Fight Aging! Newsletter, July 1st 2013

July 1st 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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  • Targeting Cancer With Engineered Viruses and Immune Cells
  • Do We Age Because We Have Mitochondria?
  • A Little More Research on the Harms of Excess Visceral Fat
  • There is Plenty Left to Discover in Alzheimer's Research
  • Examples of Progress in Regenerative Medicine for Spinal Cord Injuries
  • Latest Headlines from Fight Aging!
    • Possibly Overly Focused on Telomeres
    • Correlating Measurements of Mitochondria and Telomeres
    • Considering Replacement Parts for Cell Components
    • A Call to Action on Glucosepane
    • Increased Mcl-1 Expression Reduces Age-Related Cochlear Degeneration
    • Life Extension via Radiation Hormesis in Insects
    • On the Path to Thymic Rejuvenation
    • Comparing Ames Dwarfism and Calorie Restriction
    • Enumerating the Differences Between Old and Young Stem Cells
    • Aging and High-Density Lipoproteins


Targeting is the future of cancer treatment. The fact that treatments can be targeted to cancer cells with even a moderate level of precision is the important factor, not the nature of the mechanism used to destroy those cells. Targeting means few or no side effects, which in turn means that more potent attacks can be conducted on cancerous cells: no more will cancer therapy be a matter of finely juggling whole-body chemical infusions to kill as much of the cancer as possible without killing or crippling the patient.

Many different cell killing mechanisms have been demonstrated in the laboratory in conjunction with forms of targeting - there are any number of ways to sabotage a cell to the point at which it self-destructs, such as by dumping in enough heat, or radiation, or toxic molecules, or carefully selected sabotaging proteins that throw a spanner into cellular machinery. When nanoparticles are used as the delivery platform, researchers can even load them up with old-school chemotherapy drugs: minute amounts attached to each nanoparticle, but enormous doses for each individual cancer cell in comparison to what would be received in the standard form of presently widespread chemotherapy.

Here are two examples of other methods of targeting cancer presently under development: a gene therapy delivered by engineered virus, and altered immune cells that are programmed to attack and destroy cells with cancerous surface markers.

Targeted viral therapy destroys breast cancer stem cells in preclinical experiments

A promising new treatment for breast cancer [has] been shown in cell culture and in animal models to selectively kill cancer stem cells at the original tumor site and in distant metastases with no toxic effects on healthy cells, including normal stem cells. Melanoma differentiation associated gene-7 (mda-7), also known as interleukin (IL)-24, has been shown to directly impact two forms of cell suicide known as apoptosis and toxic autophagy, regulate the development of new blood vessels and also play a role in promoting cancer cell destruction by the immune system. In the present study, the researchers used a recombinant adenovirus vector, an engineered virus with modified genetic material, known as Ad.mda-7 to deliver the mda-7/IL-24 gene with its encoded protein directly to the tumor.

Since discovering the mda-7/IL-24 gene, Fisher and his team have worked to develop better ways to deliver it to cancer cells, including two cancer "terminator" viruses known as Ad.5-CTV and Ad.5/3-CTV. Cancer terminator viruses are unique because they are designed to replicate only within cancer cells while delivering immune-modulating and toxic genes such as MDA-7/IL-24. Coupled with a novel stealth delivery technique known as ultrasound-targeted microbubble destruction (UTMD), researchers can now systemically deliver viruses and therapeutic genes and proteins directly to tumors and their surrounding tissue (microenvironment) at both primary and metastatic tumor sites. UTMD uses microscopic, gas-filled bubbles that can be paired with viral therapies, therapeutic genes and proteins, and imaging agents and can then be released in a site and target-specific manner via ultrasound. Fisher and his colleagues are pioneering this approach and have already reported success in experiments utilizing UTMD technology and mda-7/IL-24 gene therapy in prostate and colorectal cancer models.

Modified immune cells seek and destroy melanoma

All cells express a complex known as the proteasome, which acts as the garbage disposal for the cell. There are two types of proteasomes: constitutive proteasomes (cPs), which are found in normal tissues, and immunoproteasomes (iPs), which are found in stressed or damaged cells. In a damaged cell, the iP generates protein fragments that are displayed on the surface of the distressed cells, triggering recognition by dendritic cells and subsequent destruction by the immune system.

Most cancers, including melanoma, exclusively express cPs, making it impossible for them to express the protein fragments that are recognized by the immune system. To make it easier for the immune system to find cancer cells, [researchers] engineered a specific type of immune cell, known as a dendritic cell, that recognizes protein fragments of cancer specific antigens made by cPs. The engineered dendritic cells were then injected into patients that were in remission from melanoma.

