Fight Aging!

FIGHT AGING! NEWSLETTER
July 8th 2013

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

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CONTENT

• A Slightly Different Take on the Evolution of Aging
• More New Faces at the SENS Research Foundation
• Arguing Once More Against "Death Gives Life Meaning"
• Running the Numbers on Telomere Length, Body Temperature, and Species Longevity
• Limits on Cell Life Span Have Little To Do With Limits on Organism Life Span
• Latest Headlines from Fight Aging!
  • Rapamycin Partially Reverses Accelerated Degeneration in OXYS Rats
  • NF-κB Pathway Activators as Biomarkers and Targets for New Therapies in Aging
  • Exploring Cryonics
  • Radical Life Extension Conference, September, Washington DC
  • Old Muscles Remain Surprisingly Capable of Regeneration
  • A View of Current Options for Treating Osteoporosis
  • How to Build a Heart via Decellularization
  • News of Progress in Growing Liver Tissue from Stem Cells
  • Instructing Stem Cells to Reverse Osteoporosis
  • Towards Heart Regeneration With Pluripotent Stem Cells

A SLIGHTLY DIFFERENT TAKE ON THE EVOLUTION OF AGING
https://www.fightaging.org/archives/2013/07/a-slightly-different-take-on-the-evolution-of-aging.php

The vast majority of animals undergo degenerative aging: it is evident, easy to measure, and well recorded. The remaining tiny minority may undergo degenerative aging, but due to a combination of insufficient study and individual robustness throughout life researchers can't yet accurately determine the outer limits to their life spans, or how fast they age, or definitively how and why their aging is different from ours.

Lobsters fall into this category (though possibly not for very much longer), as do hydra, some clams and mussels, and a handful of others. It's probably worth remarking on the fact that if naked mole rats were much less studied, they might also be on the list - but since researchers have colonies of thousands of naked mole rats in laboratories and are intensely focused on their peculiar biology we have a much more comprehensive idea as to how they age, what their maximum life span is, and so on. Conversely if all those naked mole rats were instead arctic quahog clams, then I'd wager clams wouldn't be on the list above. To a certain degree the list of potentially ageless animals is as much a list of ignorance as it is of interesting and resilient species.

The vast majority of animals age because aging is a necessary evolutionary strategy for success in a changing world, or at least that is the common view:

When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool.

From the perspective of individuals this is a race to the bottom, wherein lineages that result in more harm to their own members prosper and spread at the expense of those that do not. Successful it may be, and no doubt the bone mountain of history is a necessary precondition for you and I to be standing here today, but that doesn't mean it is a good thing here and now. In particular, in the decades ahead you and I will suffer decades of pain and privation leading up to an ignominious, undignified death assuming nothing is done about the situation. This is an age of biotechnology, however: now that we can do something about it, we should be doing our utmost to get rid of degenerative aging, and the suffering and death it causes, and take the reins of the future into our own hands.

Today I noticed a slightly different way of looking at the near-universality of aging as an outcome of evolutionary selection. It comes from an author who is very much in the programmed aging camp when it comes to how and why aging progresses in an individual, but for the purposes of this argument about the evolution of aging that doesn't matter all that much:

The Demographic Theory of Aging

If it weren't for aging, the only way that individuals would die would be by starvation, by diseases, and by predation. All three of these tend to be "clumpy" - that is to say that either no one is dying or everyone is dying at once. Until food species are exhausted, there is no starvation; but then there is a famine, and everyone dies at once. If a disease strikes a community in which everyone is at the peak of their immunological fitness, then either everyone can fend it off, or else everyone dies in an epidemic. And without aging, even death by predation would be very clumpy. Many large predators are just fast enough to catch the aging, crippled prey individuals. If this were not so, then either all the prey would be vulnerable to predators, or none of them would be. There could be no lasting balance between predators and prey.

Without aging, it is difficult for nature to put together a stable ecosystem. Populations are either rising exponentially or collapsing to zero. With aging, it becomes possible to balance birth and death rates, and population growth and subsequent crashes are tamed sufficiently that ecosystems may persist. This is the evolutionary meaning of aging: Aging is a group-selected adaptation for the purpose of damping the wild swings in death rate to which natural populations are prone. Aging helps to make possible stable ecosystems.

Aging as a damping function introduced into population dynamics is an interesting way of looking at it. Starting from that purely mechanistic perspective it makes one wonder why aging came to near-universally dominate as the source of that damping function - why are there no other viable alternatives to achieve that result in the natural world?

From the perspective of aging as a process caused by an accumulation of cellular and molecular damage, rather than a process caused by evolved genetic programming, longevity evolves when evolutionary success is predicated by living longer, so that better repair and maintenance mechanisms are favored. In this view, aging was a given from day one of the first evolving organism, as all complex systems suffer damage in the course of operation. Even bacteria age, putting the origins of aging far, far back in the deep past: when the first multicellular organisms emerged the fact of degenerative aging was already baked into the mix. The only question from there forward was whether and how evolutionary circumstances would lead to biological mechanisms that mitigated or repaired the damage that causes aging.

