Fight Aging! Newsletter, July 22nd 2013

July 22nd 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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  • A Couple More Articles on Moving the Mind to Machinery
  • The SENS6 Conference is Coming Up Soon
  • Ben Best Interviews Aubrey de Grey
  • Are Plants At All Relevant to Aging Research?
  • If You Are a Molecular Biology Student and Want to Work on Cutting Edge Medicine, Then You Should Connect With the SENS Research Foundation
  • Latest Headlines from Fight Aging!
    • Improving Muscle Metabolism and Endurance in Mice
    • Considering Synaptic Maintenance Over the Course of Aging
    • Inverse Occurrence of Cancer and Alzheimer Disease
    • More on Cancers Reducing Alzheimer's Risk
    • Artificial Organelles to Break Down Free Radicals
    • Another Potential Commonality in the Mechanisms of Cancer
    • What is the Role of Gut Bacteria in Calorie Restriction?
    • A Look at the Two Sides of Oxidative Stress
    • Exercise Reduces Stroke Risk
    • Let-7 and the Age-Related Decline of Neural Regeneration


To live far longer in good health our best and first course of action is to build new and better medicinal technologies: ways to repair the known and enumerated root causes of aging, the forms of low-level cellular and molecular damage that accumulate with age and eventually kill us. How this might be achieved is outlined in the SENS proposals and currently the subject of a research program that deserves far more funding and attention.

Plenty of people have other ideas about how to engineer far longer life spans. One of the more popular involves discarding our biology to move minds into software or replace the brain with some form of more easily repaired and robust machinery. This is focus of the 2045 Initiative, for example. From where I stand, this looks a lot like replacing a hard problem with a harder problem - I can't envisage a scenario for the next 20 to 40 years in which building the foundation for artificial minds can outpace rejuvenation biotechnology in terms of offering more healthy life to old people. (And when I say "old people," I of course mean "us." Time waits on no man, and clock is ever ticking).

Nonetheless, the development of an artificial mind is a popular topic. It will only become more so as large-scale funding continues to move into efforts to simulate brains. Ultimately there will be people running on software and hardware that is not biological in origin. I just don't think that's going to happen soon enough for those of us in the later half of an old-style life span. With that in mind, let me point you to a couple more articles on the topic, to append to a fair number of the same that have appeared in recent months:

Transhumanism and Mind Uploading Are Not the Same

Having a positive view of mind uploading is neither necessary nor sufficient for being a transhumanist. Mind uploading has been posited as one of several routes toward indefinite human life extension. Other routes include the periodic repair of the existing biological organism (as outlined in Aubrey de Grey's SENS project or as entailed in the concept of nanomedicine) and the augmentation of the biological organism with non-biological components (Ray Kurzweil's [view]). Transhumanism, as a philosophy and a movement, embraces the lifting of the present limitations upon the human condition.

Dmitry Itskov's 2045 Initiative is perhaps the most prominent example of the pursuit of mind uploading today. [Is] Itskov's path toward immortality the best one? I personally prefer SENS, combined with nanomedicine and piecewise artificial augmentations of the sort that are already beginning to [occur]. Itskov's approach appears to assume that the technology for transferring the human mind to an entirely non-biological body will become available sooner than the technology for incrementally maintaining and fortifying the biological body to enable its indefinite continuation. My estimation is the reverse.

We Seek Not to Become Machines, But to Keep Up with Them

Too often is uploading portrayed as the means to superhuman speed of thought or to transcending our humanity. It is not that we want to become less human, or to become like a machine. For most Transhumanists and indeed most proponents of Mind Uploading and Substrate-Independent Minds, meat is machinery anyways. In other words there is no real (i.e., legitimate) ontological distinction between human minds and machines to begin with. Too often is uploading seen as the desire for superhuman abilities. Too often is it seen as a bonus, nice but ultimately unnecessary.

I vehemently disagree. Uploading has been from the start for me (and I think for many other proponents and supporters of Mind Uploading) a means of life extension, of deferring and ultimately defeating untimely, involuntary death, as opposed to an ultimately unnecessary means to better powers, a more privileged position relative to the rest of humanity, or to eschewing our humanity in a fit of contempt of the flesh. We do not want to turn ourselves into Artificial Intelligence, which is a somewhat perverse and burlesque caricature that is associated with Mind Uploading far too often.

The notion of gradual uploading is implicitly a means of life extension. Gradual uploading will be significantly harder to accomplish than destructive uploading. It requires a host of technologies and methodologies - brain-scanning, in-vivo locomotive systems such as but not limited to nanotechnology, or else extremely robust biotechnology - and a host of precautions to prevent causing phenomenal discontinuity, such as enabling each non-biological functional replacement time to causally interact with adjacent biological components before the next biological component that it causally interacts with is likewise replaced. Gradual uploading is a much harder feat than destructive uploading, and the only advantage it has over destructive uploading is preserving the phenomenal continuity of a single specific person. In this way it is implicitly a means of life extension, rather than a means to the creation of [strong artificial intelligence], because its only benefit is the preservation and continuation of a single, specific human life, and that benefit entails a host of added precautions and additional necessitated technological and methodological infrastructures.