The trial consisted of 4 patients that were vaccinated with regular dendritic cells, 3 patients that received cells that underwent a control treatment, and 5 patients that received dendritic cells that recognized cancer-made protein fragments. Vaccination with all three types of dendritic cells elicited an immune response, which peaked after 3-4 vaccinations with dendritic cells. Patients that received the specially modified dendritic cells had a longer lasting immune response and fewer circulating melanoma cells. Of the two patients that had active disease, treatment with modified dendritic cells resulted in a partial clinical response in one and a complete clinical response in the other.

A number of other forms of targeting are further ahead in the process of development than the two examples above: there is a lot of variety in the approaches used, and that is a very good thing. Competition drives progress. It is not unreasonable to think that cancer will be a controllable part of our biology twenty years from now, gone the way of tuberculosis to become something that can only seriously harm you if you do not have access to clinical medicine.


This is the question posed and not answered by a recent paper from a German institution, accompanied by a very tersely worded abstract:

Do we age because we have mitochondria?

The process of aging remains a great riddle. Production of reactive oxygen species (ROS) by mitochondria is an inevitable by-product of respiration, which has led to a hypothesis proposing the oxidative impairment of mitochondrial components (e.g., mtDNA, proteins, lipids) that initiates a vicious cycle of dysfunctional respiratory complexes producing more ROS, which again impairs function. This does not exclude other processes acting in parallel or targets for ROS action in other organelles than mitochondria.

Given that aging is defined as the process leading to death, the role of mitochondria-based impairments in those organ systems responsible for human death (e.g., the cardiovascular system, cerebral dysfunction, and cancer) is described within the context of "garbage" accumulation and increasing insulin resistance, type 2 diabetes, and glycation of proteins.

The processes involved in mitochondria-based impairments are very similar across a large range of organisms. Therefore, studies on model organisms from yeast, fungi, nematodes, flies to vertebrates, and from cells to organisms also add considerably to the understanding of human aging.

Would we age without mitochondria? Certainly. Mitochondrial damage and dysfunction is only one of the most likely fundamental differences between young tissue and old tissue. Other similarly fundamental differences include the build up of amyloids, lipofuscin, and cross-linked proteins (the glycation of proteins mentioned in the abstract above), and there is no reasonable case to be made for those aspects of aging to be dependent on mitochondrial function. If all our mitochondria were removed and replaced with black box nanomachines that performed the same tasks for an indefinite period of time without wear or failure, then we would still suffer degenerative and eventually fatal aging due to the other forms of accumulated damage that harm our tissues.

(Replacing our mitochondria with something that doesn't fall apart and progressively sabotage us is actually a very plausible and desirable goal for the future of medicine. But the first strides in the that direction will probably take the form of simple replacement: introduce new mitochondria or new mitochondrial DNA to take up the slack).

Why do we age at all? There are plenty of species that age far less visibly than we do, suffering little reduction in vigor and resistance until very late in the game. But they have mitochondria too, so I don't think we can lay the roots of aging at the feet of mitochondrial biology. If there were no mitochondria, then the forces of natural selection would still result in the vast majority of species consisting of individuals that age to death. The only differences would be in the details of how eventually fatal damage arises and progresses. The world changes, and that favors aging as an outcome of successful strategies in evolutionary competition.

When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. [While] senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions.

This is all natural, but not good. It is natural like anthrax, dying of exposure, plague, and famine. Our ancestors toiled hard to defeat the aforementioned line items, very successfully in recent centuries, and research and development efforts continue today. Here and now we can also choose to do something about the causes of aging, an option that wasn't available until the present time: mitochondrial damage, amyloids, and the other causes of aging can all be addressed with the tools of the biotechnology revolution. So we should get on with it, and those of us without the necessary skills to work in the laboratory should help to fund those who do.


A mountain of evidence points to the conclusion that bearing excess body fat, particularly visceral fat, is harmful to long-term health. The more visceral fat and the longer you have it the worse off you are. That fat tissue causes chronic inflammation, alters metabolism in ways that harm organs and important biological systems, and raises the risk of suffering all of the common age-related diseases, including those that erode the mind. In general: visceral fat tissue damages you, and degenerative aging is at root an accumulation of damage.

So if you want to live a shorter life with larger medical expenses, more pain and suffering, and less of an ability to do the things you like to do, then by all means let your weight go. It's easy to get fat in a society this wealthy: we are swimming in a sea of low-cost calories and exceedingly attractive foodstuffs, having achieved a state of security from hunger that our ancestors of a few hundred years past could only have dreamed of.

