Fight Aging! Newsletter, August 4th 2014

August 4th 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.

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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  • Fundraising Update: $96,000 in the Matching Fund for October
  • Mitochondrially Targeted Antioxidants as a Way to Suppress Cancer Metastasis
  • A Different Car Analogy for Increased Human Longevity
  • The Healthspan Imperative
  • Replication Stress Explains Some of Blood Stem Cell Aging
  • Latest Headlines from Fight Aging!
    • More on Klotho and Neurodegeneration
    • Rapamycin and Its Effects on mTORC1 and mTORC2
    • Considering Mitochondrial DNA Deletions in Skeletal Muscle
    • Alcor Working on Field Perfusion for Remote Cryonics Cases
    • A Review of Age-Related Macular Degeneration
    • A Review of Approaches to Delay Sarcopenia
    • Resistance to Oxidative Stress in Cells of Long-Lived Species
    • More Context on the Goals of Human Longevity, Inc.
    • TRAP-1 Knockout Improves Health and Extends Life in Mice
    • Healthier, Wealthier, and Wiser


In October we'll be kicking off a grassroots fundraiser to support SENS research programs, work that is aimed at removing the technical roadblocks preventing greater funding and interest in rejuvenation research. At present we are raising a matching fund for that fundraiser, and are seeking matching fund founders. As you can see from the title, we have met with some success - but I think we can do better yet. So help us out here. Join in and push this matching fund to a nice round number at the very least. Here are the folk who have donated so far:

  • Christophe and Dominique Cornuejols
  • David Gobel (Methuselah Foundation)
  • Dennis Towne
  • Håkon Karlsen
  • Jason Hope
  • Michael Achey
  • Michael Cooper
  • Reason (Fight Aging!)

From Håkon Karlsen:

Aging will be cured at some point in time. Of that there is little doubt. Until it is cured, however, a hundred thousand lives are being lost every single day, due to aging. That's more than 35 million people in a year. Nothing even comes close to killing as many people. Curing aging may thus help billions of people avoid the many years of suffering and pain that the age related diseases often cause. Let's try to cure aging now, it might just save (or, at least, greatly improve) your life, or the life of someone you care about. Please consider making a donation to the SENS Research Foundation.

From Michael Achey:

As a primary care physician, I watch the effects of aging every day. In practice for 27 years I have observed many a healthy, hearty, happy person gradually falter physically, dwindle mentally, and give up socially. Many of the diseases responsible for the senescence and death of us folks will be solved in the process of understanding causes of aging. From a strictly selfish standpoint (me and my kids) and a global perspective, I look forward to a day when a human body can live a couple hundred or more years to travel "Where No Man Has Gone Before!"

What is rejuvenation research? By rejuvenation here I mean repair and reversal of the underlying causes of aging: the various forms of cellular and molecular damage that accumulate over time in your tissues, disrupting function, and spawning all sorts of further forms of harm and dysfunction. Like rust in complex metal structures, the many varied failures suffered by old people result from what are comparatively simple root causes.

A great deal is known about these causes of aging, despite the fact that the scientific community argues incessantly over which are more important and how exactly they relate to specific age-related diseases. We can talk in detail about mitochondrial DNA damage, accumulation of senescent cells, build up of misfolded proteins called amyloids between cells and metabolic waste called lipofuscin within cells, harmful cross-links that gum together important proteins, and so forth. For all these forms of damage there exist research plans that lead to plausible treatments. In most cases there is a trickle of progress towards establishing these solutions, ways to reverse damage accumulation and remove the harm that has been done already in old people. That trickle must become a flood if we are to see significant progress towards reversal of aging and defeat of age-related disease in our lifetimes. The first prospective treatments don't even have to fix everything - they just have to fix most of the harm in every category. We go through life in our thirties to our fifties with a fair level of damage, but comparatively low mortality rates: there is a threshold past which things spiral downwards, and for so long as we can maintain ourselves beneath that threshold of damage then we are set for a long term of health and vigor without pain or suffering or disability.

This is why it is important to raise funds for well-run organizations like the SENS Research Foundation, groups that are in a position to remove the roadblock that prevents the small amount of research today from becoming a large amount of research tomorrow. Invariably there is a tipping point in any line of research: before the point is reached every for-profit investor and institutional research fund will look for something else that is further along, with less risk. After the tipping point, the early pioneers are quickly buried and forgotten beneath a torrent of funding and mainstream research interest. Our job is to move SENS rejuvenation research to the tipping point: fund the work that builds the toolkits, the proofs of concept, the initial databases, and all the other comparatively simple, low cost items that are yet pending. We want to be buried in interest: bring it on. Biotechnology is cheap these days; a smart young researcher can undertake significant cutting edge prototype work in medical research in six months and for a few tens of thousands of dollars given an established lab to work in.

What is the greatest difference you can make in the world? To my eyes it is saving as many lives and preventing as much pain as possible. Aging and the death and suffering it causes is the worst thing we suffer, and far more should be done to stop it than is present being accomplished. If you agree with me on this point, then step up and help to do something about it! Make the world a better place in one of the few ways that will touch everyone.


