Fight Aging!

Regenerative medicine and tissue engineering are fields that emerge from the growing ability to control cells and cellular behavior. Complete control over cells will one day be the basis for the vast majority of all medicine dealing with natural, unmodified humans. Little is left beyond that arena aside from the removal of metabolic waste products that cells are not equipped to destroy. However, this is a narrow view of the future. Long before complete cellular control is achieved researchers will already be modifying cells and their components: building better and more reliable machinery, augmenting or replacing the evolved components of a cell and a body one by one. So at the same time as fields emerging from cellular control take over near-all medicine, they themselves will be transformed and made obsolete by the growing ability to replace our evolved biology with something better.

But this dynamic will play out a way down the line. It is interesting to look ahead, and also to keep an eye on areas in which replacements for evolved cellular components could happen comparatively soon, such as in the development of artificial mitochondria. If you are interested in the impact on your future health and life, it is control over - and the ability to repair - our present biology that is the most important line of research and development. That is work that has the best chance of extending healthy life spans soon enough to matter to you and I.

There is a lot going on in the energetic fields of cell research, and it is fortunate that the interests of the researchers involved are largely aligned with those of life extension supporters. Most of the medical conditions that would benefit the most from cell therapies are age-related, and thus researchers have a strong incentive to figure out how to make their work effective in old tissues. This will require them to provide solutions for a number of the aspects of degenerative aging, such as the changes in signaling protein levels that reduce stem cell activity, the dysfunction of the aged immune system, and so forth. With that in mind, here is a random selection of recent work in regenerative medicine and tissue engineering.

Self-healing engineered muscle grown in the laboratory

Every muscle has satellite cells on reserve, ready to activate upon injury and begin the regeneration process. The key to the team's success was successfully creating the microenvironments - called niches - where these stem cells await their call to duty. "Simply implanting satellite cells or less-developed muscle doesn't work as well. The well-developed muscle we made provides niches for satellite cells to live in, and, when needed, to restore the robust musculature and its function."

To put their muscle to the test, the engineers ran it through a gauntlet of trials in the laboratory. By stimulating it with electric pulses, they measured its contractile strength, showing that it was more than 10 times stronger than any previous engineered muscles. They damaged it with a toxin found in snake venom to prove that the satellite cells could activate, multiply and successfully heal the injured muscle fibers.

New Penn-Designed Gel Allows for Targeted Therapy After Heart Attack

We used a microdialysis technique to show that, after a heart attack, local enzyme levels go way up, but when the inhibitor molecules are delivered via the gel, we see the activity level of this enzyme go down. Over the next 28 days, we also used imaging techniques to show thicker cardiac walls and less expansion and dilation of the ventricle. And, as a result, we see better performance in the heart using clinical measurements like ejection fraction, the amount of the blood the heart is pumping.

While most groups working in this field are attempting to develop myocardial regenerative therapies, our team is focused on the biomechanical stabilization of the heart after heart attack. Most researchers working towards regenerative therapies often overlook an important fact, namely, that the overwhelming majority of patients who suffer heart attack initially have adequate heart function. We strongly believe that optimizing the function of the surviving heart muscle after heart attack will be a more realistic and effective strategy than trying to regenerate the muscle that is lost.

New human trial shows stem cells are effective for failing hearts

The study is the largest placebo-controlled double-blind randomized trial to treat patients with chronic ischemic heart failure by injecting a type of stem cell known as mesenchymal stromal cells directly into the heart muscle. The study included 59 patients with chronic ischemic heart disease and severe heart failure.

Six months after treatment, patients who received stem cell injections had improved heart pump function compared to patients receiving a placebo. Treated patients showed an 8.2-milliliter decrease in the study's primary endpoint, end systolic volume, which indicates the lowest volume of blood in the heart during the pumping cycle and is a key measure of the heart's ability to pump effectively. The placebo group showed an increase of 6 milliliters in end systolic volume.

Clearly we are going to be hearing a lot about the genetics and epigenetics of aging in the years ahead. The price of biotechnologies in this field has fallen, sequencing and analysis is cheap, and interest in intervening in the aging process is growing. Sadly, and as I've outlined in past posts, I don't see this as a path towards greatly extending the healthy human life span. Researchers will learn a great deal about how aging progresses, and produce benefits for other areas of medicine, but work on genetic analysis and alteration of epigenetic patterns can only be a hard and complicated path to slowing aging through manipulation of the operation of metabolism. As an end goal that is of very limited benefit to those of us who will be old before it arrives.

Here is an open access review from researchers involved in one of the current commercial ventures focusing on the genetics and epigenetics of aging:

During aging, vital bodily functions such as regeneration and reproduction slowly decline. As a result, the organism loses its ability to maintain homeostasis and becomes more susceptible to stress, diseases, and injuries. A loss of essential body functions leads to age-associated pathologies, which ultimately cause death.

Evolutionary theories of aging predict the existence of certain genes that provide selective advantage early in life with adverse effect on lifespan later in life (antagonistic pleiotropy theory) or longevity insurance genes (disposable soma theory). Indeed, the study of human and animal genetics is gradually identifying new genes that increase lifespan when overexpressed or mutated: gerontogenes. Furthermore, genetic and epigenetic mechanisms are being identified that have a positive effect on longevity.

The gerontogenes are classified as lifespan regulators, mediators, effectors, housekeeping genes, genes involved in mitochondrial function, and genes regulating cellular senescence and apoptosis. In this review we demonstrate that the majority of the genes as well as genetic and epigenetic mechanisms that are involved in regulation of longevity are highly interconnected and related to stress response.

Link: https://www.landesbioscience.com/article/28433/full_text/#load/info/all

Researcher João Pedro de Magalhães has a good page of suggestions on how to help efforts to produce treatments for - and ultimately defeat - degenerative aging. As of about a decade ago, the bottom line is largely a matter of funding provided to the right lines of research, those associated with SENS, the strategies for engineered negligible senescence. But there is always a need for the next generation of researchers, and those who can help raise funds and persuade new supporters to join the community:

Research on aging, like scientific and medical research in general, depends on having researchers with adequate funding to carry out innovative science. One obvious way to contribute to gerontology is to become a researcher or at least a professional in a research institution. Even if you do not wish to have a career in science or are at an early stage of your career but wish to contribute to research, most labs welcome volunteers and interns. No matter your level of experience and skills, there are always ways in which can help.

Not everyone is cut to do research, however. Many people interested in aging that contact me, in fact, already have careers in completely different areas. But even if you cannot become a researcher there are many other ways you can help. Provided you have the means, of course, another straightforward way to help is by funding research on aging via charitable donations or venture capital investments. A word on how scientific funding works may be in order...

While government funding exists to support scientific research, including research on aging, this is largely inadequate. The problem is not only that funding is not sufficient to allow progress at a sufficient pace, but government funding is often misdirected. (And I acknowledge this having received substantial government funding to support my lab, so this is not just a case of sour grapes.) The problem with government funding is that, because of the way funding is typically allocated via peer-review, it is a conservative process which rewards incremental advances but discourages out-of-the-box, innovative projects. Therefore, while projects that follow-up on established paradigms, such as caloric restriction, have a chance of being funded, radical projects like those inspired by SENS have no chance. (This is not to say we should cut funding from caloric restriction and provide funding for SENS, but merely illustrates the point that high-risk, high-reward projects have little or no chance of receiving government funding.)

Given the above problems with science funding, the current situation is one in which progress is being impeded by the lack of funding (and money is very tight at the moment) and the imperfect allocation of existing resources. So if you have the means to donate to the science of aging then this is extremely valuable to researchers. Of course few people have the wealth to create a foundation, but even small contributions to labs or initiatives related to aging research are valuable as they allow researchers to explore ideas that would not be supported by traditional funding sources.

Link: http://www.senescence.info/help_fight_aging.html

Today I'll point out the Ašţal Journal as something that might be of interest. The name is apparently taken from the constructed language of Ithkuil, and represents the sudden realization of possibilities when someone conveys to you an idea you've never considered before:

This is a journal of ideas that eagerly hopes to act as a place of open discussion about the intersection between longevity, overpopulation, and space exploration, as well as a general discourse on a broad range of other subjects. Through it, we wish to inform anyone interested about new and exciting developments in these fields, as well as ways in which they can contribute to the leading-edge research being carried out around the world.

The general position in the longer articles seems to be that overpopulation is a real concern, but one that can be controlled and evaded with foresight. That isn't a position I agree with at all, on the grounds that I don't see that overpopulation or the threat of it actually exists, and no more foresight is needed to maintain that state of affairs that is ordinarily deployed by every participant in the broad market of human society - just the sort of everyday economic foresight that led to the broad and successful efforts to radically improve agricultural techniques in the 1960s and 1970s in response to perceived opportunities in the market brought about by advancing technology.

There is no shortage of suffering in the world, but realize that everywhere that plague, famine, and utter poverty still exists it is maintained and enforced by avaricious, ruinous governance. Every populous region presently poor and dangerous could have had a trajectory just like that of South Korea over the past 60 years or so, from a largely agrarian to a largely information economy. That this did not happen universally is not a matter of how many people live in a region, or its level of natural resources: look instead to war, looting by political leaders, and other deliberate barriers to the growth of market economies. The inhumanity of man is the root cause of what most people casually label as overpopulation. Sufficient resources exist to support many more people than are currently alive, and those resources are constantly growing and changing with advances in technology.

A couple of items from the Ašţal Journal that are worth a glance are quoted below:

A Q&A with Aubrey de Grey

Ašţal: What are the main obstacles to reaching faster decisive breakthroughs in rejuvenation research?

Aubrey de Grey: Money, money and money. Originally there were two other obstacles: there was no plan, and there were far too few top scientists interested in the problem. One of the things I'm proudest of is that I've been able both to come up with a concrete, plausible plan (SENS itself) and also to bring a large number of world-leading scientists on board to implement it - just so long as the resources necessary to do so are available.

Ašţal: How much of an impact do you reckon private initiatives like the Calico project will have on the future landscape of longevity research?

Aubrey de Grey: Calico has the potential to be a complete game-changer, simply because their budget is so large. It's a hugely encouraging start that they've hired awesome people outside the field, such as Art Levinson and David Botstein, to head it up: that makes me pretty sure that they won't make the mistake that the Ellison Medical Foundation did of just following the failed strategies of the past. It may not work out, of course, but all the omens are really encouraging.

Ašţal: What kind of public policies would best support the goal of longevity?

Aubrey de Grey: The single most important change in public policy that is needed is to restructure medical research funding in a manner that takes account of the inextricable linkage between aging and the diseases of old age. At present, huge sums are wasted on the futile attempt to treat the diseases of old age as if they could be eliminated from the body, like infections. Once it is properly recognised that the diseases of old age are simply aspects of the later stages of a lifelong process of damage accumulation, it will also be recognised that the best way to combat those diseases is by preventative maintenance at the molecular and cellular level. Then we will see an appropriate prioritisation of research themes and a great acceleration of progress.

The Necessity of Longevity

In essence, the prejudice toward understanding senescence and death as intrinsic properties of life, together with a misconstrued notion of the goals of longevity research, are biases which have yet to be eradicated from the collective mentality. We have told each other stories for so long, that those stories have become reality and our intuitions myths. Our common sense has been demoted to second-rank reasoning, and in the process we have become the victims of our own bemusement. Of course, as long as a viable option is not brought forward we are likely to continue opposing obvious scientific progress in light of a mitigating ideal.

Notwithstanding these initial fears, the outlines of a solution are unequivocally beginning to take shape, but as long as we continue to adopt the question of longevity as a moral issue, and not a scientific one, we will not gain purchase on the far shore. There is no way to predict whether these technologies will be useful in the long-run until we try them out, but we must stop thinking about longevity and rejuvenation through the lens of individual prejudices and work towards integrating it as a viable long-term goal for the advancement of the species. I am willing to argue here that the pursuit of viable rejuvenation is the most desirable course of action in terms of the active prevention of senescence, disease, and eventually, death.

Overpopulation and Its Discontents

Overpopulation abides as the poor relation of the great world problems, eternally relegated behind the saraband of food shortages, endemic wars, diseases and epidemics, and now climate change, although all of these issues ostensibly spring from the same root cause: the very object of this essay.

Overpopulation puts humanity at existential risk, most notably at the meso-level where it threatens the life of large groups of people, both of its individual members (as a direct life threat) and of the form of life they embody (as a cultural threat). On the one hand, there is a strong case for overpopulation as a major political and philosophical issue as it will shape the problems à-venir. On the other hand, most of our current understanding remains flawed, regrettably confining it to a demographic and economic problem.

Tissue engineering offers the opportunity to augment the function of an organ without necessarily recreating the evolved natural structure of that organ. There may be numerous paths forward in which it is much easier to create a pseudo-organ or tissue sections that perform only some of the necessary functions of the real organ rather than engineer a full replica. This is more evidently the case for tissues intended to generate regulatory proteins or other biochemicals: it often isn't necessary that these tissues exist in the exact location evolution has placed them. So for example functions of the thyroid or pancreas could be augmented with tissues implanted into lymph nodes - and that is an easier prospect than recreating the whole organ in question.

Here researchers demonstrate that it is also feasible to consider distributing some of the mechanical duties of the heart. They aim to produce novel small organs that wrap blood vessels to aid blood flow:

[Researchers have] invented a new organ to help return blood flow from veins lacking functional valves. A rhythmically contracting cuff made of cardiac muscle cells surrounds the vein acting as a 'mini heart' to aid blood flow through venous segments. The cuff can be made of a patient's own adult stem cells, eliminating the chance of implant rejection. "We are suggesting, for the first time, to use stem cells to create, rather than just repair damaged organs. We can make a new heart outside of one's own heart, and by placing it in the lower extremities, significantly improve venous blood flow."

The novel approach of creating 'mini hearts' may help to solve a chronic widespread disease. Chronic venous insufficiency is one of the most pervasive diseases, particularly in developed countries. Its incidence can reach 20 to 30 percent in people over 50 years of age. It is also responsible for about 2 percent of health care costs in the United States. Additionally, sluggish venous blood flow is an issue for those with diseases such as diabetes, and for those with paralysis or recovering from surgery.

[The researchers have] demonstrated the feasibility of this novel approach in vitro and are currently working toward testing these devices in vivo.

Link: http://smhs.gwu.edu/news/gw-researcher-invents-%E2%80%98mini-heart%E2%80%99-help-return-venous-blood

The small cryonics industry has developed the means of long-term low temperature preservation of tissue over the past few decades, presently using a form of vitrification that minimizes ice crystal formation. For people who will die before the advent of rejuvenation therapies, this is the only option other than the grave: a way to preserve the structure of the brain and mind until such time as more advanced medical technologies can reverse the process, remove the signs of aging, and provide a newly tissue engineered body. None of this is impossible, just challenging and a way off into the future.

Only a few cryonics providers exist, most of which are in the US. In countries without cryonics providers there are support organizations, however, to aid the process of managing cryopreservation at the end of life for the few people who choose this option:

It's a small red-brick house just like any other, lost in the suburbs of Sheffield, in central England. The only thing that sets it apart is the yellow-and-green ambulance parked on the gravel driveway - for inside that vehicle, two men and a woman are training in the craft of defeating death itself, on the presumed road to eternity. Every three months, some 15 members of the Cryonics UK association meet for a weekend around the refrigerated container that will one day be the home of their long hibernation. They have already spent thousands of pounds sterling so that, when the day comes, their bodies will be kept at very low temperature until scientific techniques will allow for them to be "brought back to life."

Like some 2,000 people around the world, the 35 British members of Cryonics UK have applied to join the quest for immortality. With a calm smile on her face, Victoria Stevens, 38, explains that she managed to convince her husband and her two children that death was not irreversible. "When we love life, there's no shame in wanting to make it last longer."

Former engineer Mike Carter shares her point of view, and has become one of the cornerstones of the association since his retirement. "I know that the chances of being resuscitated are very slim. But apart from a bit a money for my children, there's nothing to lose. But you can't win the lottery if you don't buy a ticket!"

Cryonics UK is not a service provider, but merely a cooperative of mutual aid. Its job is to take care voluntarily of transporting the frozen bodies to the United States. "Whenever one of our members is about to die, we hurry to his house with the ambulance to be there as soon as possible," explains Carter. In such cases, a handful of volunteers put the body "on standby," which will prevent it from deteriorating during the transport across the Atlantic.

Link: http://www.worldcrunch.com/tech-science/afterlife-on-ice-inside-the-world-of-cryonics/death-life-preservation-cryonicists-legislation-ethics-freeze/c4s15149/

It is in the nature of things for people to become more accepting of the imperfect state of the world and the flawed human condition with advancing age, to lose that youthful indignation and urge to change all that causes suffering and injustice. We can blame a range of things for this, but I suspect that it has a lot to do with the growth in wealth and connections that occurs over the years for most individuals. Whatever your starting level, on average the 50-year-old you will be in a better place than the 20-year-old you. The gains you have amassed merge with nostalgia in a slow erosion of the desire to tear down walls and shake up your neighbors: things are better for you, and isn't that a good thing? Not everyone is this way, of course, but it is a dynamic to be aware of in your relationship with the world. It is human nature to measure today against yesterday, and feel good about gains that are relatively large but absolutely small.

Acceptance of death and aging is the mindset I am thinking in particular here. The unpleasant ends of life are dim and distant myths when you are young and vigorous in your search for world-changing causes. It is the rare young individual who is willing to devote his or her life in preparation for a time half a century down the road. The older folk who feel the pressures of time and encroaching frailty are those who have become more accepting, however. To fight aging and work on rejuvenation treatments is an intrinsically hard sell in comparison to many other ventures. The youth think they have time to focus on other matters first, and the old have come to terms.

Nonetheless, with rapid progress in biotechnology year after year the number of people needed to get the job done is falling rapidly. Ten million supporters willing to put in a little time or money (rather than just a wave and a good word) and the careers of a few thousand scientists and biotechnicians is probably more than is needed at this point, a level of support that lies in a similar ballpark to that of the cancer or stem cell research communities. We are not there yet, though support for scientific, medical approaches to the treatment and prevention of aging has grown in a very encouraging fashion over the past decade. At any time in the next year or so you might see mainstream press articles in noted publications favorably mention the SENS Research Foundation, regenerative medicine, Google's Calico initiative, and progress in genetic science all in the same few paragraphs.

