Fight Aging!

FIGHT AGING! NEWSLETTER
September 16th 2013

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

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CONTENTS

• Recent Research into the Mechanisms of Calorie Restriction
• Recent Research into Exercise and Aging
• More Than You Ever Wanted to Know About Sirtuin Research
• An Example of Rejuvenation in Nature
• Some Notes From the SENS6 Conference
• Latest Headlines from Fight Aging!
  • CARP's Radical Life Extension Poll
  • Producing a Map of Long-Lived Proteins
  • Towards Molecular Prosthetics
  • An Early Step Toward a Future of Implanted Biomedical Factories
  • Membrane Composition and Longevity in Flies
  • An Example of How Far Longevity Science Advocacy Has Come
  • Attempting a Crowdfunded Mouse Lifespan Study
  • MicroRNA Expression Changes in Old Muscle Reversed by Calorie Restriction
  • Thoughts on Persuasion and Advocacy for Human Longevity
  • Measuring the Recent Rate of Growth in Adult Life Expectancy

RECENT RESEARCH INTO THE MECHANISMS OF CALORIE RESTRICTION
https://www.fightaging.org/archives/2013/09/recent-research-into-the-mechanisms-of-calorie-restriction.php

A great deal of time and money in the aging research community is invested into gaining a full understanding of the mechanisms of calorie restriction: how exactly it extends life in most species and improves health. This is still a small field in comparison to the broader life sciences or medical research in general, of course. Nonetheless it is probably the case that billions of dollars have gone into these efforts in the past couple of decades, with the goal being the development of calorie restriction mimetic drugs, some way to safely and reliably replicate the benefits of calorie restriction without the dieting. So far a lot of new knowledge of metabolism and little of practical value has emerged, but that's the way that research goes - if it was certain to produce a given set of results, then it wouldn't be research.

I, and others, think that this is a sideshow, and there are far better lines of research that are far more likely to result in meaningful extension of human life, and at a lesser cost in time and money. Change on that front is slow in coming, however.

Calorie restriction has large health benefits: along with exercise, it produces effects in basically healthy people that far outweigh those of any presently widely available medical technology. So if it wasn't already the case that a person can obtain all of those benefits just by, you know, restricting calories, I'd probably be more in favor of work focused on calorie restriction mimetics and metabolic manipulation. But you can obtain the benefits just through a modicum of willpower and planning, and while significant in the scheme of what can be done today, this is a tiny, tiny set of benefits in comparison to what billions of dollars of research into the basis for human rejuvenation should attain. You can't diet your way to living to 100 with any great chance of success, but future medical technology will achieve that end and more - just not by replicating the beneficial effects of dieting.

Here are a couple of open access papers typical of the sort of work presently taking place on the genes and proteins known to be associated with calorie restriction:

Deletion of microRNA-80 Activates Dietary Restriction to Extend C. elegans Healthspan and Lifespan

Dietary restriction, limitation of calorie intake with maintained vitamin and mineral support, can extend lifespan and protect against diseases of age across many species. Elaboration of molecular mechanisms that control dietary restriction in simple animal models may therefore inform on strategies to activate health-promoting metabolism to help address clinical challenges associated with aging and age-associated disease.

We characterize a single Caenorhabditis elegans microRNA gene that keeps dietary restriction programs off when food is abundant. A mir-80 deletion exhibits beneficial features of dietary restriction regardless of food availability, including extended maintenance of mobility and cardiac-like muscle function later into life as well as lifespan extension. We identify three key longevity genes that are required for these benefits. We hypothesize that miR-80 is a core regulator by which diverse and intersecting metabolic pathways are coordinately regulated to respond to nutrient availability.

Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner

Sir2, a member of the sirtuin family of protein dacetylases, deacetylates lysine residues within many proteins and is associated with lifespan extension in a variety of model organisms. Recent studies have questioned the positive effects of Sir2 on lifespan in Drosophila. Several studies have shown that increased expression of the Drosophila Sir2 homolog (dSir2) extends life span while other studies have reported no effect on life span or suggested that increased dSir2 expression was cytotoxic.

To attempt to reconcile the differences in these observed effects of dSir2 on Drosophila life span, we hypothesized that a critical level of dSir2 may be necessary to mediate life span extension. Using approaches that allow us to titrate dSir2 expression, we describe here a strong dose-dependent effect of dSir2 on life span. Using the two transgenic dSir2 lines that were reported not to extend life span, we are able to show significant life span extension when dSir2 expression is induced between 2 and 5-fold. However, higher levels decrease life span and can induce cellular toxicity. [Our] results help to resolve the apparently conflicting reports by demonstrating that the effects of increased dSir2 expression on life span in Drosophila are dependent upon dSir2 dosage.

RECENT RESEARCH INTO EXERCISE AND AGING
https://www.fightaging.org/archives/2013/09/recent-research-into-exercise-and-aging.php

Like calorie restriction, regular exercise can reduce mortality and extend healthy life in laboratory animal populations. Unlike calorie restriction, it doesn't appear to extend maximum life span, but rather raises the average and lowers the incidence of age-related disease in study groups. It is hard to prove cause and effect in human life span studies, which instead use statistical methods to discover associations. Exercise is certainly associated with greater average human longevity, perhaps two to ten years at most, but again not with greater maximum life span. Despite the difficulties inherent in examining life span in your own species, it is far easier to obtain data on exercise in human populations: many more people exercise than practice calorie restriction, and many long-running studies have gathered exercise data over past decades, beginning long before the modern resurgence of interest in calorie restriction research. So if you go looking you'll find many more studies on the associations between exercise and life expectancy than exist for calorie restriction.

