Fight Aging! Newsletter, October 21st 2013

October 21st 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!

To subscribe or unsubscribe to the Fight Aging! Newsletter, please visit the newsletter site:


  • A Study of Mitochondrial DNA Mutations That Comes With a Supporting Visual Database
  • Crowdfunding a SENS Rejuvenation Research Project: $5,000 Raised and $2,000 To Go
  • A Spotlight on SENS Research Foundation Interns
  • Relevant Medical Research is Starting to be Crowdfunded
  • Recently Published: Why We Age
  • Latest Headlines from Fight Aging!
    • Hypothesizing on Oxygen and Carbon Dioxide Levels and Aging
    • Autophagy, Amyloid, and Alzheimer's Disease
    • Mouse Lifespan Study Crowdfunding Success
    • Finding the Causes of the Fall in Maximum Heart Rate With Age
    • A Review of Autophagy and Its Role in Cellular Damage Control
    • Growing Structured Pancreatic Tissue
    • Working on a Basis for Biomarkers of Aging
    • p53 As An Intervention Target in Aging and Cancer
    • Stem Cell Transplants to Repair Damaged Gut Tissue
    • A Popular Science Article on Tissue Engineering and Prosthetics


Each of our cells contains a herd of mitochondria, the evolved descendants of ancient symbiotic bacteria that now work to generate chemical energy stores used to power the rest of the cell. Mitochondria malfunction in aging, causing their cells to malfunction also, and it is though that this stems from damage to the comparatively fragile mitochondrial DNA. This DNA specifies essential protein machinery used in mitochondrial energy generation, but it sits right next to the ongoing and energetic set of chemical reactions that occur inside each mitochondrion. These reactions generate reactive byproducts - free radicals, reactive oxygen species, and so on - that are most likely to harm the mitochondria rather than any other portion of the cell.

Mitochondria, their state of damage, and their resistance to becoming damaged appear to be very important in determining the pace of aging and longevity of different individuals and species. In particular damage to mitochondrial DNA is important: per the mitochondrial free radical theory of aging, the chain of harm starts with chance mutations that remove just a few essential protein blueprints, but which also allow the damaged mitochondrion to evade cellular quality control mechanisms - so it can reproduce and spread its form of dysfunction.

All of this is why technologies that can replace mitochondrial DNA or move it into the cell nucleus are so important: they will repair and reverse a contributing cause of degenerative aging. Unfortunately it has proven technically challenging to obtain a good picture of what exactly is going in the mitochondrial DNA of laboratory animals, let alone people in clinics. This has probably dampened enthusiasm for the development of means to replace mitochondrial DNA over the past few decades - clinical development proceeds only after great certainty in the underlying science these days, arguably far more certainty than is actually needed to produce good, working therapies. Only comparatively recently has data started to accumulate in earnest, to the point at which it can be seriously applied to support or disprove various different forms of the mitochondrial free radical theory of aging. Here is a whole raft of data to take a look at, however, an example of what researchers are turning out today in terms of mapping mitochondrial DNA damage:

Mitochondrial DNA Rearrangements in Health and Disease - A Comprehensive Study

Mitochondrial DNA (mtDNA) rearrangements cause a wide variety of highly debilitating and often fatal disorders and have been implicated in aging and age-associated disease. Here we present a meta-analytical study of mtDNA deletions (n = 730) and partial duplications (n = 37) using information from more than 300 studies published over the last 30 years.

We show that both classes of mtDNA rearrangements are unequally distributed among disorders and their breakpoints have different genomic locations. We also demonstrate that 100% of cases with sporadic mtDNA deletions and 97.3% with duplications have no breakpoints in the 16 071 breakage hotspot site, in contrast with deletions from healthy and aged tissues. Notably, most deletions removing a section of the D-loop are found in tumours. Deleted mtDNA molecules lacking the origin of L-strand replication (OL ) represent only 9.5% of all reported cases, while extra origins of replication occur in all duplications. As previously shown for deletions, imperfect stretches of homology are common in duplication breakpoints.

mtDNA Rearrangements Database

We provide a dedicated website with detailed information on deleted/duplicated mtDNA regions to facilitate the design of efficient methods for identification and screening of rearranged mitochondrial genomes.

MitoBreak - The mitochondrial DNA breakpoints database

A comprehensive on-line resource with curated datasets of mitochondrial DNA (mtDNA) rearrangements, MitoBreak provides a complete, quality checked and regularly updated list of breakpoints.

Damage to the mitochondrial genome might occur in the form of point mutations, large deletions or duplications and DNA breakage with subsequent linearization of the mtDNA molecule. As eukaryotic cells contain many copies of mtDNA, a mutated type of mtDNA must first reach a threshold level by clonally expanding within a cell before it can cause adverse effects. The accumulation of damaged mtDNA molecules in tissues is an important cause of mitochondrial disease, a clinically heterogeneous group of disorders related with OXPHOS dysfunction. Moreover, mutated mtDNAs are suspected to contribute to the etiology of a number of age-related disorders, by accumulating with age in a variety of tissues.


