Fight Aging!

FIGHT AGING! NEWSLETTER
August 12th 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

• Targeted Myostatin Gene Editing With TALENs
• A Slightly Religious White Paper on Radical Life Extension
• Fear of an Extended Old Age of Frailty and Decrepitude
• A Video Tour of Alcor and Interview With Max More
• The Cost of Living Longer, Even in Good Health
• Latest Headlines from Fight Aging!
  • Clearing Out Damaged Mitochondrial DNA With TALENs
  • International Longevity Day, October 1st
  • When It Comes to Aging, Humans are Noticeably Different
  • Alzheimer's Research as Rejuvenation Biotechnology
  • NHR-62 Necessary for Some Calorie Restriction Benefits in Nematode Worms
  • People Want the Better End of What Exists, But More Than That Isn't Within Their Horizons
  • HLH-30 Important in Autophagy-Induced Longevity
  • And Now For Something Reprehensible
  • The Current State of Knowledge of Genetics and Longevity
  • Signs of Progress: Insurers Talk of Radical Life Extension

TARGETED MYOSTATIN GENE EDITING WITH TALENS
https://www.fightaging.org/archives/2013/08/targeted-myostatin-gene-editing-with-talens.php

As a sidebar to the recently demonstrated use of transcription activator-like effector nucleases (TALENs) to clear out damaged mitochondrial DNA, something that might be of interest as the basis for therapies to partially treat degenerative aging, I though I'd point out another recent paper on how TALENs can be put to work as tools to create effective gene therapies.

Regular readers will recall that references to work on myostatin-related gene therapies show up here every now and again. Mammalian myostatin loss of function mutants are heavily muscled, have less fat, and seem modestly more resistant to a few of the degenerations of age. It is even the case that a small number of human individuals with this mutation exist. Given the degree to which loss of muscle mass and strength occurs with aging, and the cost of that frailty in terms of mortality and quality of life, some corners of the research community are interested in finding ways to trigger the benefits of myostatin loss. By the time it came anywhere near a clinic, this would probably involve a designed drug to temporarily block myostatin signaling rather than any form of gene therapy, however.

Nonetheless, here we have an example of work taking place on a TALENs based platform for gene therapy to edit the myostatin gene. This is intended to provide the basis for further, more effective research aimed at the production of therapies based on myostatin inhibition:

Targeted Myostatin Gene Editing in Multiple Mammalian Species Directed by a Single Pair of TALE Nucleases

Myostatin (MSTN) is a transforming growth factor-β family member that plays a critical role in negatively regulating skeletal muscle mass. Genetic studies have demonstrated that myostatin gene deficiency leads to muscle hypertrophy due to a combination of increased fiber numbers and increased fiber sizes in multiple species including human, cattle, mouse, sheep, and dog without causing severe adverse consequences. Therefore, extensive efforts have been undertaken to develop effective strategies for blocking the myostatin signaling pathway as therapies for various muscle-wasting diseases such as muscular dystrophy, sarcopenia, and long bedding patients. Indeed, myostatin inhibitors have shown great promise to significantly increase muscle growth in model animals.

Here, we report a new class of reagents based on transcription activator-like effector nucleases (TALENs) to disrupt myostatin expression at the genome level. We designed a pair of MSTN TALENs to target a highly conserved sequence in the coding region of the myostatin gene. We demonstrate that codelivery of these MSTN TALENs induce highly specific and efficient gene disruption in a variety of human, cattle, and mouse cells. Based upon sequence analysis, this pair of TALENs is expected to be functional in many other mammalian species.

In summary, TALEN is an effective genome-editing tool. Application of MSTN TALENs in a variety of cell lines and species would allow further investigation of myostatin functions in mammalian animals that do not have naturally occurring mutant MSTN models yet. Moreover, this TALEN pair would also be a valuable tool for cell engineering in translational research such as myoblast transplantation therapy to replace defective genes in genetic diseases including muscular dystrophy.

A SLIGHTLY RELIGIOUS WHITE PAPER ON RADICAL LIFE EXTENSION
https://www.fightaging.org/archives/2013/08/a-slightly-religious-white-paper-on-radical-life-extension.php

Big Religion shares many aspects with Big Business and Big Government, not least of which being that after a certain point the output of functionaries in these three groups, cogs in the middle tiers of the machinery, starts to become indistinguishable. So a white paper is a white paper is a white paper, its origin and intended audience only becoming clear by way of the preface and the summary. Thus the article below on the prospects for radical life extension looks much the same as any one of a number of others from various sources in recent years, and you'd have to read it all to note that it hails from one the more traditionally religious cloisters of the practicing civic religion in the US. It's a complex business when religion goes secular at the edges, or the other way around: in both cases its rather like the snail left the shell, but no-one involved really cares all that much, as dusting the shell is what keeps them busy.