In contrast to the situation for epidemiological studies, there is far more work taking place on the molecular biology of calorie restriction than on the molecular biology of exercise: epigenetics, gene expression, alterations in signaling pathways, and so forth. Perhaps the most obvious measure of this state of affairs is that there are no looming drug candidates touted as exercise mimetics, akin to the several strong candidate calorie restriction mimetic compounds. I expect that parity here is just a matter of time, however. Research into the mechanisms and metabolic alterations by which exercise improves health and life expectancy will in due course catch up to the present level of interest in calorie restriction.

Now as I've said in the past, if it wasn't the case that near all of us can obtain all the benefits of exercise and calorie restriction for free, I'd ascribe more value to all of this research. As it is, I think the greatest benefit will be knowledge: greater knowledge of metabolism and the details of the progression of aging. But in comparison to the possibilities offered by rejuvenation research strategies such as SENS, the development of exercise or calorie restriction mimetic drugs is a dead end of little potential. It'll swallow up time and money and there will be very little to show for it at the end of the day, when we're all old and frail and needing something far more effective than a drug that just slightly slows down the aging process.

Here are some recent papers from the exercise research community: one epidemiological, the other a look at some of the possibly detrimental effects of antioxidants on exercise:

150 minutes of vigorous physical activity per week predicts survival and successful ageing: a population-based 11-year longitudinal study of 12 201 older Australian men

Physical activity has been associated with improved survival, but it is unclear whether this increase in longevity is accompanied by preserved mental and physical functioning, also known as healthy ageing. We designed this study to determine whether physical activity is associated with healthy ageing in later life.

We recruited a community-representative sample of 12,201 men aged 65-83 years and followed them for 10-13 years. We assessed physical activity at the beginning and the end of the follow-up period. Participants who reported 150 min or more of vigorous physical activity per week were considered physically active. We monitored survival during the follow-up period and, at study exit, assessed the mood, cognition and functional status of survivors. Cox regression and general linear models were used to estimate hazard rate (HR) of death and risk ratio (RR) of healthy ageing. Analyses were adjusted for age, education, marital status, smoking, body mass index and history of hypertension, diabetes, coronary heart disease and stroke.

Two thousand and fifty-eight (16.9%) participants were physically active at study entry. Active men had lower HR of death over 10-13 years than physically inactive men (HR=0.74). Among survivors, completion of the follow-up assessment was higher in the physically active than inactive group (RR=1.18). Physically active men had greater chance of fulfilling criteria for healthy ageing than inactive men (RR=1.35). Men who were physically active at the baseline and follow-up assessments had the highest chance of healthy ageing compared with inactive men (RR=1.59).

Sustained physical activity is associated with improved survival and healthy ageing in older men. Vigorous physical activity seems to promote healthy ageing and should be encouraged when safe and feasible.

Trade-offs between Anti-aging Dietary Supplementation and Exercise

In otherwise healthy adults, moderate aerobic exercise extends lifespan and likely healthspan by 2-6 years. Exercise improves blood sugar regulation, and resistance exercise increases or maintains muscle mass, and is associated with improved cognitive function. On the other hand, evidence for antioxidant supplements increasing longevity in humans is lacking. On the contrary, transient hormetic increases in ROS, for example associated with exercise, are actually associated with increased mammalian healthspan and lifespan.

Recent studies in humans suggest that antioxidants such as vitamins C, E , resveratrol, and acetyl-N-cysteine blunt the beneficial effects of exercise on glucose sensitivity and blood sugar regulation, likely through direct inhibition of ROS signaling. Together these results suggest that there are significant tradeoffs in the use of dietary supplementation for prevention and treatment of diseases associated with aging. Such tradeoffs may result from underlying intertwined homeostatic mechanisms. For most individuals, moderate exercise is of significant benefit.

MORE THAN YOU EVER WANTED TO KNOW ABOUT SIRTUIN RESEARCH
https://www.fightaging.org/archives/2013/09/more-than-you-ever-wanted-to-know-about-sirtuin-research.php

Research into sirtuins comprised the bulk of the last decade's wave of interest and funding for calorie restriction research. Sirtuin levels were found to be associated with the metabolic alterations produced by calorie restriction quite early on, and so scientists proceeded from there to work with compounds known to alter sirtuin levels in the body. Numerous research groups aimed to produce a drug candidate to recapitulate at least some of the benefits to health and longevity produced through the practice of calorie restriction. As is often the case, nothing of any great practical value has resulted for these years of work and probably in excess of a billion dollars in funding, through a lot more is known of the metabolism and genetics of calorie restriction as a result.