The Longecity community is presently raising funds for a modestly-sized rejuvenation research project to be undertaken by a SENS Research Foundation team. Grand goals are made of many small steps, and these days any given small step in the life sciences can take the form of a six month project, a few skilled post-graduate researchers with access to an established lab, and $10-30,000. Meaningful research that pushes forward the boundaries of medical science is becoming very cheap, with that fall in prices driven by accelerating progress in the tools and capabilities of biotechnology. We can see this process at work here, as this significant and useful gene therapy research can be conducted with a proposed budget of $21,000.

LongeCity Research Support 2013: Mitochondrial Gene Therapy

In this project, engineered mitochondrial genes will be used to restore function to cells that contain defective mitochondrial genes.

The SENS team is developing a unique method for targeting these genes to the mitochondria; this step has been the bottleneck in research on this topic over the last decade. In their system, the mRNA from the engineered mitochondrial gene is targeted to the mitochondrial surface before it is translated into a protein using a co-translation import strategy. Once imported, it is incorporated into the correct location in the inner mitochondrial membrane. The long-term goal of this project is to utilize this improved targeting strategy to rescue mutated mitochondrial DNA and thereby prevent and cure one of the major causes of cellular aging.

There is an open question and answer thread dedicated to the project in the Longecity forums, and the researchers have started to discuss the research in some detail. I think that you'll find it interesting:

Mitochondrial Gene Therapy: Questions

One reason [that we chose to work with the genes CyB and ATP8] that these may be both the easiest and hardest genes to achieve efficient import with. CyB has a reputation (whether or not it is deserved is a matter for some debate) in the field of being the most difficult and hydrophobic protein to import into the mitochondria. It is one of the bigger mitochondrially encoded genes, so at the very least it is a challenge. ATP8, on the other hand, is tiny and so may be considered the easiest to import. Thus we've set ourselves a task that spans the range of challenges that we think we'll encounter.

The second reason is that, strategically, OxPhos complexes III and V are the most interesting for proof of concept rescue of the entire mito genome. The reason is that they have the fewest genes that are encoded by the mitochondria. Complex III has only CyB (and thus ONLY CyB is needed to rescue the entire complex) and Complex V has only 2: ATP6 and ATP8. So if we want to study functional rescue of entire complexes then III and V are the easiest.

A third of the needed project funds - $7,000 - will be raised from the community while the remaining $14,000 will matched by Longecity: $2 for every $1 donated. Since I last mentioned this project, donors have contributed a little over $5,000 - so just $2,000 left to go, with a November deadline. If you've been on the fence about donating, then jump in! It's never too late to help build a future that we'd all like to live in, one that involves far longer, healthier lives, and complete prevention of the diseases of aging.

This mitochondrial gene therapy project is exactly the sort of crowdfunded science initiative that I like to see succeed - and that I'd like to see succeed again many times over in the years ahead. A future in which the SENS Research Foundation obtains a significant amount of its science budget from the community on a project by project basis is a bright one, I think. It isn't just a matter of money and connecting with supporters: it also generates publicity, materials, and broader interest in the research itself. At this stage in the game it is still very important to talk to the rest of the world about longevity science and the prospects for progress in the near future, and crowdfunding rejuvenation research via Longecity, Microryza, and Indiegogo - and their successors - blends fundraising, organizational transparency, advocacy, education, and persuasion in a very useful way.


One of the programs undertaken by the SENS Research Foundation is to cultivate the next generation of molecular biologists and other life scientists who will work on the foundations of rejuvenation biotechnology. The future of medicine for aging will focus on manipulating, cleaning, and repairing the protein machinery of cells, using gene therapies and carefully designed molecular machines. Working to treat and prevent degenerative aging will be just another part of the broad spectrum of advanced medical research into cells and cellular machinery - but in order for that to be the case, a research community must exist. A sizable number of today's students must decide that cutting-edge longevity science is both interesting and a growth opportunity. Which it is, but you still have to sell that to people who might have inherited the old view of gerontology as a staid field of palliative clinical medicine rather than the hotbed of new knowledge that it is today, complete with barnstorming displays of hacking living cell biology.

Hence the SRF education initiative, with online coursework and a video lecture series from noted researchers. The Foundation also accepts young researchers into intern positions: these are capable undergrads and postgrads who conduct original research and help to push the current state of the art towards readiness to implement the SENS vision for rejuvenation therapies. In the process they make the connections that will help them further their future careers in this expanding field of medical research. The SENS Research Foundation is at the center of a very wide web of relationships that spans the major aging research laboratories and scientific groups of the US and beyond: it's a very good place to be seen doing good work.

Here are recent posts by some of the last set of SRF interns, discussing the SENS6 conference and looking at the work they performed at the Foundation:

Firsthand account of Dr. Rigdon Lentz's and Dr. Jean Hebert's SENS6 presentations by intern Ariana Mirzarafie-Ahi

Everyone knows that cancer is the result of cells multiplying out of control. Our bodies have ways of identifying these cells and destroying them. However, what goes wrong in cancer? More specifically, what happens in large tumours that allows them to evade our natural defenses? Two kinds of protein, tumour necrosis factor (TNF) and interleukin-2 (IL-2) are responsible for binding to the surface of tumour cells and inducing their death. The problem, however, is that these cells continually produce too many receptors on their surface for these proteins, then shed them, so that they effectively bypass TNF- and IL-2-induced apoptosis (cell death).