The sixth Strategies for Engineered Negligible Senescence (SENS) conference will be held in Cambridge, England this coming September. There's still time to register: a group of exceptional figures in aging research and related fields in medicine and the broader life sciences will gather to talk about how to greatly extend healthy human life, with the focus being on how to best move ahead in the implementation of the SENS proposals for rejuvenation biotechnology:

The purpose of the SENS conference series, like all the SENS initiatives, is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies.

As usual, the conference has a great line up of speakers, and the range of abstracts for presentation is well worth reading if you'd like to get an idea as to what people are working on these days. Not all of it is directly relevant to SENS, but that's the way these things go: people come to learn and be swayed as much to present the work they're presently engaged in. The SENS Research Foundation staff are presently publishing a steady flow of speaker highlights for the forthcoming conference, and here are the latest in line:

SENS6 Speaker Highlight: Todd Rider

Dr. Rider's most recent efforts have led to a remarkable development within the PANACEA (Pharmacological Augmentation of Nonspecific Anti-pathogen Cellular Enzymes and Activities) project. This new treatment is known as DRACO, which stands for Double-stranded RNA Activated Caspase Oligomizer. Essentially, DRACO works by triggering apoptosis in cells that contain viral double-stranded RNA, an indicator that they have been infected by a virus. Non-infected cells, on the other hand, are not affected by the treatment. Based on the tests that have been performed so far, DRACO has the potential to be effective against nearly any virus. Trials done in vitro or in mice have shown that DRACO kills cells infected with the common cold, H1N1 influenza, dengue fever virus, a polio virus, and others. Meanwhile, the treatment has been shown to be nontoxic to all of the cell types tested, including those from humans.

SENS6 Speaker Highlight: Robin Franklin

Many diseases mirror some aspect of aging. Multiple sclerosis (MS), which is caused by the loss of the myelin coating that protects nerve cells in the brain and spinal cord, is one example: myelin is also lost and poorly replaced in normal aging. Scientists like Cambridge's Dr. Robin Franklin, a SENS6 speaker, are working hard to repair this damage.

To learn how the axons of nerve cells might best be remyelinated, Dr. Franklin has been studying the cellular and molecular aspects of the process. Stem cells in the brain differentiate into oligodendrocytes, which are responsible for remyelination. However, these stem cells have an increasingly difficult time differentiating in an aging brain. This low level of differentiation may also cause multiple sclerosis, such that true damage repair therapies for MS might also be effective against age-related neurodegeneration.

SENS6 Speaker Highlight: Alan Russell

Dr. Russell has founded several biotech companies, including Agentase, LLC and NanoSembly, LLC, and holds fourteen patents. His many honors include the R&D 100 Award, the National Academy of Engineering's Gilbreth lectureship, and the University of Manchester's Outstanding Alumnus Award. At SENS6, Dr. Russell's talk will focus on the disruptive potential of tissue engineering. He will discuss the great promise of growing new organs to replace failing ones, addressing the underlying cause of disease. He will also cover the problems that tissue engineering faces - among them, its lack of market adoption - and propose solutions. Finally, he will describe some of the research being conducted in his own leading laboratory. This includes work on engineering cell membranes, and using cytotactic surfaces to change the direction that cells roll.


This month's issue of Life Extension Magazine contains an interview with SENS Research Foundation cofounder Aubrey de Grey by Ben Best, a noted figure in the cryonics and longevity advocacy communities. The SENS Research Foundation runs a research program that aims to produce the foundation technologies to create human rejuvenation by means of repairing the low-level damage to cells and protein structures that causes aging.

As an aside, I should say that the Life Extension Foundation (LEF) and their Life Extension Magazine are a very mixed house: on the one hand the founders use some of the profits of their business to fund serious modern research, including improvements in cryonics, and through their magazine introduce a broader readership to some of the cutting edge work on the foundations of human rejuvenation presently taking place. On the other hand, this is all built upon the business of selling supplements, which is not something that can in any way greatly extend human life expectancy. The vast majority of the impact that the LEF has is to promote supplements as a way to extend life - and this simply isn't a viable path forward to the future. The world would be a far better place if everyone interested enough in long-term health to buy expensive supplements instead settled for a multivitamin and some fish oil and donated the rest of their supplement budget to medical research. The expectation value of doing that is somewhat greater than making a habit of ingesting anything you can purchase from a vitamin store.

So I have mixed feelings about these legacy organizations in the longevity advocacy community. Some are doing good by funding modern science and promoting SENS or similar research programs, but they also loudly propagate a great deal of what amounts to misinformation about what the average fellow can do, realistically, to impact the future of his aging process. At this point progress in new forms of medical science is the only thing that will significantly alter our future life spans: no combination of vitamins and supplements has been show to produce even a fraction of the benefits resulting from exercise and calorie restriction. But the existence of the LEF as an ongoing commercial concern depends upon denying this truth, vigorously and often.