So sirtuins look like something of a dead end at the current point in time, or at least a place where more years of work are required to understand why early promise didn't carry through into mammals. Nonethless, sirtuin research continues apace with ambiguous results: some signs of life extension and improved long-term health in laboratory animals such as flies, but nothing that is reliably shown to extend life in mammals. There remain many optimists in the research community, people who think that there is some useful therapy in the future of sirtuin studies. Better and brighter drug candidates for slowing aging are emerging nowadays, however, such as rapamycin and similar items, and I would expect that interest and funding will tend to migrate to fields in which there are more reliable signs of extension of healthy life in mammals.

That said, we shouldn't expect anything better than the past decade of sirtuin and resveratrol research to emerge from present studies of mTOR and rapamycin. Trying to build drugs to slightly slow aging is inherently hard, and yet will produce only marginal therapies even if successful. The researchers who take this path do so because they don't believe that repair based strategies such as SENS are in actual fact a much more efficient path towards extending healthy life and eliminating the diseases of aging. I think that they are wrong in that view, of course.

A recently published edition of Methods in Molecular Biology is entitled "Sirtuins," and contains more than most of us ever wanted or needed to know about the nuts and bolts of sirtuin research. Obviously it is to a large extent written by sirtuin optimists:

Introduction: Sirtuins in Aging and Diseases

Over the past 15 years, the number of papers published on sirtuins has exploded. The initial link between sirtuins and aging comes from studies in yeast, in which it was shown that the life span of yeast mother cells (replicative aging) was proportional to the SIR2 gene dosage. Subsequent studies have shown that SIR2 homologs also slow aging in C. elegans, Drosophila, and mice. An important insight into the function of sirtuins came from the finding that yeast Sir2p and mammalian SIRT1 are NAD+-dependent protein deacetylases. In mammals, there are seven sirtuins (SIRT1-7). Their functions do not appear to be redundant, in part because three are primarily nuclear (SIRT1, 6, and 7), three are mitochondrial (SIRT3, 4, and 5), and one is cytoplasmic (SIRT2). The past decade has provided an avalanche of data showing deacetylation of many key transcription factors. In this chapter, I will address the evidence that sirtuins mediate the effects of CR on physiology and will then turn to the evidence of a relationship between sirtuins and aging and life span. Finally, I will discuss the roles of sirtuins in diseases of aging and the prospects of translating these findings to novel therapeutic strategies to treat major diseases.

The Emerging Links Between Sirtuins and Autophagy

Evidence suggests a role for acetylation and deacetylation in regulating autophagy. In this chapter, we describe the methods useful for understanding this important connection. In particular, we discuss methods for the measurements of sirtuin deacetylase activity, in vivo acetylation detection, and the common assays used to monitor both autophagy and the more selective process of mitophagy.

Utilizing Calorie Restriction to Evaluate the Role of Sirtuins in Healthspan and Lifespan of Mice

Calorie restriction is the most powerful method currently known to delay aging-associated disease and extend lifespan. Use of this technique in combination with genetic models has led to identification of key metabolic regulators of lifespan. Limiting energy availability by restricting caloric intake leads to redistribution of energy expenditure and storage. The signaling required for these metabolic changes is mediated in part by the sirtuins at both the posttranslational and transcriptional levels, and consequently, sirtuins are recognized as instigating factors in the regulation of lifespan.

This family of class III protein deacetylases is responsible for directing energy regulation based on NAD+ availability. However, there are many effectors of NAD+ availability, and hence sirtuin action, that should be considered when performing experiments using calorie restriction. The methods outlined in this chapter are intended to provide a guide to help the aging community to use and interpret experimental calorie restriction properly. The importance of healthspan and the use of repeated measures to assess metabolic health during lifespan experiments are strongly emphasized.

AN EXAMPLE OF REJUVENATION IN NATURE
https://www.fightaging.org/archives/2013/09/an-example-of-rejuvenation-in-nature.php

Aging is near universal most likely because it provides considerable evolutionary advantages: aging species are more likely to survive changes in their environment, despite the fact that aging is a tremendous disadvantage from the perspective of the individual. The world changes, and so we and near all of our ancestors age and suffer. I did say near universal, however. The more primitive the types of organism surveyed, the more likely it is that you will see signs of agelessness: a few species of creature that, given sufficient peace, quiet, and nutrients, can repair themselves indefinitely.

Hydra may fall into this category, for example. When a species doesn't have a brain or any sort of very complex organ and configuration that is essential to the self, then aggressive regeneration is a viable strategy. That apparently stops being the case as complexity increases: there is some point at which evolution selects for a loss of regeneration in favor of ever more complicated structures. As a species we are a long, long way past that point. The most complex species capable of feats of complete regeneration of organs and limbs are small animals such as salamanders and zebrafish, and even they are nowhere near as good at it as the hydra.

Looking further down the tree of life, it was thought at one time that bacteria do not age. They do age, however, a fact uncovered not so very many years ago. Aging in bacteria is a matter of accumulating damaged materials and waste products, and the various strategies by which breakage and waste can be removed or diluted. Because the situation is comparatively simple it is possible for bacteria to stay ahead of aging just by dividing fast enough:

A microbe's trick for staying young

The team has shown that, unlike other species, the yeast microbe called S. pombe, is immune to aging when it is reproducing and under favourable growth conditions.