Dr Lentz presented his solution to this problem at SENS6. The therapy involves cycling the patient's blood through a device outside the body, so ligands (molecules which attach the receptors) can remove all those extra receptors in the blood. Once the procedure is complete and the blood returned to the patient, TNF and IL-2 should be able to bind to the cell-surface receptors of tumour cells and destroy them.

SRF Intern Ariana Mirzarafie-Ahi Improves a Protocol to Study Age-Related Cross-Linking Molecules Threefold

During her 2013 SENS Research Foundation Summer Internship, Ariana worked with the research group of Dr. William Bains at the University of Cambridge, which specializes in seeking compounds for degrading advanced glycation end-products (AGEs). AGEs are by-products of aging that accumulate in the area between cells called the extracellular matrix (ECM). The 'cross-linking' of AGEs causes wrinkles, stiff joints, hypertension, blindness, and other age-related conditions. Ariana's project focused on optimizing the decellularization step that precedes quantitation of AGEs.

"My project sought to significantly shorten the period of time required for the decellularization of tissue samples. To analyze the contribution of specific AGE cross-links to tissue aging and test possible means of breaking those cross-links, it is first important to have a quick, simple procedure for decellularizing the tissue being studied. This procedure preserves all the major ECM proteins while removing the vast majority of cellular proteins. The run-time of the original decellularization protocol was 10 days. To determine if any steps could be truncated, I measured the progress of decellularization each day during the 10-day protocol. I noted that no significant increase in decellularization occurred during several days of the protocol. Using this data, I devised a new protocol which reduces the decellularization process from 10 days down to just 3."

Ariana presented her work at the SENS6: Reimagine Aging Conference held at Queens' College, Cambridge in September 2013. The new decellularization protocol will be published in the April 2014 special edition of Rejuvenation Research.

How small molecule intervention by the Chen and Madeo labs may reverse the aging process by intern Navneet Ramesh

I was particularly drawn to two presentations at the conference, that of Dr. Danica Chen from the University of California, Berkeley and that of Dr. Frank Madeo from the University of Graz. The SENS approach calls for damage repair to maintain and restore cellular function. Both presentations focused on small molecule interventions that could reverse the effects of aging.

Dr. Chen explained how sirtuin 3 (SIRT3) can slow the rate of damage to stem cells. Sirtuins are a group of seven proteins that affect many cellular processes by activating metabolic pathways. For example, sirtuins are believed to play a role in slowing the aging process via calorie restriction. However, a direct role in repair of cellular damage has remained poorly understood until now.

Another highlight of SENS6 for me was Dr. Frank Madeo's demonstration that a compound called spermidine promotes longevity. Spermidine belongs to a class of organic compounds known as polyamines, which have been shown to decline with age. They have been identified as key regulators of genes involved in aging, but the specific details as to how they interact with these genes remains unknown. Dr. Madeo noted that spermidine treatment promoted autophagy, which is the process of degrading and destroying unneeded cellular components through the lysosome. This discovery is particularly interesting to rejuvenative medicine because diminished autophagic activity is thought to play a crucial role in the aging process.

SRF Intern Navneet Ramesh Attempts to Inhibit a Key Pathway in Tumor Cell Maintenance of Telomere Length

In most cases, tumor cells owe their indefinite longevity to the enzyme telomerase, which continuously extends their telomeres. However, 10 to 15% of tumor cells can maintain telomere length without telomerase function. This second method of telomere maintenance is referred to as "alternative lengthening of telomeres," or ALT. The exact mechanism by which ALT occurs remains unknown, but several chromatin remodeling genes have been implicated. Several types of cancer cells, especially in tissues of mesenchymal origin, exhibit the ALT phenomenon.

During my internship, I attempted to determine how the ALT mechanism could be overcome. Previous studies have demonstrated that a transcriptional regulator involved with chromatin remodeling, known as ATRX, is either deleted or abnormally expressed in cells which use the ALT mechanism. I hypothesized that introduction of ATRX could inhibit ALT activity. Therefore, I predicted that expression of ATRX in ALT-regulated cells would lead to a reduction in markers of ALT activity, such as C-circles, ALT-associated PML nuclear bodies (APBs), and, of course, telomere length. To test this hypothesis, I transfected three cell lines that utilize the ALT mechanism with an ATRX expression construct and measured the resulting effect on ALT activity. Preliminary data indicates that ATRX expression does indeed reduce ALT activity.


Crowdfunding is evolving, and it will in time make its way beyond being near-entirely devoted to the production of games, art, and gadgets. Arguably games, art, and gadgets make up the bulk of the first wave of crowdfunding growth because some parts of these industries have been discussing and trying out new business models pretty aggressively for the past decade, empowered by the communication infrastructure of the internet. They headed up the exploration and it was only a matter of time before one of those sparks led to a wildfire. Research in medicine and the life sciences, on the other hand, is an industry dominated by top-down decision-making and large, conservative funding structures. Considerably stigma attaches to scientists who step outside the ivory tower to start businesses and gather popular support for their work. I would hope that one of the consequences of the present success of crowdfunding is that any stigma associated with explaining and advocating your work as a scientist to the broader public will go away. Money talks, after all, and grant-writing is arguably a harder road for novel research, and more fraught with conflicts of interest, than obtaining funds directly from interested supporters.