We work to build the world we desire, and we are hardwired by our evolutionary past to greatly desire food without limit. It's still your choice to become fat and suffer the consequences. Easy and hardwired are no excuse, and do not remove your ability to exercise free will in the pursuit of your goals. Thin people in wealthy countries are not thin because they have magic genes, but because they choose to be thin, and put in the necessary exercise of will to stay that way.

Here are a couple more items to add to the mountain of research linking visceral fat with ill health and shorter lives. The first is of interest for the methodology the scientists are using in order to work around the primary challenge of any human epidemiological study, which is how to show cause and effect rather than just correlation:

Overweight causes heart failure - large study with new method clarifies the association

These scientists studied whether a gene variant in the FTO gene, which regulates the appetite and thereby increases the individual's [body mass index, or BMI], is also linked to a series of cardiovascular diseases and metabolism. The risk variant is common in the population, and each copy of the risk variant increases BMI by an average of 0.3-0.4 units. Since an individual's genome is not affected by lifestyle and social factors, but rather is established at conception, when the embryo randomly receives half of each parent's genome, the method is thus called "Mendelian randomization". To achieve reliable results a large study material was needed, and nearly 200,000 individuals from Europe and Australia participated.

"Epidemiological studies look for associations in large populations, but it is usually difficult to reliably determine cause and effect - what we call causality. By using this new genetic method, Mendelian randomization, in our research, we can now confirm what many people have long believed, that increased BMI contributes to the development of heart failure."

The results show that an increase of one unit of BMI increases the risk of developing heart failure by an average of 20 per cent. Further, the study also confirms that obesity leads to higher insulin values, higher blood pressure, worse cholesterol values, increased inflammation markers, and increased risk of diabetes.

Exercise benefits patients with type 2 diabetes

Moderate-intensity exercise reduces fat stored around the heart, in the liver and in the abdomen of people with type 2 diabetes mellitus, even in the absence of any changes in diet. "Based on previous studies, we noticed that different fat deposits in the body show a differential response to dietary or medical intervention. Metabolic and other effects of exercise are hard to investigate, because usually an exercise program is accompanied by changes in lifestyle and diet."

For the new study, [researchers] assessed the effects of exercise on organ-specific fat accumulation and cardiac function in type 2 diabetes patients, independent of any other lifestyle or dietary changes. The 12 patients, average age 46 years, underwent MRI examinations before and after six months of moderate-intensity exercise totaling between 3.5 and six hours per week and featuring two endurance and two resistance training sessions. The exercise cycle culminated with a 12-day trekking expedition.

MRI results showed that, although cardiac function was not affected, the exercise program led to a significant decrease in fat volume in the abdomen, liver and around the heart, all of which have been previously shown to be associated with increased cardiovascular risk.

It is in fact possible to diet your way out of type 2 diabetes via a sustained low calorie intake, even at fairly late stages in the progression of the condition. That may operate partially through the mechanism of reducing the amounts of visceral fat tissue present in the body. All in all type 2 diabetes really is a self-inflicted and self-maintained medical condition for most people these days, now that it isn't just a disease of the very old and frail. With sufficient application of effort any non-frail patient can make his or her condition largely go away at any point before its end stages.


Research runs rapidly these days. The tools of biotechnology are improving at a pace driven by the computing industry, where progress remains blisteringly fast. Today's researcher can achieve far more and at a much lower cost than the researcher of even ten years ago. Thus new knowledge is rolling in, and every part of the body is yielding up its secrets and surprises: unusually potent stem cells where none were thought to be, a better understanding of how mitochondria actually work, and so on. Amending the textbooks on any aspect of human molecular biology is a quarterly event these days.

Today I noticed two examples of what seem to be fairly significant discoveries in brain biochemistry, of importance to Alzheimer's disease and neurodegeneration in the broader sense. They are illustrative of just how much in the way of important processes may be still be left to discover and integrate into our understanding of our own biology.

In the case of this first study, you might read it while recalling that some researchers argue for Alzheimer's as a form of diabetes, a type 3 diabetes if you like. To the degree that this is the case, Alzheimer's is a largely avoidable fate for most people, just like type 2 diabetes, its prevalence a product of lifestyle choices such as becoming sedentary and putting on weight:

A second amyloid may play a role in Alzheimer's disease

A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta Αβ plaques that are associated with Alzheimer's disease. [The] study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer's disease, as well as combined deposits of amylin and plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer's.

"We've known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now. This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer's disease."

"We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the Aβ, which is the suspected cause of Alzheimer's disease. It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels. It is accumulating in the brain and we found signs that amylin is killing neurons similar to Αβ. And that might be the answer to the question of 'What makes obese and type 2 diabetes patients more prone to developing dementia?'"