In general, even symmetrically diving microbes, do not split into two exactly identical halves. Detailed investigations revealed that there are mechanism in place that ensure that one half gets older, often defective, cell material, whereas the other half is equipped with new fully-functional material. So like humans microbes, in a sense, produce offspring that is younger than the parent.

But aging is not inevitable for the common yeast, S.pombe. The newly-published work shows that this microbe is immune to aging under certain conditions. When the yeast is treated well, it reproduces by splitting into two halves that both inherit their fair share of old cell material. "However, as both cells get only half of the damaged material, they are both younger than before". At least in a sense, the yeast is rejuvenated a bit, every time it reproduces.

We should not be surprised to see rejuvenation in practice in nature. All species are capable of rejuvenation: it's how old parents produce young children. Somewhere in that process is a step in which a lot of cleaning and repair takes place, prior to the point at which the embryo is too complex to support the necessary aggressive rejuvenation programs. If those same programs were turned on in an adult, the result probably wouldn't all that pretty. Lower species like hydra can get away with constant regeneration because it doesn't greatly inconvenience them to throw away or rebuild an entire section of an individual's body. We are only in that same boat for the very earliest period following conception.

Here's the scientific paper for the research mentioned above:

Fission Yeast Does Not Age under Favorable Conditions, but Does So after Stress

Many unicellular organisms age: as time passes, they divide more slowly and ultimately die. In budding yeast, asymmetric segregation of cellular damage results in aging mother cells and rejuvenated daughters. We hypothesize that the organisms in which this asymmetry is lacking, or can be modulated, may not undergo aging. We conclude that S. pombe does not age under favorable growth conditions, but does so under stress. This transition appears to be passive rather than active and results from the formation of a single large aggregate, which segregates asymmetrically at the subsequent cell division. We argue that this damage-induced asymmetric segregation has evolved to sacrifice some cells so that others may survive unscathed after severe environmental stresses.

This sort of research provides some insight into the very early evolutionary origins of degenerative aging, and as such it is interesting to follow even though there is nothing here that will greatly affect the course of programs aimed at producing human rejuvenation.

SOME NOTES FROM THE SENS6 CONFERENCE
https://www.fightaging.org/archives/2013/09/some-notes-from-the-sens6-conference.php

The sixth SENS conference took place last week, and like the 2011 SENS5 was a fairly quiet event from the point of view of online media. The SENS conferences focus on the foundations of rejuvenation biotechnology outlined in the Strategies for Engineered Negligible Senescence (SENS) research plans, but a lot of other research is presented, not all of which is directly relevant to building the means to rejuvenate old humans. The public isn't really the immediate audience for these conferences: it's part and parcel of the SENS Research Foundation's continuing and successful efforts to build support and networks of allied researchers within the aging research community.

Once the spark takes hold, the need for the SENS Research Foundation will fade as many other organizations will arise to raise funding and perform similar work on the foundation technologies needed for future human rejuvenation therapies. That process is still underway at a comparatively early stage yet despite the tremendous successes in advocacy that have taken place over the past decade - it's the old story, working hard to open the door for the next round of working hard some more. Climb the hill to get to the mountain. Conference series like SENS are one of the more visible signs of all of this work.

You can take a look at the abstracts archive for SENS6 to see a selection of the topics that were on the program this year. Videos of the presentations from SENS5 in 2011 emerged online over the course of 2012. With luck that will be a faster process this year. Most are interesting and well worth the time taken to view.

In any case, despite the many scientists present and much networking taking place, SENS6 like SENS5 was a quiet conference with little of an online footprint while underway. Here is the only set of notes from SENS6 I've seen emerge from the folk who were present:

Strategies for Engineering Negligible Senescence - Report from SENS-6

Aubrey de Grey has rallied the world's scientific community and its funders to attack the biological basis of aging, which underlies the majority of disease and suffering in the developed world. Since 2003, he has organized bi-annual conferences, bringing together innovative biologists, medical researchers and a few policy wonks to share knowledge and perspectives, to coordinate and support each others' efforts. Below I report highlights from this year's meeting, SENS 6, which I attended last week at Queens College, Cambridge.

Exercise vs Caloric Restriction

For the last ten yeas, Luigi Fontana of Washington University St Louis has been conducting an ongoing study of two groups of people who exercise fanatically (by middle-class US standards) and who seriously restrict their food intake (same standard). Both groups have dramatically improved biomarkers compared to the average American couch potato.

DRACO - kills all virus-infected cells

Todd Rider of MIT is quietly witty on-stage and charmingly self-effacing, but his program is radically ambitious. He wants to cure all infectious disease. DRACO is an acronym for Double-stranded RNA-Activated Caspase Oligomizer. The bottom line is that DRACO molecules can find cells that are infected with any virus, distinguish them from uninfected cells, and selectively signal the cell to destroy itself. It's been tested in test tubes and in mice it cures, for example, the flu. Rider's lab is producing only tiny quantities of DRACO at present, but by year's end he hopes to ramp up production for much wider testing.

Growing a liver on a lymph node

Eric Lagasse [has] had success growing new livers from stem cells in the patient's body. Liver progenitor cells are implanted in a lymph node, which seems to provide a favorable environment for growth. In mouse models, 70% are able to grow a functional liver "ectopically", meaning in a part of the body where it does not belong.