So I'm pleased to see that modest-sized research projects that are somewhat relevant to aging, longevity, and related areas of medical science are starting to arrive and become funded. The present behemoth in the room, Kickstarter, wants nothing to do with medicine or science at this time and is ceding that part of this still-growing industry to competitors, both dedicated research crowdfunding sites like Microryza, anything-goes platforms like Indiegogo, and of course established communities that raise funds for specific goals without the benefit of flashy new dedicated crowdfunding sites, such as Longecity.

So right now, today, I can point out the successfully funded mouse lifespan study at Indiegogo, the ongoing fundraising for a SENS mitochondrial gene therapy study at Longecity, and I thought I'd also point out this brace of projects at Microryza, of varying relevance and degrees of success in funding:

Can we use 3-D printing to engineer organs affordably?

The cost of obtaining human organs for either transplant or research is a barrier in both healthcare and academia. Using off the shelf components along with common non-toxic materials used to grow in vitro blood vessels and potentially organs can significantly reduce that barrier. [The goal of this project is] to investigate the efficiency of the methods of printing carbohydrate glass for use as a sacrificial tissue structure, and replicate previous studies on printing vascularity. This research will also attempt to address whether or not the human engineered vascularities are sufficient to prevent necrosis in the resulting organ.

Targeted Drug Delivery by using Magnetic Nanoparticles

We are initially developing a patch for treating cancer, by injecting microscopic particles (or nanoparticles) into the bloodstream that can pinpoint, attach themselves to, and kill cancer cells. They are then naturally disposed by the body. This technology could potentially revolutionise health care and medicine and save millions of lives around the world as well as allow treatment of new types of cancer.

Developing A New Treatment For Neurodegenerative Diseases

In 2011, a previously unknown mechanism was discovered to control the disease characteristics of the rare genetic disorder Niemann Pick Type C (NPC). NPC is also nicknamed "Childhood Alzheimer's", because the neurological symptoms are remarkably similar to Alzheimer's disease (AD). By re-activating the mechanism, disease characteristics in NPC patient cells were successfully reversed to look like normal cells. As a proof-of-concept, normal cells developed similar characteristics to those seen in NPC patient cells when the mechanism was inhibited. This suggests that this mechanism controls the underlying cause of the disease. The goal of this research is to identify a therapeutic agent that is mechanism specific for the treatment of NPC and AD.

Can Modified Adult Stem Cells Reverse Neurological Pathologies?

Gene-modification of stem cells by transfection allows us to over-express (over-produce) neurotrophic factors (neuronal cell loving proteins) that may alleviate neurological deficits associated with disease. One protein we are interested in transfecting and over-expressing stem cells with is brain derived neurotrophic factor or BDNF. BDNF has been shown to contribute to the recovery of ischemic stroked rats. BDNF mRNA expression is reduced in the Parkinson's disease substantia nigra and improves cognition in an Alzheimer mouse model. Lastly, BDNF is neuroprotective to retinal ganglion cells (RGCs) in a rat glaucoma model.

Researchers should take note of this and do their own exploration. From the litter of failed and poorly funded relevant science projects you can find at Indiegogo it's clear that you can't just put something up and wait for people to notice. You have to go about this as the mouse lifespan project team did, and as the Longevity community does: the project site is only a business card and a place to donate, nothing more. It's a flag, and you have to put in the work to wave that flag, to talk to the community, to find your supporters and motivate them, provide updates, videos, and dialogs with the scientists involved. As more and more research groups try this, however, and establish watering holes like Microryza or Indiegogo, the halo of supporters with overlapping interests will grow, and it will become ever easier to find people who want to fund specific scientific goals.

I think that this is a grand future, one in which funding and advocacy merge naturally at the grassroots level to help advance a thousand needful projects that would otherwise have languished in the old-style funding infrastructure. It is good to see even slow progress towards that end: initial successes will encourage other forward-thinking researchers to join in and experiment, and so the landslide begins.


The programmed aging camp of aging research is a sizable minority in the field, and its members theorize that aging results from an evolved program of changes in metabolism, gene expression, and so forth. Some even think that aging processes are actively selected for rather than being a result of antagonistic pleiotropy, which occurs when a mechanism beneficial in early life is strongly selected despite the fact that it becomes harmful in later life. In later life the members of a species are no longer subject to the sort of evolutionary pressures that would lead to a better outcome for individuals. At the high level evolution only selects for reproductive success: the fate of individuals becomes irrelevant when they age beyond the point of providing meaningful contributions to the success of their offspring, and thus there is no further selection for sustaining, health- and longevity-enhancing adaptations.

Like the other big camp in aging research, the camp of those who theorize that aging is the result of a stochastic accumulation of damage to cells and molecules, programmed aging is divided into (a) researchers who think that there can be rapid progress towards radical extension of healthy life span, (b) researchers who think that only modest gains are plausible, and that even those will be hard to achieve, and (c) the silent majority who focus only on investigations of aging, not actually doing anything about it. The programmed aging approach to building therapies for aging involves altering gene expression and protein levels with the intent of changing the behavior of cellular machinery so as to turn back its operation to a more youthful mode. The researchers are often interested in furthering ongoing drug development programs such as investigations of rapamycin, as using drugs to enhance or suppress levels of specific proteins connected to aging is a step forward to their eyes, one that should lead to more sophisticated manipulations of the aging program in the future.