The process of metastasis is why malign cancers of all sorts turn out to be fatal in the end: their cells spread throughout the body to establish new tumors and outpace the ability of present treatments to keep up. The promise of the near future of cancer medicine is largely predicated on its ability to deal with metastasis. One approach is the use of targeted cell killing technologies that recognize cancer cells by their surface chemistry, capable of chasing down errant cells wherever they are in the process of spreading or building tumors. I think this is likely the type of treatment that will dominate the next generation of cancer treatments, as a range of different approaches to targeting are presently well advanced in the laboratory and clinical trials: immune therapies, simple nanomachines, engineered viruses, and so forth.

Another approach is to interfere with the process of metastasis in order to shut it down or at least suppress it, which would make many types of cancer more amenable to successful treatment with present day standards of surgery, radiotherapy, and chemotherapy. There hasn't been a great deal of success in suppressing metastasis in comparison to development of means to target cancer cells, but nonetheless a few approaches have been attempted. In the paper quoted below, researchers suggest that use of mitochondrially targeted antioxidants might be effective as a means of reducing metastasis to very low levels. If this bears out, it may attract more interest in the development of these compounds, which have been demonstrated to modestly extend life in mice as well as showing promise as treatments for a range of conditions.

Mitochondrial DNA damage is implicated in the progression of aging, and one theory is that this damage is caused by the generation of reactive oxygen species (ROS) within the mitochondria in the course of ordinary operation. So in theory life-long treatment with mitochondrially targeted antioxidants, carefully engineered compounds quite different from the antioxidants you can buy in a supplement store, will extend life by soaking up some of those ROS before they cause harm. As an approach to extending life this is poor in comparison to methods of mitochondrial damage repair, however. It can only slow the progression of aging somewhat, not turn back the clock.

Researchers at UCL identify a treatment that prevents tumor metastasis

[Researchers have] succeeded in pinpointing a family of pharmaceutical compounds whose action prevents the appearance of tumor metastasis. The researchers achieved this tour de force by studying the mitochondria in tumor cells. These organelles are considered as the cells' power station. But when their functioning is altered, as [the] researchers observed in tumor cells, the mitochondria can promote cell migration, thus leading to the formation of metastasis.

[The researchers] examined the molecular mechanism responsible for the mitochondria's ability to promote metastasis. They succeeded in showing that, under certain conditions, the mitochondria produce more free radicals known as superoxide ions (O2.-). It is this overproduction of superoxide that leads to the formation of metastasis and, consequently, the growth of a tumor. Involved in other human pathologies such as Parkinson's and Alzheimer's disease, the production of superoxide by the mitochondria can be blocked by very specific antioxidants such as MitoTEMPO. Used in models of murine and human tumors, these compounds turned out to be very efficient at blocking the migration of tumor cells and preventing the spontaneous formation of human tumor metastasis in mice.

A Mitochondrial Switch Promotes Tumor Metastasis

Metastatic progression of cancer is associated with poor outcome, and here we examine metabolic changes underlying this process. Although aerobic glycolysis is known to promote metastasis, we have now identified a different switch primarily affecting mitochondria. The switch involves overload of the electron transport chain (ETC) with preserved mitochondrial functions but increased mitochondrial superoxide production. It provides a metastatic advantage phenocopied by partial ETC inhibition, another situation associated with enhanced superoxide production. Both cases involved protein tyrosine kinases Src and Pyk2 as downstream effectors. Thus, two different events, ETC overload and partial ETC inhibition, promote superoxide-dependent tumor cell migration, invasion, clonogenicity, and metastasis. Consequently, specific scavenging of mitochondrial superoxide with mitoTEMPO blocked tumor cell migration and prevented spontaneous tumor metastasis in murine and human tumor models.


The car analogy that shows up most often in my circles relates to repair and the biological damage of aging. We, like cars, are machines. We differ only in complexity, and the same methods arising from reliability theory can be used to model progressive dysfunction and systems failure over time in both vehicles and people. Given sufficient tools and resources a car can be maintained in good working condition indefinitely, a Ship of Theseus pattern progressing forward into the indefinite future. This is something we could achieve now for any model of car in the world, but for the most part choose not to. The only reason we cannot presently achieve the same result for people is that we lack the tools, the rejuvenation toolkit outlined in the SENS research proposals, ways to repair the known forms of damage that distinguish old tissue from young tissue. In principle we could all become Ships of Theseus once rejuvenation therapies exist, with the unit of replacement being individual cells where the precise details of structure and molecular arrangements matter (largely in the brain) and anything up to whole organs elsewhere in the body. This is entirely possible and plausible, and given sufficient funding could arrive soon enough to matter for most of us.

