FIGHT AGING! NEWSLETTER
November 2nd 2015
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- You Can't Just Boost DNA Repair and Expect It to Extend Life
- A Little Recent Stem Cell and Tissue Engineering News
- At the Intersection of Autophagy and Cellular Senescence
- Articles on Neurodegeneration from ALZFORUM
- A Brief Look at Retrotope
- Latest Headlines from Fight Aging!
- Supplying Young Cells to an Involuted Thymus Produces Growth and Increased T Cell Production
- More Work on Gene Expression Changes as a Biomarker of Aging
- Healthspan, Not Lifespan
- Life Extension in Old Mice via Transplant of Bone Marrow Cells From Young Mice
- A Perspective on Stem Cell Aging and Rejuvenation
- Risk and Consequences of Stroke in Decline, While Overall Incidence Increases
- A Possible Way to Target Exhausted T-Cells For Destruction
- More on FOXN1 in the Aging Thymus
- Exercise Slows Blood-Brain Barrier Dysfunction in Aging
- Longevity Versus Frailty
YOU CAN'T JUST BOOST DNA REPAIR AND EXPECT IT TO EXTEND LIFE
The so-called accelerated aging conditions, fortunately rare, are better thought of as DNA repair deficiency disorders, caused by specific inherited or spontaneous mutations that interfere with normally very efficient DNA repair processes. The results don't encompass all of the symptoms of aging, even if the outcome appears superficially similar to the late stages of normal aging, characterized by declining stem cell activity, faltering tissue maintenance, and the resulting failure of vital organs. This is perhaps best illustrated by the fact that it is not possible to just turn the situation around and generate enhanced healthy longevity via gene therapies that aim to boost the operation of DNA repair processes. This is demonstrated by the authors of the open access paper quoted below; they tested a variety of genes associated with different parts of the DNA repair infrastructure present in cells, and obtained quite mixed results on life span.
Engineering greater longevity in animal studies should be the first choice for a minimum standard of proof for the relevance of any particular cellular mechanism to aging, with other minimum standards involving many more mutually supporting lines of evidence for those cases where the life extension studies cannot yet be carried out for technical reasons. There are all too many papers out there in which researchers claim importance in aging on the basis of breaking a mechanism and observing reduced life span as a result. This isn't good enough, as the much more likely explanation in most cases is that breakage causes damage and dysfunction of forms that are irrelevant in normal aging, but which nonetheless raise mortality risk and shorten life. To create an exaggerated example, if you disable the operation of someone's liver, their life expectancy falls dramatically, but that doesn't put the liver at the center of the aging process, and nor does it mean that adding an extra liver to a healthy individual is going to significantly extend life.
This study of mixed results from attempts at DNA repair enhancement is interesting in that it is a step forward, but nonetheless fails to add clarity to the debate over the degree to which stochastic nuclear DNA damage is a meaningful cause of aging. The damage certainly grows with age and certainly increases cancer risk, but does it do more than this? Some researchers think that it dysregulates cellular metabolism to a large enough degree to matter, some do not. The research community is still in search of a definitive study that tips the evidence one way or another, but as thus work shows that is likely to prove a complex undertaking:
Lifespan and Stress Resistance in Drosophila with Overexpressed DNA Repair Genes
Aging is a complex process that is far from being fully understood. Of the many factors that contribute to aging and the multiple changes on many levels that take place, one in need of further study at this time is the role of DNA repair. Because DNA damage does accumulate with age and appears to be associated with some of the detrimental aspects of aging, including neurodegeneration, boosting DNA repair mechanisms may be one approach to intervention.
Here, we investigated the potential life-extending effects of increasing the expression of genes known to be involved in DNA repair in Drosophila. We compared the overexpression of these genes throughout the body versus in the nervous system alone and throughout the lifespan versus in adulthood alone. We also included three known stressors. We found both positive and negative effects on lifespan, with many important variables, including gene, sex, stress exposure, extent of overexpression, developmental stage, and distribution of overexpression in the body.
The most pronounced effects of overexpression on lifespan occurred with Hus1, mnk, mei-9, mus210, spn-B, and WRNexo, which control the processes of DNA damage recognition and repair. Lifespan and stress resistance were interrelated, moreso in males than females, in that increased lifespan was associated with increased resistance to hyperthermia and oxidative stress, while decreased lifespan was associated with decreased resistance to all three stressors tested. Overexpression of DNA repair genes throughout development leads to opposite effects on lifespan when compared to adult-specific overexpression, and the direction of this dichotomy depends on whether the overexpression was ubiquitous or limited to the nervous system.