In any case, I think that the article is worth reading, and is a mark of progress. The notion that radical life extension is possible and plausible continues to spread, and over the long term of decades it is that spread of ideas and supporters that is the only reliable way to boost the odds of rejuvenation therapies arriving soon enough to make a large difference to you and I personally as we struggle with old age. In the short term tactics matter, such as the victories of the SENS Research Foundation, the conferences, the noted hierarchs of the research community putting their names to rejuvenation research. But in the long term strategy matters, and strategy is really all about money, and money is really all about the number of people who agree with your goals.

The first step on the road of agreeing with the goal of greatly extending the healthy human life span, and along the way eliminating the disease, frailty, and suffering of aging, is open discussion. The more of that taking place the better, and there remain far too many places and communities in which this topic rarely if ever arises. Growth comes from new supporters, and new supporters result from greater consideration of the science and possibilities of longevity.

To Count Our Days: The Scientific and Ethical Dimensions of Radical Life Extension

The prospect of dying has always fascinated, haunted and, ultimately, defined human beings. From the beginnings of civilization, people have contemplated their own mortality - and considered the possibility of immortality. Indeed, many of humanity's oldest and best-known stories, from the Sumerian tale of "Gilgamesh" to the Old Testament Book of Genesis to Homer's "Odyssey," feature mortality and immortality as prominent themes.

Until recently, however, the possibility of dramatically extending human life has been consigned to the realm of speculation or science fiction. Scientists' understanding of why people age - and how to stop aging - was not sophisticated enough to hold out hope that life could be extended much beyond traditional old age. But that may be changing.

Today, scientists at major universities and research institutions are talking about treatments that could extend average life spans by decades - or even longer. None of these medical prospects is yet a reality, and even the most optimistic researchers acknowledge that major breakthroughs could prove elusive. But for the first time in human history, some experts believe we may be at the threshold of a new aging paradigm, one that replaces the generally accepted limits of human life with more open-ended possibilities.

It's a fairly long piece, by the abbreviated modern standards of online publication, and manages to talk about the Strategies for Engineered Negligible Senescence and medical nanotechnology in addition to the standard quick tour of drug development. That is a hopeful sign, I think, that these are now obligatory topics for any review of this nature.

FEAR OF AN EXTENDED OLD AGE OF FRAILTY AND DECREPITUDE
https://www.fightaging.org/archives/2013/08/fear-of-an-extended-old-age-of-frailty-and-decrepitude.php

It remains the case that most people think of extended lives in terms of an extended old age, meaning ever more and greater pain, suffering, frailty, and illness. We call this the Tithonus Error, after the mythic figure who obtained the cursed form of immortality, living forever but continuing to suffer the ever worsening consequences of degenerative aging. This is one of any number of cautionary tales that illustrate the merits of carefully removing loopholes from requests made to gods, demons, and sundry other elementals. These days I don't think we're doing ourselves any favors by trying to propagate this idea under the name of the Tithonus Error, however. It's not one of the few immediately recognizable myths, and so doesn't do well as a pithy shorthand that reaches out to grab people.

Whatever you want to call this business of extended degenerative aging, however, it is simply not going to happen in the real world, and no reputable scientist in the aging research community is suggesting that it will happen. All of the various presently ongoing efforts to extend life will (if successful) extend healthy life spans, reducing illness and providing more years of health and youthful vigor. All of the life extension that has occurred as a largely unintentional side effect of broad medical progress in the past century or two has also been of this form: more youth and less age-related suffering. Exactly this - more youth and less age-related suffering - has always been the goal and the most plausible outcome: aging is a matter of accumulated damage within and around cells, and anything that the research community does to reduce the current load of damage will extend the period in which you are comparatively healthy and youthful.

Yet the world at large doesn't seem to listen to the researchers who have explained this, year in and year out, since the late 1990s. In the popular imagination life extension is still locked to the idea of gaining only decades of additional tottering frailty - not an attractive proposition at all. Arguably this misconception is the greatest obstacle to obtaining the necessary public support for truly large-scale research projects of the sort needed to build rejuvenation biotechnology over the next few decades. All it will take to implement working prototype therapies described in the SENS plan for rejuvenation is a few billion dollars, a hundred million a year over that time frame - but this requires a level of awareness and support to equal that presently existing for major named diseases such as Alzheimer's, Parkinson's, and the like.

That I can point to a recent survey by one of the big public opinion organizations on the topic of radical life extension, and to discussion of the survey through the mainstream media, is in and of itself a sign of progress. This certainly wouldn't have happened ten years ago. The ideas have spread far enough, and the science and support within the scientific community grown to the point at which it cannot be completely ignored. However the survey results show that there remains a great deal to do in order to create a world in which the average fellow in the street sees degenerative aging as just another of the big threatening diseases, something that can and should be fought with medical science.

One commentary suggests that the fear of extended decrepitude is exactly the root of ambivalence towards medical research aimed at extending human life:

Americans don't want to extend their declining years. But what if you could stay young?