This is the car analogy for rejuvenation research supporters, used as a way to help convince uninformed audiences skeptical about the prospects for prevention and reversal of aging. We can maintain cars, therefore it is reasonable to work on ways to maintain people. Insofar as thinking about maintenance goes, people and cars are basically the same class of entity. The rejuvenation research crowd are not the only set of folk thinking about extending life, however, and they are (unfortunately) far from the most numerous at this time. The majority of people inside and outside the scientific community with an interest in enhanced longevity think in terms of slowing aging and altering the operation of metabolism: incremental, small advances towards better operation of the human machine. In comparison to rejuvenation research vast sums are directed towards that goal, though it is still a very small field in comparison to medicine as a whole. As long-time readers will know by now, I think little of slowing aging as a goal: it is the expensive road to a near-useless end result. What good is slowing aging for those who are already old? Metabolism is fantastically complex and the prospects for significant progress in altering it to extend life are remote, judging by the time and money expended and lack of results obtained to date, and this is generally acknowledged as true by scientists in the field.

Outside the scientific community, people are more enthusiastic about the prospects to extend life by incremental advances in drugs, supplements, and other things I'd consider a pointless waste of time in comparison to the more serious modern applications of biotechnology in SENS research. These folk have their own car analogy, which is sketched in the post quoted below. It is a helpful read if you're looking to understand the mindset that has people chasing the mythical ever-better combination of supplements and prospective new ways to manipulate metabolism to slow aspects of aging:

What do we need to do to live longer, healthier lives? An editorial tale of cars and people

Can we expect to live longer and longer as the first part of this century rolls by? I think so, probably by a large amount. Will this extension of human lives be because of basic new scientific breakthroughs? Yes, but only in part. Collectively, such breakthroughs are likely to be important. Curiously though, I don't think that any single such breakthrough will make an immense difference. What will matter is a process issue, and whether and how such breakthroughs are applied is only one consideration.

So, how then will it happen? I argue here that extended longevity is likely to happen via a number of incremental steps,probably small ones at that. Most will involve improvements in lifestyle and diet. Others will involve selective application of stresses and consumption of health-producing phytosubstances and selected dietary supplements. I think you can move along the increasing longevity curve by pursuing a long string of incremental lifestyle and dietary modifications over time, each of which may seem to produce only modest results. Some steps may seem to be very tiny and insignificant, such as getting up from the computer and walking around a bit every hour.

Let's start by talking about, my grandmother's 1950 Chevy Bel Air, purchased new. . If you were middle class and lived in Detroit you were expected to turn your car in every year for a new car, or at least every 2-3 years. Most cars did not survive the junk heap for more than 4-5 years. A three-year-old car was a seriously old car and you could expect to put less than 50,000 miles on it before it died. [In contrast, consider] our 2005 Subaru Impreza which we purchased in 2004. Expected lifespan: 15-20 years, perhaps 200,000 miles. This 10 year old car is still healthy, vigorous and a reliable family workhorse with no known problems at 100,000 miles. No sign of rust.

What was the big scientific or technical breakthrough that made the difference in lifespan and performance between the earlier cars and our Subarus? Lifespan extension of a factor of at least four and MPG improvement by a factor of two? None! In fact, it wasn't any single big scientific or engineering breakthrough. The difference is because of thousands of incremental improvements made year after year in just about every component and system. Virtually everything has been improved to make cars more reliable, last longer and operate more economically.

To be clear, I think it is arrant nonsense to state, as the author does above, that we could incrementally move to doubling our life spans without the application of modern biotechnology, interventions that meaningfully and directly repair cellular damage. Not diet, not drugs, not random compounds dredged from the natural world because they turn out to do more good than harm, but designed applications of molecular machinery that achieve specific goals in our biochemistry, reverting most or all forms of low-level damage in and between our cells. This is a night and day difference in goals, ambition, and methodology. If you had a perfect diet and lifestyle, you'd still mostly likely die before age 90 in the environment of today's medical technology - because it is medical technology that overwhelmingly determines your life span, not your lifestyle.

Putting that aside, the rest of the article actually has little to do with specific implementation details and is more concerned with a vision of organized incremental improvement in life span. It is long and worth reading as a matter of interest.


The Healthspan Campaign is more or less the voice of the Longevity Dividend viewpoint of the next few decades of aging research and its applications in clinical medicine. This alliance of advocates and researchers favor large increases in government funding of aging science through the National Institute on Aging and a consequent series of incremental increases in healthy life span. In this vision for tomorrow these increases would be driven by exactly the same sort of mainstream research into aging that has dominated for the past decade or two. By this I mean the standard issue drug discovery process, manipulating metabolism to modestly slow the pace of aging, investigation of the mechanisms of calorie restriction, forcing reversal of epigenetic changes in aging to restore stem cell populations to greater activity, and so forth. There is a little overlap between the Longevity Dividend and the much more ambitious rejuvenation research of SENS, but only a little - just a few areas in which there is common interest.

In the Longevity Dividend view, achieving an additional seven years of healthy life expectancy is an ambitious goal that will require billions in funding and two decades to achieve. I think this is probably about right if the field continues on the present path that characterizes mainstream aging research. Altering metabolism and epigenetic patterns is a very challenging, very expensive way to make slow progress towards treatments that will be of little use for people who are already old. What benefit in slowing down aging when you are already nearly aged to death? Further, the intersection of metabolism and aging is very poorly understood and enormously complex: the whole point of SENS and any similar repair-based approach to aging is that we can bypass most of that complexity by focusing on the known differences between old and young tissue. Just fix the damage, don't worry about exactly how it progresses in detail. Unfortunately the SENS view is not yet as popular in the research community as it deserves to be.