Brain's 'garbage truck' may hold key to treating Alzheimer's and other disorders

The body defends the brain like a fortress and rings it with a complex system of gateways that control which molecules can enter and exit. While this "blood-brain barrier" was first described in the late 1800s, scientists are only now just beginning to understand the dynamics of how these mechanisms function. In fact, the complex network of waste removal, which researchers have dubbed the glymphatic system, was only first disclosed by [scientists] last August.

The removal of waste is an essential biological function and the lymphatic system - a circulatory network of organs and vessels - performs this task in most of the body. However, the lymphatic system does not extend to the brain. [One] of the reasons why the glymphatic system had long eluded comprehension is that it cannot be detected in samples of brain tissue. The key to discovering and understanding the system was the advent of a new imaging technology called two-photon microscopy which enables scientists to peer deep within the living brain. Using this technology on mice, whose brains are remarkably similar to humans, [researchers] were able to observe and document what amounts to an extensive, and heretofore unknown, plumbing system responsible for flushing waste from throughout the brain.

One of the hallmarks of Alzheimer's disease is the accumulation in the brain of the protein beta amyloid. In fact, over time these proteins amass with such density that they can be observed as plaques on scans of the brain. Understanding what role the glymphatic system plays in the brain's inability to break down and remove beta amyloid could point the way to new treatments. Specifically, whether certainly key 'players' in the glymphatic system, such as astrocytes, can be manipulated to ramp up the removal of waste.

"The idea that 'dirty brain' diseases like Alzheimer may result from a slowing down of the glymphatic system as we age is a completely new way to think about neurological disorders. It also presents us with a new set of targets to potentially increase the efficiency of glymphatic clearance and, ultimately, change the course of these conditions."


Even in the opening days of the modern era of regenerative medicine it was the case that repairing spinal cord injuries was up at the top of the to-do list. It still is: numerous research groups investigating nerve repair aim to reverse the paralysis and dysfunction produced when the spinal cord is damaged. This has proven to be more of a challenge than we'd like it to be, however: work on the regeneration of heart tissue is arguably much further ahead, and the creation of decellularized replacement organs will probably overtake nerve regeneration on the way to the widespread availability of practical and effective therapies.

This doesn't mean that progress is absent. Modest advances in nerve regeneration research show up every month these days, and far more is possible in the laboratory today than was the case ten years ago. You might look at these examples of publicity for recently published studies, representative of what is presently going on in laboratory research and clinical translation of that research:

SCI patients treated with own olfactory ensheathing cells realize neurologic improvement

A team of researchers in Poland who treated three of six paraplegics with spinal cord injury using transplanted olfactory ensheathing cells (OECs) found that the three treated patients showed neurological improvement and no adverse effects while the three control patients who did not receive transplants saw no improvement.

In a phase one of this non-randomized controlled study, the team of researchers treated the three patients with transplanted self-donated (autologous) OECs and fibroblasts isolated from olfactory mucosa combined with "intense" neuro-rehabilitation. They found the treatment "safe and feasible" one year after transplantation. There was no evidence of neurological deterioration, neuropathic pain, neuroinfection or tumor growth.

"Neurophysiological examinations showed improvement in spinal cord transmission and activity of lower extremity muscles in the surgically treated patients, but not in patients receiving only neuro-rehabilitation. We consider that the transplantation of OECs was the main factor contributing to the neurologic improvements in the three transplanted patients. Among the possible mechanisms for improvement is that the transplanted OECs may have mediated some restitution along white matter tracts in these patients."

Nerve Regeneration Restores Supraspinal Control of Bladder Function after Complete Spinal Cord Injury

A life-threatening disability after complete spinal cord injury is urinary dysfunction, which is attributable to lack of regeneration of supraspinal pathways that control the bladder. Although numerous strategies have been proposed that can promote the regrowth of severed axons in the adult [central nervous system], at present, the approaches by which this can be accomplished after complete cord transection are quite limited.

In the present study, we modified a classic peripheral nerve grafting technique with the use of chondroitinase to facilitate the regeneration of axons across and beyond an extensive thoracic spinal cord transection lesion in adult rats. The novel combination treatment allows for remarkably lengthy regeneration of certain subtypes of brainstem and propriospinal axons across the injury site and is followed by markedly improved urinary function. Our studies provide evidence that an enhanced nerve grafting strategy represents a potential regenerative treatment after severe spinal cord injury.

It isn't yet possible to fully regenerate or repair a severed spinal cord and all associated function in humans or other mammals, but it's a lot closer to being possible than it was just a handful of years ago.