Would you like to live forever? Probably not. According to a new survey by the Pew Research Center, most Americans don't want to stick around much longer than current life expectancy. Sixty percent don't want to live past 90. Thirty percent don't want to live past 80. People who make lots of money don't want longer lives any more than the rest of us do. Nor do people who think there's no afterlife. What's driving our misgivings? Much of it is uncertainty about what kind of lives we'd be living. Would medical progress keep us feeling young? Or would it only stretch out our declining years?

Why so much resistance? One likely reason is dread about the nature of extended life. Pew's survey explicitly postulated treatments that "slow the aging process." But when you're being asked about living to 120 years or beyond, it's hard not to picture spending much of that time feeling withered, afflicted, and debilitated. Although the survey didn't ask about this assumption directly, several findings are consistent with it.

1. The more you associate medical treatment with higher quality of life, the more you favor life extension.
2. The more you associate longevity with productivity, the more you favor life extension.
3. The more you see extended life as a resource burden, the more you oppose it.
4. The more you see old folks as a problem, the more you oppose life extension.
5. The older you are, the less likely you are to favor life extension.
6. The less you're looking forward to the next decade, the less you favor life extension.
7. People don't want to live past the age at which severe diseases and disabilities are expected.

If resistance to life extension is based on the assumption that the extra years would be frail and painful, look out. That resistance will dissolve in the face of contrary evidence. If modern medicine learns how to slow aging, making the average 90-year-old feel as good as a 70-year-old feels today, people will recalibrate.

As the author points out, however, changes of this nature take time - probably more time than we have to wait before the absolute last minute at which we could successfully kick-start the major research programs needed to fully realize SENS or equivalent means of human rejuvenation, technologies capable of rescuing the elderly from frailty, ill-health, and impending death. This is why advocacy and the grind of fundraising and education are so very important. Success in raising more funding for SENS will mean the difference between life and death for a large fraction of those alive today.

A VIDEO TOUR OF ALCOR AND INTERVIEW WITH MAX MORE
https://www.fightaging.org/archives/2013/08/a-video-tour-of-alcor-and-interview-with-max-more.php

Cryonics is the low-temperature storage of the brain on clinical death, preserving the fine structure of the mind for a future of more advanced technologies. It is a vitally important industry for all that it is overlooked by most of the world and rejected as an alternative to the grave by nearly everyone who has actually heard of it and considered it. Even under the most optimistic plausible course of development for rejuvenation biotechnology, billions of people will die due to degenerative aging before it can be brought under medical control. Yet the technology exists today to preserve those people for a future in which they can be restored to active life through applications of advanced medical nanotechnology.

So there is dead and there is dead and gone. The grave means dead and gone - there is no future technology that can restore you once the pattern of your mind has vanished from the world. But if your brain and the structure encoding the data of your mind is preserved then you are only dead until such time as you can be safely restored. Perhaps that will never happen, but the odds are not zero, as is the case for the traditional options of burial, cremation, and so forth.

In a better world, cryonics would be a vast industry with efficiencies of scale, offering preservation at a far lower cost than it does today. Cryopreservation would be the default traditional option at the end of life, and most people would go into the future with some chance at living again. Alas, we do not live in that world. We live in the world in which people flock to certain oblivion, in which supporting scientific work on human rejuvenation is a hard sell, and in which cryonics after four decades of existence remains a very small niche industry.

The Singularity Weblog author recently visited cryonics provider Alcor for a behind the scenes tour and to interview CEO Max More. He was kind enough to upload some of the resulting video to YouTube.

My Video Tour of Alcor and Interview with CEO Max More

Last month I had the privilege of visiting Max More at the Alcor Life Extension Foundation. Alcor is a non-profit organization founded in 1972 and located in Scottsdale, Arizona. It is the world leader in cryonics, cryonics research, and cryonics technology. [Cryonics is the science of using ultra-cold temperature to preserve human life with the intent of restoring good health when technology becomes available to do so.]

During our visit CEO Dr. More walked us through the Alcor facilities as well as the process starting after clinical death is proclaimed, through the cooling of the body and its vitrification, and ending in long term storage.

After our video tour of Alcor CEO Max More was kind enough to take another 25 minutes and answer some questions. During our conversation with Max we discuss: general affordability and prices for Alcor; long-distance membership and why minimizing cooling delays is critical for optimum body preservation; preserving pets; chemical brain preservation; the importance of preserving the neuron's micro-tubules; the potential for X-prize-type of a competition for minimizing tissue damage and improving preservation; the relationship between cryonics and transhumanism.

My favorite quote that I will take away from this interview with Max More is: "Cryonics is critical care medicine taken to the next step."

THE COST OF LIVING LONGER, EVEN IN GOOD HEALTH
https://www.fightaging.org/archives/2013/08/the-cost-of-living-longer-even-in-good-health.php

There are many comparatively simple genetic alterations that enable animals of various different laboratory species to live between 10% to 60% longer. These are changes to the operation of metabolism: perhaps more autophagy, perhaps less fat tissue, perhaps fat tissue that behaves slightly less maliciously, perhaps a more resilient immune system, and so forth. The list is long and getting longer with each passing year as researchers continue to investigate the genetics of aging and longevity.