We are here, where we are, precisely because numerous people retained a youthful fire and verve, and indignation and horror of aging and death. Despite the ever-present opposition from a mainstream that once mocked aging research, these iconoclasts put in the work that has raised funds, created organizations, and changed minds: all seeds for tomorrow's grand rejuvenation research community. This is a work in progress. But let us take a moment to admire some of the fire from those driving things along at the grassroots level:

Those Critical of Indefinite Life Extension Fear Life

Accepting death is in fact choosing it. In the face of recent discoveries and progress in science, medicine, technology - it is a matter of choice. Pretending to be fearless in the face of death isn't some form of heroism. It isn't reasonable or courageous. It is quite the opposite. It is taking the easy way out. Let's repeat it - death really is the easy way out. You fall asleep; you get a bullet; cancer kills you; some choose suicide; some accept aging and its effects as an inexorable given. The hard truth here that we should be prepared to acknowledge is: accepting death is the true cowardice, no matter the circumstances. Fighting it and choosing life is the true courage.

Critics of indefinite life extension, don't put on a snide, condescending face and tell me that you aren't afraid of death, because you are, too.

By your own knee-jerk flippancy, reactionary admission, you are also afraid of life. You're afraid of death, and you're afraid of life. You say, right to us, all the time, that you don't want to bear to deal with the drastic changes, you don't want to live without all your friends and family around, you don't want to live with war still being a reality anywhere. You can't stand all the jerks and the dangerous people, and rich people, or tyrants, controlling you for one decade longer than a traditional lifespan. The thought of it makes you want to jump into your grave right now to get away from this big, bad, scary life.

You, my friend, are afraid of life. Living scares you. You think of life and you cower. You see the challenges of life and you're too scared to face them. You wouldn't dare form and join teams and initiatives to meet those challenges on the intellectual combat fields of dialectics and action. You don't have what it takes. Life isn't for you. It's not your thing. So love your death, fear your life. Do that if that's what you want.

I am afraid of death. It scares me to think of losing my life. I value my life. I have no shame in that. That is the reasonable thing to do. What I have shame for is that anybody would think that being afraid of death might possibly be something to mock.

You mock us for being afraid of death. We are afraid of death; it's a logical and positive thing to be afraid in the face of it. It reminds a person to take action against danger. It's your being afraid of life that is to be mocked. So stand up and tell us how afraid you are of living. We promise not to look upon you with too much shame, and we promise to lend you a hand if you need help crossing over to the land of reason.

Resilient forms of advanced glycation endproduct accumulate in the body with age as a byproduct of the operation of metabolism, particularly glucosepane in tissues such as skin. Our biochemistry struggles to remove these compounds, and they cause progressively greater harm in soft tissues by damaging tissue structure so as to reduce elasticity and generating higher levels of inflammation. This is why efforts to develop the means to remove AGEs are important. The types and effects of AGEs in harder tissues are not so well understood, however:

Cross-linking of collagen by Advanced Glycation End-products (AGEs) occurs by non-enzymatic glycation (Maillard reaction). The purpose of this study was to examine whether AGEs are formed in human dentinal collagen, and to consider any possible influence of AGEs on dentinal physiology.

Mechanical characteristics, fluorescence spectra and immunohistochemical analyses of demineralized dentine sections from young subjects were compared with those of aged ones. The same investigations were performed with young dentine artificially glycated by incubation in ribose solution. Indentation measurement indicated that the sections from aged dentine were mechanically harder than those from young dentine. The hardness of young dentine increased after incubation in ribose solution. Fluorescence peak wavelength of the young dentine was shorter than that of the aged one, but shifted towards the peak wavelength of the aged one after incubation in ribose solution.

These changes were considered to be due to accumulation of AGEs. Existence of AGEs in dentinal collagen was confirmed by immunohistochemical analysis. The obtained results suggest that AGEs accumulation occurs in dentinal collagen and is affected by both human age and physiological conditions such as glucose level in blood because dentinal collagen receives nourishment via dental pulp and tubules.

Link: http://dx.doi.org/10.1016/j.archoralbio.2013.10.012

Age-related macular degeneration involves damage to the retina and consequent encroaching blindness. One of the contributing causes is a buildup of metabolic waste products in long-lived retinal cells to form lipofuscin, something that the SENS Research Foundation focuses on in their lysoSENS program. Here researchers review the evidence for a different proximate cause, the malfunction of nervous system immune cells:

In the healthy retina, microglial cells represent a self-renewing population of innate immune cells, which constantly survey their microenvironment. Equipped with receptors, a microglial cell detects subtle cellular damage and rapidly responds with activation, migration, and increased phagocytic activity.

While the involvement of microglial cells has been well characterized in monogenic retinal disorders, it is still unclear how they contribute to the onset of retinal aging disorders including age-related macular degeneration (AMD). There is evidence, that microglial activation is not solely a secondary manifestation of retinal tissue damage in age-related disorders. Thus, work in the aging rodent and human retina suggests that long-lived and genetically predisposed microglia transform into a dystrophic state, with loss of neuroprotective functions. In this concept, malfunction of aging microglia can trigger a chronic low-grade inflammatory environment that favors the onset and progression of retinal degeneration.

Link: http://dx.doi.org/10.1007/978-1-4614-3209-8_27

The amassed scientific evidence of decades tells us that regular moderate exercise and the practice of calorie restriction with optimal nutrition are both very beneficial for long term health. There is no other presently available option that will result in a better expected outcome for the average basically healthy individual. That in turn suggests that we should be putting much more effort and attention into research that will generate better ways to extend the healthy span of life available to us. Exercise and calorie restriction are free, but speeding up longevity research requires organization, effort, and above all funding.

At present a great deal more research relating to exercise and calorie restriction takes place than that relating to means of extending life to a far greater degree. Rejuvenation biotechnology is the outcast poor cousin of the research community, for all that it is the best path forward towards radical life extension. That will have to change, but in the meanwhile here are a few recent examples of mainstream research, offered without comment, but similar to studies that come and go in volume month by month:

Exercise Training Improves Health Outcomes of Women with Heart Disease More Than of Men

The clinical trial randomized 2,331 patients with heart failure and a left ventricular ejection fraction of less than or equal to 35 percent to either a formal exercise program plus optimal medical therapy, or to optimal medical therapy alone. Prior to randomization, patients underwent symptom-limited cardiopulmonary exercise tests to assess exercise capacity, as measured by peak oxygen uptake (VO2). Patients randomized to the exercise treatment arm participated in supervised walking, or stationary cycling for 30 minutes three days a week for six weeks. After completing 18 sessions, patients added 40 minutes of home-based exercise two days per week. After completing 36 supervised sessions, patients were fully transitioned to a five day per week, 40 minutes a day home-based exercise program.

The primary outcome of this analysis was a composite of all-cause mortality or hospitalization, stratified by gender. Women randomized to exercise training saw a 26 percent reduction in risk of all-cause mortality or hospitalization compared with a 10 percent reduction in risk of these outcomes for men randomized to exercise.

The Benefits of Staying Active in Old Age: Physical Activity Counteracts the Negative Influence of PICALM, BIN1, and CLU Risk Alleles on Episodic Memory Functioning

PICALM, BIN1, CLU, and APOE are top candidate genes for Alzheimer's disease, and they influence episodic memory performance in old age. Physical activity, however, has been shown to protect against age-related decline and counteract genetic influences on cognition. The aims of this study were to assess whether (a) a genetic risk constellation of PICALM, BIN1, and CLU polymorphisms influences cognitive performance in old age; and (b) if physical activity moderates this effect.

Data from the SNAC-K population-based study were used, including 2,480 individuals (age range = 60 to 100 years) free of dementia at baseline and at 3- to 6-year follow-ups. Tasks assessing episodic memory, perceptual speed, knowledge, and verbal fluency were administered. Physical activity was measured using self-reports. Individuals who had engaged in frequent health- or fitness-enhancing activities within the past year were compared with those who were inactive. High genetic risk was associated with reduced episodic memory performance, controlling for age, education, vascular risk factors, chronic diseases, activities of daily living, and APOE gene status. Critically, physical activity attenuated the effects of genetic risk on episodic memory. Our findings suggest that participants with high genetic risk who maintain a physically active lifestyle show selective benefits in episodic memory performance.

A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans

Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading to lower food intake or by feeding diluted bacterial food to the worms. In this study, we show that knocking down a mammalian MEKK3-like kinase gene, mekk-3 in C. elegans, initiates a process similar to DR without compromising food intake.

This DR-like state results in upregulation of beta-oxidation genes through the nuclear hormone receptor NHR-49, a HNF-4 homolog, resulting in depletion of stored fat. This metabolic shift leads to low levels of reactive oxygen species (ROS), potent oxidizing agents that damage macromolecules. Increased beta-oxidation, in turn, induces the phase I and II xenobiotic detoxification genes, through PHA-4/FOXA, NHR-8 and aryl hydrocarbon receptor AHR-1, possibly to purge lipophilic endotoxins generated during fatty acid catabolism.

The coupling of a metabolic shift with endotoxin detoxification results in extreme longevity following mekk-3 knock-down. Thus, MEKK-3 may function as an important nutrient sensor and signalling component within the organism that controls metabolism. Knocking down mekk-3 may signal an imminent nutrient crisis that results in initiation of a DR-like state, even when food is plentiful.

Maternal caloric restriction partially rescues the deleterious effects of advanced maternal age on offspring

While many studies have focused on the detrimental effects of advanced maternal age and harmful prenatal environments on progeny, little is known about the role of beneficial non-Mendelian maternal inheritance on aging. Here, we report the effects of maternal age and maternal caloric restriction (CR) on the life span and health span of offspring for a clonal culture of the monogonont rotifer Brachionus manjavacas.

Mothers on regimens of chronic CR (CCR) or intermittent fasting (IF) had increased life span compared with mothers fed ad libitum (AL). With increasing maternal age, life span and fecundity of female offspring of AL-fed mothers decreased significantly and life span of male offspring was unchanged, whereas body size of both male and female offspring increased. Maternal CR partially rescued these effects, increasing the mean life span of AL-fed female offspring but not male offspring and increasing the fecundity of AL-fed female offspring compared with offspring of mothers of the same age. Both maternal CR regimens decreased male offspring body size, but only maternal IF decreased body size of female offspring, whereas maternal CCR caused a slight increase.

As a rule most people interested in health and longevity lavish far too much of their attention on dietary supplements, misled by the loudest voices in the room. No supplement or combination of supplements have been shown to reliably produce even a fraction of the benefits of exercise and calorie restriction, and none of these line items will give you a good chance of living past 90. Three quarters of the most health-obsessed people die before reaching that age, despite the fact that those who exercise and remain thin usually suffer a lower incidence of disease and medical expense in later life. The only shot at a much longer healthy life available to all of us is faster progress in medical technology, an area in which comparatively small donations now can have a large effect in the decades ahead by allowing today's small disruptive initiatives in human longevity to succeed and grow.

Back to supplements, here is a reality check from someone who does spend too much time thinking about supplements and longevity:

Stephen Spindler, biochemistry prof at UC Riverside, has been warning us for years that supplements, herbal extracts and neutraceuticals are, on the whole, ineffective for healthy adults, and that some may actually shorten life expectancy. Spindler's lab has done many life extension studies on mice, almost always with negative results. One of the themes in his papers is that caloric restriction is the only thing that works consistently, and that many of the treatments that seem to offer life extension are subtley inducing caloric restriction, (and this goes unreported by the investigators). But there are so many substances to test, and each lifespan test in mice is so expensive, that Spindler has suggested gene expression profiles as a shortcut to identifying candidates for further testing.

Another approach is to test many substances at once in a mouse life extension cocktail. Another rationale for this kind of testing is that we know that natural fruits and vegetables contribute to a long and healthy life, so perhaps it takes a complex combination of nutrients to be effective. Late last year, Spindler reported on his experiments, feeding commercial "life extension" mixes to hybrid mice. The results are a bracing cold shower for those of us who take a variety of carefully-chosen supplements each day - the mice that ate the supplements and the mice that ate ordinary mouse chow had exactly the same pattern of mortality.

Link: http://joshmitteldorf.scienceblog.com/2014/03/25/life-extension-supplements-a-reality-check/

Calorie restriction with optimal nutrition involves reducing the level of calories in the diet by up to 40% or so while still maintaining sufficient intake of micronutrients. This has been shown to slow aging and extend maximum life span in most species tested to date, with most mammal studies having used mice and rats. In primate studies while calorie restriction is definitely shown to significantly improve health and reduce incidence of age-related disease, the evidence isn't so good for meaningful extension of life span.

Why would calorie restriction reliably extend life span in short lived species but not in longer-lived species? The current thinking is that this response evolved because it allows individuals better odds of surviving seasonal famines, such that they can procreate later. When you are a mouse a seasonal famine is a large fraction of a life span, but this is not the case for humans, so it makes sense to see greater plasticity of life span in response to environmental circumstances in mice. There is selection pressure for this outcome in a short-lived species that isn't present for a long-lived species.

This researcher has a different take on the origin of the calorie restriction response, in which extension of life span is not the effect being selected for. Instead enhanced longevity is a side-effect of the actual selected trait, which is greater cellular recycling and repair that enables the ability to better reproduce when food is scarce. This still leaves the open question of why life extension is large in short-lived animals but not in humans, given that the short-term measures of the effects of calorie restriction on metabolism are remarkably similar between mice and humans.

Scientists have known for decades that severely restricted food intake reduces the incidence of diseases of old age, such as cancer, and increases lifespan. This effect has been demonstrated in laboratories around the world, in species ranging from yeast to flies to mice. There is also some evidence that it occurs in primates. The most widely accepted theory is that this effect evolved to improve survival during times of famine. "But we think that lifespan extension from dietary restriction is more likely to be a laboratory artefact."

Lifespan extension is unlikely to occur in the wild, because dietary restriction compromises the immune system's ability to fight off disease and reduces the muscle strength necessary to flee a predator. "Unlike in the benign conditions of the lab, most animals in the wild are killed young by parasites or predators. Since dietary restriction appears to extend lifespan in the lab by reducing old-age diseases, it is unlikely to have the same effect on wild animals, which generally don't live long enough to be affected by cancer and other late-life pathologies."

Dietary restriction, however, also leads to increased rates of cellular recycling and repair mechanisms in the body. [The] new theory is that this effect evolved to help animals continue to reproduce when food is scarce; they require less food to survive because stored nutrients in the cells can be recycled and reused. It is this effect that could account for the increased lifespan of laboratory animals on very low nutrient diets, because increased cellular recycling reduces deterioration and the risk of cancer.

Link: http://newsroom.unsw.edu.au/news/science/new-theory-why-dietary-restriction-can-extend-lifespan

In recent years a number of research groups have made progress towards building heart tissue that is capable of beating. This is obviously quite necessary if the end goal is a completely functional heart, produced from a patient's stem cells alone, but even if considering the production of small tissue patches for an injured heart researchers must be able to produce muscle fibers that behave in the right way, otherwise it is just as likely that a treatment would prove to be harmful rather than helpful.

Decellularization is still well ahead of other approaches in terms of the ability to produce large amounts of tissue for transplant or testing, as well as in the production of tissue that accurately reproduces the complex structure of an organ. Creating the blood vessel network needed to support larger tissue sections is perhaps the greatest present challenge facing tissue engineers, though once past that a whole range of other issues related to organ structure will be next in line. The structural challenges are precisely why decellularization is out in front in terms of technical outcomes: a donor organ scaffold with all its cells stripped neatly provides the guiding structure and chemical cues needed to reconstruct the blood vessels and other details required for full function. At some point it will be necessary to break free from the need for donor organs, however. Decellularization is only a stepping stone between today and a world in which organs can be printed to order from a simple skin sample.

Here is news of recent work on the details of heart tissue engineering, with a focus on improving the electrical aspect associated with the beating of a living heart. The fine details of muscle structure are absolutely vital here, and hard to get right. There is a still a great deal of experimentation between here and a functional heart grown from cells or bioprinted, and there is a need for flexible, reliable technology platforms to enable that experimentation:

Building heart tissue that beats

When a heart gets damaged, such as during a major heart attack, there's no easy fix. But scientists working on a way to repair the vital organ have now engineered tissue that closely mimics natural heart muscle that beats, not only in a lab dish but also when implanted into animals. To tackle the challenge of engineering heart muscle, Khademhosseini and Annabi have been working with natural proteins that form gelatin-like materials called hydrogels. "The reason we like these materials is because in many ways they mimic aspects of our own body's matrix," Khademhosseini said. They're soft and contain a lot of water, like many human tissues.

His group has found that they can tune these hydrogels to have the chemical, biological, mechanical and electrical properties they want for the regeneration of various tissues in the body. But there was one way in which the materials didn't resemble human tissue. Like gelatin, early versions of the hydrogels would fall apart, whereas human hearts are elastic. The elasticity of the heart tissue plays a key role for the proper function of heart muscles such as contractile activity during beating. So, the researchers developed a new family of gels using a stretchy human protein aptly called tropoelastin. That did the trick, giving the materials much needed resilience and strength.

But building tissue is not just about developing the right materials. Making the right hydrogels is only the first step. They serve as the tissue scaffold. On it, the researchers grow actual heart cells. To make sure the cells form the right structure, Khademhosseini's lab uses 3-D printing and microengineering techniques to create patterns in the gels. These patterns coax the cells to grow the way the researchers want them to. The result: small patches of heart muscle cells neatly lined up that beat in synchrony within the grooves formed on these elastic substrates. These micropatterned elastic hydrogels can one day be used as cardiac patches. Khademhosseini's group is now moving into tests with large animals. They are also using these elastic natural hydrogels for the regeneration of other tissues such as blood vessels, skeletal muscle, heart valves and vascularized skin.

Hybrid hydrogels containing vertically aligned carbon nanotubes with anisotropic electrical conductivity for muscle myofiber fabrication

Biological scaffolds with tunable electrical and mechanical properties are of great interest in many different fields, such as regenerative medicine, biorobotics, and biosensing. In this study, dielectrophoresis (DEP) was used to vertically align carbon nanotubes (CNTs) within methacrylated gelatin (GelMA) hydrogels in a robust, simple, and rapid manner.

Skeletal muscle cells grown on vertically aligned CNTs in GelMA hydrogels yielded a higher number of functional myofibers than cells that were cultured on hydrogels with randomly distributed CNTs and horizontally aligned CNTs, as confirmed by the expression of myogenic genes and proteins. In addition, the myogenic gene and protein expression increased more profoundly after applying electrical stimulation along the direction of the aligned CNTs. We believe that platform could attract great attention in other biomedical applications, such as biosensing, bioelectronics, and creating functional biomedical devices.

Like all tissues, the brain and nervous system become damaged and dysfunctional with age. While the underlying root causes, the differences between old tissue and young tissue, are well cataloged, how this process unfolds to create specific age-related diseases is still a matter for debate and investigation. If you care about rejuvenation and repair, you don't need to know much more than we do today in order to work on treatments to reverse the differences, but most researchers aim at greater understanding of the process, rather than actually doing something about it. Here researchers look at a small slice of the process of aging and damage in one type of tissue:

In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B, H3 and H4 were not neurotoxic.

Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.

Link: http://dx.doi.org/10.12688/f1000research.2-148.v1

Visceral fat is harmful to long term health, such as through its promotion of chronic inflammation, among other mechanisms. It is known that surgical removal of visceral fat in mice can extend life, for example. So it is plausible that the mechanism of action for the genetic alteration noted in the paper quoted below is in fact lower levels of fat, but as for all such things it will require much more work to determine whether or not this is the case. So many aspects of metabolism are changed, they all impact one another, and picking apart individual mechanisms is a challenging process. There are many ways to extend life in mice through metabolic alteration, and it is fair to say that none are yet fully understood.

The HLA-F adjacent transcript 10 (FAT10) is a member of the ubiquitin-like gene family that alters protein function/stability through covalent ligation. Although FAT10 is induced by inflammatory mediators and implicated in immunity, the physiological functions of FAT10 are poorly defined.

We report the discovery that FAT10 regulates lifespan through adiposity. This phenotype is associated with metabolic reprogramming of skeletal muscle (i.e., increased AMP kinase activity, β-oxidation and -uncoupling, and decreased triglyceride content). Moreover, knockout mice have reduced circulating glucose and insulin levels and enhanced insulin sensitivity in metabolic tissues, consistent with elevated IL-10 in skeletal muscle and serum. These observations suggest novel roles of FAT10 in immune metabolic regulation that impact aging and chronic disease.

If the role of FAT10 in humans is similar to mice, then targeting of FAT10 may hold promising therapeutic impact for the treatment of various diseases including obesity and obesity-related diseases and aging associated diseases.

Link: http://dx.doi.org/10.1073/pnas.1323426111

The costs of biotechnologies relating to gene therapy and genetic analysis have fallen steeply in the last ten years, even as the capabilities of a well-equipped laboratory have increased by leaps and bounds over the same period of time. A graduate student today has more power at his or her fingertips than an entire laboratory staff of the early 90s. This has matched the economics of computing hardware, as much of biotechnology is essentially a matter of building direct interfaces between that computing hardware and the nanoscale life science world of proteins and cells. This said, until just the past year or two the available options for gene therapy and most genetic analysis remained still remained too challenging and expensive for growth into the market. They have long been practical for the work of a laboratory or research institution, but not for most potential uses in the mass market, where a single provider would be expected to churn through thousands or tens of thousands of samples in a week, with high reliability and at a minimal expense per item.

The present leap in capacity and fall in cost promises to change all of that, however, given time to work its way through the pipeline. The latest methods and technologies are so far proving to be cheap enough and reliable enough to form the basis for the mass commercialization of genetic analysis and alteration in the years ahead. This will certainly have a great impact on many areas of medicine, though we'll probably all be surprised by many of the specific outcomes. The best thing that can happen for progress in the long term is for the cost of research to fall greatly, as is presently happening. The lower the cost of entry to a field, the more experimentation and development that will take place - and this is why it is helpful to keep an eye on progress in fundamental technologies, not just on specific applications of interest, such as in the area of aging and longevity.

New DNA-editing technology spawns bold UC initiative

The technology, precision "DNA scissors" referred to as CRISPR/Cas9, has exploded in popularity since it was first published in June 2012 and is at the heart of at least three start-ups and several heavily-attended international meetings. Scientists have referred to it as the "holy grail" of genetic engineering. "The CRISPR/Cas9 technology is a complete game changer. With CRISPR, we can now turn genes off or on at will."

The new genomic engineering technology significantly cuts down the time it takes researchers to test new therapies. CRISPR/Cas 9 allows the creation in weeks rather than years of animal strains that mimic a human disease, allowing researchers to test new therapies. The technique also makes it quick and easy to knock out genes in human cells or in animals to determine their function, which will speed the identification of new drug targets for diseases.

Using the Cas9 technique, UC Berkeley immunologist Russell Vance disabled a gene in mice that regulates fur color and in just six weeks had a strain of mice with white coats instead of brown. Similar research in animal models ranging from rodents to primates is being done in labs around the world using the CRISPR/Cas9 technology. Other researchers have already adapted the technology to reprogram stem cells to regenerate damaged organs, such as the liver, and made attempts to reprogram immune cells to cure AIDS in HIV-positive patients.

Innovative technique provides inexpensive, rapid and detailed analysis of proteins

Mass Spectrometric Immunoassay (MSIA) [is] a high-throughput protein quantification technique that also provides detailed protein information. In a new study [researchers] demonstrate the power of the MSIA platform, with a vision towards clinical adoption. The research reports a high-throughput method for quantifying and characterizing insulin-like growth factor 1 (or IGF1) at a rate of more than 1,000 human samples a day.

Mass spectroscopy can readily identify genetic variants that are expressed on the protein level (for example single-nucleotide polymorphisms). Such changes may alter or disable the function of the resulting protein. Further, mass spectroscopy can pinpoint changes that may occur to the protein after it has already been produced from the gene template - so-called post-translational modifications.

Heterochronic parabiosis is the unwieldy name given to the process of linking the circulatory systems of an old and a young individual. Over the past decade, researchers have used this technique in mice to demonstrate that the declining activity of many types of old stem cells is driven more by changing protein levels in the environment than by any damage inherent to the cells themselves. Restore a youthful environment to some degree, and stem cells pick up their activities.

The decline in stem cell activity with aging, the loss of tissue maintenance and resulting frailty and dysfunction, is thought to be an evolutionary adaptation to reduce cancer risk, with the later stages of life painted as a balancing act between risk of cancer due to the activities of damaged cells on the one hand versus the need to maintain tissue function on the other. As the medical community becomes ever better at controlling cancer, there may be no real objection to removing the environmental triggers that are turning down stem cell activity. That of course requires the identification of these triggers, which is presently an ongoing topic of research.

I see this as a stop-gap approach, however. It might prove fairly beneficial, but it doesn't address the underlying reasons as to why the environment within the body has changed. That change is presumably a response to higher levels of damage to cells and macromolecules. Thus the development of rejuvenation treatments that repair that damage will lead to a restoration of the environment to youthful patterns of protein levels and cellular responses to those protein levels.

Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression.

However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells - both under control conditions and after acute demyelination.

Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination.

Link: http://dx.doi.org/10.1002/glia.22606

Gene expression is the process of generating proteins from the blueprints encoded in DNA. Most DNA is in the cell nucleus, but thirteen genes can be found in the mitochondria, the powerplants of the cell that were once, long ago, symbiotic bacteria. Alloptic expression is a form of genetic engineering wherein one or more of those mitochondrial genes is copied into nuclear DNA, and the resulting proteins transported back to the mitochondria where they are needed. It is that transportation that is the hard part, not yet accomplished for more than a couple of mitochondrial genes.

Why should we care about allotopic expression as anything more than a technical curiosity? Because mitochondrial DNA damage is one of the root causes of aging. Mutations that disable some mitochondrial genes, thus depriving mitochondria of necessary protein machinery, lead to a chain of unfortunate events that progressively produces ever more dysfunctional cells and damage to tissues and organs over the years. If researchers could create a backup source of the necessary proteins in the cell nucleus, then this contribution to aging could be completely removed - and even reversed in its later stages.

The SENS Research Foundation is more or less the only group coordinating work on allotopic expression for the treatment of aging, but a number of unaffiliated labs are using the approach in a more limited way in an attempt to address the genetic disease of Leber hereditary optic neuropathy (LHON). LHON is caused by a defective mitochondrial gene, so many of the efforts taken to cure it are also somewhat applicable to the issue of mitochondrial mutations in aging. Here researchers demonstrate effectiveness and safety of allotopic expression in this case:

We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration.

We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions.

Link: http://dx.doi.org/10.1001/jamaophthalmol.2013.7630

Live or die: why does it matter to you? Why strive, why bother? The first stoics long ago pointed out that dead is dead; fear dying by all means, but do not fear being nothing. Or, from Epicurus, we have the epitaph "I was not, I was, I am not, I care not."

I recently engaged in a passing conversation with a young lady on the topic of the progress of medical science towards enhanced longevity. She recognized that medicine was improving but chose to do nothing to improve the odds for her own future - to be a person who will take advantage of future medical advances when they arrive, but who is content to live whatever life and life span falls out of chance and the actions of others. One wonders if the many people who think and act this way have an accurate picture of the suffering involved in being aged, frail, and decrepit, but it is a common viewpoint. These folk head towards death in the distance, but feel no urgency, no urge to do anything but die alongside the rest of the herd. Yet when the damage of aging presses its claws in, these are the very same people who, decades from now, will reach out for the best medical help available. It is a puzzle to me, the absolute contradiction of individuals who intricately plan out finances and life courses for the decades ahead in all matters except helping to build the better medicine that will ease their future. Their view of technological progress is passive, that it is something that just happens, perhaps.

But why be different, why bother? Why survive at all, given the stoic view? Why live? Why put in all this effort for a shot at a life span far longer than the measly four score or so years that is all that most of us would get in the environment of today's medical technology? That is a question with no answer but the one you fill in yourself, alongside the meaning of life and the laundry list of goals you feel you are here to achieve. It is self-determination all the way down.

In the case of rejuvenation research, there are obvious and compelling reasons to work on technologies to halt and reverse degenerative aging even absent a will to avert death. Rejuvenation treatments are the only long-term reliable solution to prevent the great suffering, pain, and cost that comes with aging while still alive. Preventing the breakdown of the body is a worthy, useful, and rational goal regardless of your position today on when you'd like to die. Many young people express the desire to die on the same timescale as their parents, but few are ready to volunteer for heart disease, chronic pain, cancer, and Alzheimer's disease if the question is put to them.

Cryonics and plastination, the preservation of the brain and the mind it contains against a better-equipped future in which restoration is a possibility, has a different dynamic. Because euthanasia is illegal in much of the world - a squalid state of affairs, in which disinterested bureaucrats force you into an undignified and horrible end simply because they can - cryonics cannot be used to bypass the suffering of aging. Instead the motivation here must be survival, pure and simple. The desire to live and act and see tomorrow's news.

Here's a post on this topic from one of the folk involved in the Brain Preservation Foundation, a group that favors plastination as an approach but runs a technology-agnostic research prize for the best contending approaches, presently vitrification and plastination. It is a reminder that there are as many views on survival as there are people willing to survive:

Brain Preservation: Why Bother? Getting to the Zen of Life

This talk explores the "Why Bother?" or Zen of Mortality perspective, which I think is the main reason that most folks, and particularly secular folks, don't yet see the value of [survival via plastination]. While I acknowledge the validity and great value of the Zen of Mortality perspective, and I used to hold it myself, I think there's an even more exciting and valuable perspective, the Zen of Life, waiting patiently for all of us who are ready to embrace it.

People who know how redundant the majority of their own memes are in culture, including most of the aspects of their individual self, are often very Zen (accepting, calm, serene) about dying. Today, in surveys done by David Ewing Duncan only 1% of people in the US, roughly 3 million of us, are interested in living beyond our biological death. This percentage may be even smaller in other developed countries, and particularly in the developing world. Certainly our unique religious and cultural beliefs play a role, but I think the main reason this percentage is so small is this strong Zen of Mortality, in almost all of us who think about this issue. Most of us know, in our gut, that our individual lives really don't "need" to be preserved, and are quite similar to those others around us who will live on. So why bother?

Let me now propose another Zen state, emerging now in a few places in our society, that is even more productive and enlightening than being comfortable with death. Let's call it the Zen of Life. There's something unique about Life as a process, that causes it to continually grow, learn, progress, and even accelerate at the leading edge of change. Transhumanists tend to focus on this latter process of accelerating change, and of transcending our prior limits, of continually being able to rejuvenate, grow, and learn. Understanding and imitating Life, in our thinking and practice, is even more interesting and rewarding for us than understanding and imitating Mortality. We can accept the Zen of Mortality, if that's the hand we're dealt. But if we are industrious, and lucky, we may turn ourselves into a continually improving and renewing system as well. That is the Zen of Life.

Let me now propose a vision. I believe having the option of affordable brain preservation at death, even if far less than 1% of us exercise this option, will nevertheless powerfully shift all societies where the option exists. We can imagine that these major positive social changes would happen at the moment social adoption reaches a significant minority (say, 100,000 preserved), regardless of when or how much mental information is eventually uploaded from preserved brains into computers in the future. Everyone would begin to know someone who had made the brain preservation choice. Conversations and values would start to shift now, as a result.

A popular science piece on a new association in the biochemistry of Alzheimer's disease:

It is one of the big scientific mysteries of Alzheimer's disease: Why do some people whose brains accumulate the plaques and tangles so strongly associated with Alzheimer's not develop the disease? The memory and thinking problems of Alzheimer's disease and other dementias, which affect an estimated seven million Americans, may be related to a failure in the brain's stress response system, the new research suggests. If this system is working well, it can protect the brain from abnormal Alzheimer's proteins; if it gets derailed, critical areas of the brain start degenerating.

The research focuses on a protein previously thought to act mostly in the brains of developing fetuses. The scientists found that the protein also appears to protect neurons in healthy older people from aging-related stresses. But in people with Alzheimer's and other dementias, the protein is sharply depleted in key brain regions.

"Why should a fetal gene be coming on in an aging brain?" [Researchers] hypothesized that it was because in aging, as in birth, brains encounter great stress, threatening neurons that cannot regenerate if harmed. [Researchers] discovered that REST appears to switch off genes that promote cell death, protecting neurons from normal aging processes like energy decrease, inflammation and oxidative stress.

In people with Alzheimer's, mild cognitive impairment, frontotemporal dementia and Lewy body dementia, the brain areas affected by these diseases contained much less REST than healthy brains.This was true only in people who actually had memory and thinking problems. People who remained cognitively healthy, but whose brains had the same accumulation of amyloid plaques and tau tangles as people with Alzheimer's, had three times more REST than those suffering Alzheimer's symptoms. About a third of people who have such plaques will not develop Alzheimer's symptoms, studies show.

Link: http://www.nytimes.com/2014/03/20/health/fetal-gene-may-protect-brain-from-alzheimers-study-finds.html

Bone density declines with aging, a condition known as osteopenia, and which leads to the serious frailties of osteoporosis. One of the possible reasons for this is a growing deficiency in osteoblasts, the cells that lay down bone structure, or perhaps a widening mismatch between the behavior of osteoblasts and osteoclasts, the cells responsible for breaking down bone structure when needed. Here, researchers look into some of the details of osteoblast deficiency, and find it is complex, with differing mechanisms between the genders:

Bones adjust their mass and architecture to be sufficiently robust to withstand functional loading by adapting to their strain environment. This mechanism appears less effective with age resulting in low bone mass. In male and female young adult (17 week) and old (19 month) mice we investigated the effect of age in vivo on bones' adaptive response to loading and in vitro in primary cultures of osteoblast-like cells derived from bone cortices.

Right tibiae were axially loaded on alternate days for 2 weeks. Left tibiae were non-loaded controls. In a separate group, the number of sclerostin positive osteocytes and the number of periosteal osteoblasts were analyzed 24 hours after a single loading episode. In young male and female mice loading increased trabecular thickness and the number of trabecular connections. Increase in the number of trabecular connections was impaired with age but trabecular thickness was not. In old mice the loading-related increase in periosteal apposition of the cortex was less than in young ones. Age was associated with a lesser loading-related increase in osteoblast number on the periosteal surface but had no effect on loading-related reduction in the number of sclerostin positive osteocytes. In vitro, strain-related proliferation of osteoblast-like cells was lower in cells from old than young mice. Cells from aged female mice demonstrated normal entry into the cell cycle but subsequently arrested in G2-phase, reducing strain-related increases in cell number.

Thus in both male and female mice loading-related adaptive responses are impaired with age. This impairment is different in females and males. The deficit appears to occur in osteoblasts' proliferative responses to strain rather than earlier strain-related responses in the osteocytes.

Link: http://dx.doi.org/10.1002/jbmr.2222

Once you know enough of the basics in a field to get by as a layperson, you'll find that scientific literature is far removed from being dry and uncontroversial. There are always heretics and novel positions being advanced - most of them wrong, but all new fields and new directions start with a few heretics, and the mainstream is consistently overturned with time, to be replaced with the new consensus. Distinguishing a good speculative hypothesis from a work of overreaching fancy can be a challenge wherever you stand in the hierarchy of knowledge, and the good-looking fallacies far outnumber the seeds of tomorrow's scientific mainstream. This is why few researchers bother to spend any time on reviewing this sort of thing when there are so very many other demands on their time.

One of the SENS Research Foundation folk turned up the open access paper linked below in the course of ongoing reviews of scientific literature relevant to aging, and thought it heretical enough to share as an item of interest - as a curio well outside the current consensus, not as anything to be acted on. It makes for a good read, and is well-researched, but I think that ultimately the points being made here can be explained away by the coincidence of development of medical technology, increasing longevity, and increasing wealth. When it comes down to the biochemistry, the dots aren't really joined well enough to be very compelling.

So I offer this as an example of the fact that if you go digging around, you'll find very interesting papers that are well-researched, highly speculative, and probably wrong. The author of this paper has been advancing his theory for more than a decade, evidently without gathering much support. That is all part and parcel of the scientific process:

The Alzheimer Pandemic: Is Paracetamol to Blame?

Historical Background:

The clinical recognition of a form of dementia closely resembling Alzheimer's disease dates from around 1800. The role of analgesics derived from coal-tar in the spread of the pandemic is traced in terms of the introduction of phenacetin (PN) in 1887; its nephrotoxicity; the observation of lesions characteristic of the disease by Fischer and Alzheimer; the discovery of paracetamol (PA) as the major metabolite of PN; the linking of kidney injury and dementia with high PN usage; and the failure of PN replacement by PA to halt and reverse the exponential, inexorable rise in the incidence of Alzheimer-type dementia. Fischer observed his first case before Alzheimer; it is proposed to rename the syndrome Fischer-Alzheimer disease (F-AD).

Disease development:

PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase.

Conclusion:

F-AD is primarily a man-made condition with PA as its principal risk factor.

The ending line there is something of a bold conclusion, and as I noted above I don't think it stands too well against Occam's razor. It is simpler to point to rising wealth driving the sedentary, high-calorie lifestyle that greatly raises the risk of suffering age-related diseases such as Alzheimer's, and note that this coincides with advances in medical technology that allow for more reliable identification of the condition, progress in other technologies that improve record-keeping and reliability in medicine, and the concurrent trend in rising life spans such that more people survive to ages in which neurodegenerative conditions become a significant risk.

I still suggest you read the paper, as you'll find that a great deal of interesting historical data is referenced therein. You'll probably learn some things that you didn't know about the history of painkillers, for example.