MORE NEW FACES AT THE SENS RESEARCH FOUNDATION
https://www.fightaging.org/archives/2013/07/more-new-faces-at-the-sens-research-foundation.php

There are a good many organizations that advocate for aging research and extended healthy lives. You can find some of them listed in the resources section here at Fight Aging! There is only one organization in the world, however, that (a) is presently meaningfully focused on creating the means of human rejuvenation, (b) has the support of a broad range of researchers and philanthropists, and (c) to which folk like you and I can donate, in the secure knowledge that even small donations will go towards directly speeding the development of specific, planned, plausible therapies to repair and reverse aging.

That organization is the SENS Research Foundation, which over the past few years has moved from strength to strength in expanding its budget and convincing more and more of the aging research community to become allies and supporters of ambitious goals in longevity science. At a $3 million yearly budget, the Foundation's reach is no longer a group that you can fit into a small photograph: there are small laboratories in a number of research establishments around the world, a bunch of folk in the Bay Area, and a broad network of advisors, just to start with.

You all recognize the SENS Research Foundation cofounder Aubrey de Grey, of course, but there are many more people working away on the foundations of rejuvenation biotechnology and they deserve their time in the spotlight. So the Foundation is running a series of profiles at the moment: funded researchers, interns, volunteers, advocates, conference speakers, advisors, and others - people who are working to ensure that you and I have a shot at living much longer healthy lives while evading the pain and suffering caused by untreated aging. I linked to some of these profiles a few weeks ago, and here are more in the same vein:

SENS6 Speaker Highlight: Dr. George Church

The SENS6 conference's keynote address will be delivered by Dr. George Church, a researcher widely considered a luminary in modern biotechnology with over 300 publications to date. Dr. Church may be best known for his key role in the Human Genome Project, which he helped initiate and drive. His genomic sequencing innovations have led him to be involved with most of the companies in that field, either as a co-founder, advisor, or provider of licensed technology.

At SENS6, Dr. Church's presentation will address his cutting-edge work on bringing CRISPR-associated systems, an adaptive immune defense of some single-celled organisms that uses short strands of RNA, to human cells. He will also discuss the latest sequencing technologies, and the need to supplement genomic information with environmental and trait data.

SENS6 Speaker Highlight: Dr. Felipe Sierra

Dr. Felipe Sierra stands out for his unifying vision and deep involvement in aging research. [He is] the head of the National Institute on Aging's Division of Aging Biology (DAB). The DAB studies the aging process itself; the remits of its various branches are genetics and cell biology, the effects of cellular and molecular changes on tissue function, and animal models of human aging. Instead of funding work about the mechanisms or progression of age-related diseases, the DAB supports work that elucidates why exactly it is that older adults suffer from these diseases while younger ones do not.

At SENS6, Dr. Sierra will give a presentation about [the Geroscience Interest Group] and the fundamental process that underlies the diseases of aging. He will be joined at the conference by many other top scientists, including Harvard's George Church, the Mayo Clinic's Jan van Deursen, Carnegie Mellon's Alan Russell, and MIT's Todd Rider.

Intern Sam Curran: IDing Senescent Cell Secretion Potentially Implicated In Age-Related Decline Of Immune System Function

Senescent cells [contribute to] pathologies associated with old age, such as tissue degeneration. Is there a way to target and treat the afflicted cells responsible [here]? This is the question being addressed [by] Sam Curran. In the summer of 2012 as part of the SENS Research Foundation Summer Internship Program, Sam joined Dr. Judith Campisi's laboratory at the Buck Institute for Research on Aging to work on a project dealing with the senescence phenotype of mesenchymal stem cells.

After the success of his summer project, Sam was invited by the Campisi lab to continue his research for a year of full-time funding by the SENS Research Foundation. Since his summer internship ended, Sam has made a number of novel discoveries. For instance, the senescence-associated secretory phenotype (SASP) of MSCs may be different than other cells due to their immunosuppressive secretions. Sam has already identified one senescence-associated immunosuppressive factor that may be implicated in two important biological phenomenon: the ability of senescent cells to evade immune-surveillance and age-related decline of immune system function. Sam hopes to identify additional immunosuppressive MSC SASP factors with yet another year of funded research in the Campisi lab before pursuing a Ph.D. in bioengineering in the fall of 2014.

Haroldo Silva: Lead OncoSENS Scientist Researches Telomere Lengthening and Cancer Pathways

I was a doctoral student at the University of California, Berkeley, in the department of Bioengineering. My dissertation laboratory at UC Berkeley is known for cutting-edge aging research and that was one of the reasons I joined that group in the first place. I also attended a seminar at Berkeley given by Aubrey de Grey which really opened my eyes about the real possibilities of a novel perspective on aging research transforming the world in our lifetime.

I am the lead scientist of the OncoSENS team at SRF. Our group seeks to uncover the genetic pathways and mechanisms that enable cancer cells to acquire unlimited cellular division. One of the major hurdles cancer cells need to overcome is how to keep the ends of their chromosomes (i.e., telomeres) from shortening with each cell division. A major pathway exploited by cancer cells to elongate their telomeres is upregulation of an enzyme called telomerase. However, about 10-15% of cancers do not have any detectable telomerase activity and thus operate via another pathway called Alternative Lengthening of Telomeres (ALT). The goal of our research team is to find out which specific genes are responsible for ALT activity in these cancers. Therefore, in theory, removal of both telomerase and ALT genes from the genome should eradicate cancer completely.

Connie Wang: Microglia, Aging and Alzheimer's

During her time at Caltech, Connie has engaged in a variety of research interests. She has conducted plant genetics research to determine whether a strain of Mimulus was a distinct subspecies and also helped design an optical coherence tomography (OCT) system for use in retinal surgery.