The counterargument to this line of thinking is "so how much money have you donated to scientific research lately, Reason?" The answer to that question is "nowhere where as much as the Life Extension Foundation has." So who here is doing more good for whom?

But back to the interview, which I think you'll find is gratifyingly technical for a change, and covers some topics that haven't been touched on at all in past interviews - such as recent funding changes, opinions on mainstream research groups, and so forth:

Interview with Aubrey de Grey, PhD

LE: You recently inherited a large sum of money and chose to donate most of it to the SENS Foundation. Will you provide some details and explain your motives?

AdG: My mother died in May 2011 and I was her only child; the upshot is that I inherited roughly $16.5 million. Of that, I assigned $13 million to SENS (I won't bore you with the legal details, which were tedious in the extreme). It was pretty much a no-brainer for me: I've dedicated my life to this mission, and I dedicate all my time to it, so why not my money too? I retained enough to buy a nice house, but beyond that I have inexpensive tastes and I have no doubt that this is the best use of my wealth. It will accelerate research considerably, and also it will have indirect benefits in terms of helping us to put more resources into raising the profile of this work and garnering more support.

LE: Who are the other major donors to the SENS Foundation, and what proportion of the budget is covered by the money you donated?

AdG: My donation will be spent over a period of about five years, and it roughly doubles the budget we had previously, from $2 million annually to $4 million. The number one external donor remains our stalwart supporter Peter Thiel. Additionally, another internet entrepreneur, Jason Hope, has recently begun to contribute comparable sums.

LE: What will the SENS Foundation do when your donation money runs out?

AdG: It's hard to look ahead as far as five years, the projected duration of my donation, but we certainly have great confidence that our outreach efforts will bear fruit in that time. My hope is that five years from now we will be big enough that the expiry of my donation will go relatively unnoticed.


LE: What is advantageous and what is disadvantageous about the money spent on aging research by the National Institute on Aging (NIA, a branch of the US federal government's National Institutes of Health)?

AdG: It's pretty much all advantageous - just not nearly as advantageous as it could be. There is pitifully little money going into the search for interventions to postpone aging, and of what there is, pitifully little is focused on late-onset interventions.

LE: What do you think of the way the Ellison Medical Foundation spends money on aging research?

AdG: Exactly the same as for the NIA. The Ellison Foundation was set up with a remit to fund work that complemented the NIA, but I'm afraid to say that in practice it has merely supplemented it.


LE: How difficult would it be to eliminate lipofuscin (the cellular junk that particularly accumulates in neurons and heart muscle cells) compared to eliminating 7KC (an oxidized derivative of cholesterol that accumulates in atherosclerotic plaques) or A2E (a substance accumulating in the retina with age that causes macular degeneration and blindness) as a lysoSENS project? How much difference do you think elimination of lipofuscin would make in terms of rejuvenation?

AdG: This is a big question right now. We have a PhD student in our funded group at Rice University who is working on lipofuscin, but he is just starting. Lipofuscin is indeed harder, but what makes it harder is not the aging-versus-disease distinction but simply the nature of the substance. Lipofuscin is very heterogeneous in its molecular composition, and moreover it is mainly made of proteins, so it is hard to distinguish from material that we don't want to break down. I should note in passing that the material whose accumulation causes macular degeneration is often called lipofuscin but really should not be, because the only thing it has in common with bonafide lipofuscin is its subcellular location (the lysosome) and its fluorescence properties: its molecular composition is entirely different.

LE: In the 2011 report of the SENS Foundation, progress on mitoSENS (making copies of mitochondrial DNA in the nucleus to protect them from free-radicals generated by mitochondria) was restricted to 5 of the 13 protein-encoding mitochondrial genes. How confident are you that all 13 such genes can be copied into the nucleus in the foreseeable future? Are some of those genes more important than others, or are you simply going after the easier targets?

AdG: We're pretty confident. Some of the genes we've chosen to work on first are easy targets in the sense that other researchers have demonstrated some success with them already; other genes are chosen more because success would be high-impact, in that it would allow more clear-cut assays of efficacy. In the end, all 13 are equally important.

There's a lot more in that vein. Quite the number of people work with or for the SENS Research Foundation these days: it is at the center of a web of connections throughout the aging research community and related life science fields.

I should say that the large number of people who have criticized de Grey on various grounds in past years should all be eating their hats these days: I shouldn't have to say anything about just how admirable is his disposition of his own wealth. If de Grey didn't exist, we'd have had to invent him. Sometimes, rarely, it really is the case that one visionary arises to drag the rest of the world along into the future, kicking and screaming, long before the zeitgeist of the age would have produced a comparable figure in some other community. It is in many ways interesting to speculate on where we might be right now absent de Grey, or in a world in which he had chosen to continue to work in artificial intelligence rather than the life sciences, and I believe that the answer is that we'd probably still be waiting on a funded research program for radical life extension to emerge.