Differences in resting metabolic rate (RMR) between species of mammal correlate well with differences in life span. It has also been found that in our species RMR declines with advancing age, and a higher RMR is predictive of a greater risk of death. This study confirms these associations:

To assess the associations among age, health status, and resting metabolic rate (RMR) in a large population of older adults from the Baltimore Longitudinal Study of Aging (BLSA): 420 persons aged 40 to 96 (mean 68.2 ± 11.0) who underwent a comprehensive physical examination, cognitive assessment, RMR testing, body composition assessment, and physical function testing during a 3-day clinic visit.

Participants were assigned to Insight into the Determination of Exceptional Aging and Longevity (IDEAL) or non-IDEAL categories based on health status. IDEAL participants were defined according to the absence of physical and cognitive impairments, chronic conditions and comorbidities, and blood profile abnormalities. A three-stage linear regression model was used to assess the relationship between RMR and age, using IDEAL classification as a predictor and adjusting for sex and body composition.

Resting metabolic rate averaged 1,512.4 ± 442.9 kcal/d and was lower with older age. After adjusting for age, sex, and body composition, RMR was 109.6 kcal/d lower in IDEAL than non-IDEAL participants. Individuals who are fully functional and free of major medical conditions have lower RMR than those with disease and functional impairments. These findings suggest that health status plays a role in energy use and regulation independent of age and body composition and that elevated RMR may be a global biomarker of poor health in older persons.

Link: http://dx.doi.org/10.1111/jgs.12740

The pension and annuity industries and even some of the individual companies involved are truly massive. Vast sums are at play over the course of decades, and these industries will be greatly impacted by advances in means of extending healthy human longevity. Those involved are well aware of this: their challenge is not the fact that human lives will grow longer, but rather that there is great uncertainty over the upper limits to that growth. We are no longer in an era in which it is safe to extend the slow upward trend in adult life expectancy: work such as that of the SENS Research Foundation or any of dozens of other scientific groups could contribute to a sudden leap in healthy life span by producing the means of at least partial rejuvenation.

This is a challenge for the annuity and pension giants because in providing their services they have effectively taken on bets against a large increase in life span within our lifetimes. They will be ruined, or more likely they will taken on a form of insurance themselves and their counterparties in the broader financial industry will implode. Equally these entities are so large and have so much leverage that they will be able to have politicians bail them out, transferring the cost of being wrong to the public purse. It will be something like the fallout from the US real estate bubble, and another symptom of much that is wrong with the existence of highly centralized, powerful states and governance.

Various entities around the world are taking half-steps in the direction of reducing their financial exposure to increasing longevity - which might be an indication of what people really think about the prospects for greater longevity arising from medical science, if they have enough money at stake to carefully investigate the issue. Cynically, this might be thought of as a shifting of risk onto larger financial parties willing to take it on because they know they can engineer a state bailout at the end of the day. This is an example of the type, not particularly important in and of itself, but representative of the flow of money and responsibilities presently underway in response to changing expectations on the future of human longevity:

A Canadian company has signed an agreement to outsource its pension plan risk by buying about $500-million of annuities, spotlighting the growing interest in such purchases from companies eager to reduce the volatility of their retirement plans. The agreement, which is the largest group annuity deal of its kind in Canada, echoes a pattern that is already well established in the United States and Britain, as companies seek to "de-risk" defined-benefit pension plans.

The deals are popular because they remove companies' long-term pension risks and reduce future income volatility. "They are talked about such a lot now that it seems inevitable to me that we're going to see more of these set up."

Under a "pension buy-in," an insurer essentially takes over the risk of funding a firm's pension payments by selling the firm annuities with guaranteed payout rates to match the size of the pension obligation. The company still has ultimate responsibility for the pension plan and remains the pension plan's sponsor, and the deal does not affect the level of benefits owed or paid to retirees.

For years, U.S. and British companies have structured deals to shift the risk of their pension obligations to a third-party insurer. General Motors Co., for example, did a $26-billion (U.S.) annuity deal in 2012 to shift the obligation for its pension plan off its books, while Verizon Communications Inc. completed a $7-billion annuity deal for its pension plan in 2012.

Link: http://www.theglobeandmail.com/report-on-business/canada-sees-first-jumbo-pension-buyout/article17268309/

Hutchinson‐Gilford progeria syndrome (HGPS, or just plain progeria) is perhaps the best known of the rare but striking accelerated aging conditions caused by genetic mutation. These are not in fact accelerated aging, despite the apparent outcome, but rather DNA repair deficiencies. The water is always muddy when talking about damage and aging, however. Aging is just an accumulation of damage, and progeria is perhaps best thought of as an ordinarily fairly unimportant aspect of aging run amok to create a great deal of damage and dysfunction in cells and tissues.

Over the past decade or so researchers have come to a good understanding of the cause and mechanisms of progeria. An otherwise minor mutation in the LMNA gene leads to the generation of broken forms of a vital cellular structural protein, lamin A, and things go downhill from there: a progeria patient's cells are greatly malformed and perform poorly at the most crucial of their tasks. Interestingly, dysfunctional forms of this protein show up in small but increasing amounts over the course of normal aging, and are thought to be just as harmful - but on a much smaller scale, producing a much smaller detrimental effect. This has yet to be proven conclusively or quantified in any useful way, however.

To draw a perhaps overly simplistic analogy, if aging is running low on oil in your engine, then progeria is having a hole in your oil tank. They are similar in the sense that the end result is similar, and they share commonalities in their progression, but the root cause is completely different - and in the case of the hole in the tank, the unfortunate end result arrives a lot more rapidly. Knowing how to fix holes in oil tanks does nothing for efforts to make oil use more efficient, and it isn't of much help when it comes to repair efforts for the vast majority of engine-owners as they won't suffer oil tank holes.

It is an open question as to the degree to which small amounts of malformed lamin A contribute to degenerative aging, or even whether it is a cause or secondary effect of other forms of cellular and molecular damage that accumulate over time. The research linked below doesn't answer that question, but it certainly makes the whole area of lamin studies much more interesting - as is always the case if you can demonstrate extension of life in mice:

Antagonistic functions of LMNA isoforms in energy expenditure and lifespan

Alternative RNA processing of LMNA pre‐mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson‐Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging.

Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals.

It isn't at all clear as to how exactly the different lamins are involved in generating or avoiding this extension of life, given the resulting alterations in all sorts of interdependent aspects of metabolism, but I'm sure that other researchers will look in on this in the years ahead.

We humans live for much longer than the other large primates, and the grandmother hypothesis suggests that this longevity evolved because of our greater capacity for culture, cooperation, and communication. Once we became intelligent enough for older and less physically capable individuals to nonetheless materially assist in the survival of their descendants, longer lives were selected for.

As is the case for other theories in the evolution of aging, simulation is used to investigate the grandmother hypothesis and bolster arguments on interpretation and plausibility. Here, the researchers suggest that enhanced longevity in our ancestors in comparison to their primate peers may have predated our species:

We present a mathematical model based on the Grandmother Hypothesis to simulate how human post-menopausal longevity could have evolved as ancestral grandmothers began to assist the reproductive success of younger females by provisioning grandchildren. Grandmothers' help would allow mothers to give birth to subsequent offspring sooner without risking the survival of existing offspring. Our model is an agent-based model (ABM), in which the population evolves according to probabilistic rules governing interactions among individuals. The model is formulated according to the Gillespie algorithm of determining the times to next events. Grandmother effects drive the population from an equilibrium representing a great-ape-like average adult lifespan in the lower twenties to a new equilibrium with a human-like average adult lifespan in the lower forties.

The stochasticity of the ABM allows the possible coexistence of two locally-stable equilibria, corresponding to great-ape-like and human-like lifespans. Populations with grandmothering that escape the ancestral condition then shift to human-like lifespan, but the transition takes longer than previous models. Our simulations are consistent with the possibility that distinctive longevity is a feature of genus Homo that long antedated the appearance of our species.

Link: http://dx.doi.org/10.1016/j.jtbi.2014.03.011

Here is news of a recent demonstration of the use of stem cells in nerve regeneration:

Stem cells derived from human muscle tissue were able to repair nerve damage and restore function in an animal model of sciatic nerve injury. The researchers [found] that, with prompting from specific nerve-growth factors, the stem cells could differentiate into neurons and glial support cells, including Schwann cells that form the myelin sheath around the axons of neurons to improve conduction of nerve impulses.

In mouse studies, the researchers injected human muscle-derived stem/progenitor cells into a quarter-inch defect they surgically created in the right sciatic nerve, which controls right leg movement. Six weeks later, the nerve had fully regenerated in stem-cell treated mice, while the untreated group had limited nerve regrowth and functionality. Twelve weeks later, treated mice were able to keep their treated and untreated legs balanced at the same level while being held vertically by their tails. When the treated mice ran through a special maze, analyses of their paw prints showed eventual restoration of gait. Treated and untreated mice experienced muscle atrophy, or loss, after nerve injury, but only the stem cell-treated animals had regained normal muscle mass by 72 weeks post-surgery.

Link: http://www.upmc.com/media/NewsReleases/2014/Pages/pitt-study-stem-cells-repair-nerve-damage.aspx

There are a great many exceedingly complex and still comparatively poorly understood structures inside our cells. If you're even passingly familiar with the varied roles of mitochondrial damage or protein misfolding or the the decline of cellular housekeeping processes such as autophagy in aging, then the Golgi apparatus certainly has the look of a thing that should be more important in aging than seems to be the case. You'll find no mention of it in the Fight Aging! archives prior to today:

Cells synthesize a large number of different macromolecules. The Golgi apparatus is integral in modifying, sorting, and packaging these macromolecules for cell secretion (exocytosis) or use within the cell. It primarily modifies proteins delivered from the rough endoplasmic reticulum but is also involved in the transport of lipids around the cell, and the creation of lysosomes. In this respect it can be thought of as similar to a post office; it packages and labels items which it then sends to different parts of the cell.

Where the Golig apparatus is implicated in aging, it is in the context of Alzheimer's disease. In the brain cells of Alzheimer's patients the Golgi apparatus seems to fall apart, and researchers here suggest that this is an important step in the progression of pathological effects at the biochemical level. They identified one of the mechanisms by which the progression of Alzheimer's is sabotaging the Golgi structures, blocked it, and saw a consequent reduction in levels of the characteristic harmful amyloid beta associated with Alzheimer's disease. That is somewhat promising, even if only accomplished in cells rather than laboratory animals:

U-M scientists slow development of Alzheimer's trademark cell-killing plaques

University of Michigan researchers have learned how to fix a cellular structure called the Golgi that mysteriously becomes fragmented in all Alzheimer's patients and appears to be a major cause of the disease. They say that understanding this mechanism helps decode amyloid plaque formation in the brains of Alzheimer's patients - plaque that kills cells and contributes to memory loss and other Alzheimer's symptoms.

The researchers discovered the molecular process behind Golgi fragmentation, and also developed two techniques to 'rescue' the Golgi structure. "We plan to use this as a strategy to delay the disease development. We have a better understanding of why plaque forms fast in Alzheimer's and found a way to slow down plaque formation."

Researchers found that the accumulation of the Abeta peptide - the primary culprit in forming plaques that kill cells in Alzheimer's brains - triggers Golgi fragmentation by activating an enzyme called cdk5 that modifies Golgi structural proteins such as GRASP65. [The researchers] rescued the Golgi structure in two ways: they either inhibited cdk5 or expressed a mutant of GRASP65 that cannot be modified by cdk5. Both rescue measures decreased the harmful Abeta secretion by about 80 percent. The next step is to see if Golgi fragmentation can be delayed or reversed in mice.

Some research in the Alzheimer's field suggests that amyloid levels in the brain are fairly dynamic, and thus Alzheimer's may well be a progressive failure of processes that work to clear out harmful amyloid, not a slow accumulation of unwanted compounds. If that is the case, a way to reduce the pace of creation might be enough to tip things back over into a comparatively healthy state. The only fix in the long term, however, is to identify and eliminate the root causes of the condition, whatever they might turn out to be.

One aspect of nerve regeneration is the reconstruction of lost or severed axons, the long connecting threads that link neurons in the nervous system. Some of this damage can regenerate naturally, but as for most of the critical functions of our biology this regenerative ability declines with age. Here researchers note a possible cause, the first step towards some form of treatment or reversal of age-related loss of function:

Injuries to peripheral nerves can cause paralysis and sensory disturbances, but such functional impairments are often short lived because of efficient regeneration of damaged axons. The time required for functional recovery, however, increases with advancing age. Incomplete or delayed recovery after peripheral nerve damage is a major health concern in the aging population because it can severely restrict a person's mobility and independence.

A variety of possible causes have been suggested to explain why nervous systems in aged individuals recover more slowly from nerve damage. Potential causes include age-related declines in the regenerative potential of peripheral axons and decreases in the supply or responsivity to trophic and/or trophic factors. However, there have been few direct analyses of age-related axon regeneration. Our aim here was to observe axons directly in young and old mice as they regenerate and ultimately reoccupy denervated neuromuscular synaptic sites to learn what changes in this process are age related.

We find that damaged nerves in aged animals clear debris more slowly than nerves in young animals and that the greater number of obstructions regenerating axons encounter in the endoneurial tubes of old animals give rise to slower regeneration. Surprisingly, however, axons from aged animals regenerate quickly when not confronted by debris and reoccupy neuromuscular junction sites efficiently. These results imply that facilitating clearance of axon debris might be a good target for the treatment of nerve injury in the aged.

Link: http://dx.doi.org/10.1523/JNEUROSCI.4067-13.2013

We age in part because mitochondrial DNA accumulates mutations, probably via oxidative damage. Mitochondria exist as bacteria-like self-replicating herds within our cells, and mitochondrial function is essential to cellular processes. Mitochondria have their own DNA, distinct from that in the cell nucleus. This DNA is the blueprint for a number of essential portions of protein machinery used within mitochondria: severe mutations such as deletions can remove the ability of a particular mitochondrion to maintain itself and continue to operate correctly. Cellular quality control should destroy all such damaged mitochondria, but unfortunately some damage can cause forms of dysfunction that evade these quality control processes. This ultimately leads to cells overtaken by clones of a dysfunctional mitochondria, and which themselves become dysfunctional as a result, harming surrounding tissues.

Possible approaches to remove this contribution to degenerative aging include periodic mitochondrial DNA repair or replacement, and the SENS method of adding backup copies of the relevant genes to the cell nucleus.

Here is an example of research that supports this view, in which researchers examine the prevalence of mitochondrial DNA mutations with advancing age in human brain tissue, showing that deletion mutations increase significantly with age:

Mitochondria are unique among animal organelles in that they contain their own multi-copy genome (mtDNA). For the past 20 years it has been known that tissues like brain and muscle accumulate somatic mtDNA mutations with age. Because individual mtDNA mutations are present at very low levels, few details are known about the spectrum of mutations associated with aging.

Advances in sequencing technology now permit the examination of mtDNA mutations at high resolution. We have examined the spectrum of mtDNA mutations present in putamen, a brain region prone to the accumulation of somatic mtDNA mutations. We were able to quantify the accumulation of clonal and non-clonal deletions in the mtDNA coding region which are known to have a strong association with aging. Partial deletions and novel duplications of the mtDNA control region were also identified, and appear to be more prevalent than previously recognized, but levels showed weaker associations with age than coding region deletions. Single nucleotide variants accumulate fastest in the control region, with a skew towards the accumulation of pathogenic mutations in the coding region.

Understanding how the mitochondrial genome alters with age provides a benchmark for studies of somatic mtDNA mutations and dissection of the role they play in normal aging and degenerative diseases.

Link: http://dx.doi.org/10.1371/journal.pgen.1003990

Approximately 150,000 people die every day, two thirds of those due to the effects of aging. As a result their individuality, their minds, the pattern of data encoded in the fine structure of the cells of the brain, is destroyed and lost to oblivion. They are gone, irrevocably and irreversibly. But it doesn't have to be this way: the technologies exist to preserve most of these people at death, and store their brains - their minds, their selves - for a future in which they can be restored to life in a new body. Yet they are not used. The small and largely unappreciated field of cryonics offers the option of low-temperature preservation to await a future of profoundly capable medical technology, but barely 200 people have taken up that offer over the past four decades.

Cryonics as an industry presently consists of two established professional non-profit organizations, both decades old, a handful of supporting companies and groups offering various services other than preservation, and a few younger organizations established in recent years. The broader cryonics community seems perpetually on the cusp between young industry and growing industry: it has never managed to break out from the early niche. A great deal of ink has been spilled and many theories proposed as to why this is the case - perhaps it is a subset of the broader disinterest in living longer lives that is displayed by the public at large.

So instead of living in a rational world, in which as many people as possible have the chance to be rescued from oblivion through a competitive, large-scale cryonics industry, we live in a world in which the masses march knowingly to death and destruction, near every last one of them shunning the few paths that might prevent that end. Cryonics, research into reversal of aging, and so forth: these are greeted with yawning disinterest or mockery by the population at large.

Cryonics has become more accepted, and great strides have been made in growing support for rejuvenation research in the past ten years, I should mention. But we have incremented the counter just a few notches, and there are another hundred left to go if we want to see a research community the size of the cancer or stem cell establishment working away to produce a halt to degenerative aging. Meanwhile people still die of aging, and cryonics is the only presently available option other than the grave.

Every industry has its early disasters, and cryonics is no exception: these largely happened in the late 1960s and 1970s, when amateurs promised more than they could afford and could deliver, and as a result preserved individuals were lost. We should not forget, because when you forget these unpleasant histories you stop striving to be better. The only way to deliver good service over the long term is to adopt the rules and rigor of professionalism, just the same as in any business, whether for profit or otherwise. The established cryonics providers of today remain small organizations, but they are a world removed from the early years of amateur groups and comparatively poor preservation methods. Here is a look back:

Cryonics pioneer still hopeful

The history of any radical idea has its heroes and its villains. In cryonics, Bob Nelson has been both. He was among the first to embrace the notion that a person could be eased into a deep freeze at the moment of death, preserved indefinitely in a thermos-like container of liquid-nitrogen, and then brought back to life when advances in medicine and technology allow it.

On Jan. 12, 1967, as president of the Cryonics Society of California, he helped freeze the first man, a 73-year-old retired psychology professor from Glendale who had cancer. That pioneering experiment turned Nelson into a media sensation - TV shows, newspaper interviews, magazine covers. Twelve years later, sensation gave way to scandal. Nine bodies Nelson was preserving in a cemetery vault in Chatsworth thawed, halting their journey to a better tomorrow. Some of the relatives sued Nelson and a colleague and won $800,000.