The Healthspan Campaign puts out a regular newsletter and is working on an long term advocacy campaign leading towards the end goal of much greater public funding and support among members of related institutional research organizations. To that end there is a fair amount of effort taking place to raising awareness among the public, and this tends to raise the water for all boats, whether the Longevity Dividend or initiatives like SENS with better prospects for producing meaningful results in our lifetimes. It is very important to have this outreach, in which researchers stand up and sign their names to the idea that we can do something about degenerative aging and thereby increase healthy life spans. Most of the public are either unaware of the potential, or reflexively opposed to longevity research because they think, wrongly, that it would mean being older for longer rather than younger for longer. So at this point every well-forged publicity effort such as this one below moves the needle for all initiatives:

The Healthspan Imperative

The Healthspan Imperative looks at our country's next great priority: solving the challenges brought about by the aging of the American population. Narrated by Emmy Award-winning television show host and bestselling author Martha Stewart, it features exclusive interviews from leading scientists and aging research experts.

For more than a century, the human race has enjoyed an unprecedented increase in its lifespan. Through advances in science and technology, many can expect to live life well into their 80s, 90s and beyond. But this increase in longevity has not come without consequences. With each passing year, the percentage of people in the United States - and much of the world - over age 65 increases. This "Silver Tsunami" is expected to bring a flood of chronic disease and disabilities of aging. A flood which could overwhelm the health care systems of many nations.

It's an issue that has come to the forefront of our national consciousness and a challenge that has been undertaken by some of the world's best scientists, doctors and professionals. The goal: Increase not just our lifespan but our healthspan, the length of time we spend free of the costly and harmful conditions of old age.

The Healthspan Imperative explores the challenges created by the longevity revolution. And the potential of aging research to turn back the clock. Not to make us older for a longer time, but so that we might enjoy more years of healthy, vigorous life. A clear call to action on an issue that affects everyone, The Healthspan Imperative will change the conversation on how we view aging.


The stem cells responsible for generating blood, hematopoietic stem cells, are of considerable importance because they are the origination point for new immune cells. Much of the ongoing investigation into mechanisms that cause the age-related decline of the immune system focus on the thymus, where T cells develop, and on structural deficiencies in the immune system's operation that lead to memory T cells crowding out the naive T cells needed to destroy pathogens. There is a great deal in those two areas that might be done to restore the old immune system to former strength: rejuvenate the thymus to boost the pace at which immune cells come to readiness after creation, or selectively destroy excess memory T cells to prompt the generation of fresh replacement naive T cells.

Here, however, is another line of thinking and another contribution to the reduced influx of new immune cells. It is based on a form of damage to hematopoietic stem cells, though as for many of these things it is unclear at this point as where the observed changes stand in the hierarchy of damage and reactions to damage. Most stem cell populations have evolved to decline in function with age, most likely because this reduces the risk of cancer: the longer human life span in comparison to other primates is somewhat linked with this balance between failing tissue maintenance and lowered cancer risk. Different populations of stem cells may have achieved this decline in wildly divergent ways, however, and so a whole range of entirely different mechanisms are probably involved. Investigations of muscle stem cells strongly suggest that these mechanisms are largely reactions to damage and can be reversed by suitable signals or epigenetic changes - or in theory by repairing the damage, such as via SENS rejuvenation therapies. Again, however, this isn't necessarily the case for every stem cell population in the body. Biology is enormously complex, and finding similarities should be the more surprising outcome, not finding differences.

Key to Aging Immune System Is Discovered

Blood and immune cells are short-lived, and unlike most tissues, must be constantly replenished. The cells that must keep producing them throughout a lifetime are called "hematopoietic stem cells." Through cycles of cell division these stem cells preserve their own numbers and generate the daughter cells that give rise to replacement blood and immune cells. But the hematopoietic stem cells falter with age, because they lose the ability to replicate their DNA accurately and efficiently during cell division.

In old blood-forming stem cells, the researchers found a scarcity of specific protein components needed to form a molecular machine called the mini-chromosome maintenance helicase, which unwinds double-stranded DNA so that the cell's genetic material can be duplicated and allocated to daughter cells later in cell division. In their study the stem cells were stressed by the loss of activity of this machine and as a result were at heightened risk for DNA damage and death when forced to divide.

The researchers discovered that even after the stress associated with DNA replication, surviving, non-dividing, resting, old stem cells retained molecular tags on DNA-wrapping histone proteins, a feature often associated with DNA damage. However, the researchers determined that these old survivors could repair induced DNA damage as efficiently as young stem cells. "Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated. Everybody talks about healthier aging. The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning."

Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells

Haematopoietic stem cells (HSCs) self-renew for life, thereby making them one of the few blood cells that truly age. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in degraded blood production and impaired engraftment following transplantation. While many drivers of HSC ageing have been proposed, the reason why HSC function degrades with age remains unknown.