Monday, June 24, 2013

A simplistic view of telomere length seems to be percolating into the public view of aging, judging by some of the recent discussions on the topic I've encountered. The average disinterested fellow in the street might now have the idea that telomeres somehow get shorter and in doing so cause aging. I expect that this mistaken echo from the halls of science will be reinforced as new telomere assessment services flush with venture funding continue to publicize themselves via the mainstream media.

In fact, telomere length is fairly dynamic and varied, and a lot of uncertain remains in its role in aging. In immune cells the average telomere length seems to correlate well with general health on a statistical basis across a population, being on average shorter in ill people. There are ways to measure telomere length in some animal species that do a good job of predicting likely life expectancy. Delivering additional telomerase, the enzyme that lengthens telomeres, to mice increases their life span. Nonetheless, it's very much up in the air as to whether reduced telomere length is a cause of aging versus a secondary effect of other processes that nonetheless causes some harm of its own, versus just being a marker of the progression of degenerative aging. That telomerase therapy might be extending life through some unrelated function of telomerase, perhaps one involving reducing the level of mitochondrial damage in cells.

Of the mechanisms of aging cataloged in the SENS rejuvenation research proposals, only cancer prevention involves telomeres. All of the other ways in which your metabolism becomes damaged over time have nothing much to do with telomere length. But here is a recent article on science and longevity that focuses on telomeres:

[Telomeres are] tiny structures at the ends of your chromosomes that keep them from fraying and losing crucial bits of genetic information. What interests researchers who study aging is that when cells divide, their telomeres get shorter. Once they get too short, cells stops dividing and may die. Played out across the whole body, there's mounting evidence that shorter telomeres translate into increased susceptibility to diseases and the gradual wearing out of tissues that is the hallmark of old age.

It's tempting to think of our telomeres as the cellular equivalents of the grim reaper's hourglass, counting out our predetermined life spans. But the hourglass can get periodic refills - thanks to an enzyme called telomerase, which acts to build telomeres back up. And the rise of telomere testing for consumers is also pegged to evidence that telomere length is not just an inherited inevitability but may be influenced by factors such as stress, exercise and nutrition. The thinking is, if you can regularly monitor your telomere length, you'll be more apt to do the right things to slow the rate at which they're burning away.

Despite media reports, telomeres do not actually tell you how long you are going to live. That's because there's a huge variation between individuals. A teenager can have shorter telomeres than a 70-year-old, yet that teenager is far more likely to still be around in 20 years. The correlation between telomere length and lifespan is something that emerges when larger numbers of individuals are analyzed as a group.

With the field still trying to figure out exactly how telomeres relate to aging and health, some researchers express strong reservations about telomere testing for health assessment - and taking tests at face value. "It's easy to get correlations in aging, because many, many things are affected as you get older," says David Harrison, a gerontologist at the Jackson Laboratory in Bar Harbor, Me. While he doesn't rule out that telomeres play a role in aging, he is not persuaded that their role is clear or that telomere testing is meaningful. And he is wary, he says, when researchers in the field have a commercial interest in the testing technology.

Monday, June 24, 2013

A number of lines of research have suggested that telomere length and mitochondrial damage are linked in some way. The research result below is noted with the caveat that it is very easy to find correlations in aging, however, as aging is a global process in which everything declines.

Both telomere length and mitochondrial function are accepted as reflective indices of aging. Recent studies have shown that telomere dysfunction may influence impaired mitochondrial biogenesis and function. However, there has been no study regarding the possible association between telomere and mitochondrial function in humans. Therefore, the purpose of the study was to identify any relationships between mitochondrial and telomere function. The present study included 129 community-dwelling, elderly women. The leukocyte mitochondrial DNA copy number and telomere length were measured using a quantitative real-time polymerase chain reaction method.

Leukocyte mtDNA copy number was positively associated with telomere length. With a stepwise multiple regression analysis, telomere length was found to be an independent factor associated with leukocyte mtDNA copy number after adjustment for confounding variables including age [and] body mass index. Our findings suggest that telomere function may influence mitochondrial function in humans.

Tuesday, June 25, 2013

Earlier this month, I pointed out a series of articles that examined how we might go about developing the means to gradually replace neurons in the brain with nanomachines that serve the same purpose and integrate fully with the remaining natural neurons. If the pace of that process is slow, on a par with natural levels of neurogenesis and cell turnover, then we could argue that you remain you even though the end result is a completely artificial brain: the self is preserved.

This sort of process is a necessary precondition to live for much longer than a few thousand years following the development of rejuvenation biotechnology that can indefinitely prolong healthy, youthful life. Accidents happen, and the best way to reduce the chance of a fatal accident to negligible levels is to switch out the body and brain for more durable machinery.