In 2012, she participated in the SENS Research Foundation Summer Internship Program. During her time at the SRF Research Center in Mountain View, California, she developed microglial cell assays that helped lay the groundwork for studying the relationship between microglia, aging, and Alzheimer's Disease. This summer, Connie is working with the Reichert lab at Duke University to develop an angiogenesis-promoting system for glucose sensors planted under the skin with the goal of making them a viable long-term solution for insulin-dependent diabetics. She will return to Caltech in the fall to begin her final year of study before applying to graduate school in 2014.

ARGUING ONCE MORE AGAINST "DEATH GIVES LIFE MEANING"
https://www.fightaging.org/archives/2013/07/arguing-once-more-against-death-gives-life-meaning.php

Deathism is a label of convenience for any philosophy or outlook that regards death as a good thing. These worldviews also tend to be in favor of both degenerative aging and the involuntary nature of death - that we are forced to die regardless of what we might think on the subject. A deathist is someone who holds such a viewpoint. One of the more sensible comments I've seen on deathism in general is this:

Such is human nature, that if we were all hit on the head with a baseball bat once a week, philosophers would soon discover many amazing benefits of being hit on the head with a baseball bat: It toughens us, renders us less fearful of lesser pains, makes bat-free days all the sweeter. But if people are not currently being hit with baseball bats, they will not volunteer for it. Modern literature about [death and the prospects for radical life extension through medical science] is written primarily by authors who expect to die, and their grapes are accordingly sour.

One of the hoary old arguments put out by near everyone in favor of unavoidable death is that "death gives life meaning." The conceit here is that life is somehow meaningless until you can draw a line under it and assess, or perhaps that no-one would do anything if they didn't have a timer counting down their own personal extinction. I've never been able to grasp the essence of the first point, which just seems so much nonsense to me: why draw the line on death? Why not somewhere else? The past at any point is fixed and up for evaluation, but why draw lines at all for that matter?

The second point can be thrown out on the grounds that humans with an adult life expectancy of 80 behave remarkably similarly to humans with an adult life expectancy of 40-something, as any exploratory expedition through the better-recorded sections of Roman history will demonstrate. Where differences exist they certainly don't involve people lazying around as the expectation of additional years grows, but are rather changes in the nature of the tasks that people busy themselves with. A longer time horizon means that you can undertake better, more ambitious, more profitable projects by virtue of having longer in which to complete them. Competition if nothing else drives that process.

Since various deathists persist in arguing that involuntary death (without or without the suffering and pain of aging) is necessary to give life meaning, there is a steady flow of articles from the radical life extension advocacy community to point out just how ridiculous the deathist position is. Here is one of the more recent examples:

Death is Dumb!

One common argument against indefinite lifespans is that a definitive limit to one's life - that is, death - provides some essential baseline reference, and that it is only in contrast to this limiting factor that life has any meaning at all. In this article I refute the argument's underlying premises, and then argue that even if such premises were taken as true, its conclusion - that eradicating death would negate the "limiting factor" that legitimizes life - is also invalid, because the ever-changing state of self and of world can constitute such a limiting factor just as well as death can, which can be seen lucidly in the simple fact that opportunities once here are now gone, and that it is not death but life itself that is responsible for that.

Culture is in constant upheaval, with new opportunity's opening up(ward) all the time. Thus the changing state of culture and humanity's upheaved hump through time could act as this "limiting factor" just as well as death or the changing self could. What is available today may be gone tomorrow. We've missed our chance to see the Roman Empire at its highest point, to witness the first Moon landing, to pioneer a new idea now old. Opportunities appear and vanish all the time.

Indeed, these last two points - that the changing state of self and society, together or singly, could constitute such a limiting factor just as effectively as death could - serve to undermine another common argument against the desirability of limitless life: boredom. Too often is this rather baseless claim bandied about as a reason to forestall indefinitely-extended lifespans - that longer life will lead to increased boredom. That self and society are in a constant state of change means that boredom should become increasingly harder to maintain.

RUNNING THE NUMBERS ON TELOMERE LENGTH, BODY TEMPERATURE, AND SPECIES LONGEVITY
https://www.fightaging.org/archives/2013/07/running-the-numbers-on-telomere-length-body-temperature-and-species-longevity.php

Back in 2008 or so, a group of researchers crunched the numbers to argue that most of the variation in longevity between mammal species (which spans the range from small rodents that live a couple of years to whales that live a couple of centuries) is largely determined by resting metabolic rate and variations in mitochondrial DNA. Our mitochondria are the power plants of the cell, the descendants of symbiotic bacteria with their own DNA, and they toil to produce chemical energy stores to power the rest of the cell machinery. They occupy a central role in our biology, and this is one of many papers that point to the significance of mitochondria in aging.

For an introduction on why mitochondria and their composition are important, you might look back in the Fight Aging! archives, or investigate the membrane pacemaker hypothesis of aging. The short version of the story is that mitochondria produce damaging reactive byproducts in the course of their operation: anything that can react with protein machinery and disrupt its operation is harmful to a cell, though most such incidences are quickly repaired. The cell components that suffers the brunt of the damage are of course the mitochondria themselves, which only makes the situation progressively worse. Some species are better at soaking up the reactive compounds with natural antioxidant proteins, while others have mitochondria and cell structures that are more resistant to damage, some can better repair damaged mitochondria, and yet more have more efficient mitochondria that emit fewer damaging molecules - all of these things tend to lead to a longer life when present.