Here is a question: if all these changes are so simple, just minor genetic alterations, how is it that evolution failed to get there first? Why is it that researchers can alter the mouse genome in many different ways to extend the lives of laboratory mice? Why is the local optimal evolved state of the modern mouse short-lived in comparison to a great many close, easily-reached neighboring states?

The answer to these questions is that additional longevity is only one of many possible advantages to be obtained in evolutionary competition, and probably not a terribly good advantage in the grand scheme of things. In theory, and if individuals successfully evade natural hazards and predators, a longer life span means that a lineage can outbreed its competitors over time. Judging by the fact that very few species are unusually long-lived in comparison to their peers, however, we might conclude that longevity is only rarely more beneficial than other strategies for evolutionary success.

When researchers examine long-lived mutant mice, worms, and other short-lived species, they see signs that these lineages would be outmatched in the wild. Minor genetic changes to enhance longevity, even ones such as improved cellular maintenance that seem wholly beneficial, are not free. They come with attached costs in terms of success in the only game that matters over evolutionary time, which is the competition to propagate copies of your genome.

Hormesis and longevity with tannins: Free of charge or cost-intensive?

Hormetic lifespan extension is, for obvious reasons, beneficial to an individual. But is this effect really cost-neutral? To answer this question, four tannic polyphenols were tested on the nematode Caenorhabditis elegans. All were able to extend the lifespan, but only some in a hormetic fashion.

Additional life trait variables including stress resistance, reproductive behavior, growth, and physical fitness were observed during the exposure to the most life extending concentrations. These traits represent the quality of life and the population fitness, being the most important parameters of a hormetic treatment besides lifespan. Indeed, it emerged that each life-extension is accompanied by a constraining effect in at least one other endpoint, for example growth, mobility, stress resistance, or reproduction. Thus, in this context, longevity could not be considered to be attained for free and therefore it is likely that other hormetic benefits may also incur cost-intensive and unpredictable side-effects.

Laboratory selection for increased longevity in Drosophila melanogaster reduces field performance

Drosophila melanogaster is frequently used in ageing studies to elucidate which mechanisms determine the onset and progress of senescence. Lines selected for increased longevity have often been shown to perform as well as or superior to control lines in life history, stress resistance and behavioural traits when tested in the laboratory. Functional senescence in longevity selected lines has also been shown to occur at a slower rate.

However, it is known that performance in a controlled laboratory setting is not necessarily representative of performance in nature. In this study the effect of ageing, environmental temperature and longevity selection on performance in the field was tested. Flies from longevity selected and control lines of different ages (2, 5, 10 and 15 days) were released in an environment free of natural food sources. Control flies were tested at low, intermediate and high temperatures, while longevity selected flies were tested at the intermediate temperature only. The ability of flies to locate and reach a food source was tested.

Flies of intermediate age were generally better at locating resources than both younger and older flies, where hot and cold environments accelerate the senescent decline in performance. Control lines were better able to locate a resource compared to longevity selected lines of the same age, suggesting longevity comes at a cost in early life field fitness, supporting the antagonistic pleiotropy theory of ageing.

If you are a member of a species with access to advanced medical technology, none of this much matters any more, of course. The future of longevity under those circumstances is determined by progress in technology rather than evolution: natural selection just sets the scene, and ensures that we are all dissatisfied with the hand we have been dealt.

LATEST HEADLINES FROM FIGHT AGING!

CLEARING OUT DAMAGED MITOCHONDRIAL DNA WITH TALENS
Monday, August 5, 2013
https://www.fightaging.org/archives/2013/08/clearing-out-damaged-mitochondrial-dna-with-talens.php

Mitochondria are the power plants of the cell, and slowly accumulating damage to the DNA that they contain, distinct from the DNA in the cell nucleus, is thought to be an important contribution to degenerative aging. Further, a range of inherited conditions are caused by genetic errors in mitochondrial DNA, such as Leber's hereditary optic neuropathy.

The SENS Research Foundation is working on ways to eliminate the effects of accumulated mitochondrial DNA (mtDNA) damage in order to build a therapy for aging, and other groups are working on methods of mitochondrial repair aimed at treating inherited mitochondrial disease. Below you'll find recent news of progress from one of those groups. The researchers have a method that should be applicable as a means to reverse the mitochondrial DNA damage that contributes to aging. That damage is centered on thirteen important genes, so can in principle targeted by any one-gene-at-a-time method like the one demonstrated here:

Searching for strategies to repair mitochondrial gene defects, a group of [investigators] explored proteins called transcription activator-like (TAL) effectors. In nature, TAL effectors are found only in certain types of plant-infecting bacteria. They enable the bacteria to use plant DNA to multiply and spread infection.