It is difficult to explain these effects on the basis of the available experimental or published data. Aging research is still in need of basic studies to address a wide variety of unanswered questions. This study presents a valuable set of preliminary data on the role of DNA repair in aging and points to a promising set of DNA repair genes and experimental conditions to pursue in greater detail in future studies that incorporate both transcription-level and protein-level effects on a wider variety of lifespan- and aging-related parameters.
A LITTLE RECENT STEM CELL AND TISSUE ENGINEERING NEWS
Here I'll point to a recent selection of news and research relating to tissue engineering and organ regeneration. If you look around at the state of this field, organoids and proto-organs and pseudo-organs are everywhere. Many laboratories are making strides in the generation of small sections of functional or partly functional complex organ tissue. Alongside and overlapping this work is the young field of bioprinting, the use of 3-D printers to create tissue from scratch, layer by layer, depositing scaffold biomaterials, protein solutions, and cells in precise locations and amounts to form complex structures that themselves self-assemble in further growth. Further, there is the parallel approach of regenerating and rebuilding existing organs in situ, built on the same underlying knowledge, but aiming to deliver cells and protein signals to spur regrowth inside the body that would otherwise not happen.
These lines of work are entwined with one another, linked together in often novel ways. For example, much of the present focus in organ engineering is not in fact to produce complete and fully functional tissues for transplantation, as that still lies a way in the future for most complex organs, but rather to create tools to speed up life science research. Organoids and proto-organs, even if only partly functional, are a much better and cheaper option than animal models when it comes to studying both diseased and healthy tissues. Anything that lowers the cost and increases the quality of the tools needed for research will speed up progress. So the researchers aiming to understand the molecular biology of regeneration sufficiently well to steer it in the body will in years ahead be working with tissue engineering organoids for their early stage research and initial technology demonstrations.
I don't think it overly ambitious at this point to expect the late 2020s to be a time of comprehensive organ engineering, with the production of most tissues - to order, as needed - being a widely available option in clinical practice. It will be interesting to see the degree to which transplantation flourishes in the face of the growing ability to instruct cells in the body to repair existing organs. After all, removing the need for potentially traumatic, expensive, and risky major surgery is a big incentive to improve stem cell therapies and regenerative medicine to their theoretical limits rather than focus on building new patient-matched organs for transplant.
Researchers hack off-the-shelf 3-D printer towards rebuilding the heart
"We've been able to take MRI images of coronary arteries and 3-D images of embryonic hearts and 3-D bioprint them with unprecedented resolution and quality out of very soft materials like collagens, alginates and fibrins. 3-D printing of various materials has been a common trend in tissue engineering in the last decade, but until now, no one had developed a method for assembling common tissue engineering gels like collagen or fibrin. The challenge with soft materials - think about something like Jello that we eat - is that they collapse under their own weight when 3-D printed in air. So we developed a method of printing these soft materials inside a support bath material. Essentially, we print one gel inside of another gel, which allows us to accurately position the soft material as it's being printed, layer-by-layer." One of the major advances of this technique, termed FRESH, or "Freeform Reversible Embedding of Suspended Hydrogels," is that the support gel can be easily melted away and removed by heating to body temperature, which does not damage the delicate biological molecules or living cells that were bioprinted.
Lab-grown guts show promise in mice and dogs
Starting with stem cells from the small intestines of human infants and mice, Hackam and his colleagues have for the first time grown intestinal linings on gut-shaped scaffolds that could one day treat bowel disorders like necrotizing enterocolitis and Crohn's disease. They have found that the tissue and scaffolding are not rejected, but instead readily assimilate in lab animals. Most strikingly, the scaffold allowed dogs to heal from damage to the colon lining, restoring healthy bowel function. The scaffold is made from a material similar to surgical sutures that can be formed into any desired intestinal size and shape, and is tube-shaped like a real gut, with tiny projections on the inner surface to help the tissue grow into functional small intestine villi, tiny fingers of tissue that help absorb nutrients. To grow the gut lining in the lab, the researchers painted the scaffold with a sticky substance containing collagen, dribbled it with a solution of small intestine stem cells, and then let it incubate for a week. They found that adding connective tissue cells, immune cells, and probiotics - bacteria that help maintain a healthy gut - helped stem cells mature and differentiate.