Following on from that, here is a consideration of some of the details of replacing just portions of a cell with artificial components that perform the same function, but are immune by design to the degraded function known to occur in aging:

In this essay I argue that technologies and techniques used and developed in the fields of Synthetic Ion Channels and Ion-Channel Reconstitution, which have emerged from the fields of supramolecular chemistry and bio-organic chemistry throughout the past 4 decades, can be applied towards the purpose of gradual cellular (and particularly neuronal) replacement to create a new interdisciplinary field that applies such techniques and technologies towards the goal of the indefinite functional restoration of cellular mechanisms and systems.

In earlier essays I identified approaches to the synthesis of non-biological functional equivalents of neuronal components (i.e., ion-channels, ion-pumps, and membrane sections) and their sectional integration with the existing biological neuron. It has only recently come to my attention that there is an existing field emerging from supramolecular and bio-organic chemistry centered around the design, synthesis, and incorporation/integration of both synthetic/artificial ion channels and artificial bilipid membranes (i.e., lipid bilayer). The potential uses for such channels commonly listed in the literature have nothing to do with life-extension, however, and the field is, to my knowledge, yet to envision the use of replacing our existing neuronal components as they degrade (or before they are able to).

I argue here that the very technologies and techniques that constitute the field (Synthetic Ion Channels and Ion-Channel/Membrane Reconstitution) can be used towards the purposes of indefinite longevity and life-extension through the iterative replacement of cellular constituents so as to negate the molecular degradation they would have otherwise eventually undergone.

Tuesday, June 25, 2013

Advanced glycation endproducts (AGEs) are one of the root causes of aging. Many different types of AGE are created as a byproduct of ordinary metabolic operation and also arrive in the diet. Their levels rise and fall over time depending on circumstances and the body's efforts to clear out these unwanted compounds. The hardiest forms of AGE are a challenge, however: they lurk in your tissues in growing amounts as the years pass, disrupting important biological machinery, provoking chronic inflammation, and altering cellular behavior for the worse. Of these various types of AGE the most important by far in human tissues is glucospane, but very little attention is given to finding ways to break down and clear glucosepane from the body despite the consensus that this is a desirable goal.

So the SENS Research Foundation funds work on developing a glucosepane-clearing therapy, and is one of only two or three research organizations in the world to do so - and none of those programs are particularly large or active. The SENS work might be the largest glucosepane research program in the world at this point. Still, it looks like at least some other researchers are knowledgeable enough in this area to issue their own calls to action, and that is welcome, even when those calls to action are mild in comparison to those of the SENS program. A greater diversity of funding and more research groups focused on glucosepane can only be a good thing:

Advanced glycation end products (AGEs) represent a family of protein, peptide, amino acid, nucleic acid and lipid adducts formed by the reaction of carbonyl compounds derived directly or indirectly from glucose, ascorbic acid and other metabolites such as methylglyoxal. AGE formation in diabetes is of growing importance for their role as markers and potential culprits of diabetic complications, in particular retinopathy, nephropathy and neuropathy.

Development of sensitive and specific assays utilizing liquid chromatography mass spectrometry with isotope dilution method has made it possible to detect and quantitate non-UV active AGEs such as carboxymethyl-lysine and glucosepane, the most prevalent AGE and protein crosslink of the extracellular matrix.

The results of [studies on AGE formation in two skin biopsies] show that while several AGEs are associated and predict complication progression, the glucose/fructose-lysine/glucosepane AGE axis is one of the most robust markers for microvascular disease, especially retinopathy, in spite of adjustment for past or future average glycemia. Yet overall little biological and clinical information is available on glucosepane, making this review a call for data in a field of growing importance for diabetes and chronic metabolic diseases of aging.

Wednesday, June 26, 2013

Researchers here stop the reduction in number of sensory cells in the ear, one of the causes of progressive age-related deafness, by slowing the pace of programmed cell death (apoptosis). If employed as a general strategy for reducing losses in any important cell population this will probably lead to an increased risk of cancer: researchers are in effect making damaged cells work for longer. It is unclear at this point as to whether that is either true or a meaningful risk in any specific case, however, especially when small numbers of cells are involved:

Mcl-1 is an anti-apoptotic member of the Bcl-2 family that modulates apoptosis-related signaling pathways and promotes cell survival. We have previously demonstrated a reduction of Mcl-1 expression in aging cochleae. To investigate whether restoring Mcl-1 expression would reduce aging-related cochlear degeneration, we developed a rat model of Mcl-1 overexpression.