Today's nearest neighbors to the Strategies for Engineered Negligible Senescence (SENS) are either very recent and quite clearly inspired by it, such as the proposals put forward by some of SENS Research Foundation advisors and their allies, or are largely focused on strategies related to programmed aging, such as the materials of the Science for Life Extension Foundation and associated members of the Russian biogerontology community. In no case I'm aware of are these proposals funded to even the modest level that currently exists for SENS.

Further, it's clear that the activities of the SENS Research Foundation, and to a greater degree the Methuselah Foundation before it, have had an enormous positive effect over the past decade with respect to changing the culture of the research community. The aging research community of fifteen years past was one in which researchers could not openly talk about extending healthy human life span, or at least not if they wanted to retain their funding. The research community today is quite the opposite, and that goes a long way towards making it possible for competitors and allies for radical life extension programs to arise at all.


A great deal of research into fundamental mechanisms associated with aging and the way in which metabolism determines variations in natural longevity has been carried out - and is still carried out - using yeast cells. The phenomenon of enhanced health and longevity with calorie restriction exists in yeast, for example, and involves similar mechanisms to those found in mammals. It is not the only common point of reference.

Yeasts are not animals, but rather forms of fungus, or at least belong to various branches of that large taxonomy. But what about the kingdom of plants? Plants age, and that fact can be investigated, and the mechanisms compared with those of mammals. Yet their cells are are arguably more different from ours than are those of yeast, so can the study of aging in plants be expected to yield anything that is of practical value when it comes to intervening in mammalian aging to extend healthy life? There are researchers who think so, and this open access paper serves as an overview of some of their arguments, with pointers to other papers in a recent issue of the Journal of Ecology:

Plants do not count... or do they? New perspectives on the universality of senescence

Surprisingly, little is known about the general patterns, causes and consequences of whole-individual senescence in the plant kingdom. There are important differences between plants and most animals, including modular architecture, the absence of early determination of cell lines between the soma and gametes, and cellular division that does not always shorten telomere length. These characteristics violate the basic assumptions of the classical theories of senescence and therefore call the generality of senescence theories into question.

Most classical theories of senescence were developed with an implicit general animal or explicit human bias in mind. In spite of taxonomic biases, understandably driven by an anthropocentric interest in delaying death and improving life quality at advanced ages, the claim has been made that senescence is universal. Hamilton stated that senescence should occur even 'in the farthest reaches of almost any bizarre universe'. His assertion is of broad interest to evolutionary biologists in general and plant ecologists in particular because (i) it suggests the existence of a universal rule of ecology and evolution that is yet to be tested, and (ii) it obviously suggests that plants are not immune from senescence.

The universality of senescence rests on the assumption that the wear-and-tear of life is cumulative and inescapable over an organism's life span because time flows only in one direction. Yet, plants show extreme plasticity, being able to retrogress to juvenile stages under specific conditions. Chen et al. recently showed that the genetic and physiological activity of grafted stems of Sequoia sempervirens is the same as that in juveniles and very distinct from that of ungrafted adults. Plants have been historically considered as populations of modules in a continuous state of renewal and replacement, allowing continuous whole-plant rejuvenation. The relationship between leaf senescence, module senescence and whole-plant senescence remains largely unexplored, and yet full of potential. For instance, many species (e.g. the orchid Spiranthes spiralis) completely renew their photosynthetic and below-ground storage tissues annually. These species are potentially in a state of 'perpetual somatic youth'.

The field of senescence is by historical inertia dominated by research on humans. The main emphasis of research into senescence to date has been on whether and how humans can slow it down, and even postpone it. We argue that there are at least three reasons why human demographers, animal ecologists and plant population ecologists should work together.

First, all three parties are currently asking the same questions, although perhaps with different terminology. Human demographers are interested in how cultural background and migration affect population dynamics and senescence rates, whereas animal and plant population ecologists are interested in maternal effects and dispersal.

Second, senescence is a phenomenon caused by evolutionary processes, and the comparative method has previously proved useful in ascertaining the ecological and physiological processes necessary for its evolution. Research that ignores taxonomic boundaries will advance our understanding of evolutionary senescence.

Thirdly, for decades, animal demographers have been developing robust statistical tools to explore the evolution of senescence that account for differences between individuals within populations with imperfect long-term data. All of these techniques could prove useful in the plant world too, particularly in the examination of long-lived species. Furthermore, we argue that the transfer of knowledge between these research factions should be tri-directional. For instance, the work by Caswell & Salguero-Gómez [introduces] a novel method for quantifying selection gradients on age and stage in plants that is equally applicable to the analyses of data from humans and the rest of the animal kingdom.