If you are in the aging as damage camp, as I am, this all looks like the slow road to nowhere, however. The cart is before the horse: damage causes change in gene expression and metabolic operations, not vice versa. This is an important distinction to make, because the research and development strategy that works well in a world in which aging is damage works poorly in a world in which aging is an evolved program - and vice versa. Thus one of these groups is achieving little other than to expand our knowledge of biology and aging.

In any case, this recently published book, while written from a programmed aging perspective, comes recommended. The interesting thing about the divide between the programmed aging and aging as damage camps is that their members largely agree on all of the fundamental observations and science of aging as established to date - the facts are what they are, and the difference is all in the interpretation of those facts. The book is an easy read, aimed at the layperson, but still educational, and the author holds that agelessness can be achieved in the decades ahead with sufficient funding of suitable research programs. I'm always pleased to see more people in the community espousing ambitious views, as ambition for radical change is the first step towards actually making progress.

Why we age: Insight into the cause of growing old

Why are we mortal? What are the causes of aging, and how, if at all, can the process be halted? The issue of aging, which so thoroughly consumes our youth-loving culture today, has only gained traction in the last century. Prior to this, disease, accident, or other misfortune caused the majority of deaths, rather than the effects of old age. As medicine advanced, vanquishing many diseases and adding decades to life expectancies, so old age and the natural shutting down of the human body became a trial for all to bear.

Dr Walker brings to light a real possibility in this age of advanced scientific prowess: the extension of the biological human lifespan beyond its current natural limits. By examining the aging process, scientists can isolate what causes our bodies to age, and therefore, also learn how to control this mechanism. Dr Walker believes that we could be seeing huge advances in this area before the end of the century, and here he explains why.

The book is organized into sections which each deal with a specific theory or question of aging, progressing historically through the often misunderstood relation between aging and death, the effects of aging, the theories on why we age, and ending with a tantalizing glimpse of a future without aging. Dr Walker takes a measured look at these complex issues, giving weight to each discussion with key evidence from several scientific fields. He discusses how "biological immortality" could be possible, by systematically examining evidence and theories to show why this concept could be achievable sooner than we think. The book is not designed as an academic thesis; rather, it is aimed at the average reader keen to understand their own experiences of aging and learn about the exciting advances scientists are making into this field of research.

I notice that Aubrey de Grey wrote a short review:

Although I myself am a proponent of the current mainstream view that aging is a non-programmed, damage-driven process, and I dispute Walker's arguments in this book for rejecting that view, I nonetheless believe that the book has great value: firstly because the model set out here is not one that I believe can be rejected out of hand, secondly because in the event (however unlikely in my view) that it is correct it would point the way to a far simpler and more easily implementable approach to medical postponement of age-related ill-health than would otherwise be available, and last but by no means least that the book is extremely well-written for a general audience, expounding in highly accessible but yet detailed terms a wide variety of aspects of this fascinating and vitally important field. I therefore recommend this book to anyone who is seeking a basic introduction to the biology of aging.


Monday, October 14, 2013

Here is an experimental methodology that I haven't seen advocated recently, though it bears on some of the theorizing regarding the evolutionary origins of naked mole rat longevity, since they live in comparatively oxygen-poor tunnel environments.

The negative relation between metabolism and life span is a fundamental gerontological discovery well documented in a variety of ontogenetic and phylogenetic models. But how do the long-lived species and populations sustain lower metabolic rate and, in more general terms, what is the efficient way to decline the metabolism?

The suggested 'pull and push back' hypothesis assumes that decreased O2 (hypoxia) and/or increased CO2 (hypercapnia) may create preconditions for the declined metabolic and aging rates. However, wider implementation of such ideas is compromised because of little advances in modification of the metabolic rate. Artificial atmosphere with controlled O2 and CO2 levels could be a promising approach because of the minimal external invasions and involvement of the backward and forward loops ensuring physiological self-regulation of the metabolic perturbations.

General considerations and existing data indicate that manipulations of CO2 levels may be more efficient in life span extension than O2 levels. Thus, maximum life span of mammals positively correlates with the blood CO2 and HCO3- but not with O2 levels. Yet, proportional decease of the body O2 and increase of CO2 seems the most optimal regime ensuring lower losses of the energy equivalents. Furthermore, especially rewarding results could be expected when such changes are modeled without major external invasions using the animals' inner capacity to consume O2 and generate CO2, as it is typical for the extreme longevity.

Monday, October 14, 2013

Autophagy is the name given to a collection of housecleaning and recycling processes that take place within cells. Research indicates that more autophagy is a good thing, leading to fewer damaged cellular components and metabolic waste products lingering to cause issues. Most of the methods demonstrated to extend life in laboratory animals are linked to enhanced levels of autophagy, and artificially increasing levels of autophagy might form the basis for future medical therapies.

