plenty of room for innovation regarding the ethics of immortality; experts are looking at everything from examinations of near-death experiences to comparative religious ideas about the afterlife to gain a better understanding of the phenomenon. By the time the project concludes in 2015, Fischer hopes to have set the foundation for a discussion about potential criteria for ethical long-term living. Call it a life-hack for immortality - because it's one thing to live forever, and another to live forever well.

"Innovation" is not a word I'd apply to ethics, the secular theology of our times. It must be a pleasant job to be paid to make up new myths that will be used by believers to justify interference with the process of saving lives through better medicine. That said, it is way too early for anyone to be spending large sums of money agonizing over potential, not yet actual, perhaps nonexistent moral issues relating to greatly enhanced human longevity. We're all still dying here and now, today, on a short timeframe, and where are the establishment foundations spending money to address the moral aspects of that important concern? Meanwhile the medical research projects that might put a halt to aging and age-related disease in the decades ahead are very poorly funded indeed. At this time $5 million would fund a full year of SENS research and advocacy, for example.

But it isn't news that priorities are badly askew in this world of ours.

LATEST HEADLINES FROM FIGHT AGING!

A NOVEL FORM OF CANCER IMMUNOTHERAPY
Monday, June 23, 2014
https://www.fightaging.org/archives/2014/06/a-novel-form-of-cancer-immunotherapy.php

The immune system is very complex and one of the least understood areas of our biology, which is reflected in the presently poor knowledge of the causes of autoimmune disorders and lack of effective treatment options. There is a lot of work taking place on manipulating the immune system to attack cancer, however, and this and other work on immunity will in the years ahead establish the understanding that is presently lacking. This research is an example of the type, and may ultimately turn out to be more valuable for what it reveals about the immune system rather than its use in cancer treatment:

A class of drug currently being used to treat leukaemia has the unexpected side-effect of boosting immune responses against many different cancers. The drugs, called p110δ inhibitors, have shown such remarkable efficacy against certain leukaemias in recent clinical trials that patients on the placebo were switched to the real drug. Until now, however, they have not been tested in other types of cancer.

The team showed that inhibiting p110δ in mice significantly increased cancer survival rates across a broad range of tumour types, both solid and haematological cancers. For example, mice in which p110δ was blocked survived breast cancer for almost twice as long as mice with active p110δ. Their cancers also spread significantly less, with far fewer and smaller tumours developing.

"When we first introduced tumours in p110δ-deficient mice, we expected them to grow faster because p110δ is important for the immune system. Instead, some tumours started shrinking. When we investigated this unexpected effect, we found that p110δ is especially important in so-called regulatory T cells which are suppressive immune cells that the tumours engage to protect themselves against immune attack. Our work shows that p110δ inhibitors can shift the balance from the cancer becoming immune to our body's defences towards the body becoming immune to the cancer, by disabling regulatory T cells. This provides a rationale for using these drugs against both solid and blood cancers, possibly alongside cancer vaccines, cell therapies and other treatments that further promote tumour-specific immune responses."

WORKING ON THE NEXT GENERATION OF PROTOTYPE ARTIFICIAL VISION
Monday, June 23, 2014
https://www.fightaging.org/archives/2014/06/working-on-the-next-generation-of-prototype-artificial-vision.php

Artificial vision devices are presently very crude: grids of electrodes embedded in the retina that can stimulate retinal cells to create the appearance of a pattern of glowing dots based on what a camera sees. This is enough to pick out letters, navigate a room, or distinguish faces with practice, which is a big step up from being absolutely blind. These are still prototypes, however, steps on the way to better things. Researchers are laying the groundwork for more a subtle integration between microelectronic devices and retinal cells:

Just 20 years ago, bionic vision was more a science fiction cliché than a realistic medical goal. But in the past few years, the first artificial vision technology has come on the market in the United States and Western Europe, allowing people who've been blinded by retinitis pigmentosa to regain some of their sight. While remarkable, the technology has its limits. "It's very exciting for someone who may not have seen anything for 20-30 years. It's a big deal. On the other hand, it's a long way from natural vision."

Although much of visual processing occurs within the brain, some processing is accomplished by retinal ganglion cells. There are 1 to 1.5 million retinal ganglion cells inside the retina, in at least 20 varieties. Natural vision - including the ability to see details in shape, color, depth and motion - requires activating the right cells at the right time. The new study shows that patterned electrical stimulation can do just that in isolated retinal tissue. In laboratory tests, researchers [focused] their efforts on a type of retinal ganglion cell called parasol cells. These cells are known to be important for detecting movement, and its direction and speed, within a visual scene. When a moving object passes through visual space, the cells are activated in waves across the retina.