LATEST HEADLINES FROM FIGHT AGING!

CARP'S RADICAL LIFE EXTENSION POLL
Monday, September 9, 2013
https://www.fightaging.org/archives/2013/09/carps-radical-life-extension-poll.php

Following on from the recent Pew Research poll on radical life extension, the Canadian organization CARP ran their own similar poll on a selection of older people. It makes for an interesting comparison, but again it is clearly the case that advocates for longevity science - extending healthy life and eliminating the diseases and degenerations of aging - have a lot of work left to do:

It has to be pointed out that Pew poll was taken among a general population sample, weighted to reflect current US census data, and therefore containing all ages. The CARP sample is made up of members, whose average age is about 70. This will lead to significant differences in attitudes to health care and longevity between the two samples. CARP members are aware that there are radical life extension possibilities but are unlikely to embrace it for themselves. They are much less supportive than their American counterparts - even allowing for age differences in the sample - and cite resource pressures, think it is fundamentally unnatural and would not lead to a more productive economy.

When asked in detail, most CARP members think radical life extension is a bad thing, because it will lead to resource depletion and seniors will run out of savings. CARP members are half as interested in taking part in these life extension techniques as Americans, and much less convinced than Americans that others would like to take part. If they did take part in these treatments, CARP members are most concerned that their extra years would be healthy, not necessarily well-provided for.

CARP members expect to live as long as Americans wish to live, but they wish to live even longer, which may be reflection of greater confidence in our health care system. In a similar vein, CARP members are more confident humans will routinely live to be 120 years old by the year 2050 than Americans are. In a curious and counter-intuitive finding, CARP members are less likely than Americans to say these treatments would be available to everyone, and are more likely to say they will be reserved for the wealthy when they are available.

CARP members are more likely than Americans to agree these techniques would strain natural resources, are equally likely to find them fundamentally unnatural and are much less likely to think they will lead to a more productive economy. Most CARP members say they would not change what they are doing if they had an additional 20 years, while others say they will travel or volunteer.

PRODUCING A MAP OF LONG-LIVED PROTEINS
Monday, September 9, 2013
https://www.fightaging.org/archives/2013/09/producing-a-map-of-long-lived-proteins.php

Some of the cells in the body are never replaced across a life span, which leads to forms of system failure and degeneration due to accumulating damage and metabolic waste products not found elsewhere. Interestingly it appears that some of the individual proteins within those cells might not be replaced either. It is unclear as to how much of a long-term challenge that will present once researchers are past the first hurdles in extending healthy human life.

Among these long-lived proteins are those that form nuclear pores, a structure that appears to become damaged in old cells in the nervous system and may contribute to age-related degeneration. Here researchers further investigate, finding that the situation is not as static as first thought:

Most proteins live only two days or less, ensuring that those damaged by inevitable chemical modifications are replaced with new functional copies. [Researchers] have now identified a small subset of proteins in the brain that persist for longer, even more than a year, without being replaced. These long-lived proteins have lifespans significantly longer than the typical protein, and their identification may be relevant to understanding the molecular basis of aging.

The new study [provides] a system-wide identification of proteins with long lifespans in the rat brain, a laboratory model of human biology. The scientists found that long-lived proteins included those involved in gene expression, neuronal cell communication and enzymatic processes, as well as members of the nuclear pore complex (NPC), which is responsible for all traffic into and out of the nucleus. Furthermore, they found that the NPC undergoes slow but finite turnover through the exchange of smaller sub-complexes, not whole NPCs, which may help clear inevitable accumulation of damaged components.

[Researchers] previously found that NPC deterioration might be a general aging mechanism leading to age-related defects in nuclear function. Other laboratories have linked protein homeostasis, or internal stability, to declining cell function and, thus, disease. The new findings reveal cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process. "Now that we have identified these long-lived proteins, we can begin to examine how they may be affected in aging and what the cell does to compensate for inevitable damage. We're starting to think about how to get functionality back to that younger version of the protein."

TOWARDS MOLECULAR PROSTHETICS
Tuesday, September 10, 2013
https://www.fightaging.org/archives/2013/09/towards-molecular-prosthetics.php

This is a line of research that will come to be increasingly important as it new technologies make it ever easier and more cost effective to both identify specific components of the protein machinery of biology and manufacture replacements or augmented alternative versions. It is not just important for genetic diseases, in which specific proteins are missing or malformed, but also in patching over the changes of aging and enhancing the human body to better resist aging:

"Artificial limbs replace the function of an arm or leg that's missing due to injury. Some diseases occur because proteins in the body are missing or not working properly. Molecular prosthetics envisions treating those diseases with medicines that replace the functions of the missing proteins."

[Researchers] described advances to simplify and speed up the synthesis of the small molecules needed for molecular prosthetics. More than 90 percent of today's medicines use active ingredients that are small molecules. These substances can be processed into tablets and capsules and taken by mouth. They can dissolve in the gastrointestinal tract, go into the blood and travel to and work in almost every part of the body. The rest of today's medicines are large molecules or "biologics" that like insulin cannot be taken by mouth.