Here, however, researchers show that extracellular levels of amyloid in Alzheimer's disease are reduced in mice with deficient autophagy, which is not the expected result, but nonetheless makes sense in context:

Pathological hallmarks of Alzheimer's disease (AD) include the aggregation of amyloid beta (Aβ) peptides inside neurons and the accumulation of extracellular Aβ plaques. Previously, the mechanisms by which Aβ leaves neurons were unknown, and it has been controversial whether the intracellular or extracellular accumulation of Aβ plays a larger role in AD-associated symptoms.

[Researchers] crossed mice deficient in autophagy in forebrain neurons with transgenic animals that produce abnormally high levels of the Aβ precursor protein. They found that the offspring had far fewer extracellular Aβ plaques than the transgenic mice that showed normal autophagy. "We know that autophagy is the cleaning system within the cell. Our expectation was that if we delete autophagy, we would get more of the Aβ plaques outside the cell. But we saw the contrary, so we were really surprised by that, and we had to work hard to understand why."

In order to understand the reason that autophagy-deficient mice had fewer Aβ plaques, the researchers measured Aβ release from neurons isolated from the mice. They observed a drastic decrease in Aβ secretion, which led to accumulation of Aβ inside the cells. [This in turn] led to neurodegeneration and memory impairment in the mice, consistent with earlier reports "that intracellular Aβ is toxic, or is at least contributing to the toxicity" in neurons. "We have brought some light to the issue, but of course it is not known yet how the toxicity is mediated. That remains to be elucidated." But the question of whether intracellular versus extracellular Aβ accumulation mediates the effects of AD remains contentious. "The field is divided."

"What this study is telling us, too, is that one of the mechanisms that protects the cells is getting rid of the Aβ that's in the cells and putting it outside the cell. Sure, it may still be toxic under those conditions, but the real toxicity is being generated by its accumulation and disruption of intracellular processes."

Tuesday, October 15, 2013

Reseachers and advocates associated with Heales and the International Longevity Alliance successfully crowdfunded a modest mouse life span study via Indiegogo. It's worth looking at how they went about structuring the research (a short term project using old mice, which benefited from having a group of suitably aged mice to hand now) and managing publicity. Now if we could just manage the same sort of outcome for a range of more ambitious SENS-related mini-projects in rejuvenation research rather than combinatorial drug tests for slowing aging...

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. The largest life extension in mice so far resulted from a similar effort, where one mouse lived very close to 5 years (mice usually live 2-3 years)! The result should be key to to optimally search for additional years of healthy life.

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. The results will help in the search for life prolonging treatments for both animals and humans. Analogous experiments have hardly been done in mammals and have usually been done only for the immediate short-term effects, without checking the effects on the animal's entire lifespan. For these reasons in many cases you never know for sure whether the drugs you take shorten your lifespan or make you live longer and healthier.

There are *right now* in the lab a sufficient number of aged mice (~20 months old) - male and female - which belong to the C57Bl6 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.

Tuesday, October 15, 2013

Every detrimental change that occurs with aging is directly caused by some collection of cellular mechanisms, but that is only the second to last link in the chain. The deeper cause is an accumulation of unrepaired molecular damage, spiraling outward to create that chain of changes, reactions, and forms of secondary damage. While the list of fundamental damage that causes aging is enumerated and well understood, the final proximate cause of an age-related condition can be challenging to identify and understand - our biology is very complex indeed. You might look at the amount of work and funding that has gone into Alzheimer's research, for example, and the decades it has taken to make any sort of meaningful progress there. Sometimes an immediate cause can turn out to be fairly clear and localized, however, given sufficiently advanced tools for investigation:

[Researchers] have new insight into the age-old question of why maximum heart rate (maxHR) decreases with age. This decrease in maxHR not only limits the performance of aging athletes but it is also a leading cause for nursing home admittance for otherwise-healthy elderly individuals who no longer have the physical capacity required for independent living.

One of the reasons for the age-dependent reduction in maximum heart rate is that aging depresses the spontaneous electrical activity of the heart's natural pacemaker, the sinoatrial node. "I utilized a method to record ECGs from conscious mice and found that maximum heart rate was slower in older mice, just as it is in older people. This result wasn't unexpected. But what was completely new was that the slower maxHR was because the individual pacemaker cells - called sinoatrial myocytes, or 'SAMs' - from old mice just couldn't beat as fast as SAMs from young mice."

The slower beating rate was due to a limited set of changes in the action potential waveform, the electrical signal that is generated by the cells. The changes were caused by altered behavior of some ion channels in the membranes of the older cells. Like most initial discoveries in basic science, this study opens many more questions and avenues for further research. But the significance of the study is that it raises the possibility that sinoatrial ion channels and the signaling molecules that regulate them could be novel targets for drugs to slow the loss of aerobic capacity with age.

Wednesday, October 16, 2013

Cells are constantly suffering damage, the protein machinery harmed by reactive metabolic byproducts, other waste chemicals building up, and various subsystems failing. Efficient repair processes run continually, but at varying paces in response to circumstances. Degenerative aging is nothing more an accumulation of unrepaired damage in and between cells, and many of the ways to slow degenerative aging in laboratory animals are associated with a higher level of the cellular repair and housekeeping processes known as autophagy.