Scientists recently began using TAL effectors to modify DNA in a variety of organisms. In the lab, TAL effectors can be fused with DNA-breaking proteins called nucleases. These TAL effector nucleases (TALENs) can be used to add or remove specific genes or correct gene mutations - techniques that fall under the broad category of genome editing. During the past few years, scientists have begun adapting TALENs and other genome-editing tools for gene therapy. Until now, scientists had only used TALENs to edit genes in the cell nucleus. Today's report marks the first time TALENs have been used to edit mitochondrial genes.

Using cells in the lab, the investigators designed mitoTALENs to bind and cut mitochondrial DNA that had a specific mutation in the gene Complex I, which causes LHON. The scientists then tested whether the mitoTALENs eliminated the mutant mtDNA. Analysis revealed a temporary drop in cells' total mtDNA, which was due to a reduction in mutant mtDNA. "Once the mitoTALENs bound and cut the DNA at the specified target, the mutant mtDNA was degraded. The drop in total mtDNA stimulated the cells to increase their mtDNA by replicating the unaffected molecules. Two weeks later, mtDNA levels had returned to normal. But since the mutant mtDNA was destroyed, the cells had mostly normal mtDNA. A modest reduction in mutant mtDNA is likely sufficient to effectively treat disease."

INTERNATIONAL LONGEVITY DAY, OCTOBER 1ST
Monday, August 5, 2013
https://www.fightaging.org/archives/2013/08/international-longevity-day-october-1st.php

Members of the International Longevity Alliance, an advocacy and political action group supportive of modern work on longevity science such as that carried out in the SENS program, are proposing October 1st to be International Longevity Day. This is a way to place the goal of extending healthy human life through medical science into the public eye for one more day each year, and as a methodology for doing so it seems fairly reliable if it can get a little impetus behind it:

Some time ago the idea was raised to celebrate a special day by the longevity movement - the Longevity Day. Now an excellent opportunity to do this is coming -the 1st of October, the official United Nations International Day of Older Persons. Let us make the Longevity Day on that day - the 1st of October this year! Let us hold meetings and other events globally!

The day is especially significant as, on that day, we have an excellent opportunity to link in the public mind the issue of aging with the issue of anti-aging research that is probably the only means to truly address and ameliorate the problem of aging. Nowadays, the issues of aging and anti-aging are often considered separately. We can change this pattern of thought and say on that day: deteriorative aging is a problem, and anti-aging research for healthy longevity can provide the solution!

Organize pro-longevity meetings in your area! There is a precedent. On March 1 this year, meetings in support of longevity and longevity research have been held in over 20 countries. We can organize more meetings in more countries now. The range of the meetings (conferences/ seminars/ study groups/ public demonstrations) can range from large scale, to just meeting with a few friends. Every kind and scope of activity is precious.

Engage mainstream public media! The fact that this is an official international UN day of older persons, and the fact that such pro-longevity events are being organized all across the world - gives you an excellent opportunity to directly approach representatives of public media and offer them to cover the topic. This is an opportunity that should not be missed. In the same way, you can approach politicians, public officials and other decision makers in your area. Point them to that day and the international organization around it, and attempt to raise their interest in the issue of longevity research.

WHEN IT COMES TO AGING, HUMANS ARE NOTICEABLY DIFFERENT
Tuesday, August 6, 2013
https://www.fightaging.org/archives/2013/08/when-it-comes-to-aging-humans-are-noticeably-different.php

Humans are long lived in comparison to other primates and similarly sized mammals. In addition some characteristics of human aging are unusual in comparison to those of neighboring species. Aging is near universal but its specific evolved manifestations are highly varied:

Women rarely give birth after ∼45 y of age, and they experience the cessation of reproductive cycles, menopause, at ∼50 y of age after a fertility decline lasting almost two decades. Such reproductive senescence in mid-lifespan is an evolutionary puzzle of enduring interest because it should be inherently disadvantageous. Furthermore, comparative data on reproductive senescence from other primates, or indeed other mammals, remains relatively rare. Here we carried out a unique detailed comparative study of reproductive senescence in seven species of nonhuman primates in natural populations, using long-term, individual-based data, and compared them to a population of humans experiencing natural fertility and mortality.

In four of seven primate species we found that reproductive senescence occurred before death only in a small minority of individuals. In three primate species we found evidence of reproductive senescence that accelerated throughout adulthood; however, its initial rate was much lower than mortality, so that relatively few individuals experienced reproductive senescence before death. In contrast, the human population showed the predicted and well-known pattern in which reproductive senescence occurred before death for many women and its rate accelerated throughout adulthood. These results provide strong support for the hypothesis that reproductive senescence in midlife, although apparent in natural-fertility, natural-mortality populations of humans, is generally absent in other primates living in such populations.