Here we show that cycling old HSCs in mice have heightened levels of replication stress associated with cell cycle defects and chromosome gaps or breaks, which are due to decreased expression of mini-chromosome maintenance (MCM) helicase components and altered dynamics of DNA replication forks. Nonetheless, old HSCs survive replication unless confronted with a strong replication challenge, such as transplantation. Our results identify replication stress as a potent driver of functional decline in old HSCs, and highlight the MCM DNA helicase as a potential molecular target for rejuvenation therapies.


Monday, July 28, 2014

High levels of the protein produced by the klotho gene are associated with longevity in mammals, and recently it has also been associated with greater cognitive performance. Here is another small piece of evidence to add to all that:

Alzheimer's disease (AD) is the most frequent age-related dementia affecting 5.4 million Americans including 13 percent of people age 65 and older and more than 40 percent of people over the age of 85. In AD the cognitive decline and dementia result from the death of nerve cells that are involved in learning and memory. The amyloid protein and the excess of the neurotransmitter glutamate are partially responsible for the neuronal demise.

Nerve cells were grown in petri dishes and treated with or without Klotho for four hours. Amyloid or glutamate then were added to the dish for 24 hours. In the dishes where Klotho was added, a much higher percentage of neurons survived than in the dishes without Klotho. "Finding a neuroprotective agent that will protect nerve cells from amyloid that accumulates as a function of age in the brain is novel and of major importance. We now have evidence that if more Klotho is present in the brain, it will protect the neurons from the oxidative stress induced by amyloid and glutamate."

Klotho is a large protein that cannot penetrate the blood brain barrier so it can't be administered by mouth or injection. However in a separate study the researchers have identified small molecules that can enter the brain and increase the levels of Klotho. "We believe that increasing Klotho levels with such compounds would improve the outcome for Alzheimer's patients, and if started early enough would prevent further deterioration. This potential treatment has implications for other neurodegenerative diseases such as Parkinson's, Huntington's, ALS and brain trauma, as well."

Monday, July 28, 2014

The immunosuppressant compound rapamycin has been demonstrated to slow aging in mice, though with unpleasant side-effects, and some debate over whether this is in fact a slowing of aging or just a reduction in cancer incidence. The present consensus on its mode of operation is that it produces longevity-related effects by suppressing the generation of two protein complexes, mTORC1 and mTORC2, both of which include the mTOR protein that has long been associated with rapamcyin. Of these two complexes, the effects of lowered levels of mTORC1 are better understood and more clearly beneficial. Here researchers delve into mechanisms associated with mTORC2, which are much more of a mixed bag. For the research groups involved in this work, the goal is to design new drugs that only trigger the beneficial alterations from the full set of those induced by rapamycin:

The nematode worm Caenorhabditis elegans provides a powerful system for elucidating how genetic, metabolic, nutritional, and environmental factors influence aging. The mechanistic target of rapamycin (mTOR) kinase is important in growth, disease, and aging and is present in the mTORC1 and mTORC2 complexes. In diverse eukaryotes, lifespan can be increased by inhibition of mTORC1, which transduces anabolic signals to stimulate protein synthesis and inhibit autophagy. Less is understood about mTORC2, which affects C. elegans lifespan in a complex manner that is influenced by the bacterial food source. mTORC2 regulates C. elegans growth, reproduction, and lipid metabolism by activating the SGK-1 kinase, but current data on SGK-1 and lifespan seem to be conflicting.

Here, by analyzing the mTORC2 component Rictor (RICT-1), we show that mTORC2 modulates longevity by activating SGK-1 in two pathways that affect lifespan oppositely. RICT-1/mTORC2 limits longevity by directing SGK-1 to inhibit the stress-response transcription factor SKN-1/Nrf in the intestine. Signals produced by the bacterial food source determine how this pathway affects SKN-1 and lifespan. In addition, RICT-1/mTORC2 functions in neurons in an SGK-1-mediated pathway that increases lifespan at lower temperatures.

RICT-1/mTORC2 and SGK-1 therefore oppose or accelerate aging depending upon the context in which they are active. Our findings reconcile data on SGK-1 and aging, show that the bacterial microenvironment influences SKN-1/Nrf, mTORC2 functions, and aging, and identify two longevity-related mTORC2 functions that involve SGK-regulated responses to environmental cues.

Tuesday, July 29, 2014

The organelles known as mitochondria play the role of power plant in the cell, generating energy stores to power cellular operations. As for all cellular components, mitochondria are built of proteins derived from DNA blueprints, but unlike all other cellular components mitochondria have their own DNA, separate from that in the cell nucleus. They are descendants of symbiotic bacteria, and continue to replicate like bacteria within our cells. Certain types of damage to mitochondrial DNA are one of the contributing causes of degenerative aging: mitochondria missing certain proteins become dysfunctional, ultimately taking over a small fraction of all cells by old age, and causing widespread harm in surrounding tissues.