The researchers placed patches of retina on a 61-electrode grid. Then they sent out pulses at each of the electrodes and listened for cells to respond, almost like sonar. This enabled them to identify parasol cells, which have distinct responses from other retinal ganglion cells. It also established the amount of stimulation required to activate each of the cells. Next, the researchers recorded the cells' responses to a simple moving image - a white bar passing over a gray background. Finally, they electrically stimulated the cells in this same pattern, at the required strengths. They were able to reproduce the same waves of parasol cell activity that they observed with the moving image.

"There is a long way to go between these results and making a device that produces meaningful, patterned activity over a large region of the retina in a human patient. But if we can handle the many technical hurdles ahead, we may be able to speak to the nervous system in its own language, and precisely reproduce its normal function."

THE SENS APPROACH TO MITOCHONDRIAL DAMAGE IN AGING
Tuesday, June 24, 2014
https://www.fightaging.org/archives/2014/06/the-sens-approach-to-mitochondrial-damage-in-aging.php

It is always good to more respectful attention given to the Strategies for Engineered Negligible Senescence (SENS) approach to rejuvenation treatments. Rendering us immune to mitochondrial DNA damage and its consequences is just one of a number of future therapies that will be needed to reverse all of the underlying causes of aging, but in and of itself this is perhaps the most technically interesting of the biotechnologies adopted and advocated by SENS:

In this fast-paced talk by Dr. Aubrey de Grey, we hear about a breathtakingly radical approach to forestalling aging, which (in a nutshell) involves moving all remaining mitochondrial genes into the nuclear DNA, so that mutations in mitochondrial DNA, per se, are rendered irrelevant. This technique of "obviation" of mitochondrial-DNA breakdown isn't a new idea (it's been around for at least 30 years). What's new is that, technologically, we're in a position to make it happen.

Most mitochondrial genes are, of course, already in the nucleus. The majority of scientists accept that mitochondria got their start as bacterial endosymbionts; a long-ago ancestor of today's alphaproteobacteria took up residency in an anaerobe. The anaerobe provided the invading bacterium with a nutrient-rich environment in which to live, while the bacterium provided oxygen-detoxification services (and a lot of adenosine triphosphate) to the host. Most likely, the invading bacterium had around 1,500 genes. Over time, ~500 redundant genes were lost and the remaining 1,000 or so migrated to the host cell's nuclear DNA (a much safer environment for DNA than the mitochondrion), leading to the present-day situation where (human) mitochondria have an extremely small circular chromosome encoding just 13 proteins. But we know mitochondria actually contain around 1,000 different proteins, most of which are encoded in nuclear genes.

The majority of mitochondrial genes (in the nucleus) encode proteins that are made in cytoplasm and imported into the mitochondrion. For import, proteins must be in an unfolded state. Some proteins (the most hydrophobic ones) are actually made on the surface of the mitochondrion and slurped into the interior of the mitochondrion as they're being made. Folding of the proteins then takes place inside the organelle.

Can the remaining 13 mitochondrial protein genes be moved to the nucleus? If we succeed in doing that, will cells live longer? What technical obstacles remain? What progress has been made? These and other questions are addressed in Aubrey de Grey's talk, which is well worth a listen.

SPECULATIVE CALORIE RESTRICTION RESEARCH IN NEMATODES
Tuesday, June 24, 2014
https://www.fightaging.org/archives/2014/06/speculative-calorie-restriction-research-in-nematodes.php

Calorie restriction extends life and slows progression of near all measurable aspects of aging in near all species tested to date. The underlying mechanisms are inherited from the deep evolutionary past and are therefore very similar even between yeast, nematode worms, mice, and humans. One of the most interesting things about the calorie restriction response is that researchers can study nematodes and then have a fair expectation that much of what is learned will have some relevance to human biochemistry.

There are of course limits to the degree to which one can take findings in lower animals and expect them to hold up in humans. Nematodes for example have a dauer stage in growth that they enter and exit based on environmental circumstances: it is a form of stasis in which they can survive for great lengths of time in comparison to their normal life span. Effects that involve the dauer stage are unlikely to be of any great relevance to higher species that do not have this capability, however. So I think it is very speculative that this research will have any great application to human metabolism, for all that it is well crafted:

Organisms in the wild often face long periods in which food is scarce. This may occur due to seasonal effects, loss of territory, or changes in predator-to-prey ratio. During periods of scarcity, organisms undergo adaptations to conserve resources and prolong survival. When nutrient deprivation occurs during development, physical growth and maturation to adulthood is delayed. These effects are also observed in malnourished individuals, who are smaller and reach puberty at later ages.