ALZHEIMER'S RESEARCH AS REJUVENATION BIOTECHNOLOGY
Tuesday, August 6, 2013
https://www.fightaging.org/archives/2013/08/alzheimers-research-as-rejuvenation-biotechnology.php

In the view of the SENS Research Foundation, some of the present large-scale scientific work to reverse the accumulation of beta-amyloid protein (Aβ) associated with Alzheimer's disease (AD) is a form of rejuvenation biotechnology. Amyloids of all sorts are on the list of aging-associated changes that should be repaired in order to revert old tissue to the same state it had when young. The hope here is that many of the technologies developed by the Alzheimer's research community can be repurposed to address other types of unwanted compounds that accumulate between cells:

A key target for rejuvenation biotechnologies to prevent and arrest the course of AD is the removal of aggregated beta-amyloid protein (Aβ) from the brain. Amongst the constellation of factors playing some role in the pathogenesis of AD, there is now a strong case for the thesis that Aβ aggregates are at the root of its aetiology. Moreover, Aβ has also been implicated in the cognitive deficits clinically present in other age-related neurological diseases. For example, brain Aβ deposits and abnormally low levels of Aβ42 in the cerebrospinal fluid (CSF) discriminate people suffering from Parkinson's disease dementia and dementia with Lewy bodies from those suffering from Parkinson's disease but whose cognition remains intact. And even amongst people whose cognition is still within the normal range, the presence of Aβ plaque as detected [on] Positron Emission Tomography (PET) is associated with cognitive deficits and increased rate and extent of gray mattter atrophy.

The need for disease-modifying therapies in AD, and the strength of the case for Aβ as a target, have recently driven substantial regulatory reform and innovations in clinical trial design to accommodate more effective testing of Aβ immunotherapies targeting the removal of Aβ from the brain. The first fruits of these changes are the initiation of a series of large, late-stage clinical trials of Aβ vaccines in the early clinical or even preclinical phases of the disease. These reforms have wider and even more hopeful implications, because they open up the path for faster and more meaningful clinical trials of other rejuvenation biotechnologies as they emerge.

The move by scientists and regulators to begin administering Aβ immunotherapy not only early in clinical dementia, but during the preclinical phase of the disease, is an extremely important development. The new regulatory posture responds to the recognition that the volunteers in these trials are not merely "at high risk of Alzheimer's," but are fated to dementia (and to the many other diseases and disabilities of aging) unless rescued by rejuvenation biotechnology - a fate, it must be emphasized, shared by us all, as part of the degenerative aging process.

NHR-62 NECESSARY FOR SOME CALORIE RESTRICTION BENEFITS IN NEMATODE WORMS
Wednesday, August 7, 2013
https://www.fightaging.org/archives/2013/08/nhr-62-necessary-for-some-calorie-restriction-benefits-in-nematode-worms.php

Calorie restriction extends life in most short-lived species where this effect can be measured in a practical amount of time. It is suspected that the effect is smaller in long-lived species such as we humans, but nonetheless calorie restriction produces large benefits to health in human studies, far greater than can be obtained by any presently available medical technology applied to a basically healthy individual. Thus for some years researchers have been working on understanding the exceedingly complex mechanisms of calorie restriction, so as to find out how to recreate the benefits without the reduced calorie intake. It's a challenging task, nowhere near completion: calorie restriction changes just about everything in the operation of metabolism.

This research result, in which researchers shut off part of the life extension of calorie restriction, convincingly adds to the data suggesting that calorie restriction operates through several distinct mechanisms running in parallel:

The roundworm Caenorhabditis elegans lives only about 20 days. This makes it an ideal research subject, as the complete lifecycle of the worm can be studied in a short time. Also, the worm consists of less than a thousand cells, and its genetic make-up has been extensively analysed, and contains many genes similar to humans. [Results] indicate that the receptor NHR-62 must be active for reduced dietary intake to fully prolong the life of worms. If NHR-62 is inactive, Caenorhabditis elegans will live 25% longer under dietary restriction than if this receptor is inactive. "It seems that there is an as yet unknown hormone which regulates lifespan using NHR-62. If we can identify this hormone and administer it to the worm, we may prolong its life without having to change its calorie intake."

A restricted diet also affects the expression of genes dramatically: out of the approximate 20,000 worm genes, 3,000 change their activity, and 600 of these show a dependence on NHR-62. It follows that there are many other candidates for improving life expectancy. Since humans have receptors similar to NHR-62, so-called HNF-4α, the [scientists] suspect that the hormone receptors may not only control the maximum lifespan of roundworms, but might affect human beings as well.

PEOPLE WANT THE BETTER END OF WHAT EXISTS, BUT MORE THAN THAT ISN'T WITHIN THEIR HORIZONS
Wednesday, August 7, 2013
https://www.fightaging.org/archives/2013/08/people-want-the-better-end-of-what-exists-but-more-than-that-isnt-within-their-horizons.php

For the species defined by the fact that we create change, humans are surprisingly conservative. Ask anyone what they want and in the vast majority of cases you'll hear a story involving the better end of what exists: they want to be as rich as their well-off neighbors, or live as long as the older folk who do so in good health. Ambition and vision, to see how to make new options that don't yet exist, and to want to put in the work to make it happen, are in desperately short supply.