"For molecular prosthetics to become a reality, we must overcome two major challenges. First, it can take months or even years to synthesize just one molecule. With our new platform, we could reduce that to a few days. The second challenge is to fundamentally understand the capacity for small molecules to operate like proteins in the context of living systems. That understanding is critical to being able to design the most effective molecules."

Amphotericin B, currently used to treat fungal infections, [inserts] itself into the membrane that surrounds and encloses cells in the body. Once in the membrane, amphotericin B forms channels that enable the transport of ions into and out of the cell, an activity that mirrors many proteins whose function is critical in health and disease. A whole group of human diseases, sometimes called channelopathies, result from malfunction of ion channel proteins. Among them: migraine, epilepsy and cystic fibrosis. The team is working to use amphotericin B as a basis for making small molecules that replace the missing or malfunctioning ion channel proteins and thereby treat these diseases.

"We realized early in our studies that the lack of efficiency and flexibility with which small molecules can be prepared in the lab represented a major bottleneck in our efforts to develop small molecules with protein-like functions. We are now excited to find that our new synthesis platform can help relieve this important bottleneck and thereby enable us to focus more of our time on the key functional studies. Drug companies also have this problem with the long timelines needed to synthesize small molecules. That's part of the reason why it takes so long to develop new medicines. This is a broad problem, and our goal is to help speed up this process and thereby have an important impact on science and medicine."

AN EARLY STEP TOWARD A FUTURE OF IMPLANTED BIOMEDICAL FACTORIES
Tuesday, September 10, 2013
https://www.fightaging.org/archives/2013/09/an-early-step-toward-a-future-of-implanted-biomedical-factories.php

Much of the future of medicine will involve altering the mix of protein machinery and signals that drive our metabolism, instructing cells to take specific actions, and delivering new protein machines that can perform tasks that our existing biology cannot, such as clearing out otherwise resistant metabolic waste products. The current model in medicine is for the work of mixing up the necessary new materials to take place outside the body, which are then delivered in the form of infusions, injections, pills, and so on. In the future, we will probably see the creation of therapeutics move inside the body, in the form of increasingly sophisticated, reactive, and programmable implanted medical factories.

The work noted here is an early step in this direction: a single-function implant that alters the behavior of immune cells on an ongoing basis, an alternative to periodically drawing cells from a patient, altering them in culture, and then returning them to the body.

A cross-disciplinary team of scientists, engineers, and clinicians announced today that they have begun a Phase I clinical trial of an implantable vaccine to treat melanoma, the most lethal form of skin cancer. Most therapeutic cancer vaccines available today require doctors to first remove the patient's immune cells from the body, then reprogram them and reintroduce them back into the body. The new approach, which was first reported to eliminate tumors in mice [in 2009], instead uses a small disk-like sponge about the size of a fingernail that is made from FDA-approved polymers. The sponge is implanted under the skin, and is designed to recruit and reprogram a patient's own immune cells "on site," instructing them to travel through the body, home in on cancer cells, then kill them.

The technology was initially designed to target cancerous melanoma in skin, but might have application to other cancers. In the preclinical [study], 50 percent of mice treated with two doses of the vaccine - mice that would have otherwise died from melanoma within about 25 days - showed complete tumor regression.

MEMBRANE COMPOSITION AND LONGEVITY IN FLIES
Wednesday, September 11, 2013
https://www.fightaging.org/archives/2013/09/membrane-composition-and-longevity-in-flies.php

The membrane pacemaker hypothesis suggests that the composition of cell membranes - such as those that wrap mitochondria - is an important determinant of species longevity because of consequent differences in resistance to oxidative damage. Here researchers find correlations between membrane composition and longevity within one species, but not for the same reasons:

Various compositions of fatty acids can produce cell membranes with disparate fluidity and propensity for oxidation. The latter characteristic, which can be evaluated via the peroxidation index (PI), has a fundamental role in the development of the "membrane-pacemaker theory" of aging. This study tried to evaluate differences between the membrane phospholipid fatty acid (PLFA) profile of longevity-selected (L) and corresponding control (C) lines of Drosophila melanogaster with age (3, 9, 14 and 19 days) and its consequences on phase transition temperature as a function of membrane fluidity.

Despite an equal proportion of polyunsaturated fatty acids, PI and double bond index over all ages in both experimental groups, monounsaturated fatty acids showed significant variation with advancement of age in both L and C lines. A significant age-associated elevation of the unsaturation vs. saturation index in parallel with a gradual reduction of the mean melting point was observed in longevous flies. PLFA composition of the L vs. C lines revealed a dissimilarity in 3-day old samples.

The findings of this study are not in agreement with the principle of the "membrane pacemaker theory" linking PI and longevity. However, the physiochemical properties of PLFAs in longevity lines may retard the cells' senescence by maintaining optimal membrane functionality over time. Identical susceptibility to peroxidation of both types of lines underlines the involvement of other mechanisms in protecting the bio-membrane against oxidation, such as the reduced production of mitochondrial reactive oxygen species or improvement of the antioxidant defense system in longer-lived phenotypes. Concurrent assessments of these mechanisms in relation to cell membrane PLFA composition may clarify the cellular basis of lifespan in this species.