Here is a short open access review that providing an introduction to the processes of autophagy and their significance, with diagrams to clarify some of the descriptions:

Cellular damage occurs in response to genetic perturbations, nutrient deprivation, aging, and environmental toxins. The task of managing general and specific cellular damage is largely under the control of the highly regulated process called autophagy. The term autophagy is used to describe lysosomal-mediated degradation of intracellular contents, which can be divided into 3 basic mechanisms: (1) chaperone-mediated autophagy, (2) microautophagy, and (3) macroautophagy.

Macroautophagy is the most extensively studied autophagy process. One major function of macroautophagy is the control of accumulation of over-produced, long-lived or damaged proteins. Deficiencies of macroautophagy may contribute to accumulation of protein aggregates, which are apparent in a number of neurodegenerative diseases.

Chaperone-mediated autophagy, initiated by chaperone Hsc70, recognizes one protein at a time, and Hsc70 carries the protein to the lysosomes via binding to the lysosomal associated membrane protein (LAMP2A). Whether additional chaperones and lysosomal receptors participate in chaperone-mediated autophagy is unknown.

Microautophagy is achieved by invagination of lysosomal membranes. Lipid, protein or organelles can be degraded through this pathway. Whether lipid, organelles and other proteins are marked by specific modifications to be recognized by the lysosomes is highly likely but the majority of these have yet to be defined.

Autophagic removal of mitochondria is important for mitochondrial quality control. Poor quality mitochondria may enhance cellular oxidative stress, generate apoptosis signals, and induce cell death. Because healthy mitochondrial function is essential for cell survival, selective removal of a subset of dysfunctional mitochondria is a highly regulated process and requires coordinated functions of mitochondrial and cytosolic proteins. This is controlled by a complex array of proteins which are constantly being revised and enhanced.

Wednesday, October 16, 2013

Tissue engineers have demonstrated the ability to grow small amounts of structured organ tissue called organoids in recent years, and have done so with liver, kidney, and now pancreatic cells, among others:

[Researchers] have developed a three-dimensional culture method which enables the efficient expansion of pancreatic cells. The new method allows the cell material from mice to grow vividly in picturesque tree-like structures. The method offers huge long term potential in producing miniature human pancreas from human stem cells. These human miniature organs would be valuable as models to test new drugs fast and effective - and without the use of animal models.

The cells do not thrive and develop if they are alone, and a minimum of four pancreatic cells close together is required for subsequent organoid development. "We found that the cells of the pancreas develop better in a gel in three-dimensions than when they are attached and flattened at the bottom of a culture plate. Under optimal conditions, the initial clusters of a few cells have proliferated into 40,000 cells within a week. After growing a lot, they transform into cells that make either digestive enzymes or hormones like insulin and they self-organize into branched pancreatic organoids that are amazingly similar to the pancreas."

"We think this is an important step towards the production of cells for diabetes therapy, both to produce mini-organs for drug testing and insulin-producing cells as spare parts. We show that the pancreatic cells care not only about how you feed them but need to be grown in the right physical environment. We are now trying to adapt this method to human stem cells."

Thursday, October 17, 2013

If you have a therapy that supposedly slows or reverses aging, how do you determine whether or not it works? Waiting to evaluate life span and health trajectory is the only presently available methodology, and that makes studies in mice very expensive and studies in humans impractical. If there were instead a range of short-term measures that could be reliably mapped to the state of degenerative aging, then research could proceed that much faster. So there is some interest in the search for biomarkers of aging, and this is an example of the sort of work presently taking place:

To investigate general health deterioration and loss of homeostasis in aging, we attempted to determine 1) the dynamics of biological processes during aging and 2) correlate patho-physiological aging end points to transcriptomic responses, which are generally believed to determine the cellular phenotype. Previously, large scale studies provided valuable new insights into aging mechanisms in multiple species, tissues and genotypes. Several of these studies focused on young versus old comparisons, making correlation studies difficult to execute.

We attempted to fill part of the hiatus between chronological aging rate and its associated patho-physiological patterns in the mouse by full genome gene expression profiling of five organs at six ages covering the entire lifespan in mice. Firstly, using the intercurrent gene expression profiles from the six time points, we were able to follow the dynamics of biological processes during chronological aging. For instance, energy homeostasis, lipid metabolism, IGF-1, PTEN and mitochondrial function in liver were slightly up-regulated during the first half of the lifespan but declined during the last 25% of the lifespan. These processes have previously been correlated to chronological aging by others, but interpreting the dynamics of biological functions throughout the lifespan in multiple tissues has been proved difficult so far. Our data can contribute to unravelling the dynamics of functional pathways throughout time in several tissues.

Results indicate that, besides existing overlap between chronological and pathological aging processes (e.g. mitochondrial processes and lipid metabolism), many divergent functional responses were revealed using a (often tissue-specific) pathological scale. These divergent responses leave us with numerous interesting anchor points for future aging research to correlate age-related biological pathways to actual patho-physiological end-points and reveal possible underlying mechanisms, as exemplified for hepatic lipofuscin accumulation.