In this paper researchers consider the process by which one bad mutation in one mitochondrion eventually fills the cell with duplicates of itself. This is one of the areas in which there is plenty of room for argument: does it happen because it confers the ability to replicate more readily, because it allows damaged mitochondria to evade quality control mechanisms, or for some other reason? As is often the case negative results in studies still add information to the overall picture:

Large-scale mitochondrial DNA (mtDNA) deletions are an important cause of mitochondrial disease, while somatic mtDNA deletions cause focal respiratory chain deficiency associated with ageing and neurodegenerative disorders. As mtDNA deletions only cause cellular pathology at high levels of mtDNA heteroplasmy, an mtDNA deletion must accumulate to levels which can result in biochemical dysfunction - a process known as clonal expansion. A number of hypotheses have been proposed for clonal expansion of mtDNA deletions, including a replicative advantage for deleted mitochondrial genomes inferred by their smaller size - implying that the largest mtDNA deletions would also display a replicative advantage over smaller mtDNA deletions.

We proposed that in muscle fibres from patients with mtDNA maintenance disorders, which lead to the accumulation of multiple mtDNA deletions, we would observe the largest mtDNA deletions spreading the furthest longitudinally through individual muscle fibres by means of a greater rate of clonal expansion. We characterized mtDNA deletions in patients with mtDNA maintenance disorders from a range of 'large' and 'small' cytochrome c oxidase (COX)-deficient regions in skeletal muscle fibres. We measured the size of clonally expanded deletions in 62 small and 60 large individual COX-deficient f regions. No significant difference was observed in individual patients or in the total dataset. Thus no difference existed in the rate of clonal expansion throughout muscle fibres between mtDNA deletions of different sizes; smaller mitochondrial genomes therefore do not appear to have an inherent replicative advantage in human muscle.

Tuesday, July 29, 2014

The state of infrastructure technologies in the cryonics industry is improving slowly over time. Most organizations in the community are volunteer based, which puts a greater burden on the few professional groups to work on research and development. Nonetheless, cryonics today is a more reliable undertaking than at any point in the past decades of its existence as an option, even if there is still a lot of room for improvement. That improvement can only arrive rapidly given an expansion of the industry, however, something that has stubbornly refused to occur for a long time now:

For decades Alcor has welcomed members residing overseas, and pledged to attempt to cryopreserve members who suffer legal death while traveling outside the United States. However options for responding to overseas cases have been very limited. Historically there has been a choice between shipping on water ice near 0 degrees Celsius (with or without blood replacement) and attempting subsequent cryoprotective perfusion at Alcor to eliminate or minimize ice formation, or so-called "straight freezing" to dry ice temperature of -79 degrees Celsius without cryoprotective perfusion and shipping to Alcor.

Cryoprotective perfusion after a prolonged period of cold ischemia is usually very difficult, typically leading to the difficult decision to "straight freeze" overseas cases to dry temperature prior to shipping. Freezing without cryoprotectant is extremely damaging to tissue. About all that can be said for it is that it is better than the alternative of not being cryopreserved at all.

There is now a better alternative. Alcor has developed a simple system for perfusing cryoprotectant solution in a remote field setting instead of requiring patients to first arrive at Alcor's facility. After completion of this field cryoprotection, patients can be cooled to dry ice temperature (-79 degC) for shipment to Alcor with less time urgency and a slower rate of biological damage than at 0 degrees. Once at Alcor, cooling is resumed to the temperature of liquid nitrogen (-196 degC) at which temperature tissue is stable for practically unlimited lengths of time.

Alcor's initial implementation of field cryoprotection is still crude compared to cryoprotective perfusion in Alcor's operating room. Temperature and pressure control are limited, the cryoprotectant concentration rises more rapidly than is ideal, and the perfusion time is comparatively brief. Very importantly, the present field cryoprotection procedure only perfuses the head and brain with cryoprotectant, so the body of whole body members receiving field cryoprotection will still be frozen without cryoprotectant. However, this is obviously a better outcome than the entire body, including the brain, being frozen without cryprotectant.

Wednesday, July 30, 2014

Age related macular degeneration (AMD) is one of the first prospective targets for prototype rejuvenation treatments. This is because the relationship between the condition and one of the primary forms of change between young and old tissue is both direct and comparatively well understood: certain hardy metabolic waste compounds accumulate in long-lived retinal cells to cause increasing dysfunction over the timescale of a human life span, and this occurs because our cellular recycling machinery cannot effectively break down these compounds. The best solution is to develop drugs or make use of tools such as bacterial enzymes that can do this for us; comparatively few groups are working on this angle, however.

Ageing disorders can be defined as the progressive and cumulative outcome of several defective cellular mechanisms as well as metabolic pathways, consequently resulting in degeneration. Environment plays an important role in its pathogenesis. Age related macular degeneration (AMD) is one such retinal degenerative disorder which starts with the progression of age. Metabolism plays an important role in initiation of such diseases of ageing. Cholesterol metabolism and their oxidized products like 7-ketocholesterol have been shown to adversely impact retinal pigment epithelium (RPE) cells. These molecules can initiate mitochondrial apoptotic processes and also influence the complements factors and expression of angiogenic proteins like VEGF etc.

Age related macular degeneration (AMD) is described by irreversible vision loss in older age. The disease pathology emerges with the degeneration of macula which forms the central part of retina. The macula consists of photoreceptor (rods and cones) important for central vision. As AMD symptoms appear, characteristic features such as formation of drusen, consisting of active and inactive complement associated inflammatory products, aggregate of lipoprotein, cell debris, oxysterols, oxidized phospholipids and Alu RNA deposits begin to emerge later in life.