While engineering humans to have better mitochondria is going to happen sooner or later, there are also other and arguably better near term options for dealing with the issue. A number of research groups are working towards ways to repair or replace mitochondria in living tissue, and thus removing their contribution to degenerative aging. This is a very necessary part of the rejuvenation toolkit of future medicine, but like much of the present work in this field it is poorly funded and proceeding far more slowly than it might be.

The researchers mentioned above, who investigated correlations between metabolic rate and longevity, recently published this open access paper in which there is some more number crunching to probe associations between various measures and species maximum life span (MLS):

Telomere length and body temperature - independent determinants of mammalian longevity?

We have previously shown that body mass (BM) or resting metabolic rate alone explain around 40-50% of the variation in mammalian longevity, whereas their combination with mitochondrial DNA (mtDNA) GC content could explain over 70% of the MLS variation. Consequently, we hypothesized that other putative players in MLS determination should have relatively small contribution or their effects should be mediated by the above factors.

Recent finding by Gomes et al. (2011) demonstrating a strong negative correlation between telomere length and MLS in 59 mammalian species calls for re-evaluation of this hypothesis. Indeed, the coefficient of MLS determination calculated using the data in their paper indicates that the telomere length could alone explain more than 1/3 of the variation in the lifespan of mammals. Here, we explore whether the telomere length has an independent impact on mammalian longevity or its effect is attributed to co-variation with other determinants of MLS, such as BM and mtDNA GC content.

Partial correlation and multivariate analyses showed that the telomere length has an independent impact on longevity determination. The partial correlation analysis allows eliminating the co-variation effects. We found that the correlative links between telomere length and BM or mtDNA GC do not significantly alter its association with longevity. That is, the telomere length could explain part of the variation in the mammalian longevity which is not explained by the BM and mtDNA GC.

In attempt to discover [other possible] still unaccounted factors, we further included in the analysis an additional variable closely related but not identical to the metabolic rate - body temperature (Tb). Gomes et al. (2011) hypothesized that the evolution from exothermic to homeothermic organisms was accompanied by telomere shortening as a tumor protective adaptation to an enhanced mutation load caused by high Tb. Yet, within mammalian species we did not observe any significant correlation between the telomere length and typical Tb.

Unexpectedly, we found that Tb [may] explain some cases of considerable deviations from the MLS predicted by BM, mtDNA GC, and telomere length. For example, the naked mole-rat (Heterocephalus glaber) and North American pika (Ochotona princeps) have similar values of BM, mtDNA GC content and telomere length, yet the naked mole-rat lives 4.4 times longer. This apparent "discrepancy" could be largely attributed to the difference in Tb which, in the sample analyzed, is the lowest for the naked mole-rat (32.1°C) and the highest for the North American pika (40.1°C).

LIMITS ON CELL LIFE SPAN HAVE LITTLE TO DO WITH LIMITS ON ORGANISM LIFE SPAN
https://www.fightaging.org/archives/2013/07/limits-on-cell-life-span-have-little-to-do-with-limits-on-organism-life-span.php

Higher organisms like we humans are made of cells, of several hundred distinct types if you exclude all of the symbiotic bacterial species that we carry along with us. The vast majority of cells have short finite life spans: they stop reproducing and self-destruct or become senescent after a number of reproductive divisions. You might be familiar with the Hayflick limit in relation to this topic: it is the number of times a cell divides before it removes itself from the cell cycle to a fate of destruction or senescence. Similarly you have probably heard of telomeres, the repeating DNA sequences at the end of our chromosomes. The length of telomeres shortens with each cell division, forming a sort of countdown clock, and too-short telomeres is one of mechanisms by which cell division is halted.

The reality on the ground is much more complex than this simple view of a cell division countdown. Some cells don't divide and last you a lifetime, such as many of those in the central nervous system. Other cells, such as stem cell populations, have their telomeres repeatedly extended by the enzyme telomerase. Different cells in different parts of the body have very different life spans, and the complex array of processes that determine those life spans is highly variable, reacting to the environment and to each other.

None of this really has much direct bearing on the life span of an organism, however. You can't just wave a wand that would extend the life of all cells, and expect to see a similar extension of life in the organism - whether that happens or not depends on the intricate details of how cells relate to organs and systems. The life span of cells is all the way down there in the depths of the machine, details internal to low-level components that are decoupled from how the machine behaves in aggregate. There is no particular reason for cell life spans to have anything to do with how long the machine as a whole can last. Some of our tissues are designed to cycle through and replace all of their cells very rapidly, in a matter of days. Other cells are never replaced and live as long as we do.

Cell behavior is subordinate to the needs of the organ or system that they are a part of. The cells of a given type evolved to have their present behavior and typical life spans because, when acting as a system in conjunction with other cell types, they produce a working organ or system that provides some evolutionary advantage. If that can be done with lots of cell turnover and short cell life spans, it will be. If it can be done with little cell turnover and long cell life spans, it will be also - but either path can produce a long-lived and reliably functional organ. This point is one that a recent article comes to eventually, after a tour of the Hayflick limit and telomere biology:

Lust for life: Breaking the 120-year barrier in human aging

It is true that as we get older our telomeres shorten, but only for certain cells and only during certain times. Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear.