I would argue that continuous renewal seen in some plant species is similar in relevance to the exceptional regeneration of hydra, or the strange life cycle of the jellyfish Turritopsis Dohrnii - by which I mean interesting, but not of any great relevance to human aging. Plants and hydra and jellyfish all lack the complex structures that higher animals possess. We can't just regenerate everything or throw away the majority of our body or regress back to earlier life stages because we have minds and other systems that are bound to the physical structure and specific existing cells of our nerve and brain tissue. Becoming complex seems to have the attached cost of a loss of regenerative capacity, except when it comes to our germ cells and early embryos, which seem quite capable of rejuvenation when needed. But then they are not possessed of complex structures, and arguably have more in common with the hydra than with an adult individual.


It is no big secret that connections make the world go round - though it certainly took me far too long to realize the primacy of networking over talent, hard work, and all the other virtues. You can be exceptional, but that contributes little to your chances of success in life if no-one knows about it. If you want to work at the best and most important tasks in your field, then you have to make connections with the people who are doing that already. No-one collaborates with random folk from out of the blue: they hire the people they know and they form companies with the people they know. It is routinely the case that connections will put you in the position to become good far more reliably than being good will put you in the position to make connections.

If you are a successful, motivated student in the medical life sciences, working in a field such as genetics, molecular biology, bioinformatics, and so on, then you are already good, a cut above the average. But are you setting yourself up for mediocrity and a hard time in your industry by virtue of failing to put yourself out there? Internships are one way to build the connections needed to get the choice opportunities that only come to those in the network, but don't wait to go through formal channels. There are no rules to these things. Do you like the work that a particular laboratory is doing? Then contact the people working on it and say something. Reach out and make the connection.

Even in an exciting, rapidly growing, changing, revolutionary industry like the intersection of biotechnology and medicine there are the doldrums and the bad jobs and the make-work and the dross. Molecular biologists with connections have the choice of filtering that out to attempt world-changing research in young companies or well-known laboratories - while the rest get to slog through the job market looking for something that is work, not a vocation.

My recommendation for today: the most important research of the next few decades revolves around rejuvenation, the repair of the causes of aging, and producing cures for age-related conditions that work in entirely new ways. At the center of all the myriad connections and relationships in this research community are the folk who work with the SENS Research Foundation. The Foundation is very interested in producing the molecular biology community of the future to expand work in this area and see it through to completion, and hence they offer many opportunities to students: internships, the opportunity to build connections, and so on. But to hell with the structure of it - that's just a suggestion, not a set of rules carved in stone. If you can read the Foundation's research reports, and look at the cutting edge work that they sponsor and be excited about it, then just open up a dialog. Reach out, let them know you exist and are interested: that already puts you far ahead of the rest of the field.

Becoming known to the SENS Research Foundation principals and researchers is something that you can make pay off: not just the chance to do things that are truly meaningful in medical research, but also to forge the connections that will allow you to have the career that you want to have, rather than the career that you have to settle for. The Foundation staff know everyone who is anyone in the life science fields and laboratories that are important to aging and future medicine to prevent and reverse aging.

So, look, let me point out exactly what I mean by all of this, by way of directing your attention to the outcome of a 2012 internship at the SENS Research Foundation:

Jennie received her B.A. with majors in Molecular Cellular and Developmental Biology, Integrative Physiology, and Neuroscience, from the University of Colorado at Boulder in May 2012. During her internship with SENS Research Foundation (SRF) in Mountain View, CA, Jennie attempted to identify genes involved in the Alternative Lengthening of Telomeres (ALT) Mechanism.

After completing her summer internship, Jennie was recruited by former SRF researchers in Central New York and co-founded Ichor Therapeutics, Inc. The company works to develop and commercialize research and clinical products in the field of regenerative medicine. She is listed as co-author on the company research and business proposal that landed a $450,000 seed grant from Life Extension Foundation. In addition to her work at Ichor, she is currently a laboratory assistant at the lab of Dr. Sarah E. Hall at Syracuse University's College of Arts and Sciences.

Other interns have similar stories of success and impressive placements. People do not get randomly recruited by startups, or randomly raise funds from the LEF - it happens because of who you know. The best opportunities only arise because of the people that you know, and because of the people who know that you exist. So make connections, and more to the point take the actions that will raise the odds of you being able to make high quality connections in your industry. If you are in molecular biology, bioinformatics, or a similar field, then you should talk to the SENS Research Foundation, take it from me. They have a very impressive network, and they are the ground floor of what will be the dominant medical industry of the 2020s and later decades.


Monday, July 15, 2013

If the method of improving endurance in mice found by these researchers actually works in the way they think that it works, then it should also increase mouse life span:

The drug candidate, SR9009, is one of a pair of compounds [described] as reducing obesity in animal models. The compounds affect the core biological clock, which synchronizes the rhythm of the body's activity with the 24-hour cycle of day and night. The compounds work by binding to one of the body's natural molecules called Rev-erbα, which influences lipid and glucose metabolism in the liver, the production of fat-storing cells and the response of macrophages (cells that remove dying or dead cells) during inflammation.