These aggregates deposit in the extra-cellular space between Bruch's membrane and retinal pigment epithelium cells (RPE). Gradual and consistent effects of these aggregates gradually cause degeneration of these cells followed by global atrophy of RPE cells, commonly known as geographic atrophy (GA). Besides, active inflammatory components of these deposits between Bruch's membrane and RPE, stimulate angiogenic factors (e.g., VEGF, TGFB etc.) which act on choriocapillary network beneath the Bruch's membrane and stimulate proliferation to new blood vessels (a process called neovascularization). These newly formed blood vessels can outgrow into the RPE cells and result in disruption of RPE cell integrity and function which is well preserved in early life.

Wednesday, July 30, 2014

Sarcopenia is the name given to age-related loss of muscle mass and and strength, although by the time it is processed through the regulatory system into a formal, final disease definition, it will be restricted to referring to only severe levels of loss. Average loss of muscle mass and strength will be called normal, just a part of aging, and therefore something that shouldn't be treated - and indeed, that it is forbidden to treat, as in regulatory systems like that of the FDA in the US, everything that is not explicitly permitted is illegal. This is a major systemic problem with the present system of medical regulation, one that has to be changed, and soon. It is no wonder that we see only slow progress in research and fundraising when treating degenerative aging is largely forbidden, especially any focus on causes and prevention rather than patching over late stage consequences after the fact.

Here is an open access review of a range of approaches in mainstream research aimed at slowing the onset and progression of sarcopenia, most of which haven't made it as far as drug development yet. As for so many of these topics it overwhelmingly focuses on alteration of metabolic processes rather than repair of root causes: slowing the progression of damage only, not reversing it.

The term sarcopenia was originally created to refer age-related loss of muscle mass with consequent loss of strength. There are now four international definitions of sarcopenia. In essence they all agree, requiring a measure of walking capability [either low gait speed or a limited endurance (distance) in a 6-min walk], together with an appendicular lean mass of [less than 2 standard deviations below] of a sex and ethnically corrected normal level for individuals 20-30 years old. Sarcopenia is a prevalent health problem among the elderly. On average, 5-13% and 11-50% of people aged 60-70 years and ≥80 years, respectively suffer sarcopenia with higher prevalences (68%) been reported in nursing home residents ≥70 years.

Sarcopenia needs to be differentiated from cachexia, which is a combination of both muscle and fat loss and is usually attributable to an excess of catabolic cytokines associated with a disease process. Sarcopenia is a prime component of the frailty syndrome, and both sarcopenia and frailty are associated with increased disability, falls, hospitalization, nursing home admission, and mortality.

Medical efforts to develop treatments aiming at preventing aging sarcopenia as well as acute muscle atrophy and frailty in critical patients are considered a step forward in public health. Several hormonal therapies have been proposed for this purpose. However, the secondary effects associated with these therapies make it necessary to find novel non-toxic and non-hormonal therapies. In this way, elderly or bedridden patients may improve muscle function and decrease the degree of dependence associated with these populations. New drugs such as allopurinol or losartan, all of them approved by the Food and Drugs Administration (FDA) and actually prescribed for the treatment of other diseases, could be useful in preventing loss of muscle mass in the described susceptible populations yet new pharmacological targets are needed.

As an essential step for the prevention of aging-related diseases, and specifically, sarcopenia, more basic research is needed on the main cellular hallmarks of muscle senescence. There is a plethora of potential molecular signals that are candidates to be targeted in future treatment strategies aiming at combating sarcopenia, a devastating effect of aging that is often overlooked.

Thursday, July 31, 2014

Here is a small slice of broader efforts to investigate and understand the range of differences in longevity and cellular biochemistry between species. It seems likely that these research programs will provide additional helpful information beyond that derived from the straightforward study of human biochemistry when it comes to work on treating aging:

Species differ greatly in their rates of aging. Among mammalian species life span ranges from 2 to over 60 years. Here, we test the hypothesis that skin-derived fibroblasts from long-lived species of animals differ from those of short-lived animals in their defenses against protein damage. In parallel studies of rodents, nonhuman primates, birds, and species from the Laurasiatheria superorder (bats, carnivores, shrews, and ungulates), we find associations between species longevity and resistance of proteins to oxidative stress after exposure to H2O2 or paraquat. In addition, baseline levels of protein carbonyl appear to be higher in cells from shorter-lived mammals compared with longer-lived mammals.

Thus, resistance to protein oxidation is associated with species maximal life span in independent clades of mammals, suggesting that this cellular property may be required for evolution of longevity. Evaluation of the properties of primary fibroblast cell lines can provide insights into the factors that regulate the pace of aging across species of mammals.