He disappeared from public view, changed his name, and settled into what he was before cryonics captured his imagination: a TV repairman. About 20 years ago, he moved to Oceanside. "I swore I would never ever even say the word cryonics again," he said.

Mike Perry, a cryonics historian who is a case services manager for Alcor, said Nelson deserves credit for helping to freeze the first person, but the "horrific" failure at Chatsworth still "burns in people's minds" as a cautionary tale. "We have to be sure there is adequate funding before committing ourselves to the demanding task of long-term maintenance of persons in cryogenic storage," Perry said.

To be clear, a preserved individual is still an individual. They still have the potential to return in the future. Nelson offered a rescue from an otherwise fatal situation, failed to carry through successfully, and was judged and still is judged on that. That most people and the legal system consider cryopreserved individuals to in effect no longer be people, nor to have rights, nor a voice beyond the murky law of wills and posthumous trusts, is somewhat beside the point.

Too many ways to modestly slow aging in lower animals are being discovered nowadays to mention them all. These methods generally involve altering levels of one or more proteins, and then observing the resulting effects on metabolism and life span. As knowledge of the various pathways and mechanisms involved expands, it is becoming clear that most interventions discovered over the past two decades are linked to one another, being just different points of influence in the same larger set of mechanisms. So it isn't unusual at all for a novel method of life extension in laboratory animals to be connected to other, previously discovered methods, and that is the case here:

Inhibition of translation by mutations of a growing number of genes involved in protein synthesis could extend healthy lifespan in yeast, worm, fly and mouse as well. These genes vary from translation initiation factors to structural components of ribosomes and ribosomal RNA processing factors.

Eukaryotic initiation factor 5 C-terminal domain containing protein (ECP) is a novel ribosome associated protein. Previous data supports the involvement of this gene in long term memory formation and exon guidance in Drosophila probably through its still unconfirmed functions in protein synthesis. However, the exact molecular function of ECP is still largely unknown.

Our findings here show that fly lifespan could be significantly extended in ECP RNAi flies. Meanwhile, the locomotion ability of elder ECP RNAi flies was also improved remarkably. Further studies revealed an increase of mitochondria Complex IV activity in these ECP RNAi flies. A decrease of AKT and S6K phosphorylation level in contrast to an increase of AMPK phosphorylation level could also be detected in these flies. Together, these findings support a positive effect of ECP on longevity and delaying age-related impairment in locomotor behavior probably through activation of AMPK and enhancement of mitochondrial function via insulin/IGF-1 and TOR pathway.

Link: http://dx.doi.org/10.1016/j.bbrc.2014.02.133

The membrane pacemaker hypothesis suggests that composition of cell membranes, especially those of mitochondria, is an important determinant of longevity differences between species - and possibly between individuals within a species as well. One specific proposed mechanism is the degree to which membranes contain unsaturated fatty acids, as these are more vulnerable to oxidative damage. Oxidative damage is connected to aging, but its role is subtle and complex: look back in the archives for an outline of the mitochondrial free radical theory of aging, for example, in which oxidative damage inside cells is only the initiator for a long chain of consequences.

Here researchers make an attempt to demonstrate the relevance of the membrane pacemaker hypothesis by running a life span study in mice wherein membrane unsaturated fatty acid levels are lowered. They achieve the expected results in mouse biochemistry, changes that look a lot like slowing of aging, but without any resulting extension of life - an outcome that they blame on side-effects of the method used:

The membrane fatty acid unsaturation hypothesis of aging and longevity is experimentally tested for the first time in mammals. Lifelong treatment of mice with the β1-blocker atenolol increased the amount of the extracellular-signal-regulated kinase signaling protein and successfully decreased one of the two traits appropriately correlating with animal longevity, the membrane fatty acid unsaturation degree of cardiac and skeletal muscle mitochondria, changing their lipid profile toward that present in much more longer-lived mammals.

The atenolol treatment also lowered visceral adiposity (by 24%), decreased mitochondrial protein oxidative, glycoxidative, and lipoxidative damage in both organs, and lowered oxidative damage in heart mitochondrial DNA. Atenolol also improved various immune (chemotaxis and natural killer activities) and behavioral functions (equilibrium, motor coordination, and muscular vigor). It also totally or partially prevented the aging-related detrimental changes observed in mitochondrial membrane unsaturation, protein oxidative modifications, and immune and behavioral functions, without changing longevity.

Side effects of the drug could have masked a likely lowering of the endogenous aging rate induced by the decrease in membrane fatty acid unsaturation. We conclude that it is atenolol that failed to increase longevity, and likely not the decrease in membrane unsaturation induced by the drug. The lack of modification of total body and organ weights (except for a decrease in kidney weight) and the absence of detection of variations in food intake indicate that the many observed beneficial effects of atenolol are not due to caloric restriction.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12205/full

As I mentioned yesterday, the biology of aging, the actual dance of proteins and mechanisms and environment that progressively kills us, is enormously complex in its progression from day to day and year to year. Decades and billions of dollars have only scratched the surface, even in this age of rapidly advancing biotechnology. Researchers have focused on a handful of starting point proteins and their roles and are making painstaking inroads into greater understanding, year by year, but we stand a very long way from being able to use modern medicine safely and effectively adjust the operation of metabolism to slow aging - because that would require reproducing or at least understanding a fair fraction of the great complexity of the ongoing dance. Exercise and calorie restriction remain by far the best presently available options if slowing aging is your goal, and I don't expect to see them greatly improved on for a good fifteen to twenty years yet.

Fortunately there is an entirely different and much better path towards lengthening healthy life, which is to identify and repair the forms of cellular and molecular damage that cause aging. Researchers know what these forms of damage are because comparing the detailed structure of old and young tissue has been well within our capabilities for several decades. Remove all the differences between old flesh and young flesh and old cells and young cells and what you have is young flesh and young cells: a process of rejuvenation by biochemical repair. The old could be restored to youthful health and function, and young never become damaged by age. The big deal about this approach is that (a) we know very well how to go about building treatments to do it, and (b) it doesn't require any further understanding of how aging actually happens at the detail level. We know enough now.

But I'm not talking about that today. Today is a return to one of the proteins under investigation by researchers whose primary goal is understanding, and whose slowly growing secondary goal is to try to build some sort of treatment to slow aging that looks enough like a drug to be palatable to the FDA - where the bureaucrats don't accept treatment of aging as a valid activity and will not presently approve any sort of approach to lengthening life through tackling the aging process itself. That is well known and echoes all the way back down the funding chain from commercial development to primary research. What this means in practice is that it is much harder to try to build a great way of preventing age-related disease by tackling aging than it is to try to build yet another mediocre advance in patching over the consequences of age-related disease after the fact. It's a messed-up world that we live in.

The protein of interest is IGF-1, long known to be involved in a range of mechanisms of interest to aging. As for most such culprit proteins it has many roles, as evolution likes reuse. The picture is very complex and challenging to pick apart into its component pieces, but here is a representative human study in which researchers identify a correlation between IGF-1 levels and remaining life expectancy in the elderly. As for most such things it isn't a straightforward correlation, however, and in this case it exists for women only.

Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity

Individuals with exceptional longevity comprise an advantageous group for the study of mechanisms that promote healthy aging, as many of them have delayed onset or have been spared from age-related diseases. Diminished IGF-1 signaling may be one such mechanism. Our group showed that a functional mutation in the IGF-1 receptor, which confers partial IGF-1 resistance, was more prevalent in centenarians, as compared to controls without familial longevity. Based on these observations in humans and other species, we hypothesized that lower IGF-1 levels are predictive of extended survival in generally healthy nonagenarians.

We tested the hypothesis that IGF-1 levels in nonagenarians (n = 184), measured at study enrollment, predict the duration of their incremental survival. In the Kaplan-Meier analysis, females with IGF-1 levels below the median had significantly longer survival compared with females with levels above the median. However, this survival advantage was not observed in males.

If you look back in the Fight Aging! archives you'll find a paper showing a correlation between high IGF-1 and increased survival in old men:

In this study, researchers evaluated 376 healthy elderly men between the ages of 73 and 94 years. A serum sample was taken from each subject at the beginning of the study and researchers were contacted about the status of the participants over a period of eight years. Subjects with the lowest IGF-1 function had a significantly higher mortality rate than subjects with the highest IGF-1 bioactivity. These results were especially significant in individuals who have a high risk to die from cardiovascular complications.

But in general, yes, the bulk of animal studies on IGF-1 lean the other way: less is better. Still, is this simple, clear, and well understood? No, of course not. Don't hold your breath waiting for ways to significantly extend life to emerge from this field - most of the participants are not interested in that outcome, and even if they were this is an expensive, long, confusing road to the poor end result of merely slowing aging, not reversing it.

Researchers working on viral immunotherapy for cancer have uncovered an unexpectedly beneficial mechanism:

The study evaluated a combination therapy in which the Newcastle disease virus (NDV), a bird virus not ordinarily harmful to humans, is injected directly into one of two melanoma tumors implanted in mice, followed by an antibody that essentially releases the brakes on the immune response. The researchers report that the combination induced a potent and systemically effective anti-tumor immune response that destroyed the non-infected tumor as well. Even tumor types that have hitherto proved resistant to checkpoint blockade and other immunotherapeutic strategies were susceptible to this combined therapy.

[Researchers] found that an inflammatory immune response induced in the tumor by NDV primarily accounts for the efficacy of the therapy. The checkpoint blockade antibody used in this study binds CTLA-4, a molecule found on immune cells that acts like a brake (or "checkpoint") on the immune response. A version of this antibody is already used for cancer therapy, and it has proved potent in a clinical trial evaluating its combination with another immunotherapy as well. The researchers noticed that when NDV was injected into a tumor implanted in mice, cancer-killing immune cells flooded into that tumor. "But we also found, to our surprise, that a similar infiltration of activated immune cells occurred in a distant tumor, one in which the virus was never detected."

The researchers show that NDV infection alerts T cells of the immune system to the presence of cancer cells, which otherwise suppress immune surveillance and attack. Subsequent injection of the anti-CTLA-4 antibody dials up the incipient anti-tumor response so dramatically that it overcomes the tumor's immune suppression and destroys both NDV-exposed tumors and unexposed tumors. And the effect appears to be durable. When the same tumors are reintroduced into treated animals, they are swiftly eliminated.

Link: http://www.eurekalert.org/pub_releases/2014-03/lifc-gvt030314.php

The whole cardiovascular system becomes increasingly calcified with advancing age. As is also the case for the accumulation of advanced glycation endproducts (AGEs) this process increases vascular stiffness and otherwise degrades the functionality of heart and blood vessel tissues. A few researchers have proposed a similar strategy to that adopted for AGEs, which is to find drugs to remove the calcification. Here, however, an alternative approach is suggested:

Cardiovascular calcification (deposits of minerals in heart valves and blood vessels) is a primary contributor to heart disease, the leading cause of death among both men and women in the United States. "Unfortunately, there currently is no medical treatment for cardiovascular calcification, which can lead to acute cardiovascular events, such as myocardial infarction and stroke, as well as heart failure. We have not found a way to reverse or slow this disease process, which is associated with aging and common chronic conditions like atherosclerosis, diabetes, and kidney disease."

A team of [researchers] has discovered certain proteins in osteoclasts, a precursor to bone, that may be used in helping to destroy cardiovascular calcification by dissolving mineral deposits. The research suggests a potential therapeutic avenue for patients with cardiovascular calcification. Mature osteoclasts are not typically found in the vasculature. Using unbiased global proteomics (study of proteins), the researchers were able to examine osteoclast-like cells in the vasculature to determine which proteins induced osteoclast formation. They identified more than 100 proteins associated with osteoclast development. Follow-up study validated six candidate proteins, which serve as targets for possible medications that may help promote osteoclast development in the vasculature.

"To advance this research, we need to further understand why osteoclasts are not prevalent in the vaculature, despite active calcification of the heart valves and blood vessels, and determine the difference between calcification in vasculature compared with calcification in bone. Then, we may examine ways to form osteoclasts in the vasculature."

Link: http://brighamandwomens.org/about_bwh/publicaffairs/news/pressreleases/PressRelease.aspx?sub=0&PageID=1687

The trouble with trying to slow down aging by manipulating metabolism is that the interaction of day to day metabolism and the processes driving aging is fantastically complex. So much so that the investigation of even tiny little slices of it by multiple research teams can span a decade or more, consume millions of dollars, and yet produce no great advance in understanding of the big picture over that time. This is the story for the role of p66shc in aging and mitochondrial metabolism: data is gathered and scientists are at work, but the high level explanation of what is known remains much the same as it was ten years ago. Reducing or removing the protein p66shc may or may not extend life in mice, and may or may not be a meaningful target for age-slowing drugs in humans.

The researchers quoted below, like other teams, investigate p66shc in the context of mitochondria and aging. As in past research, the fact that p66shc has an influence on reactive oxygen species production in mitochondria makes it plausible that it might have some role in the pace of aging. Numerous genetic alterations that extend life in lower animals are accompanied by either an increase or reduction in the production of reactive oxygen species. The theory here is that a reduction means less oxidative damage to cellular components and an increase means that cellular housekeeping mechanisms are spurred into greater action, with the same end result of a net lowering of oxidative damage. (This is to be compared with other alterations that reduce life span while either lowering or raising generation of reactive oxygen species. Nothing is ever simple). The reality under the hood is probably more complicated than present theories in many of these cases, and there is plenty of room for new data, new interpretations, and new arguments as to how these established means of life extension via slowing aging actually work.

Again, it comes back to the fact that this is all enormously complex. Adjusting metabolism in a desired way is very hard at our present level of technology and understanding. Consider, for example, that we have calorie restriction and exercise as examples of ways to reliably reproduce desirable alterations in metabolism. They are right in front of us to study whenever we want, in as much detail as we want, and yet despite that fact, some fifteen years of work and billions of dollars have so far failed to find ways to safely and reliably recreate even a fraction of these altered metabolic states.

In any case, this paper is more grist for the mill of plausibility when it comes to p66shc levels influencing the course of aging. The researchers also make some interesting comments on the differences between mice and humans in the discussion:

Prooxidant Properties of p66shc Are Mediated by Mitochondria in Human Cells

p66shc is a protein product of an mRNA isoform of SHC1 gene that has a pro-oxidant and pro-apoptotic activity and is implicated in the aging process. Mitochondria were suggested as a major source of the p66shc-mediated production of reactive oxygen species (ROS), although the underlying mechanisms are poorly understood.

We studied effects of p66shc on oxidative stress induced by hydrogen peroxide or by serum deprivation in human diploid human dermal fibroblasts (HDFs). An shRNA-mediated knockdown of p66shc suppressed and an overexpression of a recombinant p66shc stimulated the production of ROS in the both models. This effect was not detected in the mitochondrial DNA-depleted ρ0-RKO cells that do not have the mitochondrial electron transport chain (ETC). Mitochondria-targeted antioxidants SkQ1 and SkQR1 also decreased the oxidative stress induced by hydrogen peroxide or by serum deprivation. Together the data indicate that the p66shc-dependant ROS production during oxidative stress has mitochondrial origin in human normal and cancer cells.

Noteworthy, most studies challenging functions of p66shc in mitochondria were performed in mouse models. However, the impact of oxidative stress that hypothetically may serve as a rheostat for the lifespan regulation differs substantially in the mouse and the human models. Human cells are more resistant to oxidative stresses and have at least two-fold lower mitochondria ROS production rate. Therefore, some mechanisms related to p66shc and their significance could also differ in human cells. More focused studies on p66shc mechanisms in human cells would provide valuable clues for treatment and prevention of accelerated aging and numerous diseases associated with elevated ROS.

Many research groups around the world are all gnawing away at their own little pieces of the very large and complex web of interactions between proteins in particular areas of age-related degeneration. Here is work focused on a narrow portion of the biochemistry of progressive loss of muscle mass and function:

The loss of muscle mass in older subjects, termed sarcopenia, not only decreases muscle strength, contributing to a high incidence of accidental falls and injuries but also compromising the quality of life of elderly subjects. Identification of mechanisms and contributors to aging-induced muscle loss could lead to new therapeutic strategies for preventing and treating sarcopenia. Thus, we examined mechanisms causing sarcopenia and the development of muscle cell senescence in both mice and rats, [and] found that the microRNA miR-29 can initiate muscle cell senescence leading to aging-induced sarcopenia. miR-29 was increased in muscles of both mice and rats and it was associated with the presence of higher levels of cellular arrest proteins and lower levels of cell proliferation.

Expression of miR-29 suppressed the expression of IGF-1 and p85α and B-myb and led to induction of senescence in vivo. Thus, the presence of senescent cells that are derived from muscle progenitor cells (MPCs) would contribute to an exhaustion of MPCs regeneration, contributing to the development of muscle atrophy and sarcopenia. In vivo, electroporation of miR-29 into muscles of young mice suppressed the proliferation and increased levels of cellular arrest proteins, recapitulating aging-induced responses in muscle. A potential stimulus of miR-29 expression is Wnt-3a since we found that exogenous Wnt-3a stimulated mir-29 expression 2.7-fold in primary cultures of MPCs. The increase in miR-29 provides a potential mechanism for aging-induced sarcopenia.

Link: http://www.impactaging.com/papers/v6/n3/full/100643.html

A big mess of correlations exists between social status, wealth, intelligence, education, stress, life expectancy, and a range of aspects of our biology linked to variations in longevity, such as telomere length, epigenetic patterns of DNA methylation, and so forth. There are many moving parts here and the situation is complex enough that I imagine people will still be gathering data and arguing over interpretations long after the research community has created means of rejuvenation, ways to extend healthy life by far greater amounts than the present natural variations in human life span, that will make all of this irrelevant:

Epigenetic programming and epigenetic mechanisms driven by environmental factors are thought to play an important role in human health and ageing. Global DNA methylation has been postulated as an epigenetic marker for epidemiological studies as it is reflective of changes in gene expression linked to disease. Insufficient maternal care or diet can be reflected in the methylation status of their offspring. Indeed, an inherited sensitivity to stress, influenced by the mood of the mother during pregnancy, has also been reported. These observations suggest that there may be an adaptive mechanism which allows for epigenetic plasticity in response to environmental changes. A broad range of environmental factors may therefore impact on global DNA methylation status and consequently health. This is important to the understanding of the impact of socio-economic drivers of ill health, which may be predominant in communities where there is also a higher prevalence of classical risk factors for disease.

The aim of this study was to investigate the relationship between socio-economic and lifestyle factors and epigenetic status, as measured by global DNA methylation content, in the pSoBid cohort, which is characterized by an extreme socio-economic and health gradient. Global DNA hypomethylation was observed in the most socio-economically deprived subjects. Job status demonstrated a similar relationship, with manual workers having 24% lower DNA methylation content than non-manual. Additionally, associations were found between global DNA methylation content and biomarkers of cardiovascular disease (CVD) and inflammation, including fibrinogen and interleukin-6 (IL-6), after adjustment for socio-economic factors.