In the new study, [researchers] demonstrated that mice lacking Rev-erbα had decreased skeletal muscle metabolic activity and running capacity. [They] showed that activation of Rev-erbα with SR9009 led to increased metabolic activity in skeletal muscle in both culture and in mice. The treated mice had a 50 percent increase in running capacity, measured by both time and distance. "The animals actually get muscles like an athlete who has been training. The pattern of gene expression after treatment with SR9009 is that of an oxidative-type muscle - again, just like an athlete."

The authors of the new study suggest that Rev-erbα affects muscle cells by promoting both the creation of new mitochondria (often referred to as the "power plants" of the cell) and the clearance of those mitochondria that are defective.

Monday, July 15, 2013

An open access review paper here looks at some of the low-level processes involved in late-life neurodegeneration, the decline of brain functionality. If following a SENS-like viewpoint of the causes of degenerative aging, we would say that these are secondary processes, a loss in the ability of brain tissue and brain cells to maintain themselves due to forms of accumulated damage that occur at an even lower functional level in our biology.

The core point of the SENS proposals for rejuvenation biotechnology is that we don't need to understand the very complex middle layers of degeneration and maintenance in order to halt and reverse aging - we just need to fix the lowest-level causes of aging, which are presently well known. All have associated strategies that will lead to repair or reversal of their effects. Still, most of the research community continues to focus instead on generating a complete understanding of the exceedingly complex processes of aging, starting from the mid-layers and working out:

Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional.

This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseases is largely unclear.

In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration.

Tuesday, July 16, 2013

This is an intriguing finding, and I have no suggestions for either possible underlying mechanisms or possibilities for systematic error in the research. So far as I am aware the common risk factors for cancer are also risk factors for Alzheimer's disease (AD), so one would not expect to see the correlations shown here:

This was a cohort study in Northern Italy on more than 1 million residents. Cancer incidence was derived from the local health authority (ASL-Mi1) tumor registry and AD dementia incidence from registries of drug prescriptions, hospitalizations, and payment exemptions. Expected cases of AD dementia were calculated by applying the age-, sex-, and calendar year-specific incidence rates observed in the whole population to the subgroup constituted of persons with newly diagnosed cancers during the observation period (2004-2009). The same calculations were carried out for cancers in patients with AD dementia. Separate analyses were carried out for the time period preceding or following the index diagnosis for survivors and nonsurvivors until the end of 2009 and for different types and sites of cancer.

The risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced. This relationship was observed in almost all subgroup analyses, suggesting that some anticipated potential confounding factors did not significantly influence the results. The occurrence of both cancer and AD dementia increases exponentially with age, but with an inverse relationship; older persons with cancer have a reduced risk of AD dementia and vice versa. As AD dementia and cancer are negative hallmarks of aging and senescence, we suggest that AD dementia, cancer, and senescence could be manifestations of a unique phenomenon related to human aging.

Tuesday, July 16, 2013

A second group of researchers recently demonstrated that cancer patients have a lower risk of Alzheimer's disease, providing data that adds to the puzzling nature of this finding:

[Researchers] found that most types of cancer were associated with a reduced risk of Alzheimer's, which has no cure. Survivors of liver cancer had the most protection, a 51 percent reduced risk. Cancers of the pancreas, esophagus, lung, and kidney, as well as leukemia, also appeared to be "protective," reducing risk between 22 and 44 percent. The study, released just days after publication of a similar report from Italian researchers, is by far the largest to establish such a link.

Notably, the researchers also found that certain cancers apparently conferred no reduced Alzheimer's risk, including melanoma (a cancer of the skin), prostate, and colorectal cancers. Breast cancer was not studied because there were too few cases in the database the researchers analyzed of nearly 3.5 million veterans, 98 percent of them men, who received care between 1996 and 2011.

The scientists said the reduced risk of Alzheimer's was not simply because cancer patients die young, before they can develop the dementia. Cancer survivors lived long enough and even appeared to be at increased risk to develop other typical age-related diseases, including stroke, osteoarthritis, cataracts, and macular degeneration. And they found that most cancer survivors also had an increased risk for non-Alzheimer's dementia. The protective effect of most cancers seemed to extend only to Alzheimer's. [What] surprised the team was the other finding: Cancer patients treated with chemotherapy enjoyed a reduced Alzheimer's risk. They were 20 to 45 percent less likely to develop Alzheimer's than cancer survivors who were not treated with chemotherapy.

Wednesday, July 17, 2013

One future path for medical technology is to augment the internal functions of our cells with artificial versions of natural organelles, membrane-enclosed sacks of protein machinery that do some form of useful work - such as produce therapeutic proteins, or remove harmful waste products that natural organelles struggle with.

The research noted below is one of a number of early experiments along these lines, but it isn't clear that it would be very beneficial as built. Neutralizing free radicals via the introduction of additional antioxidants is not generally beneficial: while they are damaging to protein machinery both inside and outside cells, they are also a part of numerous signaling systems, such as those relating to cellular maintenance and repair processes, or the benefits produced by exercise. Removing free radicals is only demonstrated to extend life and improve health over the long term when localized to the mitochondria of the cell, where it might not be practical to insert an entire new organelle.