Yet still there is enormously rapid progress in creating new technologies, new options, new bounds of wealth and choice and, yes, greater longevity. The people who today tell you that they only want to live a little beyond the present median human life span will almost certainly be lining up to take advantage of rejuvenation biotechnologies that enable a person to live for centuries, when such things are available, but they won't do anything to help the development of those technologies. Yet for rejuvenation of the old and the defeat of age-related disease to arrive within our lifetimes, many of these same people must decide to help, to understand the possibilities, to support the research. It's a challenge.

The survey, conducted from March 21 to April 8, 2013, among a nationally representative sample of 2,012 adults, examines public attitudes about aging, health care, personal life satisfaction, possible medical advances (including radical life extension) and other bioethical issues. The telephone survey was carried out on cell phones and landlines, in all 50 states, with an overall margin of error for the full sample of plus or minus 2.9 percentage points.

Asked how long they would like to live, more than two-thirds (69%) cite an age between 79 and 100. The median ideal life span is 90 years - about 11 years longer than the current average U.S. life expectancy, which is 78.7 years. The public also is optimistic that some scientific breakthroughs will occur in the next few decades. For example, about seven-in-ten Americans think that by the year 2050, there will be a cure for most forms of cancer (69%) and that artificial arms and legs will perform better than natural ones (71%). And, on balance, the public tends to view medical advances that prolong life as generally good (63%) rather than as interfering with the natural cycle of life (32%). About half (54%) agree with the statement that "medical treatments these days are worth the costs because they allow people to live longer and better-quality lives," but 41% disagree, saying medical treatments these days "often create as many problems as they solve."

Only 7% of respondents say they have heard or read a lot about the possibility that new medical treatments could in the future allow people to live much longer; 38% say they have heard a little about this possibility, and about half (54%) have heard nothing about radical life extension prior to taking the survey. At this early stage, public reaction to the idea of radical life extension is both ambivalent and skeptical. Asked about the consequences for society if new medical treatments could "slow the aging process and allow the average person to live decades longer, to at least 120 years old," about half of U.S. adults (51%) say the treatments would be a bad thing for society, while 41% say they would be a good thing.

HLH-30 IMPORTANT IN AUTOPHAGY-INDUCED LONGEVITY
Thursday, August 8, 2013
https://www.fightaging.org/archives/2013/08/hlh-30-important-in-autophagy-induced-longevity.php

Many methods of extending life by slowing aging in laboratory animals depend upon increased autophagy, the processes of cellular maintenance that clear out damaged components and proteins. Calorie restriction is one of these methods, for example: some studies have shown that if autophagy is disabled then calorie restriction no longer extends life to a significant degree.

[Scientists] have identified a key factor that regulates the autophagy process, a kind of cleansing mechanism for cells in which waste material and cellular debris is gobbled up to protect cells from damage, and in turn, modulates aging. [The researchers] found a transcription factor - an on/off switch for genes - that induces autophagy in animal models, including the nematode C. elegans. [This] transcription factor, called HLH-30, coordinates the autophagy process by regulating genes with functions in different steps of the process. Two years ago, researchers discovered a similar transcription factor, or orthologue, called TFEB that regulates autophagy in mammalian cells.

"HLH-30 is critical to ensure longevity in all of the long-lived C. elegans strains we tested. These models require active HLH-30 to extend lifespan, possibly by inducing autophagy. We found this activation not only in worm longevity models, but also in dietary-restricted mice, and we propose the mechanism might be conserved in higher organisms as well."

HLH-30 is the first transcription factor reported to function in all known autophagy-dependent longevity paradigms, strengthening the emerging concept that autophagy can contribute to long lifespan. In a previous study, [researchers] discovered that increased autophagy has an anti-aging effect, possibly by promoting the activity of an autophagy-related, fat-digesting enzyme. With these findings, scientists now know a key component of the regulation of autophagy in aging. Autophagy has become the subject of intense scientific scrutiny over the past few years, particularly since the process - or its malfunction - has been implicated in many human diseases, including cancer, Alzheimer's, as well as cardiovascular disease and neurodegenerative disorders. HLH-30 and TFEB may represent attractive targets for the development of new therapeutic agents against such diseases.

AND NOW FOR SOMETHING REPREHENSIBLE
Thursday, August 8, 2013
https://www.fightaging.org/archives/2013/08/and-now-for-something-reprehensible.php

There is no technology so beneficial that someone somewhere isn't thinking about how to use it to hurt people. That even holds true for means of rejuvenation, ways to eliminate the vast and terrible cost of degenerative aging, all of the suffering, the tens of millions of deaths each and every year. Some people look at the possibilities for near future human rejuvenation and think "I've figured out a way to use this to more effectively hurt the groups of people that we don't like."