A plasmid encoding human Mcl-1/enhanced green fluorescent protein was applied to the round window of the cochlea. This in vivo treatment transfected both the sensory and supporting cells of the cochlear sensory epithelium and enhanced Mcl-1 expression at both the mRNA and the protein level. The upregulation of Mcl-1 expression reduced the progression of age-related cochlear dysfunction and sensory cell death. Furthermore, the transfection of Mcl-1 exerted its protective effect by suppressing cochlear apoptosis at the mitochondrial level. This study demonstrates that the genetic modulation of Mcl-1 expression reduces the progression of age-related cochlear degeneration.

Wednesday, June 26, 2013

Hormesis is the way in which a minor amount of damage can be beneficial to an organism: it awakens cellular repair and maintenance mechanisms that fix that damage and then go on to more energetically fix other damage for an extended period of time. So the net result is a more robust, better maintained individual with a longer life expectancy. There are hormetic components to the benefits of exercise, calorie restriction, mild heat stress, and so on.

Mild radiation damage is one of the ways in which hormesis can be achieved, as examined in this review paper:

This paper assesses the capacity of ionizing radiation to extend the lifespans of experimental insect models based on the peer-reviewed literature. Ionizing radiation biphasically affects the lifespans of adult males and females for a broad range of insect models with high doses reducing lifespan whereas lower doses can enhance lifespan, typically in the 20-60% range.

The average adult insect lifespan can be increased when ionizing radiation exposure is administered during early developmental stages or during the adult stage. The effective dose inducing the average adult insect lifespan enhancement may vary considerably depending upon which life stage is exposed. Recent findings have identified specific genes affecting anti-oxidant defenses, DNA repair, apoptosis and heat shock proteins as well as several cell signaling pathways that mediate the longevity enhancing hormetic response.

Thursday, June 27, 2013

The immune system declines with age in part because it is limited in the number of cells it can support, and too many of those cells become specialized memory cells over time, unable to contribute to the fight against new pathogens. A variety of approaches might be developed to address this issue: remove the excess memory cells, generate new immune cells from stem cells and regularly infuse them into the patient, or cause the body to start producing more new immune cells than it otherwise would.

Immune cells are created in the thymus, an organ which atrophies and diminishes its output of cells quite early in life: its evolved job is to generate an effective immune system in youth, not to keep pumping out immune cells at a high pace throughout life. Rejuvenation of the thymus to youthful activity is thus a way to boost native immune cell production, and some work in this direction is funded by the SENS Research Foundation:

SENS Research Foundation has made substantial investments in research on regenerative therapies for the aging immune system, with the aim of maintaining and restoring youthful immune function throughout life, eliminating the disparate burden of morbidity and mortality from infectious disease that falls disproportionately persons over the age of 60. We have targeted research dollars toward developing rejuvenation biotechnologies to repair the two forms of aging damage that are the most widely accepted drivers of immunosenescence.

In the lab of Dr. Janko Nikolich-Žugich at the Arizona Center on Aging, we are funding a project testing the clearance of dysfunctional, "senescent" cytotoxic CD8+ T-cells - cells that exert suppressive effects on the expansion and response of other, functional T-cells. And at the Wake Forest Institute for Regenerative Medicine, SENS Research Foundation is supporting Dr. John Jackson's efforts to apply the decellularized scaffold tissue engineering technique to the engineering of a transplantable thymic neo-organ.

[Researchers have recently] derived functioning [thymic epithelial progenitor cells (TEP)] from [embryonic_stem_cells], and found a way to further develop TEP into [thymic tissue] capable of supporting the development of mature T-cells from T-lymphoid progenitor cells in vivo. The success of this new study is remarkable, not only for what the investigators achieved, but for what it suggests can be achieved when its relatively crude system of thymic epithelial cell derivation and transplantation is superseded by the engineeering of true thymic neo-organs, such as those that are in development in Dr. Jackson's SENS Research Foundation-funded lab at this writing.

Already, Dr. Jackson's lab team have succeeded in seeding epithelial cells onto decellularized mouse thymus scaffolds, and they are now in the process of completing the initial characterization proliferation and coverage of these cells on the scaffolds. Soon, the reseeding procedure will be completed by seeding bone marrow stem cells purged of T-cells onto the epithelial-seeded scaffold. Once this is achieved, the production of mature T-cells by the bioengineered neo-organs will be evaluated. Advances already achieved in bioengineering other organs with decellularized scaffolds suggest a successful outcome; moreover, the thymus scaffold specifically provides the structural elements necessary for the cells that are grown on it to assume the complex microenvironmental relationships of a mature thymus.