[Researchers] have successfully developed artificial organelles that are able to support the reduction of toxic oxygen compounds. This opens up new ways in the development of novel drugs that can influence pathological states directly inside the cell. Free oxygen radicals are produced either as metabolic byproduct, or through environmental influences such as UV-rays and smog. Is the concentration of free radicals inside the organism elevated to the point where the antioxidant defense mechanism is overwhelmed, the result can be oxidative stress, which is associated with numerous diseases such as cancer or arthritis.

The aggressive molecules are normally controlled by endogenous antioxidants. Within this process, organelles located inside the cell, so-called peroxisomes, play an important part, since they assist in regulating the concentration of free oxygen radicals. [The] researchers developed a cell organelle based on polymeric nanocapsules, in which two types of enzymes are encapsulated. These enzymes are able to transform free oxygen radicals into water and oxygen. In order to verify the functionality inside the cell, channel proteins were added to the artificial peroxisome's membrane, to serve as gates for substrates and products. The results show that the artificial peroxisomes are incorporated into the cell, where they then very efficiently support the natural peroxisomes in the detoxification process.

Wednesday, July 17, 2013

Any method to distinguish or interfere with cancer cells that is broadly applicable to a majority of cancer types will greatly reduce the threat of cancer in old age. Cancer is dangerous precisely because it is so very varied, both between types and between individual tumors. I remain confident that there must be numerous commonalities in the low-level mechanisms of cancer that reflect the commonalities in its behavior, however. There is, for example, the need for lengthening of telomeres that forms the basis of the SENS approach to eliminate cancer as a possibility in human biology.

Some other candidates are emerging, such as targeting CD47 with antibodies to strip cancer cells of a method they all appear to use to avoid destruction by the immune system. Here is news of another potentially actionable mechanism that might be shared by many cancer types:

Cancer cells grow and divide much more rapidly than normal cells, meaning they have a much higher demand for and are often starved of, nutrients and oxygen. We have discovered that a cellular component, eEF2K, plays a critical role in allowing cancer cells to survive nutrient starvation, whilst normal, healthy cells do not usually require eEF2K in order to survive. Therefore, by blocking the function of eEF2K, we should be able to kill cancer cells, without harming normal, healthy cells in the process. A treatment that could block this protein could represent a significant breakthrough in the future of cancer treatment.

Traditional chemotherapy and radiotherapy cause damage to healthy cells, and other more targeted treatments are usually only effective for individual types of cancer. Contrastingly, this new development does not damage healthy cells and could also be used to treat a wide variety of different cancers. [Researchers] are now working with other labs, including pharmaceutical companies, to develop and test drugs that block eEF2K, which could potentially be used to treat cancer in the future.

Thursday, July 18, 2013

Researchers here explore changes that occur in gut bacteria populations as a result of the practice of calorie restriction. The challenge for assigning causes to the extended longevity produced by a calorie restricted diet in laboratory species such as mice is that calorie restriction changes near every measurable aspect of metabolism: it is a system-wide and sweeping alteration of state. So we should not be surprised to see that populations of bacteria in the body also change - but is that an important effect in comparison to other fundamental alterations in cellular metabolism?

Calorie restriction has been regarded as the only experimental regimen that can effectively lengthen lifespan in various animal models, but the actual mechanism remains controversial. The gut microbiota has been shown to have a pivotal role in host health, and its structure is mostly shaped by diet. Here we show that life-long calorie restriction on both high-fat or low-fat diet, but not voluntary exercise, significantly changes the overall structure of the gut microbiota of C57BL/6 J mice.

Calorie restriction enriches phylotypes positively correlated with lifespan, for example, the genus Lactobacillus on low-fat diet, and reduces phylotypes negatively correlated with lifespan. These calorie restriction-induced changes in the gut microbiota are concomitant with significantly reduced serum levels of lipopolysaccharide-binding protein, suggesting that animals under calorie restriction can establish a structurally balanced architecture of gut microbiota that may exert a health benefit to the host via reduction of antigen load from the gut.

Thursday, July 18, 2013

Damaging reactive oxygen species (ROS) and other free radicals are generated within your cells, largely as a result of the day to day operations of mitochondria, the power plants of the cell that produce chemical energy stores used by cellular processes. Too many free radicals produce the state called oxidative stress, in which a cell struggles to keep up with the repair of its protein machinery. Oxidative stress increases with age: this is thought to be due to increasing dysfunction in mitochondria, and to be a root cause of degenerative aging.

It's not quite so simple, however, as the presence of oxidative molecules in our biology is vital to life. Evolution eagerly uses and reuses every cog, nut, and bolt that happens to be to hand, and so ROS are involved in a range of essential cellular mechanisms. Low levels of ROS are usually beneficial and necessary, while high levels are usually damaging and bad. (Unless you are a naked mole rat, in which case high levels seem to be business as usual and something to be shrugged off in the course of living for an exceedingly long time). Biology is a complex business, and it is always the case that the details matter: you can't just talk about ROS levels, but have to talk about where, when, how they change, and their interaction with other processes.