Apparently using the Hayflick limit and telomere length to judge maximum human lifespan is akin to understanding the demise of the Roman empire by studying the material properties of the Colosseum. Rome did not fall because the Colosseum degraded; the Colosseum degraded because the Roman Empire fell.

Within the human body, most cells do not simply senesce. They are repaired, cleaned or replaced by stem cells. Your skin degrades as you age because your body cannot carry out its normal functions of repair and regeneration.

The processes that cause degenerative aging occur at the level of cells and specific protein machinery within cells, harming their ability to perform as they should. Old, damaged cells produce more old, damaged cells when they divide. Old, damaged stem cells simply fail to keep up with their tasks of tissue maintenance. Long-lived cells become progressively more damaged and incapable, or die back, either of which causes very visible issues when it happens in the nervous system and brain.

Aging is simply a matter of damage. But how that damage translates into system failure is not a straightforward matter of cells living longer or cells dying sooner - except when it is for some long-lived cell types. Every tissue fails through the same general processes, but those processes produce a very wide range of failure modes, depending on the character of the tissue and the cells that make it up. Go beyond the comparative simplicity of the root causes of aging, and everything becomes progressively ever more complex as you move towards describing the highly varied biology of fatal age-related diseases. This is why intervening in the root causes is absolutely the best and most cost-effective strategy, the only one likely to produce meaningful progress towards human rejuvenation in our lifetimes.

As a final note, for my money, I'd wager that forms of amyloidosis are the present outermost limiting condition on human life span. The evidence suggests that this is what ultimately kills supercentenarians, the resilient individuals who have made it past the age of 110, avoiding or surviving all of the fatal age-related medical conditions that claimed their peers.

LATEST HEADLINES FROM FIGHT AGING!

RAPAMYCIN PARTIALLY REVERSES ACCELERATED DEGENERATION IN OXYS RATS
Monday, July 1, 2013
https://www.fightaging.org/archives/2013/07/rapamycin-partially-reverses-accelerated-degeneration-in-oxys-rats.php

OXYS rats are a laboratory breed engineered to show accelerated aging. They exhibit higher levels of oxidative free radicals than other rats, and degenerate more rapidly. Animal lineages are engineered this way to reduce the cost and duration of exploratory studies of aging or specific conditions of aging.

Here researchers show that rapamycin, demonstrated to extend life in mice in recent years, can partially reverse accelerated degeneration in OXYS rats. This is an expected result given the range of other work on rapamycin to date. It is, however, worth noting that enthusiasm for rapamycin is driven as much by the fact that it is already an FDA-approved drug as for its merits as a basis for treatments. The cost of obtaining new drug approval is very high and takes a long time, so that funding sources are steered towards favoring the development of marginal new uses for existing drugs rather than better forms of entirely new medicine:

Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span in C elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months.

Here we show that rapamycin treatment decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci.

Levels of Tau [were] increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. We conclude that rapamycin in low chronic doses can suppress brain aging.

NF-κB PATHWAY ACTIVATORS AS BIOMARKERS AND TARGETS FOR NEW THERAPIES IN AGING
Monday, July 1, 2013
https://www.fightaging.org/archives/2013/07/nf-b-pathway-activators-as-biomarkers-and-targets-for-new-therapies-in-aging.php

NF-κB shows up in a range of research on longevity and aging. It's one of a number of central pieces of biological machinery that appear to be altered by methods of extending life in laboratory animals, but which influence (usually indirectly) so very many processes and mechanisms that understanding how it all fits together becomes an enormous task. In this open access paper researchers look at NF-κB in the context of the immune system failure and systematic chronic inflammation that occurs with aging:

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together.

An excessive activation of NF-κB signaling pathway characterizes the entropic ageing process, responsible of inflammageing and SASP phenotype, and the consequent onset of several age-related diseases. This is plausible since nearly all insults enhancing the ageing process are well-known activators of NF-κB signaling system.

Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In addition, we also suggest [these biomarkers] as targets for the development of new therapeutic strategies against ageing and age-related diseases.

In the programmed view of aging, targeting things like the NF-κB signaling pathway is the logical first step, as aging is thought by that school to be caused by changes in gene expression and behavior of signaling pathways. In the more mainstream view of aging as caused by accumulated cellular and molecular damage, however, altering gene expression and pathway behavior is only a patch on the real problem. Those changes are a reaction to various forms of molecular damage in and between cells, and changing the response to damage rather than repairing that damage is only of limited benefit. It's a little like changing the oil in your car and hoping rather than replacing worn engine components.

Unfortunately despite the fact that most of the research community supports damage-based theories of aging, scientists still largely pursue research that better fits the programmed view of aging - i.e. that seeks only to alter biological reactions to the cause of aging rather than directly addressing the damage that is the cause. Only by repairing the damage, such as by implementing the SENS proposals for rejuvenation therapies, can we create truly effective therapies for aging.