Developmental arrest in response to nutrient scarcity requires a means of sensing changing nutrient conditions and coordinating an organism-wide response. How this occurs is not well understood. We assessed the developmental response to nutrient withdrawal in the nematode worm Caenorhabditis elegans. By removing food in the late larval stages, a period of extensive tissue formation, we have uncovered previously unknown checkpoints that occur at precise times in development. Development progresses from one checkpoint to the next. At each checkpoint, nutritional conditions determine whether animals remain arrested or continue development to the next checkpoint.

Diverse tissues and cellular processes arrest at the checkpoints. Insulin-like signaling and steroid hormone signaling regulate tissue arrest following nutrient withdrawal. These pathways are conserved in mammals and are linked to growth processes and diseases. Given that the pathways that respond to nutrition are conserved in animals, it is possible that similar checkpoints may also be important in human development.

A REVIEW OF IMMUNOTHERAPY FOR ALZHEIMER'S DISEASE
Wednesday, June 25, 2014
https://www.fightaging.org/archives/2014/06/a-review-of-immunotherapy-for-alzheimers-disease.php

Why build a completely new method of removing unwanted proteins or destroying unwanted cells, when a system capable of these tasks already exists in the body? That is the idea behind the many different forms of immune therapy, technology platforms that will come to be commonplace in medicine over the next few decades. Here is an open access review of the recent past and near future approaches to enlisting a patient's immune system to treat Alzheimer's disease:

Vaccination has been an instrument in the tool chest of the clinician since the late 18th century when Edward Jenner first used the related cowpox virus to immunize patients against small pox. The basic concept of active immunization is to prime the immune system to recognize an antigen as a foreign protein in order to mount a response against it. It has only been recently that investigators have attempted to utilize the human immune system to rid the body of potentially harmful or toxic proteins that are endogenously produced.

Alzheimer's disease (AD) is an incurable, progressive, neurodegenerative disorder affecting over 5 million people in the US alone. This neurological disorder is characterized by widespread neurodegeneration throughout the association cortex and limbic system caused by deposition of Aβ resulting in the formation of plaques and tau resulting in the formation of neurofibrillary tangles. Active immunization for Aβ showed promise in animal models of AD; however, the models were unable to predict the off-target immune effects in human patients. A few patients in the initial trial suffered cerebral meningoencephalitis.

Recently, passive immunization has shown promise in the lab with less chance of off-target immune effects. Several trials have attempted using passive immunization for Aβ, but again, positive end points have been elusive. The next generation of immunotherapy for AD may involve the marriage of anti-Aβ antibodies with technology aimed at improving transport across the blood-brain barrier (BBB). Receptor mediated transport of antibodies may increase central nervous system exposure and improve the therapeutic index in the clinic.

DRUG DISCOVERY IN SEARCH OF WAYS TO BOOST AUTOPHAGY
Wednesday, June 25, 2014
https://www.fightaging.org/archives/2014/06/drug-discovery-in-search-of-ways-to-boost-autophagy.php

There is a wealth of evidence to show that benefits to health and longevity result from increased levels of autophagy in various species. Autophagy refers to processes of cellular housekeeping that remove damaged components, and which have been found to operate with greater enthusiasm as a result of a range of different interventions in laboratory animals that increase life span and slow the progression of aging. Indeed, some researchers believe that increased autophagy is an important contribution to all of these longevity-enhancing approaches.

Given this it is surprising to see so little effort going towards drug discovery with safely increased autophagy as the primary target. As is usually the case, where drug discovery is undertaken, efforts are first focused on repurposing existing drugs that are already approved, even if the effects are marginal. This is because it costs much less to try to obtain regulatory approval for a new use of an existing drug than to push through a completely new medical technology - one of the many ways in which medical regulation distorts the research process in the direction of deliberately aiming for inferior results and slower progress towards new knowledge.

Aging has been defined as a gradually decreasing ability to maintain homeostasis and increasing risk to die. Growing evidence supports malfunctioning with age of quality control system. At an older age, accumulation of altered macromolecules and membranes may impair cell functioning; accumulation of altered mitochondria and peroxisomes may boost the yield of ROS per unit of produced energy and accelerate the aging process.

Evidence was produced that autophagy, an essential part in cell housekeeping during fasting, may help removal of altered membranes, mitochondria and peroxisomes selectively and account for the antiaging effects of caloric restriction. Stimulation of autophagy may improve innate and adaptive immunity; decrease the risk of myopathy, heart disease, liver disease, neurodegeneration and cancer; and retard aging. Functioning of autophagy may decline in well fed adults and is almost negligible at older age. Induction of autophagy may result in "cleaner cells" lower in oxidative status and more resistant to injury and disease.