AN EXAMPLE OF HOW FAR LONGEVITY SCIENCE ADVOCACY HAS COME
Wednesday, September 11, 2013
https://www.fightaging.org/archives/2013/09/an-example-of-how-far-longevity-science-advocacy-has-come.php

Unlike the case ten to fifteen years ago, it is now mainstream and acceptable within the research community to talk openly about slowing aging. That is half of a very necessary change that has to take place in order to speed work on extending healthy human life. The other half is for the scientific community to move their focus and the public discussion from merely slowing aging to the aim of actual rejuvenation of the old and an acknowledgement that maximum human life span will grow greatly. That is still a work in progress, and researchers remain reluctant to talk about radical life extension. But talk they must if there is to be a good change of raising large-scale funding and creating dedicated research programs at scale to achieve this goal. Large-scale research only comes into being in an environment of widespread public support and understanding.

Here is an article that wouldn't have existed in the late 1990s, because the people in higher level positions in a noted research institute would not have openly talked about slowing human aging, for fear of a negative impact on their fundraising:

The University of Florida's Institute on Aging is dedicated to research on slowing or reversing certain aging processes that can sour the golden years. The institute itself started eight years ago and has expanded to include more research on cognitive decline and not just physical decline related to aging. "If we can slow the process (of aging) it will be a great success ... and expand active life expectancy," said Marco Pahor, the institute's director, at its fourth annual research day. Pahor added that much of the institute's research focuses on compressing the "disabled years" in which people often live with chronic inactivity and pain - conditions that are both physically unpleasant and costly. "This is a major burden on the health care system. So far most of the interventions are reactive. But we want to prevent physical and cognitive decline," just as there have been successful preventive measures for cancer and heart disease.

Roger Fillingim, a professor at the UF College of Dentistry and director of UF's newly formed Pain Research and Intervention Center of Excellence (PRICE), spoke about the prevalence of pain among the elderly. About 100 million people in the U.S. suffer from pain, which costs the health care system about $635 billion annually, Fillingim said, citing Institute of Medicine data. That's more than the expenditures for cancer, AIDS and heart disease combined. "Our goal is to reduce pain-related suffering with cutting-edge research. Pain is a major public health issue so we need all the help we can get."

ATTEMPTING A CROWDFUNDED MOUSE LIFESPAN STUDY
Thursday, September 12, 2013
https://www.fightaging.org/archives/2013/09/attempting-a-crowdfunded-mouse-lifespan-study.php

A European and Russian group of researchers are attempting to crowdfund a modest amount for a short-term mouse life span study, using mice that are already old to see if various compounds have much of an effect on slowing aging in old mice. This sort of study design has the advantage of being comparatively cheap as it only runs for half a year or so:

Life is precious. Health too. This is why communities of researchers and citizens dedicate our lives to discover new ways to gain additional years of healthy life. As research progresses, more and more compounds are believed to be good to maintain health over long periods of time. But wouldn't that take decades of clinical trials to verify it? A key step is to do such a clinical trial... in mice : that is what we call a mouse lifespan test. Mouse lifespan tests are infrequent because of their length, their costs and the required environments; but it is crucially needed to continue adding years of healthy life.

Here, we step on the shoulders of giants : by contributing you can help us test a combination of drugs shown to extend healthy lifespan in mice. This experiment has something unique. It is the first time in the world that crowdfunding is used to test a combination of the most potent nongenetic-interventions known to extend the lifespan.

There are *right now* in the lab a sufficient number of aged mice (~20 months old) - male and female - which belong to the C57BL/6 strain to start a lifespan test. The mice will be divided into 2 test groups (females and males) and 2 control groups (24 animals per each group). The test will be blind. The food of the treated mice will contain: 1) An α-adrenergetic receptor blocker (metoprolol). Potential action: Prevents too fast heart beats. 2) An mTOR inhibitor (everolimus, similar action as rapamycin). Potential action: Puts cells in an active and resistant mode. 3) Metformin. Potential action: Normalizes blood and IGF-1 values at low levels. It also has potential similarities with everolimus. 4) Simvastatin. Action: Decreases the amount of LDL cholesterol (considered as 'bad' by some) in the blood. 5) Ramipril: an ACE inhibitor. Action: Prevents hypertension. 6) Aspirin. When small doses are used, it is believed to have reduced side effects while improving blood flow and therefore reducing cardiovascular risks, and potentially also preventing incidence of some cancers.

MICRORNA EXPRESSION CHANGES IN OLD MUSCLE REVERSED BY CALORIE RESTRICTION
Thursday, September 12, 2013
https://www.fightaging.org/archives/2013/09/microrna-expression-changes-in-old-muscle-reversed-by-calorie-restriction.php

In the course of improving health and extending life - to a lesser degree in long-lived species, unfortunately - the practice of calorie restriction produces sweeping changes in near every aspect of metabolism. The deeper you look the more there is to find. Here is one of many examples:

Age-related alterations in the composition of skeletal muscle are linked to functional limitations, disability and metabolic disorders. Alterations in muscle damage and repair during aging can have deleterious consequences that lead to muscle degeneration and inflammation; most of the age-related declines in muscle homeostasis and function can be prevented by caloric restriction (CR) in laboratory animals. Changes in gene expression critically govern the age-related alterations in muscle mass and function.