Under normal physiological conditions, reactive oxygen species (ROS) serve as 'redox messengers' in the regulation of intracellular signalling, whereas excess ROS may induce irreversible damage to cellular components and lead to cell death by promoting the intrinsic apoptotic pathway through mitochondria. In the aging process, accumulation of mitochondria DNA mutations, impairment of oxidative phosphorylation as well as an imbalance in the expression of antioxidant enzymes result in further overproduction of ROS. This mitochondrial dysfunction-elicited ROS production axis forms a vicious cycle, which is the basis of mitochondrial free radical theory of aging. In addition, several lines of evidence have emerged recently to demonstrate that ROS play crucial roles in the regulation of cellular metabolism, antioxidant defence and posttranslational modification of proteins.

We first discuss the oxidative stress responses, including metabolites redistribution and alteration of the acetylation status of proteins, in human cells with mitochondrial dysfunction and in aging. On the other hand, autophagy and mitophagy eliminate defective mitochondria and serve as a scavenger and apoptosis defender of cells in response to oxidative stress during aging. These scenarios mediate the restoration or adaptation of cells to respond to aging and age-related disorders for survival.

In the natural course of aging, the homeostasis in the network of oxidative stress responses is disturbed by a progressive increase in the intracellular level of the ROS generated by defective mitochondria. Caloric restriction, which is generally thought to promote longevity, has been reported to enhance the efficiency of this network and provide multiple benefits to tissue cells. In this review, we emphasize the positive and integrative roles of mild oxidative stress elicited by mitochondria in the regulation of adaptation, anti-aging and scavenging pathway beyond their roles in the vicious cycle of mitochondrial dysfunction in the aging process.

Friday, July 19, 2013

Exercise extends average life spans (but not maximum life spans) in laboratory animals and improves long term health. In human epidemiological studies it is associated with better health and greater life expectancy. Here is another of the many, many examples of this relationship:

In a study of more than 27,000 Americans, 45 years and older who were followed for an average of 5.7 years, researchers found: 1) One-third of participants reported being inactive, exercising less than once a week. 2) Inactive people were 20 percent more likely to experience a stroke or mini-stroke than those who exercised at moderate to vigorous intensity (enough to break a sweat) at least four times a week. 3) Among men, only those who exercised at moderate or vigorous intensity four or more times a week had a lowered stroke risk. 4) Among women, the relationship between stroke and frequency of activity was less clear.

"The stroke-lowering benefits of physical activity are related to its impact on other risk factors. Exercise reduces blood pressure, weight and diabetes. If exercise was a pill, you'd be taking one pill to treat four or five different conditions." The study - the first to quantify protective effects of physical activity on stroke in a large multiracial group of men and women in the United States - supports previous findings that physical inactivity is second only to high blood pressure as a risk factor for stroke.

Friday, July 19, 2013

The microRNA let-7 has been shown to be involved in maintenance of stem cell populations. It was mentioned in research in flies from last year: let-7 levels rise with aging, causing other changes in various proteins which result in a reduced number of stem cells that are active and maintaining tissues. Here researchers investigate let-7 in nematode worms in connection with the regenerative capacity of nerve tissue:

Like mammalian neurons, C. elegans neurons lose regeneration ability as they age, but it is not known why. C. elegans is a soil worm with its brain wiring diagram being mapped entirely - every connection between every nerve cell. Forty percent of genes identified in the worm genome have a counterpart in humans. Genes that allow neurons to connect with each other to form functional neuronal circuits and to regenerate themselves after injury are highly similar between worms and humans. Thus, what we learn in worms will likely be relevant to the development and regeneration of the human nervous system. The let-7 microRNA and its target, the LIN-41 tripartite motif protein, were recently shown to function as neuronal timers in worms to time the decline of the ability of neurons to regenerate as they age

Since let-7 and lin-41 genes are broadly expressed in different types of neurons, their roles in neuronal regeneration may be widespread. In addition to let-7, many microRNAs are also expressed in postmitotic neurons, raising the possibility that other microRNAs could also contribute to developmental decline in neuronal regeneration. In C. elegans, many aged neurons display a further decline in axon regeneration. In [at least some] aged neurons, a reduced let-7 remains able to enhance axon regeneration so it is likely that let-7 continues to contribute to the further decline in axon regeneration in aged neurons.

These discoveries have important implications in treating brain and spinal cord injury or neuro-degenerative diseases as they show that it may be possible to improve the ability of neurons in the adult brain to regenerate after injury through therapeutic inhibition of the let-7 microRNA, and thereby restore their youthful regenerative capacity. The idea of slowing down neuronal aging to promote axon regeneration after injury is an appealing possibility.


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