Some argue that retributive punishment (reactionary punishment, such as imprisonment) should be replaced where possible with a forward-looking approach such as restorative justice. I imagine, however, that even opponents of retributive justice would shrink from suggesting that [the worst of offenders] should escape unpunished. I assume - in line with the mainstream view of punishment in the UK legal system and in every other culture I can think of - that retributive punishment is appropriate in [some cases].

Within the transhumanist movement, the belief that science will soon be able to halt the ageing process and enable humans to remain healthy indefinitely is widespread. Dr Aubrey de Grey, co-founder of the anti-ageing SENS Research Foundation, believes that the first person to live to 1,000 years has already been born. The benefits of such radical lifespan enhancement are obvious - but it could also be harnessed to increase the severity of punishments. In cases where a thirty-year life sentence is judged too lenient, convicted criminals could be sentenced to receive a life sentence in conjunction with lifespan enhancement. As a result, life imprisonment could mean several hundred years rather than a few decades. It would, of course, be more expensive for society to support such sentences. However, if lifespan enhancement were widely available, this cost could be offset by the increased contributions of a longer-lived workforce.

When the state enforces a monopoly on criminal dispute resolution, as is the case in most regions of the world these days, the only interests served are those of the state employees and appointees involved. Even in legitimate cases you end up with the worst of all worlds: the system remains based upon serving a desire for vengeance and appeasing the mob, imprisonment (as opposed to banishment or outlawing) removes the ability for an offender to work towards restitution, and those with the greatest interest in obtaining justice and resolution are cut out of the decision-making process. There is worse, however. The methods and traditions created for the worst offenders are soon enough applied to everyone without sufficient power and influence to buy their way clear. Modern systems of state justice are terrible impersonal engines, set upon expansion, and all too quickly used for self-empowerment and suppression of dissent by politicians and bureaucrats.

THE CURRENT STATE OF KNOWLEDGE OF GENETICS AND LONGEVITY
Friday, August 9, 2013
https://www.fightaging.org/archives/2013/08/the-current-state-of-knowledge-of-genetics-and-longevity.php

The interaction between genes, metabolism, and natural variations in longevity is an enormously complex space. This complexity is why efforts to slow aging by altering metabolism are doomed to be a very slow, very expensive undertaking, one which is unlikely to produce meaningful results within the next few decades. It will be much easier to instead identify the forms of damage that cause aging and periodically repair them without trying to otherwise change our genes or metabolic processes. We know the metabolism we have when young works just fine, so the focus of longevity science should be on reverting the limited set of changes in and around cells that differentiate old tissues from young tissues.

Here is a good short summary of the current state of knowledge of genetics and longevity, illustrating that researchers are really only just at the outset of a very long process of obtaining a full or at least actionable understanding:

Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25%. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages.

Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences.

GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity.

Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.

SIGNS OF PROGRESS: INSURERS TALK OF RADICAL LIFE EXTENSION
Friday, August 9, 2013
https://www.fightaging.org/archives/2013/08/signs-of-progress-insurers-talk-of-radical-life-extension.php

I had somehow missed this event from earlier in the year, a provocative (by mainstream standards) ad campaign mounted by a portion of the insurance industry: "The First Person To Live To 150 Is Alive Today." I take the existence of such a campaign as a sign of progress in ongoing efforts to spread the twofold message that (a) much longer lives are possible in the future, and (b) it is necessary to support the research process in order to make this happen soon enough to matter to you and I. Most of the children born today in wealthier parts of the world will have the opportunity to live for centuries at the very least, but the odds of people presently in mid-life are far more dependent on the pace of medical progress, and whether or not the right research strategies are nurtured.

By the side of an expressway the other afternoon, I saw a billboard paid for by Prudential, the big insurance and financial-services company. The message, in letters large enough that no motorist zipping by could miss them: "The First Person To Live To 150 Is Alive Today."

For centuries, scientists have been debating theories about just how long, with proper health care and judicious personal habits, the human lifespan can extend. In recent years, the 150 number has been up for discussion. Some have scoffed at that prospect, but insurance-company actuaries and retirement-planning accountants are not known for wacky practical jokes - they are as somber-eyed as funeral directors as they calculate just how big a risk they run while writing policies for their customers of various ages - so the sight of that Prudential billboard was a little jarring.

I contacted Prudential's corporate headquarters, and the company forwarded to me a table of federal statistics showing the lengthening average lifespans in the U.S. over the past 80 or so years. In 1930, the average life expectancy (measured at birth) of Americans was 59.7 years. By 1940, it had grown to 62.9. 1950: 68.2. 1960: 69.7. 1970: 70.8. 1980: 73.7 1990: 75.4. 2000: 77. 2010: 78.7.

Whether infants born today are entering a world in which 150th birthdays will eventually become if not common then at least possible, the thought raises separate issues for insurance and financial-planning firms than it does for the rest of us. For those companies, the prospect provides marketing opportunities. But for everyone else, it prompts the vexing question: Would you really want to live that long?