Link: http://ije.oxfordjournals.org/content/41/1/151.full

There are a range of mechanisms associated with the health costs of becoming fat, some of which are much more iron-clad than others when it comes to the supporting evidence. On the leading edge, there is the comparative lack of exercise usually associated with gaining weight. It is also probably the case that increased levels of methionine intake that come with a larger calorie intake lead to an unfavorable adjustment of metabolism. Once you have excess visceral fat tissue, the inner fat tissue that accumulates around your abdominal organs, this acts to further alter metabolism in harmful ways - it is much more active in this respect than other fat tissue in the body. It also leads to increased levels of chronic inflammation, and is associated with higher mortality and a raised risk of suffering most of the common fatal age-related conditions.

This visceral fat is so damaging to health that you can pick out its effects just by looking at measures of body shape that preferentially capture visceral fat over other aspects of weight gain. Body mass index is useful but a little too insensitive to weight distribution, for example, which is why researchers tend to come up with other proposed categorization systems for epidemiological studies such as the body shape index noted last month. But even very simple approaches such as measuring waist circumference can distinguish the impact of visceral fat on health in large studies:

Large Waist Linked to Poor Health, Even Among Those in Healthy Body Mass Index Ranges

Having a big belly has consequences beyond trouble squeezing into your pants. It's detrimental to your health, even if you have a healthy body mass index (BMI). Men and women with large waist circumferences were more likely to die younger, and were more likely to die from illnesses such as heart disease, respiratory problems, and cancer after accounting for body mass index, smoking, alcohol use and physical activity.

The researchers pooled data from 11 different cohort studies, including more than 600,000 people from around the world. They found that men with waists 43 inches or greater in circumference had a 50 percent higher mortality risk than men with waists less than 35 inches, and this translated to about a three-year lower life expectancy after age 40. Women with a waist circumference of 37 inches or greater had about an 80 percent higher mortality risk than women with a waist circumference of 27 inches or less, and this translated to about a five-year lower life expectancy after age 40.

Importantly, risk increased in a linear fashion such that for every 2 inches of greater circumference, mortality risk went up about 7 percent in men and about 9 percent in women. Thus, there was not one natural "cutpoint" for waist circumference that could be used in the clinic, as risk increased across the spectrum of circumferences. Another key finding was that elevated mortality risk with increasing waist circumference was observed at all levels of BMI, even among people who had normal BMI levels.

All in all getting fat seems like a poor plan and staying fat a worse one. Medical science may well advance rapidly enough to rescue you from the consequences at some point later in your life, and almost certainly so if you are presently young, but why roll the dice and endure those consequences at all if you don't have to?

The brain does generate new neurons over a lifetime, a process known as neurogenesis, but at a sedate pace. Various methods have been shown to boost the rate of neurogenesis in laboratory animals, in order to somewhat reverse age-related loss of memory or turn back some of the other symptoms of neurodegenerative conditions. It isn't always clear that the generation of new neurons is in fact the direct cause of such benefits, however:

[Researchers] have discovered that by reestablishing a population of new cells in the part of the brain associated with behavior, some symptoms of Alzheimer's disease significantly decreased or were reversed altogether. The research [was] conducted on mouse models; it provides a promising target for Alzheimer's symptoms in human beings as well. "Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you aged or as the result of injury or disease. We now know that stem cells can be used to regenerate areas of the brain."

After introducing stem cells in brain tissue in the laboratory and seeing promising results, [researchers] leveraged the study to mice with Alzheimer's disease-like symptoms. The gene (Wnt3a) was introduced in the part of the mouse brain that controls behavior, specifically fear and anxiety, in the hope that it would contribute to the [expression] of genes that produce new brain cells. Untreated Alzheimer's mice would run heedlessly into an unfamiliar and dangerous area of their habitats instead of assessing potential threats, as healthy mice do. Once treated with the gene that increased new neuron population, however, the mice reverted to assessing their new surroundings first, as usual.

"Normal mice will recognize the danger and avoid it. Mice with the disease, just like human patients, lose their sense of space and reality. We first succeeded in showing that new neuronal cells were produced in the areas injected with the gene. Then we succeeded in showing diminished symptoms as a result of this neuron repopulation."

Link: http://www.aftau.org/site/News2?page=NewsArticle&id=19829

Below is a pointer to a recent radio interview with Craig Venter on the subject of his new venture Human Longevity, Inc. It is my belief that genetic data and analytics at the large scale will benefit medicine as a whole, the quality of cancer treatments especially, but the direct utility of this field to radical life extension is limited. Beyond a few narrow applications it does not have a large role in the creation of a toolkit of rejuvenation treatments, which is the best road ahead. On the other hand, it will be very helpful to attempts to identify longevity-associated genes and genetic variations, or slow aging via metabolic manipulation, but those have never been very plausible paths to greatly extend human life. Slowing aging is an expensive, slow road to a poor outcome: treatments that won't produce a large effect, have to be applied constantly over an entire life span, and which cannot greatly help anyone already old.

Aging. It's a universal disease, and an inescapable killer. As more of us escape traumatic deaths, life expectancy has grown dramatically in our time. As more and more individuals in the developed world manage to escape premature death, life expectancy has grown dramatically in our time. Diseases like cancer and dementia can be understood as consequences of a deteriorating body for reasons science still doesn't understand. We're exploring what might be considered the natural limits of the human body, and some believe that we can choose to push those limits out. What is a human lifespan? Is there any reason why we can't function biologically and mentally for 200 years?

One of the best known and respected genomic and synthetic life scientists, J. Craig Venter, says aging is a phenomenon we can control and arrest through genomic science. He believes that by aggressively accelerating human mapping we can better understand - and prevent - the consequences of human aging. His new project is called Human Longevity Inc., and the company aims to combine genetic and medical data at a massive scale to come up with new ways to predict, prevent and treat diseases of aging, such as cancer, heart disease and Alzheimer's.

To crack the question of aging, Venter says his new project will connect layers of information that have never been put together, starting with the entire human genome and then layering in the genetic code of the microbes, in addition to measuring proteins and chemicals. "We'll be doing tests that people won't necessarily be able to get anywhere else, and combining that all together. We're trying to get the whole picture and create a database that can actually become really predictive of what's associated with disease and what's associated with health."

Link: http://www.thetakeaway.org/story/j-craig-venter-living-longer-healther-lives/

Bitcoin is the best known of the now numerous distributed cryptography protocols that are usually represented in the form of a currency or commodity. Use in payments is probably the least of the future applications that will arise from the ability to use cryptography to solve important problems in trust and coordination - consider decentralized arbitration and escrow wherein there is no need for any third party to be trusted with funds, for example - but for now the trading of coins is where much of the attention lies.

With the growth of Bitcoin, all of the other various cryptocurrencies have seen their values rise. In effect, to my eyes, what is being valued here is the current or potential ability of a given cryptocurrency network to perform trust operations - such as payment, arbitration, escrow, validation of identity, and so forth - more efficiently than the old-fashioned methodologies, largely by removing the need for a central trusted party and single point of failure. A lot of early adopters are suddenly doing rather well for themselves, and that includes charities fortunate enough to have supporters who helped them to receive bitcoins or other cryptocoins prior to the present level of attention. The Lifeboat Foundation, for example, found themselves with several hundred thousand dollars in bitcoins, and more power to them.

I note that one of the initial investors in another cryptocurrency, NXT, has made praiseworthy donations in coin to some of the cryonics and cryonics-related charities in the community. Good for him:

Androklis Polymenis Donates 1 Million NXT to Alcor

Androklis Polymenis, a digital currency entrepreneur, has recently donated 1 million NXT coins to the Alcor Life Extension Foundation located in Scottsdale, Arizona. After Alcor converted the 1 million NXT coin donation by Polymenis to bitcoins (and then to dollars) the end result was an approximately $44,000 donation to Alcor. The donation will be used to enhance marketing efforts, special projects and continued day to day operations at Alcor.

Alcor President, Max More, said that "This was a wonderful surprise to our foundation. Alcor would like to extend our sincerest gratitude to Mr. Polymenis for his kindness and generous financial contribution. This donation will help us continue our research and bring greater awareness of the possibilities of cryonics to a wider audience."

Androklis Polymenis Donates 1 Million NXT Coins to Brain Preservation Foundation

The Brain Preservation Foundation (BPF) has received a one million NXT coin ($43,000) donation from the digital currency entrepreneur Androklis Polymenis. The donation goes toward supporting its research into the development of a scientifically-proven medical procedure capable of preserving a person's unique neural circuitry at death with the hope of allowing that person to eventually be brought back to life by future technology.

This large donation will be used by the BPF to help fund its electron microscopic evaluation of cryonically and chemically preserved animal brains which are provided to the BPF by the research groups competing in its Brain Preservation Technology Prize. This is a challenge prize offered to any research group which can rigorously demonstrate a technique capable of preserving an entire human brain with such fidelity that the structure of every neuronal process and synaptic connection remains intact and traceable using today's electron microscopic imaging techniques.

Mr. Polymenis' generous donation will also help fund targeted research grants to scientific labs with the skills needed to overcome current limitations in cryonic and chemical preservation protocols.

It is worth noting that NXT is very different to Bitcoin in near all of its fundamental aspects, and some of those differences are not viewed well by all within the cryptocoin community. Your opinions may differ, but caveat emptor is always the rule of the day. A great deal of experimentation is presently underway in cryptocurrencies, and I suspect that only a small percentage of those currently in circulation will survive the test of time - as is the case for most traditional ventures in business and collaboration. This is the way in which progress works; a great deal of trial and error accompanies each new discovery.

A novel approach in the tissue engineering of teeth is covered in this piece. It shows promise, but is still in the early stages of development in comparison to other methodologies in which researchers have actually created whole functional teeth:

[Researchers] investigated a process called mesenchymal condensation that embryos use to begin forming a variety of organs, including teeth, cartilage, bone, muscle, tendon, and kidney. In mesenchymal condensation, two adjacent tissue layers - loosely packed connective-tissue cells called mesenchyme and sheet-like tissue called an epithelium that covers it - exchange biochemical signals. This exchange causes the mesenchymal cells to squeeze themselves tightly into a small knot directly below where the new organ will form. By examining tissues isolated from the jaws of embryonic mice, [researchers] showed that when the compressed mesenchymal cells turn on genes that stimulate them to generate whole teeth composed of mineralized tissues, including dentin and enamel.

[The researchers then] set out to develop a way to engineer artificial teeth by creating a tissue-friendly material that accomplishes the same goal. Specifically, they wanted a porous sponge-like gel that could be impregnated with mesenchymal cells, then, when implanted into the body, induced to shrink in 3D to physically compact the cells inside it. They chemically modified a special gel-forming polymer called PNIPAAm that scientists have used to deliver drugs to the body's tissues. PNIPAAm gels have an unusual property: they contract abruptly when they warm. Ultimately, they developed a polymer that forms a tissue-friendly gel with two key properties: cells stick to it, and it compresses abruptly when warmed to body temperature.

[Researchers worked to] load mesenchymal cells into the gel, then implant the gel beneath the mouse kidney capsule - a tissue that is well supplied with blood and often used for transplantation experiments. The implanted cells not only expressed tooth-development genes; they also laid down calcium and minerals, just as mesenchymal cells do in the body as they begin to form teeth. In the embryo, mesenchymal cells can't build teeth alone - they need to be combined with cells that form the epithelium. In the future, the scientists plan to test whether the shrinking gel can stimulate both tissues to generate an entire functional tooth.

Link: http://www.seas.harvard.edu/news/2014/03/shrinking-gel-prompts-tooth-tissue-formation

Cross-links between proteins are formed by advanced glycation end-products and become a growing problem with advancing age. The best understood consequences are the degradation of elasticity in skin and blood vessels, but there are many other forms of harm that result from this interference with tissue structure. There is too little research presently taking place on methods of safely breaking cross-links, but this is something that the SENS Research Foundation seeks to change - the means to make an impact on aging here is one of the forms of rejuvenation treatment that might be developed comparatively rapidly, given the funding.

Here is an example of another form of harm created by cross-links, this time in the structure of tendons. The molecular structure of tissues determines their properties, such as mechanical strength and elasticity, and damage to that structure leads to loss of function:

Recent molecular modeling data using collagen peptides predicted that mechanical force transmitted through intermolecular cross-links resulted in collagen triple helix unwinding. These simulations further predicted that this unwinding, referred to as triple helical microunfolding, occurred at forces well below canonical collagen damage mechanisms. Based in large part on these data, we hypothesized that mechanical loading of glycation cross-linked tendon microfibers would result in accelerated collagenolytic enzyme damage.

This hypothesis is in stark contrast to reports in literature that indicated that individually mechanical loading or cross-linking each retards enzymatic degradation of collagen substrates. Using our Collagen Enzyme Mechano-Kinetic Automated Testing (CEMKAT) System we mechanically loaded collagen-rich tendon microfibers that had been chemically cross-linked with sugar and tested for degrading enzyme susceptibility. Our results indicated that cross-linked fibers were more than 5 times more resistant to enzymatic degradation while unloaded but became highly susceptible to enzyme cleavage when they were stretched by an applied mechanical deformation.

Link: http://dx.doi.org/10.1016/j.matbio.2013.11.005

The SENS Research Foundation (SRF) has enough of a budget these days to be funding a fair number of distinct research projects relevant to aging and longevity - too many for me to be familiar with all of them at this point. Some are fairly indirect, fundamental research that aims to build the foundations needed to even start in on projects that cut to the heart of the matter, the construction of rejuvenation biotechnologies that can reverse the course of degenerative aging. Bear in mind that as research progresses, it will not be the Foundation that funds or accomplishes the bulk of the work needed to make human rejuvenation a reality: these are still the early days, and it is as important to provide groundwork that opens the doors for other groups, or makes a field more financially attractive for development, as it is to make direct headway.

One of the Foundation's areas of interest is cancer and its causes, and this is where you'll find a lot of the more indirect work. There is a broad outline in WILT - whole body interdiction of lengthening of telomeres - as a path to build the ultimate cure for cancer, but it is also the case that a large amount of fundamental genetic science and tool-building is needed to validate and make progress on that path. For my money, I see cancer research as being in much the same state as stem cell research, by which I mean that a massive research edifice is already heading in roughly the right direction, making fair progress towards therapies that a few decades from now will be good enough to get by for the foreseeable future. Stem cells and cancer treatments are not presently set to be the limiting factors for the future of treating and reversing aging, in my opinion.

I'm not running the SRF, of course, and if you look over the Foundation's annual reports you'll see quite a lot of interest in specific tool-building at the intersection of genetics and cancer to arrive at more radical solutions for cancer than those pursued by the present mainstream. (The next generation of cancer therapies emerging from that mainstream are based on selective targeting of cancer cells, offering the promise of few side-effects and high effectiveness - which sounds pretty good to me). You can read an introduction to this area of work at the SENS website, and note that it may well also overlap with means of generating data relevant to questions on aging that are of greater interest than rejuvenation to the research mainstream, such as whether there is any merit at all in programmed aging theories, or whether there are any significant and widespread genetic contributions to longevity in humans.

One area of interest here is the generation and analysis of epigenetic data, something that I'm generally not so hot on as a point of relevance to human longevity, given its usual association with the development of drugs to slow aging or other ways to manipulate metabolism without addressing the underlying causes of dysfunction. Those are the slow roads, unlikely to produce great gains in healthy life span. But here is a piece by philanthropist Jason Hope on the way in which one SRF-funded research program is using epigenetic tools to arrive at a potentially better grasp on cancer at the opening stage, in its very earliest development:

Epimutations  -  Identifying Changes in Structures Controlling the Genetic Code

With funding from SENS Research Foundation, Albert Einstein College of Medicine (AECOM) Team members Dr. Vijg and Dr. Gravina have developed novel ways of identifying changes in the "scaffolding" that structures and controls the expression of the genetic code. These innovative approaches also help scientists determine if these changes in DNA are a response to environmental exposure or the result of damage to the scaffolding, leading to accumulating errors in the regulation of the DNA code. These methods may someday change the way doctors diagnose illnesses, such as cancer, and slow or reverse some of the debilitating effects of aging.

Dr. Gravina and the team tested the new evaluation method by analyzing DNA methylation in thousands of single liver cells, each from a different mouse. The researchers looked at specific locations in DNA scaffolding that control whether the genes are methylated or demethylated. This approach allowed scientists to compare the distinctive methylation and demethylation of individual cells with the widespread patterns of methylation occurring in a larger scale throughout the entire liver.

In other words, Dr. Gravina and his team found a way to determine whether changes in methylation were responses to environmental conditions common to many cells in the liver or were aberrant patterns unique to individual cells  -  widespread changes are likely the response to environmental stimuli whereas single cell deviations from the wider pattern are likely to be the result of damage to the epigenetic structure. The new approach developed with the support of SENS Research Foundation funding could be the foundation for new technologies for identifying cancers at their earliest stages.

You can probably see how this work will be of interest to researchers studying genetics and longevity, especially those who think that aging is a programmed set of epigenetic changes. As to cancer: the advantage of very early detection of cancer is that we don't need radical new technologies to eliminate early cancers with a high degree of reliability and comparatively little trauma. That goal is achievable with incremental advances in medical technology in the near term. Getting rid of very early stage cancer is very possible for many cancers even today, but the trouble is that by the time cancer is discovered it is almost always well past that stage. So there is a path here towards making the mainstream initiatives in targeted cancer treatment far, far more effective than would otherwise be the case. But again, I see this all happening on a good schedule with or without the help of the SRF: work on early detection of cancer is already an established line of research. This thus looks like tool-building, a process of making technologies that are needed for other Foundation work, and which also happen to have much broader applications in mainstream medicine.

Data on the degree to which various age-related conditions contribute to mortality is actually a lot less precise than most people assume it to be. Cause of death in old age is often either ambiguous or ambiguously recorded, leading to the need for estimation and correction via statistical methods. This opens the door to arguments as to the plausibility of data for any particular age-related condition, claiming that it is either more or less of a threat than previously thought. Here, for example, epidemiologists argue that Alzheimer's disease causes far more deaths than are officially reported as being due to this condition:

Data came from 2,566 persons aged 65 years and older (mean 78.1 years) without dementia at baseline from 2 cohort studies of aging with identical annual diagnostic assessments of dementia. Because both studies require organ donation, ascertainment of mortality was complete and dates of death accurate. Mortality hazard ratios after incident AD dementia were estimated per 10-year age strata from proportional hazards models. Population attributable risk percentage was derived to estimate excess mortality after a diagnosis of AD dementia. The number of excess deaths attributable to AD dementia in the United States was then estimated.