The administration of antilipolytic drugs to fasted animals was shown to intensify autophagy in a physiologically appropriate manner, to enhance submaximal antiaging effects of low level of caloric restriction, to rapidly rescue older cells from the accumulation of altered mtDNA and older peroxisomes, to increase urinary 8-OHdG levels, and counteract the age-related hypercholesterolemia in rodents. In conclusion, benefits of long-lasting stimulation of autophagy and protein and organelle turnover shows that antilipolytic drugs might find a novel therapeutic application in antiaging medicine.

A LOWER MORTALITY RATE FOR VEGETARIANS
Thursday, June 26, 2014
https://www.fightaging.org/archives/2014/06/a-lower-mortality-rate-for-vegetarians.php

Studies show that vegetarians tend to have modestly lower mortality rates, but as for all such observations of human populations there is plenty of room to debate why this is the case. All the normal arguments can be deployed: that a vegetarian diet tends to result in a lower calorie intake and thus less excess fat tissue, that it is more often practiced by people who are more health-conscious in the first place, that it is associated with greater wealth and education, that it results in a lower intake of dietary advanced glycation end products, and so forth. But which of those factors are more important? Therein lies the question.

The development of better medical technologies in the future has the goal of making all of this sort of debate over health practices irrelevant. Rejuvenation biotechnology and other forms of new medicine should render it moot as to how you lived your life: the benefits provided to health and longevity will be enormous in comparison to those derived by living well. But we are not there yet, and there are decades yet to get past if we want to benefit from the rejuvenation treatments presently in very early development. These research press materials are an odd mix of environmentalist and health concerns, and I point it out for the latter, not the former:

The mortality rate for non-vegetarians was almost 20 percent higher than that for vegetarians and semi-vegetarians. On top of lower mortality rates, switching from non-vegetarian diets to vegetarian diets or even semi-vegetarian diets also helps reduce greenhouse gas emissions. The vegetarian diets resulted in almost a third less emissions compared to the non-vegetarian diets. Modifying the consumption of animal-based foods can therefore be a feasible and effective tool for climate change mitigation and public health improvements, the study concluded. "The takeaway message is that relatively small reductions in the consumption of animal products result in non-trivial environmental benefits and health benefits."

The study drew data from the Adventist Health Study, which is a large-scale study of the nutritional habits and practices of more than 96,000 Seventh-day Adventists throughout the United States and Canada. The study population is multi-ethnic and geographically diverse. "The study sample is heterogeneous and our data is rich. We analyzed more than 73,000 participants. The level of detail we have on food consumption and health outcomes at the individual level makes these findings unprecedented." The analysis is the first of its kind to use a large, living population, since previous studies relating dietary patterns to greenhouse gas emissions and health effects relied on simulated data or relatively small populations to find similar conclusions. "To our knowledge no studies have yet used a single non-simulated data set to independently assess the climate change mitigation potential and actual health outcomes for the same dietary patterns."

IMPROVING THE INFRASTRUCTURE FOR THERAPEUTIC TRANSFER OF T CELLS
Thursday, June 26, 2014
https://www.fightaging.org/archives/2014/06/improving-the-infrastructure-for-therapeutic-transfer-of-t-cells.php

I suspect that we'll see spreading use of immune cell transfer therapies in the years ahead. The time is right for it: stem cell researchers are continually improving their ability to generate cells to order, knowledge of how the immune system works in detail is growing, and so is the understanding of just how important immune system decline is in aging. Somewhere between today and a future in which an age-damaged immune system can be completely restored to youthful function lies a span of decades in which regular infusions of tailored immune cells are a routine part of older life, a treatment that temporarily enhances immune system function across the board, or which can be used to attack specific targets such as an infection or a cancer.

For this to come to pass the infrastructure for such therapies must improve, becoming more efficient, more reliable, and much less costly than is presently the case. This is happening now, step by step, such the progress cited in this article. It is aimed at use for transplant patients, but should be relevant to a range of similar future applications:

Therapeutic transfer of virus-specific T cells to immunocompromised patients can help battle life-threatening infections, but the process for generating such cells is lengthy and laborious. A [recently published] paper suggests a speedy alternative. Ten days in culture was all it took for researchers to generate multivirus-specific T cells that, when transferred into transplant patients, could wipe out multiple infections at once. "The original manufacturing processes were really convoluted and complicated." They involved using live viruses to infect donor B cells, and then using those cells to stimulate T cells. "With all that, we are talking 10 to 12 weeks of manufacturing." Furthermore, the live viruses in question are considered biohazards. When a procedure is that difficult and hazardous, "it's never going to go beyond specialized academic centers."