EXPLORING CRYONICS
Tuesday, July 2, 2013
https://www.fightaging.org/archives/2013/07/exploring-cryonics.php

Cryonics is the low-temperature preservation of the brain and body on death, so as to preserve the tissue structures that hold the data of the mind. This offers a chance of future restoration to life via advanced medical technologies, which is more than can be said for the other post-mortem options presently available to us. Here is an interview with Max More of the Alcor Life Extension Foundation, one of the two long-established cryonics providers in the US:

Somebody might opt to be placed into biostasis at the end of their natural life [for] the same reason that a person might choose to have open heart surgery or an experimental cancer treatment. Essentially, we see cryonics as an extension of critical care medicine. If you were unlucky enough to go into cardiac arrest whilst walking down the street 50 years ago, you would probably have been pronounced dead at the scene. Nowadays, paramedics routinely use defibrillators and cardiopulmonary resuscitation (CPR) to revive patients who would simply have died in the past.

Cryonicists recognise that what we call 'dead' is somewhat arbitrary; it depends largely on the level of medical technology that is available at a particular point in time. When today's doctors declare a person clinically dead, they are not saying that that person is biologically dead. They are not saying that all of their brain cells have exploded or disappeared. They are simply stating that the person in question has become non-functional in a way that they are unable, or unwilling, to fix. So, why give up on that person? They're still potentially there; their brain is intact. As cryonicists, we are looking towards the future. We can do things today that weren't possible 50 years ago. It's clearly going to be the case that in 50 years' time, we will be capable of achieving things that are not possible today. In the future, we will be able to fix many things that we cannot fix at present. Hopefully, this will include the ageing process itself.

If you look deeper into cryonics, you will begin to recognise how it is connected to other sciences. Organ donation, for example, is a current research area that shares several commonalities with cryonics. The initial procedures that we conduct in order to maintain biological viability are much the same as those carried out when preserving a donor organ. Moreover, there is plenty of evidence to suggest that what we are doing is working. Electron microscope studies have demonstrated that when we place a person into biostasis, the connections between their brain cells persist. Given what we know about human memory, this indicates that the person is still potentially there.

Cryonics is beginning to make sense within the context of medical advances that are taking place across a range of sectors. People are putting the pieces together and arriving at their own conclusions. Nobody knows whether or not cryonics will ultimately succeed, but it certainly isn't crazy. In fact, it looks a whole lot more plausible today than it did in the past.

RADICAL LIFE EXTENSION CONFERENCE, SEPTEMBER, WASHINGTON DC
Tuesday, July 2, 2013
https://www.fightaging.org/archives/2013/07/radical-life-extension-conference-september-washington-dc.php

Supporters of radical life extension research are organizing a conference in Washington, DC, this coming September 22nd:

ImmortalLife.info is presenting a conference in the capitol of the USA on September 22. Space is limited to 300 seats. "Radical LIfe Extension - Are You Ready to Live 1,000 Years?" is co-sponsored by LongeCity and Maximum LIfe Foundation. LongeCity is an international, not-for-profit, membership-based organization (501-3-c status in the United States). It's mission is "to conquer the blight of involuntary death". LongeCity is providing ImmortalLife.info with airfare for speakers. Maximum Life Foundation, led by David A. Kekich, intends to "Reverse Aging by 2029." Maximum Life Foundation serves as ImmortalLife.info's fiscal sponsor.

We will have 11 speakers discussing Immortality / Life Extension from a wide variety of perspectives: scientific, political, social, poetic, religious, atheistic, economic, demographic, moral, etc. Everyone who preregisters for the event will receive a free e-book titled "Human Destiny is to Eliminate Death - essays and rants on immortalism." Many of the 35 articles that it includes are written by speakers at our event.

Immortality is a potent word with many associations, as well as being the first resort of the lazy press when talking about longevity science, and there are those in the advocacy community who don't like it being slung around. Success in advocacy is accompanied by a move to moderation in message and a distancing from more radical opinions, for example, and this is just as true in aging research as anywhere else. But there is definitely a role for people willing to plant a flag out there and argue for the most extreme plausible proposal no matter how much it rocks the boat: without someone pushing the bounds of the conversation, how will there be progress?

OLD MUSCLES REMAIN SURPRISINGLY CAPABLE OF REGENERATION
Wednesday, July 3, 2013
https://www.fightaging.org/archives/2013/07/old-muscles-remain-surprisingly-capable-of-regeneration.php

You might recall that in some ways muscle tissue shows a surprising lack of degeneration associated with aging. Not every measure and biological mechanism declines greatly. It's not all that comforting, as evidently we're all still aging into frailty regardless, but it does suggest that perhaps a larger fraction of muscle aging than previously thought is under our control, the result of poor lifestyle choices such as sedentary behavior.

While the general understanding of muscle regenerative capacity is that it declines with increasing age due to impairments in the number of muscle progenitor cells and interaction with their niche, studies vary in their model of choice, indices of myogenic repair, muscle of interest and duration of studies.

We focused on the net outcome of regeneration, functional architecture, compared across three models of acute muscle injury to test the hypothesis that satellite cells maintain their capacity for effective myogenic regeneration with age. Muscle regeneration in extensor digitorum longus muscle (EDL) of young (3 mo-old), old (22 mo-old) and senescent female mice (28 mo-old) was evaluated for architectural features, fiber number and central nucleation, weight, collagen and fat deposition.

Histological analyses revealed successful architectural regeneration following [injury] with negligible fibrosis and fully restored function, regardless of age. In comparison, the regenerative response to injuries that damaged the neurovascular supply [was] less effective, but similar across the ages. The focus on net regenerative outcome demonstrated that old and senescent muscle has a robust capacity to regenerate functional architecture.