Over an average of 8 years, 559 participants (21.8%) without dementia at baseline developed AD dementia and 1,090 (42.4%) died. Median time from AD dementia diagnosis to death was 3.8 years. The mortality hazard ratio for AD dementia was 4.30 for ages 75-84 years and 2.77 for ages 85 years and older (too few deaths after AD dementia in ages 65-74 were available to estimate hazard ratio). Population attributable risk percentage was 37.0% for ages 75-84 and 35.8% for ages 85 and older. An estimated 503,400 deaths in Americans aged 75 years and older were attributable to AD dementia in 2010.

[Thus] a larger number of deaths are attributable to AD dementia in the United States each year than the number (less than 84,000 in 2010) reported on death certificates.

Given that there were overall 2.5 million deaths in the US in 2010, with the largest attributed causes being cancer and heart disease, this paper is suggesting that a large systematic miscategorization exists, not just the need for a modest correction.

Link: http://dx.doi.org/10.1212/WNL.0000000000000240

Researchers review the evidence from animal studies suggesting that stem cell transplants are a beneficial treatment for degenerative disc disease. This is a treatment that has been available via medical tourism for some years now, though it is still only just entering clinical trials in the US:

Stem cell transplant was viable and effective in halting or reversing degenerative disc disease of the spine, a meta-analysis of animal studies showed, in a development expected to open up research in humans. Recent developments in stem cell research have made it possible to assess its effect on intervertebral disc (IVD) height. Not only did disc height increase, but stem cell transplant also increased disc water content and improved appropriate gene expression. "These exciting developments place us in a position to prepare for translation of stem cell therapy for degenerative disc disease into clinical trials."

The increase in disc height was due to restoration in the transplant group of the nucleus pulposus structure, which refers to the jelly-like substance in the disc, and an increased amount of water content, which is critical for the appropriate function of the disc as a cushion for the spinal column. What they found was an over 23.6% increase in the disc height index in the transplant group compared with the placebo group. None of the 6 studies showed a decrease of the disc height index in the transplant group. Increases in the disc height index were statistically significant in all individual studies.

"A hallmark of IVD degenerative disease is its poor self-repair capacity secondary to the loss of IVD cells. However, current available treatments fail to address the loss of cells and cellular functions. In fact, many invasive treatments further damage the disc, causing further degeneration in the diseased level or adjacent levels. The goal of tissue engineering using stem cells is to restore the normal function and motion of the diseased human spine."

Link: http://www.newswise.com/articles/stem-cell-transplant-shows-landmark-promise-for-treatment-of-degenerative-disc-disease-mayo-clinic

The immune system becomes unruly and ineffective in old age: on the one hand it generates ever greater levels of harmful chronic inflammation, while on the other it no longer has a sufficient population of effective cells able to tackle new threats, scan for cancerous cells, and eliminate senescent cells from the body. It becomes overactive and underachieving, and a sizable portion of the more obvious aspects of age-related frailty stem from the lack of a robust immune response.

Why does this happen? No doubt the normal culprits leave their mark: the forms of accumulated cellular and molecular damage that degrade tissues and cell populations, including those involved in generating and maintaining immune cells. Beyond this, however, there are problems that inevitably arise due to the evolved structure of the immune system: it has what are in effect built-in limits. The first is a limit to the number of immune cells that can be supported at any one time, as the potential supply of new cells diminishes to a trickle quite early in adulthood, as an organ necessary for their creation - the thymus - atrophies. The second limit of interest stems from the fact that the adaptive immune system devotes cells to remembering threats, and thanks to persistent threats like herpesviruses, ever more of the available cell population is devoted to memory rather than action. So the end result is an evolved system that is front-loaded for early success, but which systematically falls apart much later.

What can be done about this? Destroying unwanted and duplicative memory cells looks promising, as that will trigger replacement with fresh cells capable of action. Increasing control over stem cells offers the possibility of periodic infusions of large numbers of immune cells generated from a recipient's own cells. This would surmount the natural immune capacity at the upper end. Another approach that might achieve the same result is to restore the thymus, and thus restore a youthful flow of new immune cells. This would use the approaches of tissue engineering and regenerative medicine to either build a new thymus for transplantation, or regrow the existing thymus in situ.

The SENS Research Foundation has been putting a modest amount of funding into spurring greater progress towards thymic regeneration, and this year one of the young researchers in the undergraduate program will be working on this project, established in partnership with the Wake Forest Institute for Regeneration Medicine:

Julie Marco: SRF Undergraduate Research Scholar at the Wake Forest Institute for Regenerative Medicine

My early research experience investigating how age affects regeneration is what sparked my interest in the SENS Research Foundation (SRF). I wanted to be able to learn and see new techniques that are being used to try to help slow down or reverse the process of aging.

As an undergraduate student, I have had the honor of continuing to explore my research interests working at the Wake Forest Institute for Regenerative Medicine (WFIRM) under the mentorship of Dr. James Yoo on the skin bioprinting project - a project designed to create safer and scar-less treatments for people in need of skin grafts. Successful Dr. John Jackson. The thymus is the primary lymphoid organ for the production of T cells. It is comprised of two compartments, the cortex and the medulla. The T cells undergo maturation in the cortex section of the thymus and positive selection for a functional T cell receptor. The medulla is important for the negative selection of T cells to eliminate self-reactive T-cells and is also the region where mature T cells exit from the thymus.

As we age, the thymus decreases in immune function. This leads to a shift toward a greater and greater proportion of memory T cells compared to naïve T cells. In order to reverse this effect and enhance immune response, there is a need to regenerate thymus tissue and increase naïve T cell population. This project aims to regenerate the thymus using natural thymus scaffolds which have been reseeded with cells.

The prevailing wisdom is that the introduction of effective means to treat aging will reduce health care costs. After all, most expenditures are generated in the final stages of life, during the expensive and eventually futile process of trying to prevent the failure of constantly near-failing organs and systems. Operating a damaged machine is expensive and challenging: there is no way around that without repairing the damage. This is as true for us as for a car or a lawnmower, and the ability to repair the underlying causes of aging will indefinitely postpone the end stage of frailty and high mortality rates, and indefinitely prolong the low-cost stage of life in which little is spent on medicine.

At present, however, changes in life expectancy are not driven by treatments for aging. Rather there is an incidental increase due to generally better medicine throughout life, leading to a somewhat lower level of damage at a given age, and then there are improvements in the ability to postpone mortality without repairing the underlying causes of age-related disease. Better treatments for heart disease, stem cell therapies to temporarily revert some of the damage caused by aging, and so forth. So the dynamic is different, and leaves room to argue that increasing life expectancy under the present model of medical development can increase costs. Even so, it is clearly and obviously the case that adoption of the better approach - addressing the causes of aging - will lower costs.

It is still an open question whether increasing life expectancy as such causes higher health care expenditures (HCE) in a population. According to the "red herring" hypothesis, the positive correlation between age and HCE is exclusively due to the fact that mortality rises with age and a large share of HCE is caused by proximity to death. As a consequence, rising longevity - through falling mortality rates - may even reduce HCE. However, a weakness of many previous empirical studies is that they use cross-sectional evidence to make inferences on a development over time.

In this paper, we analyse the impact of rising longevity on the trend of HCE over time by using data from a pseudo-panel of German sickness fund members over the period 1997-2009. Using (dynamic) panel data models, we find that age, mortality and 5-year survival rates each have a positive impact on per-capita HCE. Our explanation for the last finding is that physicians treat patients more aggressively if the results of these treatments pay off over a longer time span, which we call "Eubie Blake effect". A simulation on the basis of an official population forecast for Germany is used to isolate the effect of demographic ageing on real per-capita HCE over the coming decades. We find that, while falling mortality rates as such lower HCE, this effect is more than compensated by an increase in remaining life expectancy so that the net effect of ageing on HCE over time is clearly positive.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24585039

A small but significant number of cells become overtaken by damaged, dysfunctional mitochondria over a lifetime, and this process is one of the contributing causes of degenerative aging. Mitochondria are important to many cellular processes, and quality control mechanisms aim to either repair damage or remove and replace damaged mitochondria. Mitochondrial theories of aging postulate ways in which some forms of damage subvert quality control, allowing dysfunctional mitochondria to preferentially avoid recycling, leading to the end result described above.

This review paper looks at what is known of natural mitochondrial quality control mechanisms:

Repairing or disposing of a malfunctioning object is an everyday dilemma. Replacing an item may be quicker than repairing it, but may also be more costly. Cells are faced with the same options when their organelles are challenged. Ensuring the health of the mitochondrial network is of utmost importance for cellular health and, not surprisingly, mitochondrial quality control can take both the repair and disposal routes. Spectacular advances have been made in recent years and a picture is starting to emerge of what drives a cell to take one or the other path. Interestingly, mitochondrial quality control seems to be deficient in various medically relevant conditions, such as neurodegeneration and aging.

Since the original observations that calorie restriction could extend lifespan, a close connection exists between energy metabolism and aging. Mitochondria, as an important source of reactive oxygen species, have long been considered a prime suspect for causing cellular aging. However, a different picture emerges from recent studies. In a screen for long-lived worm mutants, Andrew Dillin's lab found that creating imbalance in the assembly of respiratory chain subunits caused increased lifespan. That phenomenon was soon related to an activation of the mitochondrial unfolded protein response (UPR). Indeed, this increase in lifespan did not correlate to a reduced activity of the mitochondria, but to an activation of mitochondrial UPR, since increase in lifespan is blunted in mutants incapable of mounting a mitochondrial UPR. Thus, although direct causality between mitochondrial UPR induction and lifespan extension is not clearly established, it seems that mitochondrial quality control, more than mitochondrial activity, contributes to aging regulation. These observations, originally made in worms, could be extended to mice, where a large-scale genomic association study found that longevity was associated with variations in genes encoding mitochondrial proteins.

Link: http://dx.doi.org/10.12703/P6-15

I had just yesterday mentioned one of the ventures that researcher Alex Zhavoronkov is involved in, and today I hear that he and a team are launching In Silico Medicine in the US. No doubt the announcement was pushed forward to benefit from publicity associated with the recent launch of Human Longevity, as both groups are in the same business: the application of computing power, data analysis, and new genetic technologies to make inroads into treating aging.

Thus everything I said about Human Longevity applies here too. A great deal will be achieved in many areas of medical science through advances in genetics, but it doesn't seem likely to me that meaningfully extending healthy life spans over the next few decades will be among the plausible outcomes of genetic advances that focus on gathering and analyzing genetic data. Beyond a few very narrow and targeted applications, such as mitochondrial DNA repair or rescue, genetic and epigenetic engineering do not have much of a presence in a rejuvenation research portfolio focused on damage repair. Instead, genetics is the primary tool for slowing aging through manipulation of the operation of metabolism, a goal that is going to be very, very challenging and expensive to achieve safely. Even then that path cannot produce great gains in life span in the near term of the next few decades, and will not prove beneficial to people who are already old. So given the choice between rejuvenation and slowing aging, we should focus on rejuvenation. It should be more easily created, and requires only incremental new research rather than massive across-the-board advances in knowledge and biotechnology to achieve.

But these are all well worn arguments, made many times at Fight Aging! Clearly a lot of money is going to pour into work at the intersection of genetics and aging regardless of what think on the matter, and as I note above, the likely outcome is that noteworthy benefits will be realized in many areas of medicine. Just not, I expect, in human longevity. Here is a little from Zhavoronkov via email, and a pointer to the press materials for the launch of his company:

I got interested in aging when I was still a child and even before school was looking for ways to combat aging venturing from nutraceuticals and yoga to pharmaceuticals and neuroinformatics. Like many of you, when I met Aubrey de Grey, my life changed for the better as I saw his first comprehensive strategy to combat aging. But Aubrey's brilliant projects are stretched in time and we need to have a medium-term plan to be able to live until they bear dramatic longevity benefits. In Silico Medicine will help find these medium-term solutions and may even help with SENS research going forward by looking for molecules that activate the various endogenous mechanisms that are involved in damage repair. We would like to stand with Calico and Human Longevity Inc that recently stepped out to pursue a similar goal.

In Silico Medicine Inc. Launches in the US to Use Advances in Technology to Combat Aging and Age-related Diseases

One of the reasons why pharmaceutical companies failed to develop business models for increasing productive human longevity is because human lifespans are much longer than that of the many model organisms and it takes decades to evaluate the effects of any drug. Some of the known drugs have been on the market for many decades and only recently scientists started finding clues to their oncoprotective, cardioprotective and geroprotective effects. Moreover, many drugs that work on model organisms including mice do not have the same effects in humans. There is an urgent need for intelligent systems that will cost-effectively predict the effectiveness of the many drugs on the population, but also on the individual levels.

"We built our platform on years of experience of a large international team who specialize in using gene expression data from individual patient's tumor to predict the effectiveness of targeted compounds and improve clinical decision making. We are reinventing this system for drug discovery in cancer and aging," said Alex Zhavoronkov, PhD, the CEO of In Silico Medicine. "The recent wave of startups looking to employ big data to find solutions for aging, including Google's Calico and Human Longevity, should give everyone hope that we may see the time when both the medical institutions and pharmaceutical companies will start saving lives so every human being on the planet will benefit."

In Silico Medicine

Since 2008 the In Silico Medicine research team worked hard to develop a comprehensive database of tissue-specific gene expression profiles from a large number of healthy patients, who lost their lives in accidents. This database was thoroughly analyzed, categorized and annotated. In parallel, we constructed multiple databases of gene expression from many cancer biopsies, before and after treatment. We developed tools to map gene expression data onto signaling pathways and developed algorithms for evaluating the individual pathway activation strengths and to analyze and measure the state of the overall signaling pathway cloud.

We then developed an annotated database of just over 150 targeted compounds acting on various molecular targets and network elements. We developed another set of algorithms to evaluate the activity of these drugs on the signaling pathway cloud to predict the effectiveness of these drugs on each patient's tumor. This research laid the foundation for the development of the OncoFinder, which was purchased by and is now the flagship product of the Hong Kong-based, Pathway Pharmaceuticals, the main research and business partner of In Silico Medicine.

In Silico Medicine took the concept of OncoFinder further, but instead of the normal and cancer cells, we evaluate the effects of various drugs on the pathway cloud constructed from gene expression and epigenetic data from cells taken from the old patients with those taken from the young patients with the intent to bring the state of the "old cells" as close to the signaling pathway cloud activation profile of the young cells.

These researchers propose that declining proteostasis with aging is something that starts abruptly in nematode worms, which they take as evidence for programmed aging - such as perhaps a coordinated lapse or other unfavorable change in cellular housekeeping and stress response mechanisms has evolved to occur comparatively early in life in this species:

Protein aggregation is associated with many age-related disorders, and increased protein oxidation, mislocalization, and aggregation are observed in aged organisms. Intuitively, these findings can be explained by a gradual decline in protein biosynthetic and quality control pathways and a progressive accumulation of protein damage. However, recent findings in Caenorhabditis elegans challenge this view, suggesting that a decline in proteome integrity may be the result of early programmed events rather than the consequence of a random and gradual accrual of molecular damage.

Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes. Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species. As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans.

Link: http://dx.doi.org/10.12703/P6-7

This review looks over progress in the use of stem cells treatments as a way to impact chronic inflammation and treat non-healing wounds:

A chronic wound develops when a wound fails to heal within an expected time frame and fails to achieve functional closure. There are many factors that impede healing, including co-morbid clinical conditions, aging, poor tissue perfusion, malnutrition, unrelieved pressure to the surface of the wound, immune suppression, malignancy, infection, obesity, and a number of medications. The usual patient with a nonhealing wound has a combination of several of the factors mentioned earlier, making any one therapeutic option unlikely to succeed.

One common thread with almost all nonhealing wounds is a persistent inflammatory state. Macrophages, known to mediate inflammation, influence healing in a positive way through increasing angiogenesis, decreasing bacterial loads, phagocytosing debris, and providing matrix deposition. If, however, a persistent inflammatory state develops in which the macrophages are dysregulated and become skewed toward a type I inflammatory phenotype, impeding progress toward wound repair and regeneration. Another potential explanation for the nonhealing wound is the presence of intrinsically dysfunctional or senescent cells that are incapable of responding to normal biochemical signals.

A number of treatment modalities are currently used to accelerate wound healing. The use of stem cell therapy has been hypothesized as a potentially useful adjunct for nonhealing wounds. Specifically, mesenchymal stem cells (MSCs) have been shown to improve wound healing in several studies. Immune modulating properties of MSCs have made them attractive treatment options. MSCs may be more useful if they are preactivated with inflammatory cytokines such as tumor necrosis factor alpha or interferon gamma.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842880/

In a better world, the US research community would receive the same level of comparatively enthusiastic and well-informed public support for longevity science that is seen in Russia, while the Russian research community would enjoy the same greater level of access to funding as is found in the US. Or at the very least, the greater funding and greater public support would coincide, rather than each being in the most inconvenient location, as is the case at present.

I've kept half an eye on what is going on in the Russian longevity research community these past few years, ever since the advent of free and borderline usable automated translation tools. That community has its own enthusiastic advocates and organizations that are analogous in their roles to the Methuselah Foundation and SENS Research Foundation - working to generate greater public support and funding for their preferred means to extend healthy human life and eliminate age-related disease. The Science for Life Extension Foundation is one such group, and the UMA Foundation is another more recent addition to that network of people and organizations:

UMA Foundation

We believe scientists change the world. Not politicians, not oligarchs, scientists do. They create technologies that save people's lives, make our life style more comfortable, improve our health and make us age later. Thanks to scientists work we are able to see entire world in a life time, understand each other better, communicate and most wise of us - unite based on work for better world and added value.

We think scientists work (especially young ones) is undervalued by our government and society. Many laws need improvement, too many labs need new equipment, new people, new ideas. Modernization and innovative technologies are impossible without fundamental science in Russia.

Today bio science not only can bring a fortune to researchers but make ones life fuller, bring creativity beyond even art and make young scientist name legendary. Join us! Apart from uniting on social media, we organize interesting conferences, events. We also help receiving funding for fundamental research and development and explain / explore some possible career paths in science in Russia.

While the declared mission is general improvement of the prospects for science and the scientific community in Russia, the specific projects funded by the UMA Foundation are largely focused on the life sciences and somewhat weighted towards longevity research and related projects. The Foundation was a sponsor of the 2012 Genetics of Aging and Longevity conference, for example. For this, we can look to the presence of Alex Zhavoronkov on the board: in addition to working with UMA Foundation he is a director of the UK Biogerontology Research Foundation, runs the International Aging Research Portfolio, and is a point of connection to other reaches of the longevity science community. Networking makes the world turn.