Thursday, July 31, 2014

The company Human Longevity was recently founded to work on the genetics of aging and health. My thinking is that genetics is a hot field, and there is much to be done in the general context of medicine, but that insofar as longevity goes it is the wrong place to be looking for large benefits. Epigenetic and gene expression changes are secondary consequences in aging, not the root cause, and natural genetic variations have a small effect on aging in comparison to what might be possible through repair biotechnologies such as those of the SENS vision. So for aging the outcome of Human Longevity is likely to be incremental advances in the present day practice of ignoring the comparatively simple causes of degeneration, the accumulation of damage, while trying to patch over the very complex end states by tinkering with enormously complex dysregulations of metabolism and biological systems that occur in response to damage. This is doomed to only marginal success, just like the medicine of today.

Here is a piece that provides more context on where Human Longevity is headed in the near term: undoubtedly useful, just not so much for aging. We all age in the same way, due to the same root causes involving an accumulation of specific, known forms of damage to cells and molecular tissue structures. Fix those causes by repairing them and near all but the most rare and catastrophic genetic variations are irrelevant. They simply don't matter.

Genome scientist and entrepreneur J. Craig Venter is best known for being the first person to sequence his own genome, back in 2001. This year, he started a new company, Human Longevity, which intends to sequence one million human genomes by 2020. Venter says that he's sequenced 500 people's genomes so far, and that volunteers are starting to also undergo a battery of tests measuring their strength, brain size, how much blood their hearts pump, and, says Venter, "just about everything that can be measured about a person, without cutting them open." This information will be fed into a database that can be used to discover links between genes and these traits, as well as disease. But that's going to require some massive data crunching.

In my view there have not been a significant number of advances [in genomics]. One reason for that is that genomics follows a law of very big numbers. I've had my genome for 15 years, and there's not much I can learn because there are not that many others to compare it to. Until now, there's not been software for comparing my genome to your genome, much less to a million genomes. We want to get to a point where it takes a few seconds to compare your genome to all the others. It's going to take a lot of work to do that.

Understanding the human genome at the scale that we are trying to do it is going to be one of the greatest translation challenges in history. Everything in a cell derives from your DNA code, all the proteins, their structure, whether they last seconds or days. All that is preprogrammed in DNA language. Then it is translated into life. People are going to be very surprised about how much of a DNA software species we are.

Friday, August 1, 2014

Cancer researchers here stumble upon a way to alter mitochondrial function to improve health and extend life in mice. A range of the known ways to slow aging through genetic alteration work through similar mechanisms to those shown here, creating somewhat dysfunctional mitochondria that can still perform their necessary functions but which generate a raised level of damaging oxidative molecules in the process. This spurs cells to increase cellular housekeeping activities in response, which in turn leads to a net gain in cellular health and function. Over the lifespan of an organism these small differences in every cell add up.

The mice, which lack the TRAP-1 protein, demonstrated less age-related tissue degeneration, obesity, and spontaneous tumor formation when compared with normal mice. TRAP-1 is a member of the heat shock protein 90 (HSP90) family, which are "chaperone" proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria.

The researchers found that in their knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which then triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This causes mitochondria in knockout mice to produce deregulated levels of ATP, the chemical used as an energy source to power all the everyday molecular reactions that allow a cell to function.

This increased mitochondrial activity actually creates a moderate boost in oxidative stress ("free radical damage") and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation - slowing growth down to allow the cell's natural repair mechanisms to take effect. "Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity. I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions."

Friday, August 1, 2014

It is known that greater health throughout life, greater wealth, greater social status, and greater intelligence are all associated with greater life expectancy. Untangling the nature of these linked correlations is ever a challenge, however, since they all associate with one another as well. There are any number of plausible explanations as to why the wealthy or the more intelligent live longer, and some interesting speculation besides, such as the association of intelligence with physical robustness, but rarely is there any way to prove these explanations true in the data obtained from population studies. Correlations are what is obtained, and it is then usually a matter of retreating to animal studies where it is possible to structure the work to prove causation - but of course this is somewhere between hard and impossible to achieve for intelligence and social status.

This paper reminds us of the tendency for age-matched cohorts to become on average healthier, wealthier, and wiser over time. This isn't a matter of self-improvement, though any of us can work on that, but occurs because those who were not comparatively healthy, wealthy, and wise are more likely to be dead already:

The gradual changes in cohort composition that occur as a result of selective mortality processes are of interest to all aging research. We present the first illustration of changes in the distribution of specific cohort characteristics that arise purely as a result of selective mortality. We use data on health, wealth, education, and other covariates from two cohorts (the AHEAD cohort, born 1900-23 and the HRS cohort, born 1931-41) included in the Health and Retirement Survey, a nationally representative panel study of older Americans spanning nearly two decades (N=14,466). We calculate sample statistics for the surviving cohort at each wave. Repeatedly using only baseline information for these calculations so that there are no changes at the individual level (what changes is the set of surviving respondents at each specific wave), we obtain a demonstration of the impact of mortality selection on the cohort characteristics.

We find substantial changes in the distribution of all examined characteristics across the nine survey waves. For instance, the median wealth increases from about $90,000 to $130,000 and the number of chronic conditions declines from 1.5 to 1 in the AHEAD cohort. The mortality selection process changes the composition of older cohorts considerably, such that researchers focusing on the oldest old need to be aware of the highly select groups they are observing, and interpret their conclusions accordingly.


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