Thursday, June 27, 2013

Ames dwarf mice are among the longest lived longevity mutants so far created. They lack growth hormone, and this has a large effect on their metabolism, size, and pace of aging. Here researchers compare this extension of life with that produced by calorie restriction in mice:

Since 1996, aging studies using several strains of long-lived mutant mice have been conducted. Among these studies, Ames dwarf mice have been extensively examined to seek clues regarding the role of the growth hormone/insulin-like growth factor-1 axis in the aging process. Interestingly, these projects demonstrate that Ames dwarf mice have physiological characteristics that are similar to those seen with calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, this introduces the question of whether Ames dwarf and calorie-restricted (CR) mice have an extended lifespan through common or independent pathways.

To answer this question, we compared the disease profiles of Ames dwarf mice to their normal siblings fed either ad libitum (AL) or a CR diet. Our findings show that the changes in age-related diseases between AL-fed Ames dwarf mice and CR wild-type siblings were similar but not identical. Moreover, the effects of CR on age-related pathology showed similarities and differences between Ames dwarf mice and their normal siblings, indicating that calorie restriction and Ames dwarf mice exhibit their anti-aging effects through both independent and common mechanisms.

It is worth noting that a similar mutant, in which growth hormone receptor is removed rather than growth hormone, has a corresponding small human population in which this mutation occurred naturally, a condition known as Laron syndrome. While the mice are exceedingly long-lived in comparison to their peers, people with Laron syndrome do not appear to exhibit significantly extended lives. They are, however, somewhat resistant to diabetes and cancer.

Friday, June 28, 2013

If researchers have a good catalog of the biochemical differences between old and young stem cells, such as the ways in which the cell surface markers are different, then they can start act on those differences: measure the effects of rejuvenation therapies; attempt to change stem cell state to restore youthful appearance and activity; and so forth. This work is a step in the direction of that catalog:

A chemical code scrawled on histones - the protein husks that coat DNA in every animal or plant cell - determines which genes in that cell are turned on and which are turned off. [Researchers have now] identified characteristic differences in "histone signatures" between stem cells from the muscles of young mice and old mice. The team also distinguished histone-signature differences between quiescent and active stem cells in the muscles of young mice.

Stem cells in several tissues of older mice, including muscle, seemed to act younger after continued exposure to younger mice's blood. Their capacity to divide, differentiate and repopulate tissues, which typically declines with an organism's advancing age, resembled those of their stem-cell counterparts in younger animals. This naturally led to curiosity about exactly what is happening inside a cell to rejuvenate it. [One] likely place to look for an answer was histones, to see if changes in the patterns of the chemical marks on them might reveal any secrets, at the cellular level, of the aging process we all experience - and, perhaps, whether there might be anything we can do about it.

The differences between quiescent and activated cells [are] mirrored by those between young and old quiescent satellite cells. "With age, there's an uptick in repressive markers. A lot more genes are locked in the 'off' position. In a division-capable cell, as opposed to the nondividing, differentiated muscle cells that activated satellite cells may someday become, it may be important to maintain a high level of repression with age. Maybe this increase in repression is a kind of tumor-suppression mechanism, keeping aging satellite cells - which could have accumulated some dangerous mutations over the passing months and years - in check."

The description of the histone-code differences between young and old cells constitutes a yardstick allowing investigators to ask which of these differences are important in aging and in rejuvenation. "We don't have the answers yet. But now that we know what kinds of changes occur as these cells age, we can ask which of these changes reverse themselves when an old cell goes back to becoming a young cell" - as appeared to be the case when tissues of older mice were exposed to blood from younger mice.

Friday, June 28, 2013

An association between greater levels of high-density lipoproteins and lower mortality rates in old age showed up in studies of centenarians some years back, and has since been confirmed in other research. There is still the question of what this association means, however: correlation is not causation. Here is a little more on this topic:

Most coronary deaths occur in patients older than 65 years. Age associated alterations in the composition and function of high-density lipoproteins (HDL) may contribute to cardiovascular mortality. The effect of advanced age on the composition and function of HDL is not well understood. HDL was isolated from healthy young and elderly subjects. HDL composition, cellular cholesterol efflux/uptake, anti-oxidant properties and endothelial wound healing activities were assessed.

We observed a 3-fold increase of the acute phase protein serum amyloid A, an increased content of complement C3 and proteins involved in endopeptidase/protease inhibition in HDL of elderly subjects, whereas levels of apolipoprotein E were significantly decreased. HDL from elderly subjects contained less cholesterol but increased sphingomyelin. Most importantly, HDL from elderly subjects showed defective antioxidant properties, lower paraoxonase 1 activity and was more rapidly taken up by macrophages, whereas cholesterol efflux capability was not altered.

These findings suggest that aging alters HDL composition, resulting in functional impairment that may contribute to the onset/progression of cardiovascular disease.


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