Mitochondria are bacteria-like organelles inside our cells tasked with the production of chemical energy stores, among other tasks. Like all organelles their collection of intricate protein machinery is wrapped by a membrane - or rather two membranes in this case, inner and outer.

The membrane pacemaker hypothesis advances the idea that membrane resistance to oxidative damage is an important determinant of differences in life span between species: there are correlations in the data from various different species. Mitochondria generate damaging reactive oxygen species as a consequence of their packaging of chemical energy stores, and are vulnerable to self-damage as a result. Some forms of that damage can spiral out to cause further harm that contributes to degenerative aging.

It is not yet completely clear that all these dots can actually be joined in the obvious way - that long-lived animals are long-lived because their mitochondria are more resistant to self-harm, and thus they suffer little from this cause of degenerative aging. Efforts to repair mitochondrial damage to see what happens may overtake efforts to build a better understanding, but work proceeds nonetheless. This paper is open access, but the full text is PDF format only at this point:

Mitochondria play vital roles in metabolic energy transduction, intermediate molecule metabolism, metal ion homeostasis, programmed cell death and regulation of the production of reactive oxygen species. As a result of their broad range of functions, mitochondria have been strongly implicated in aging and longevity. Numerous studies show that aging and decreased lifespan are also associated with high reactive oxygen species production by mitochondria, increased mitochondrial DNA and protein damage, and with changes in the fatty acid composition of mitochondrial membranes.

It is possible that the extent of fatty acid unsaturation of the mitochondrial membrane determines susceptibility to lipid oxidative damage and downstream protein and genome toxicity, thereby acting as a determinant of aging and lifespan. Reviewing the vast number of comparative studies on mitochondrial membrane composition, metabolism and lifespan reveals some evidence that lipid unsaturation ratios may correlate with lifespan. However, we caution against simply relating these two traits. They may be correlative but have no functional relation.

Link: http://dx.doi.org/10.1186/2046-2395-3-3

This open access study has something for everyone to argue about, no matter your previous position on diet and health. The basic idea that lower dietary protein levels are beneficial and increase life expectancy is straightforward and supported by research on calorie restriction and methionine restriction. But the results showing that low protein intake becomes disadvantageous and increases mortality in old age run contrary to past studies that demonstrated calorie restriction to be beneficial in old age.

This is not even to start in on talking about competing theories as to why animal protein may be worse for health over the long term than plant protein: because vegetarians tend to be more health-conscious in other ways; because of greater levels of dietary AGEs in cooked meat; because of greater methionine intake associated with meat eating; and so forth.

So this all suggests, as usual, that greater complexity is buried here. This is all interesting, but of course somewhat irrelevant to the future of longevity, which will arrive via new medical technology to repair the damage of aging, not via dietary changes. You'll want to click through and look at the infographic at the head of the paper for a better summary of the findings than the description in the abstract:

Mice and humans with growth hormone receptor/IGF-1 deficiencies display major reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1 activity, we examined links between protein intake and mortality.

Respondents aged 50-65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death risk during the following 18 years. These associations were either abolished or attenuated if the proteins were plant derived. Conversely, high protein intake was associated with reduced cancer and overall mortality in respondents over 65, but a 5-fold increase in diabetes mortality across all ages.

Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors, but also the detrimental effects of a low protein diet in the very old. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.

Link: http://www.cell.com/cell-metabolism/fulltext/S1550-4131(14)00062-X?switch=standard

Technological progress happens in waves, and this is just as much the case in longevity science as elsewhere. Ideas spread within a community, and are acted upon by diverse groups around the same time. Funding is found, companies and laboratories are established, work is accomplished across a few years, and in the course of that new ideas arise. A few more years pass as new connections are forged and the new ideas digested, and then the cycle starts anew. This takes around a decade or so in a fast moving field, and we are, I think, at that overlapping time of the end of the current cycle and the beginning of the next.

The last cycle of development and research included the creation of the SENS research programs and the Methuselah Foundation, attempts to apply sirtuin research and the rest of the first batch of unsuccessful attempts to build calorie restriction mimetics, a great sea change in research community attitudes towards longevity science, and took place over a period in which the tools of genetics have shifted abruptly from costly to cheap.

Given a growing acceptance of the prospects for treating aging to extend healthy life, and the plummeting price of DNA sequencing and genetic engineering, it seems that we will see new large-scale initiatives established at the intersection of genetics and aging. My suspicion is that this is where Google's Calico venture will spend much of its time, for example. Hopefully I will be proven wrong on that count, however. It strikes me that outside of very narrow and specific applications of genetic engineering - such as the SENS approach of allotopic expression to eliminate mitochondrial damage as a cause of aging - focusing on gene sequencing in the context of life extension is very much a case of searching for the keys where the light is good, not in the dark where you dropped them.

Based on the large amount of data accumulated to date on the genetics of longevity, we should expect it to be a very complex domain. There will be thousands of contributing genes, every one of which has a tiny, near-insignificant effect on its own, an effect which is very dependent on other variations, and which will be different in every regional population and lineage. With very few exceptions, it has proven challenging to reproduce associations noted between specific genetic variations and human longevity: the association in one study population is non-existent in others, and wasn't large at all to begin with.

Similarly, manipulation of epigenetic patterns, the decorations on our genes that determine whether and how much of a protein is produced from its genetic blueprint, and which change rapidly in response to circumstances, is also an enormously complex undertaking. It is an extension of targeted drug discovery, really, where researchers aim for ever more precise ways to change the expression of specific genes so as to produce beneficial effects. Given so far unsuccessful struggle of the past decade to try to recapitulate even just a fraction of the benefits of the known and cataloged epigenetic changes that accompany calorie restriction - something that is not expected to extend life in humans by much more than five years - I'm not anticipating great benefits to longevity to arise from this path ahead, or at least not soon enough to matter.

But genetics is cheap now, and while human longevity may not benefit greatly over the next few decades, many other aspects of medicine will. So people will try:

In Pursuit of Longevity, a Plan to Harness DNA Sequencing

Dr. Venter announced on Tuesday that he was starting a new company, Human Longevity, which will be focused on figuring out how people can live longer and healthier lives. To do that, the company will build what Dr. Venter says will be the largest human DNA sequencing operation in the world, capable of processing 40,000 human genomes a year. The huge amount of DNA data will be combined with other data on the health and body composition of the people whose DNA is sequenced, in hopes of gleaning insights into the molecular causes of aging and age-related illnesses like cancer and heart disease.

Slowing aging, if it can be done, could be a way to prevent many diseases, an alternative to treating one disease a time. "Your age is your number one risk factor for almost every disease, but it's not a disease itself," Dr. Venter said in an interview. Still, his company will also work on treating individual diseases of aging as well. Human Longevity said it had raised $70 million, most of it from wealthy individuals, some of whom have backed his existing company, Synthetic Genomics.

My comments above aside, a rising tide floats all boats. If the next ten years brings ever-greater legitimacy for longevity science, and ever-greater public support for the goal of eliminating age-related disease from the human condition, then I'm fine with that even if a lot of the participants are barking up the wrong tree, or taking the slow and expensive road that generates data and little else.

As I note with great regularity, we don't actually need a complete understanding of aging in order to effectively treat it. Developing that complete understanding will cost far, far more to than to simply act on what we know already: list the known root causes of degenerative aging and repair them. Given that the research community already has a well-defined list of the differences between old tissues and young tissues, we can skip the exceedingly complex and expensive part of development in which it is determined exactly and in great detail as to how these changes progress and interact with our biology. Researchers know what the changes are, and there exist plausible plans to develop the means to revert these alterations. More knowledge is always good, but it isn't strictly necessary, and certainly isn't as important as saving lives through a greater focus on implementation of clinical therapies.

This essay was written a few years back by the founder of the Brain Preservation Prize, but apparently not published until more recently. I had not read it, so will assume that is probably also true for many of the readers here.

Whatever your position on cryonics and mind uploading, many of the points made in the piece generalize well to the current situation for rejuvenation research: so much potential, but so little support from the public. If we die due to aging, it will be because we collectively chose not to make a serious effort to build rejuvenation treatments, not because we were incapable of achieving that goal:

[Our grandchildren] will say that we died not because of heart disease, cancer, or stroke, but instead that we died pathetically out of ignorance and superstition. They will say we were killed by our "bad philosophy". In one hundred years they will ask in disbelief, "Our grandparents had the technology to preserve the precise neural circuitry of their brains for long‐term storage. The best science of our grandparent's era stated unequivocally that this unique patterning of neural circuitry was the seat of the self; in it was written all memories, skills, and personality. Our grandparents seemed to grasp the quickening pace of technology, and understood that full brain scanning and simulation was around the corner. Why then did grandpa and the rest of his generation reject brain preservation and mind uploading as a means of overcoming death?" And, after considering the evidence, our grandchildren will come to the sad conclusion that we were killed by our "bad philosophy" - no matter how clear the science was, we simply could not really accept the fact that we were physical machines.

By the year 2110 such mind uploading will probably be as common place as laser eye surgery is today. No one will be seriously bothered by the philosophical questions that mind uploading provokes today. No one will ask "Sure it will have my memories, it will act like me, and it will even think it is me, but will it really be me?" Once the procedure has been performed a few times this question will be as silly as us asking today if a person having undergone a PHCA procedure is still the same person, or for that matter if a person who receives a heart transplant is really the same person.

It is notoriously difficult to get people to clearly articulate the reasoning behind their rejection of mind uploading - it is often stated as simply an intuition that it will not work. However, it is important to clearly articulate the reasoning behind this intuition so that it can be evaluated in light of the available scientific facts. After all, the history of science and technology is filled with overturned intuitions. To this end, I will attempt to clearly articulate the main philosophical intuition people express for rejecting mind uploading, and then show why this intuition is wrong.

Link: http://www.brainpreservation.org/content/killed-bad-philosophy

It is a common viewpoint that researchers advocating various theories of aging, each of which implies a different approach to developing ways to treat, slow, or reverse degenerative aging, are in competition with one another for a limited pool of research funding. In the short term this has truth to it: the most visible funding for science comes from public institutions with fixed budgets, where increasing those budgets is a major undertaking. Scientists themselves usually behave as though working within a zero-sum game, and I myself tend to imply as much at times when talking about the growth in support for programmed aging theories.

Public funding accounts only accounts for about a third of all scientific research, however, and in the long term science and money works in roughly the same way as business and money: you can increase overall global funding for your field to the degree that you can persuade people that you are doing something that they want to pay for. Competition is good, and aging research has so very little funding at the moment in comparison to other aspects of medicine that growing the funding pool for all approaches seems a realistic goal.

That is not the first impulse for researchers, however: consensus is the aim, the search for truth and the elimination of competition in theories by determining which is correct. This remains an ongoing challenge for aging, and thus there is tension in the field - though I would suggest that the tension introduced by the disruptive advent of SENS-style rejuvenation as a research goal is ultimately more important to the future than the programmed/non-programmed dispute that SENS presently a part of.

This piece was written by an advocate for programmed aging theories, but the points would be the same if approached from the other side of the fence:

Some dedicated proponents of non-programmed aging feel that it is impossible that their theory could be wrong. They therefore feel that any fair discussion of the programmed/non-programmed controversy is adverse to medicine because it will lead to directing at least some effort and funding toward the wrong theory. Because of the "zero-sum game" that generally applies to medical research, any resources directed toward the wrong theory will inevitably subtract from the efforts directed at the right theory - thus, in their view, delaying medical progress. They therefore use their considerable influence on gerontology publications and other research and educational venues in efforts to prevent publication of articles favorable to programmed aging and consider that doing so benefits medical research. Obviously they oppose any activity that entails admitting that programmed aging has any validity whatsoever, such as participating in symposia or workshops specifically directed at discussing the programmed/non-programmed issue. They also oppose fairly funding experiments or activities specifically directed at distinguishing between programmed and non-programmed theories. They fervently hope that, if only they hold fast, eventually the programmed/non-programmed issue will simply go away and they can return to the earlier happier times when everybody who was anybody believed in non-programmed mammal aging.

This approach is shortsighted for three reasons. First, it is now rather obvious that the programmed/non-programmed controversy is not going to simply go away. As someone once said, once the toothpaste is out of the tube it is very difficult to get it back in. New evolutionary mechanics concepts have eliminated the main objection to programmed aging. Journals are increasingly willing to publish pro-programmed aging articles. There is now even a journal that is oriented towards programmed aging research (Biochemistry [Moscow] Phenoptosis). Programmed aging books and papers keep appearing. The popularity of programmed aging is increasing.

Second, attempts to suppress dialog on this subject only delay the development of a consensus. For more or less 150 years, science has been unable to arrive at a strong consensus on what certainly seems to be an issue of monumental importance: Why do we age? There is now not only a programmed/non-programmed controversy but also various non-programmed theories still attack each other.

Third, the lack of consensus poisons research funding. Funding sources can look at the current situation (there is no scientific agreement regarding even the fundamental nature of aging) and reasonably conclude that significantly funding research in this area is premature at best and possibly even foolish. Even worse, lack of any scientific consensus tends to lend credence to the fundamental limitation theories. If science is unclear, why not believe in the fundamental limitation theories, which suggest that aging is unalterable and therefore that aging research is strictly "academic" and has little practical value? After all, the fundamental limitation theories provide the best fit with evolution theory as understood by most of the science-oriented public. Trying to understand cancer, heart disease, or other massively age-related disease without agreement on even the fundamental nature of aging seems at least faintly ridiculous, so lack of consensus negatively affects attitudes about age-related disease research.

Link: http://online.liebertpub.com/doi/full/10.1089/rej.2014.1548

We live in the age of "too long; didn't read," tl;dr for short. Attention is limited in scope, but demands for attention increase year after year. The flow of information of potential interest to any one individual has grown to a torrent, a flood, and continues to multiply. Many people respond to this by rejecting all but summaries. No summary? Then begone! Time is too short! I have a thousand more emails, posts, and articles to skim this week! This is a choice of course. One could go the other way and avoid the flow entirely, choosing only to search out dense blocks of information at leisure, accepting the fact that we can never know everything.

I have in the past discussed simplifying Fight Aging! as a part of attempting to broaden the audience, reach more people who might become supporters of longevity-enhancing scientific research. Fight Aging! has always been a wall of text, though I'm sure those of you who have been around for a while recall that it used to be less accessible than it is at present. The layout is an improvement these days, and I try to make more of an effort to provide context to scientific papers that I find interesting. Nonetheless, the topic is science and science is information-dense. You can lead in with bullet-points but trying to summarize study results in a few lines is very likely to miss most of the interesting points for those who are following a particular line of research. All of this is one of the many reasons why science sites tend to have smaller audiences than, say, sports sites.

The following email turned up in my in-box recently, I'm guessing from someone for whom English is a second language:

Your website is an excellent source for reverse-aging news, but it is kinda wordy. When I read your website, I feel that I was reading some very lengthy and boring research papers with a lot of technical terms that I don't understand. I am not sure how many people is like me, but I find it easier to read from online newspapers than from your website, so I usually only google those news and read.

If you can summarize your articles into short sentences and highlight significant breakthrough and if possible add some images too, then it will be a lot better, at least for people like me.

If you are keeping up with the attention stream in a language other than your own, the demands only become greater - which is not even to consider that science is involved, which is a language all to itself, making everything harder to translate.

So I put this out there again for the purposes of discussion: how much value is there is adding a layer of bullet-point tl;dr summarization to this wall of text on science? On the one hand it seems to me that the tl;dr-ing of everything, everywhere is already happening without the need for much intervention on the part of content creators, and I'm old enough to feel less than enthusiastic about this unfolding digestion of nuanced long-form to skimmed short-form. On the other hand, I'm already pretty far down that road if you stop to look back at the pace and prose of yesteryear. Fight Aging! is very deliberately a stream, a continuous signal of some sort to indicate that things are going on and human rejuvenation is a topic open to participation. Posts occasionally have summaries and sometimes even conclusions. Where does it all end?

People without the necessary time to understand and follow longevity science nonetheless want to be able to understand and follow longevity science. Is it possible to provide a useful summary in the sort of 15-second attention chunks desired, or can you only provide the illusion of a useful summary? There is so much misrepresentation taking place in the industries associated with aging that I think one has to be wary of contributing more of the same, even with the best of intentions. We might have to accept that some things cannot or should not be digested to two lines of text if you are doing something more than just counting page views and cents from advertisers.

I would of course be interested to see someone take the Creative Commons licensed content here and try their own tl;dr experiment, see how it goes. The same goes for translations. The more people out there experimenting with delivery and messaging, the more likely it is that new people find the longevity science community. Lack of attention at first doesn't necessarily mean lack of attention forever.

Ways to spur greater regeneration following major organ failures that occur in aging are an improvement over the present situation, but better healing of the consequences of a high-mortality event after the fact is nowhere near as good as preventing that event from occurring in the first place. Some of the approaches that spur greater healing may indeed help in that regard, if delivered up front to boost organ maintenance by stem cells, or via similar mechanisms, but the best option is to revert the low-level cellular and molecular damage that causes systemic organ failure.

Here researchers show that via gene therapy it is possible to spur greater cellular activity and regeneration in pig hearts following heart attack:

Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response.

We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs.

Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.

Link: http://dx.doi.org/10.1126/scitranslmed.3007668

The authors of this study suggest that they are measuring the degree to which greater body mass is less harmful when it consists of muscle versus fat tissue - the measures often used in older studies, such as body mass index, are not very discriminating in this sense. It is fairly easy to suggest that the lifestyle choices required in order to have more muscle than your peers, such as greater levels of deliberate exercise, may play a role here:

This study was designed to test the hypothesis that greater muscle mass in older adults will be associated with lower all-cause mortality. All-cause mortality was analyzed by the year 2004 in 3,659 participants from the National Health and Nutrition Examination Survey III, who were 55 years (65 years if women) or older at the time of the survey (1988-94). Individuals who were underweight or died in the first 2 years of follow-up, were excluded so as to remove frail elders from the sample.

Skeletal muscle mass was measured using bioelectrical impedance and muscle mass index was defined as muscle mass divided by height squared. Modified Poisson regression and proportional hazards regression were used to examine the relationship of muscle mass index with all-cause mortality risk and rate respectively, adjusted for central obesity (waist hip ratio) and other significant covariates.

In adjusted analyses, total mortality was significantly lower in the fourth quartile of muscle mass index compared to the first: adjusted risk ratio 0.81 and adjusted hazard ratio 0.80. This study demonstrates the survival predication ability of relative muscle mass and highlights the need to look beyond total body mass in assessing the health of older adults.

Link: http://dx.doi.org/10.1016/j.amjmed.2014.02.007