A VIEW OF CURRENT OPTIONS FOR TREATING OSTEOPOROSIS
Wednesday, July 3, 2013
https://www.fightaging.org/archives/2013/07/a-view-of-current-options-for-treating-osteoporosis.php

Bone weakens with age, a condition known as osteoporosis. Like many aspects of aging it appears that this can be partially slowed by means of calorie restriction, but prevention is going to require new medical technology. Patching over the underlying causes, such as by interfering in the behavior of cells that create and destroy bone tissue, is the focus of the research mainstream. The better approach is to repair the underlying damage that causes aging, as detailed in the SENS proposals, and thereby eliminate the changes in our cell populations that cause bone to weaken.

One of the interesting aspects of presently available treatments for osteoporosis is the outcome of bisphosphonate use: one study showed an unusually large increase in life expectancy for patients undergoing biphosphonate therapy, and I've been waiting to see if this is replicated in other data. Here is a review article that surveys the present and near future options for treating osteoporosis:

Osteoporosis is caused by an uncoupling of bone resorption from bone formation such that the activities of osteoclasts far outweigh those of the osteoblasts. Peak bone mass is achieved in early adulthood and, following this point, both women and men lose bone with increasing age. As a stepping stone to determining a genetic link in osteoporosis, twin and family studies have shown that up to 85% variation in bone mass density (BMD) can be attributed to genes. Although initially genome-wide scans revealed no significant association to individual genes due to low sensitivity, later genome-wide association studies showed single nucleotide polymorphisms (SNPs) associated with variation in BMD. Many of these genes are associated with regulation of bone mineral homeostasis.

Bisphosphonates are the most commonly used drugs for the treatment of osteoporosis. They avidly bind to bone and are internalized by osteoclasts to inhibit resorption. They are administered both orally and intravenously and are divided into two classes - the low potency non-nitrogen containing bisphosphonates and the potent nitrogen-containing bisphosphonates. These two classes have distinct intracellular targets and molecular mechanisms of action that lead to inhibition of osteoclast-mediated bone resorption. As bisphosphonates have an apparent half-life of more than 10 years due to selective adherence to the bone surface, successive treatment over years would not only have a cumulative effect, but may actually be detrimental for bone health by preventing the cyclical changes required to maintain normal bone architecture.

Over recent years, stem cell therapy in musculoskeletal research has exploded, and there is a wide range of possible clinical applications for such technologies, many focusing on tissue repair following damage, including bone fractures, cartilage lesions, or ligament and tendon injuries. One hurdle in the development of therapies exploiting endogenous mesenchymal stem cells (MSCs) is their lack of capacity to home to bone surfaces. A recent study indicated the possibility of directing endogenous MSCs to the bone surface using piggyback technology in which LLPA2, the ligand for integrin α4β1 expressed by MSCs, is administered in vivo, piggybacked onto [an existing bisphosphonate treatment for osteoporosis]. When LLPA2 binds to MSCs, the bisphosphonate directs those stem cells to the bone surface where osteoblastic differentiation and subsequent bone regeneration takes place.

HOW TO BUILD A HEART VIA DECELLULARIZATION
Thursday, July 4, 2013
https://www.fightaging.org/archives/2013/07/how-to-build-a-heart-via-decellularization.php

Decellularization is the process of taking a donor organ and stripping its cells, leaving behind the extracellular matrix and all its chemical cues. The organ can then be repopulated with a patient's cells, producing working tissue for transplant that will not be rejected. The donor organ doesn't even have to be human: decellularization greatly improves the prospects for xenotransplantation, such as obtaining hearts or kidneys from pigs. So far decellularization has only been used in human medicine for comparatively simple tissue structures, such as the trachea, but researchers are not very many years away from trials for decellularized hearts and other major organs. This article goes into detail on the challenges still to be surmounted at every step of the way:

The strategy is simple enough in principle. First remove all the cells from a dead organ - it does not even have to be from a human - then take the protein scaffold left behind and repopulate it with stem cells immunologically matched to the patient in need. Voilà! The crippling shortage of transplantable organs around the world is solved. In practice, however, the process is beset with tremendous challenges. Researchers have had some success with growing and transplanting hollow, relatively simple organs such as tracheas and bladders. But growing solid organs such as kidneys or lungs means getting dozens of cell types into exactly the right positions, and simultaneously growing complete networks of blood vessels to keep them alive. The new organs must be sterile, able to grow if the patient is young, and at least nominally able to repair themselves. Most importantly, they have to work - ideally, for a lifetime.

The leading techniques for would-be heart builders generally involve reusing what biology has already created. Suspended by plastic tubes in a drum-shaped chamber made of glass and plastic is a fresh human heart. Nearby is a pump that is quietly pushing detergent through a tube running into the heart's aorta. The flow forces the aortic valve closed and sends the detergent through the network of blood vessels that fed the muscle until its owner died a few days before. Over the course of about a week [this] flow of detergent will strip away lipids, DNA, soluble proteins, sugars and almost all the other cellular material from the heart, leaving only a pale mesh of collagen, laminins and other structural proteins: the 'extracellular matrix' that once held the organ together.