We hope our results contribute to a new paradigm in aging and medical research taking into account individual and tissue-specific aging levels. For this however, as a next step, a systems biology approach is required to decipher causal age-related mechanisms. Correlating pathophysiological aging endpoints to gene expression and other cellular signatures will become a focus in current aging research to explore loss of homeostasis and general health decline on individual or organ-specific level.

Thursday, October 17, 2013

The protein p53 is involved in many cellular mechanisms, and seems to be an important part of the evolved balance between cancer risk and degenerative aging. This balance manifests as an ongoing decline in the activity of stem cell populations, and thus a progressive failure of tissue maintenance - but the lowered activity of these cell populations reduces the chances of damaged cells spawning cancer. In recent years researchers have demonstrated clever ways to manipulate p53 levels that can both reduce cancer risk and slow aging, so it is possible to both have your cake and eat it too in the case of this mechanism.

p53 is well known for suppressing tumors but could also affect other aging processes not associated with tumor suppression. As a transcription factor, p53 responds to a variety of stresses to either induce apoptosis (cell death) or cell cycle arrest (cell preservation) to suppress tumor development. Yet, the effect p53 has on the non-cancer aspects of aging is complicated and not well understood. On one side, p53 could induce cellular senescence or apoptosis to suppress cancer but as an unintended consequence enhance the aging process especially if these responses diminish stem and progenitor cell populations. But on the flip side, p53 could reduce growth and growth-related stress to enable cell survival and ultimately delay the aging process. A better understanding of diverse functions of p53 is essential to elucidate its influences on the aging process and the possibility of targeting p53 or p53 transcriptional targets to treat cancer and ameliorate general aging.

There are multiple ways to target p53 as an anti-cancer therapeutic. However, directly targeting p53 to suppress aging phenotypes would be difficult considering the delicate balance that is needed among arrest, senescence, and apoptosis. Animal models highlight these complexities [and] imply that specific and narrow interventions to either up or downregulate p53 activity might be suitable for cancer but not effective for general aging. Instead, broad interventions that reduce growth (rapamycin, calorie restriction, resveratrol) or mimic reduced growth (metformin, AICAR) may be the best candidates to alter p53 function in a manner that ameliorates or slows aging.

Friday, October 18, 2013

Researchers continue to find new potential applications in regenerative medicine based on the transplantation of stem cells:

A source of gut stem cells that can repair a type of inflammatory bowel disease when transplanted into mice has been identified by researchers. The findings pave the way for patient-specific regenerative therapies for inflammatory bowel diseases such as ulcerative colitis. The team first looked at developing intestinal tissue in a mouse embryo and found a population of stem cells that were quite different to the adult stem cells that have been described in the gut. The cells were very actively dividing and could be grown in the laboratory over a long period without becoming specialised into the adult counterpart. Under the correct growth conditions, however, the team could induce the cells to form mature intestinal tissue.

When the team transplanted these cells into mice with a form of inflammatory bowel disease, within three hours the stem cells had attached to the damaged areas of the mouse intestine and integrated with the gut cells, contributing to the repair of the damaged tissue. "We found that the cells formed a living plaster over the damaged gut. They seemed to respond to the environment they had been placed in and matured accordingly to repair the damage. One of the risks of stem cell transplants like this is that the cells will continue to expand and form a tumour, but we didn't see any evidence of that with this immature stem cell population from the gut."

Friday, October 18, 2013

Between them tissue engineering and prosthetics offer replacement parts for a fair number of organs, but none yet as good as the original. This article somewhat overstates of the case with regard to how far the research and development has progressed, but it is certainly true that both biological and artificial replacement organs as good as or better than the evolved versions lie not so very far in the future:

Growing a human organ is a bit like baking a layer cake, says Dr. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine. Let's say the "cake" we want is a kidney. After harvesting cells from the patient's kidney and coaxing them to multiply - mixing up the cake batter - Atala's team bastes those cells onto a biodegradable scaffold, one painstaking layer at a time. "Once there's the right amount," he says, "we put it in an oven-like device that has the same conditions as the human body." The kidney "bakes" inside the bioreactor for a couple of weeks, where it's also exercised. Then it's ready for implant. Eventually, the scaffold melts away, leaving the new organ.

A donor kidney was the first organ to be successfully transplanted into a patient, in 1954. Five decades later, we're building new ones from scratch - growing them on scaffolds or printing them with modified desktop printers that shoot cells instead of ink. About 14 years ago, Atala's team implanted bioengineered bladders into patients and, he says, "they've lasted all these years." He and other scientists are moulding jumbles of cells into heart valves, ears, stomachs and skin. They're building advanced prosthetics, including bionic hands and legs, which mimic natural function and can even be controlled by our minds. More and more people will live their lives with these artificial parts integrated into their bodies.

To Atala, human organs fall into one of four categories, ranging from simplest to make to most difficult. First come flat parts, like skin. Then there are tubular organs, including the windpipe and blood vessels. Next are hollow, non-tubular parts, such as the stomach or bladder. The last, and most difficult to create, are solid organs, like the heart, liver, lung and kidneys. "Up to this point, we've implanted the first three types," says Atala. "We have not yet implanted a solid organ." But it can't be all that far off. In his lab, he's growing human fingers.


Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.