[The researchers] streamlined the process, bypassing the live virus and B cell steps, and instead stimulating the T cells directly with peptides. A similar technique has been used previously to generate T cells specific for fighting cytomegalovirus. But the new method extends the concept, using a mix of peptides that together cover the antigenic proteins of five of the most common viruses to infect transplant patients.

When active T cell preparations were transferred into bone marrow transplant patients suffering viral infections the cells led, in almost all cases, to resolution of the infections. In eight patients treated, 15 of 18 total infections among the individuals were resolved, while one was reduced. Three additional patients were given the T cells prophylactically and remained infection-free for more than three months. The varying ability of the T cell preparations to tackle multiple viruses is thought to be due to the donor's prior exposure to the viruses in question. That is, if the donor has not tackled the virus before then, their blood would lack the necessary memory T cells. A future goal would be "generating such antigen-specific T cells from naive cells as opposed to people who have already got a T cell memory to the antigens."

LONGEVITY CORRELATES WITH CHILDBIRTH AT LATER AGES
Friday, June 27, 2014
https://www.fightaging.org/archives/2014/06/longevity-correlates-with-childbirth-at-later-ages.php

There is a natural range of variation in the pace of aging that is largely determined by lifestyle until later old age, at which point genetic influences become more important. Aging is a global phenomenon throughout the body: if someone ages more rapidly, it tends to be the case that every manifestation of aging is worse at any given chronological age. So when researchers find ways to measure an aspect of aging at one age, it should be expected that this measure correlates statistically with differences in future life span.

Women who are able to have children after the age of 33 have a greater chance of living longer than women who had their last child before the age of 30. "Of course this does not mean women should wait to have children at older ages in order to improve their own chances of living longer. The age at last childbirth can be a rate of aging indicator. The natural ability to have a child at an older age likely indicates that a woman's reproductive system is aging slowly, and therefore so is the rest of her body."

The study was based on analysis of data from the Long Life Family Study (LLFS) - a biopsychosocial and genetic study of 551 families with many members living to exceptionally old ages. The study investigators determined the ages at which 462 women had their last child and how old those women lived to be. The research found that women who had their last child after the age of 33 years had twice the odds of living to 95 years or older compared with women who had their last child by age 29.

The findings also indicate that women may be the driving force behind the evolution of genetic variants that slow aging and decrease risk for age-related genes, which help people live to extreme old age. "If a woman has those variants, she is able to reproduce and bear children for a longer period of time, increasing her chances of passing down those genes to the next generation." The results of this study are consistent with other findings on the relationship between maternal age at birth of last child and exceptional longevity. Previously, the New England Centenarian Study found that women who gave birth to a child after the age of 40 were four times more likely to live to 100 than women who had their last child at a younger age.

FASTING MAY BE A USEFUL ADDITION TO MANY MEDICAL PROCEDURES
Friday, June 27, 2014
https://www.fightaging.org/archives/2014/06/fasting-may-be-a-useful-addition-to-many-medical-procedures.php

Intermittent fasting can extend life in laboratory animals and was recently demonstrated to improve immune function under at least some circumstances. There is a fair amount of research that demonstrates the benefits of fasting in conjunction with standard cancer treatments. The changes in metabolism that take place during fasting may make it a useful addition to a range of medical procedures, improving outcomes and survival rates. Here is one example of supporting evidence for this assertion:

Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice.

Male and female F1-FVB/C57BL6-hybrid mice, average age 73 weeks weighing 47.2 grams, were randomized to preoperative ad libitum feeding or 3 days fasting, followed by renal IRI. Body weight, kidney function and survival of the animals were monitored until day 28 postoperatively. Kidney histopathology was scored for all animals and gene expression profiles after fasting were analyzed in kidneys of young and aged male mice.

Preoperative fasting significantly improved survival after renal IRI in both sexes compared with normal fed mice. Fasted groups had a better kidney function shown by lower serum urea levels after renal IRI. Histopathology showed less acute tubular necrosis and more regeneration in kidneys from fasted mice. Similar to young-lean, healthy male mice, preoperative fasting protects against renal IRI in aged-overweight mice of both genders. These findings suggest a general protective response of fasting against renal IRI regardless of age, gender, body weight and genetic background. Therefore, fasting could be a non-invasive intervention inducing increased oxidative stress resistance in older and overweight patients as well.