Through trial and error, scaling up the concentration, timing and pressure of the detergents, researchers have refined the decellularization process on hundreds of hearts and other organs. It is probably the best-developed stage of the organ-generating enterprise, but it is only the first step. Next, the scaffold needs to be repopulated with human cells. 'Recellularization' introduces another slew of challenges. "One, what cells do we use? Two, how many cells do we use? And three, should they be mature cells, embryonic stem cells, iPS [induced pluripotent stem] cells? What is the optimum cell source?" Using mature cells is tricky to say the least. "You can't get adult cardiocytes to proliferate. If you could, we wouldn't be having this conversation at all" - because damaged hearts could repair themselves and there would be no need for transplants.

NEWS OF PROGRESS IN GROWING LIVER TISSUE FROM STEM CELLS
Thursday, July 4, 2013
https://www.fightaging.org/archives/2013/07/news-of-progress-in-growing-liver-tissue-from-stem-cells.php

Last year Japanese scientists published on their work in growing small amounts of liver tissue from stem cells. Here is more on this line of research:

The researchers found that a mixture of human liver precursor cells and two other cell types can spontaneously form three-dimensional structures dubbed "liver buds." In the mice, these liver buds formed functional connections with natural blood vessels and perform some liver-specific functions such as breaking down drugs in the bloodstream. It's possible the technique will work with other organ types, including the pancreas, kidney, or lungs. The study is the first demonstration that a rudimentary human organ can be produced using induced pluripotent stem (iPS) cells. These iPS cells are made by converting mature cells such as skin cells into a state from which they can develop into many other cell types.

The researchers took a creative approach to building the proto-liver [by] co-mingling three different cell types: liver cell precursors derived from human iPS cells, blood vessel precursors called endothelial cells, and connective tissue precursor cells called mesenchymal stem cells. Both the blood vessel and connective tissue precursor cells were harvested from umbilical cords.

To demonstrate the therapeutic potential of the liver bud method, [the researchers] transplanted a dozen liver buds into the abdomen of mice whose natural liver function was shut down with a drug. The liver bud transplants kept these mice alive for the month they were watched. The liver buds did not achieve all the functions of a mature liver. For instance, the buds did not form a bile duct system. However, in ongoing research, the team has found that by transplanting the buds into an existing liver, the body seems to make use of the existing bile system.

One potential therapeutic use of the method could involve delivering microscopic liver buds to human patients through a large vein that connects to the liver to improve survival after liver failure. [The researchers are] optimistic that as much as 30 percent of liver function could be restored through this method, [but] estimated that such a treatment is at least 10 years away. In the meantime, the method must be improved so that the liver buds can be produced much more efficiently.

INSTRUCTING STEM CELLS TO REVERSE OSTEOPOROSIS
Friday, July 5, 2013
https://www.fightaging.org/archives/2013/07/instructing-stem-cells-to-reverse-osteoporosis.php

This study was mentioned in a recent review of treatment options currently under development for osteoporosis, the systematic loss of bone mass and strength with age:

Bone regeneration by systemic transplantation of mesenchymal stem cells (MSCs) is problematic due to the inability to control the MSCs' commitment, growth and differentiation into functional osteoblasts on the bone surface. Our research group has developed a method to direct the MSCs to the bone surface by conjugating a synthetic peptidomimetic ligand (LLP2A) that has high affinity for activated α4β1 integrin on the MSC surface, with a bisphosphonates (alendronate) that has high affinity for bone (LLP2A-Ale), to direct the transplanted MSCs to bone.

Our in vitro experiments demonstrated that mobilization of LLP2A-Ale to hydroxyapatite accelerated MSC migration that was associated with an increase in the phosphorylation of Akt kinase and osteoblastogenesis. LLP2A-Ale increased the homing of the transplanted MSCs to bone as well as the osteoblast surface, significantly increased the rate of bone formation and restored both trabecular and cortical bone loss induced by estrogen deficiency or advanced age in mice. These results support LLP2A-Ale as a novel therapeutic option to direct the transplanted MSCs to bone for the treatment of established bone loss related to hormone deficiency and aging.

TOWARDS HEART REGENERATION WITH PLURIPOTENT STEM CELLS
Friday, July 5, 2013
https://www.fightaging.org/archives/2013/07/towards-heart-regeneration-with-pluripotent-stem-cells.php

As these authors note, progress towards heart regeneration via stem cell therapies is ongoing. Numerous important steps forward in the control and manipulation of heart cells and stem cells have been demonstrated in the laboratory in recent years:

Damage in cardiac tissues from ischemia or other pathological conditions leads to heart failure; and cell loss or dysfunction in pacemaker tissues due to congenital heart defects, aging, and acquired diseases can cause severe arrhythmias. The promise of successful therapies with stem cells to treat these conditions has remained elusive to the scientific community. However, recent advances in this field have opened new opportunities for regenerative cardiac therapy.

Transplantation of cardiomyocytes derived from human pluripotent stem cells has the potential to alleviate heart disease. Since the initial derivation of human embryonic stem cells, significant progress has been made in the generation and characterization of enriched cardiomyocytes and the demonstration of the ability of these cardiomyocytes to survive, integrate, and function in animal models.

The scope of therapeutic potential from pluripotent stem cell-derived cardiomyocytes has been further expanded with the invention of induced pluripotent stem cells, which can be induced to generate functional cardiomyocytes for regenerative cardiac therapy in a patient specific manner. The reprogramming technology has also inspired the recent discovery of direct conversion of fibroblasts into cardiomyocyte-like cells, which may allow endogenous cardiac repair. Regenerative cardiac therapy with human pluripotent stem cells is now moving closer to clinic testing.