Fight Aging!

FIGHT AGING! NEWSLETTER
March 10th 2014

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

To subscribe or unsubscribe to the Fight Aging! Newsletter, please visit the newsletter site:
http://www.fightaging.org/newsletter/

CONTENTS

• The TL;DR Issue
• Genetics and Aging Venture Human Longevity Launched
• Pointing Out the UMA Foundation
• In Silico Medicine Launches
• Small Steps Towards Thymus Regeneration at the SENS Research Foundation
• Latest Headlines from Fight Aging!
  • Muscle Mass Somewhat Correlates With Remaining Life Expectancy
  • Gene Therapy Improves Heart Regeneration
  • The Perceived Zero-Sum Game of Aging Theories
  • Killed By Bad Philosophy
  • The Effects of Protein Intake on Mortality
  • Considering Mitochondrial Membranes in Aging and Longevity
  • Building Stem Cell Treatments for Non-Healing Wounds
  • A Sudden Switch to Declining Proteostasis in Nematodes
  • Mitochondrial Quality Control: Use It, Break It, Fix It, Trash It
  • An Analysis of Health Care Expenditures and Life Expectancy

THE TL;DR ISSUE
https://www.fightaging.org/archives/2014/03/the-tldr-issue.php

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.

GENETICS AND AGING VENTURE HUMAN LONGEVITY LAUNCHED
https://www.fightaging.org/archives/2014/03/genetics-and-aging-venture-human-longevity-launched.php

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.

POINTING OUT THE UMA FOUNDATION
https://www.fightaging.org/archives/2014/03/pointing-out-the-uma-foundation.php

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.

IN SILICO MEDICINE LAUNCHES
https://www.fightaging.org/archives/2014/03/in-silico-medicine-launches.php

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.

SMALL STEPS TOWARDS THYMUS REGENERATION AT THE SENS RESEARCH FOUNDATION
https://www.fightaging.org/archives/2014/03/small-steps-towards-thymus-regeneration-at-the-sens-research-foundation.php

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 bioprinting would mean people with severe burns would experience less pain and suffering during the healing process and less trauma and stress as a result of a memory-triggering scar. Using skin cells directly taken and cultured from a large animal model, we printed each layer of skin onto a wound and studied the levels of regeneration over an 8-week period. We found that our printed wounds healed faster, better, and with a less pronounced scar than the untreated wounds. Recently, I have been trying to find a way to print a skin graft that has both pigmentation and hair that could then be implanted onto a wound.

This semester (Spring 2014), as a SRF-WFIRM undergraduate research scholar, I will be working on a thymus tissue regeneration project in the laboratory of 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.

LATEST HEADLINES FROM FIGHT AGING!

MUSCLE MASS SOMEWHAT CORRELATES WITH REMAINING LIFE EXPECTANCY
Monday, March 3, 2014
https://www.fightaging.org/archives/2014/03/muscle-mass-somewhat-correlates-with-remaining-life-expectancy.php

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.

GENE THERAPY IMPROVES HEART REGENERATION
Monday, March 3, 2014
https://www.fightaging.org/archives/2014/03/gene-therapy-improves-heart-regeneration.php

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.

THE PERCEIVED ZERO-SUM GAME OF AGING THEORIES
Tuesday, March 4, 2014
https://www.fightaging.org/archives/2014/03/the-perceived-zero-sum-game-of-aging-theories.php

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.

KILLED BY BAD PHILOSOPHY
Tuesday, March 4, 2014
https://www.fightaging.org/archives/2014/03/killed-by-bad-philosophy.php

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.

THE EFFECTS OF PROTEIN INTAKE ON MORTALITY
Wednesday, March 5, 2014
https://www.fightaging.org/archives/2014/03/the-effects-of-protein-intake-on-mortality.php

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.

CONSIDERING MITOCHONDRIAL MEMBRANES IN AGING AND LONGEVITY
Wednesday, March 5, 2014
https://www.fightaging.org/archives/2014/03/considering-mitochondrial-membranes-in-aging-and-longevity.php

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.

BUILDING STEM CELL TREATMENTS FOR NON-HEALING WOUNDS
Thursday, March 6, 2014
https://www.fightaging.org/archives/2014/03/building-stem-cell-treatments-for-non-healing-wounds.php

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.

A SUDDEN SWITCH TO DECLINING PROTEOSTASIS IN NEMATODES
Thursday, March 6, 2014
https://www.fightaging.org/archives/2014/03/a-sudden-switch-to-declining-proteostasis-in-nematodes.php

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.

MITOCHONDRIAL QUALITY CONTROL: USE IT, BREAK IT, FIX IT, TRASH IT
Friday, March 7, 2014
https://www.fightaging.org/archives/2014/03/mitochondrial-quality-control-use-it-break-it-fix-it-trash-it.php

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.

AN ANALYSIS OF HEALTH CARE EXPENDITURES AND LIFE EXPECTANCY
Friday, March 7, 2014
https://www.fightaging.org/archives/2014/03/an-analysis-of-health-care-expenditures-and-life-expectancy.php

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.