MicroRNAs (miRNAs) regulate gene expression by recruiting the RNA‐induced silencing complex (RISC) to a target messenger RNA with which it shares partial complementarity, causing a reduction in the stability of the messenger RNA and/or its rate of translation. The relevance of miRNAs in disease development, muscle aging, and progression and prognosis of skeletal muscle diseases is not fully understood.

The profiling of miRNAs in aged tissues can provide direct links between aging, age-dependent regulation of miRNA abundance, and the involvement of miRNAs in normal aging and age-related diseases. In this study, changes in miRNAs in skeletal muscle from rhesus monkeys of different ages were assessed using RNA sequencing. Our results showed clear differences in muscle miRNA levels when comparing old and young animals, and that CR influences these age-induced changes in miRNA expression. Novel miRNAs were also identified in muscle of old and young rhesus monkeys, which could potentially be expressed in human skeletal muscle. Together, our study provides further support for the role of miRNAs in skeletal muscle aging and reveals the impact of CR on miRNA expression.

THOUGHTS ON PERSUASION AND ADVOCACY FOR HUMAN LONGEVITY
Friday, September 13, 2013
https://www.fightaging.org/archives/2013/09/thoughts-on-persuasion-and-advocacy-for-human-longevity.php

Large scale research requires widespread support to raise the necessary funds and gather a sizable scientific community, and this is just as true of work on human rejuvenation as anything else. When it comes to the persuasion needed to gain that support, there is some debate over whether the incremental softly-softly approach of advocacy for a living a little longer and tackling age-related disease is better or worse than talking about the end goals of agelessness and radical life extension of centuries or more of health and vigor. Here are comments from someone more in favor of toning down the rhetoric:

One of the biggest challenges we face as transhumanists, is conveying our philosophy to the uninitiated in a manner that is successful and productive. For the purpose of this article, I will be speaking of cryonics and transhumanism in the same context. Cryonics really isn't a separate idea, but in my view, a tool in the transhuman ordinance to attain one of its most fundamental goals, which is radical life extension. Essentially it is a Plan B.

I have advocated for cryonics for 17 years. In that time I have encountered very few people who on first glance, found it to be something they could imagine for themselves. Very recently, I have devoted much time to the study of transhumanism, and have found the same barriers. People don't tend to like what we have to offer. I have struggled for a long time to come to terms with this fact, and have spent a great deal of energy trying to understand why.

One of the first things I feel we are doing wrong is speaking to the public about immortality. We are jumping to the end of the story, and expecting others to buy it without ever having learned about all of the other steps. Immortality is an unrealistic expectation that makes us sound like fundamentalist zealots. We can never prove to be immortal, no matter how long we live, so why come out of the gate running with it? It's not the right approach to take with the Everyman and seems to be a poor sales tactic. I think that simply going with the concept of extending one's life - for a decade or a century - seems to be an easier concept to sell. Let's worry about immortality later.

MEASURING THE RECENT RATE OF GROWTH IN ADULT LIFE EXPECTANCY
Friday, September 13, 2013
https://www.fightaging.org/archives/2013/09/measuring-the-recent-rate-of-growth-in-adult-life-expectancy.php

Adult life expectancy is a little more interesting than life expectancy at birth as a measure of modern medical progress towards healthy life extension. Much of the innovation now is in ways to treat age-related conditions rather than in ways to reduce childhood mortality and control the more obvious infectious diseases. Removing childhood from the picture when considering the data narrows the focus to the effectiveness of medical technologies deployed in later life.

Here is a recent study that measures gains obtained in the past couple of decades, none of which is really due to any attempt to deliberately extend human life or tackle aging. Progress here stems from the deployment of incrementally better medical technology across the board. Once the research community begins to address aging in earnest, I'd expect the pace of growth in life expectancy to accelerate considerably - especially if the better path of SENS, rejuvenation, and repair of cellular damage is chosen over efforts to slow aging via metabolic manipulation.

Thanks to medical advances, better treatments and new drugs not available a generation ago, the average American born today can expect to live 3.8 years longer than a person born two decades ago. Despite all these new technologies, however, is our increased life expectancy actually adding active and healthy years to our lives? That question has remained largely unanswered - until now. In a first-of-its-kind study, [researchers] have found that the average 25-year-old American today can look forward to 2.4 more years of a healthy life than 20 years ago while a 65-year-old today has gained 1.7 years.

Synthesizing data from multiple government-sponsored health surveys conducted over the last 21 years [researchers] were able, for the first time, to measure how the quality-adjusted life expectancy (QALE) of all Americans has changed over time. The data shows that Americans are living longer, reporting fewer symptoms of disease, have more energy and show fewer impairment in everyday tasks such as walking than a generation ago. According to the study authors, a 25-year-old person today can expect to live 6 percent or 2.4 quality years longer than their 1987 counterpart.

Bear in mind that life expectancy is effectively a measure of what would happen if all change and progress was frozen where it is today. It measures past progress, not future outcomes. We are in the midst of a revolutionary period of change and acceleration in biotechnology and medicine, comparatively little of which has yet percolated into available medical technologies. So adjust your expectations for the future accordingly.