Study Finds Thyroid Function May Be Restored by Using Patient-Derived Human Cells
"With this paper, we've identified the signaling pathways in thyroid cells that regulate their differentiation, the process by which unspecialized stem cells give rise to specialized cells during early fetal development." After deciphering this natural differentiation process, the investigators duplicated it in the laboratory dish by adding a sequence of proteins, called growth factors, to the fluid bathing the stem cells. The team then used murine pluripotent stem cells to regenerate thyroid function in a murine model of hypothyroidism.
Tissue-engineered colon from human cells develop different types of neurons
A study has shown that tissue-engineered colon derived from human cells is able to develop the many specialized nerves required for function, mimicking the neuronal population found in native colon. These specialized neurons, localized in the gut, form the enteric nervous system, which regulates digestive tract motility, secretion, absorption and gastrointestinal blood flow. In healthy intestines, food is moved along the digestive tract through peristalsis - a series of wave-like contractions. Special nerve cells called ganglion cells are required for this movement, but there is also a rich mixture of other types of nerve cells. "The diversity of neuron types that grew within the human tissue-engineered colon was a revelation to our team, because previously we had only documented that some ganglia were present."
An accessible approach to making a mini-brain
If you need a working miniature brain - say for drug testing, to test neural tissue transplants, or to experiment with how stem cells work - a new paper describes how to build one with relative ease and low expense. The little balls of brain aren't performing any cogitation, but they produce electrical signals and form their own neural connections - synapses - making them readily producible testbeds for neuroscience research. Just a small sample of living tissue from a single rodent can make thousands of mini-brains. The recipe involves isolating and concentrating the desired cells with some centrifuge steps and using that refined sample to seed the cell culture in medium in an agarose spherical mold. The mini-brains, about a third of a millimeter in diameter, are not the first or the most sophisticated working cell cultures of a central nervous system, the researchers acknowledged, but they require fewer steps to make and they use more readily available materials.
AT THE INTERSECTION OF AUTOPHAGY AND CELLULAR SENESCENCE
Researchers have recently mapped a specific mechanism by which autophagy is connected with the onset of cellular senescence. Both autophagy and cellular senescence are important topics in aging research, associated with aging and longevity.
Autophagy is a set of complex recycling processes used by cells to eliminate damaged components and some forms of unwanted waste. In its most familiar form, autophagy involves tagging a cellular component such as a damaged mitochondrion, wrapping it in a membrane, and transporting it to a lysosome where it is dismantled. Enhanced autophagy has been observed in many of the methods and interventions shown to modestly slow aging in animal studies, though as is the case for calorie restriction it is very hard to pick out the degree to which any one change is responsible for slowing the pace of aging. Everything in the operation of cellular metabolism is interconnected, it is an enormously complex set of feedback loops and relationships, and nothing can be altered in isolation. That said, some studies in which researchers deliberately set out to increase the level of autophagy have shown life extension in lower animals, and it is not unreasonable to believe that increased cellular housekeeping should result in slower aging. Some researchers believe that autophagy is the important mechanism in most methods of slowing aging demonstrated to date. There is some interest in the research community in producing treatments based on enhancement of autophagy, but as yet there has been little concrete movement in this direction beyond early-stage investigations.
Cellular senescence is an evolved response to stresses, toxicity, and damage in tissues that, among other things, serves to reduce the risk of cancer by removing cells from the cycle of replication. A senescent cell ceases to divide and secretes signals that encourage nearby cells to also become senescent. Unfortunately this only works when comparatively few senescent cells exist. Once many of them accumulate, as happens by the time later life rolls around, their presence produces a range of very harmful effects on organs and tissues, and they even corrupt the local environment to the point of encouraging cancer growth. Senescent cells are removed by the immune system to some degree, but this also fails with aging. One of the most promising near-future rejuvenation therapies involves clearance of senescent cells, which might be achieved via any form of targeted cell destruction technology that can clearly identify the characteristic senescent cell chemistry from that of a normal cell. A proof of concept in mice showing improved health as a result of clearance was published earlier this year, and separately Oisin Biotechnology was seed funded to develop another method of clearance applicable to humans. A clearance method that reduces senescent cell levels to those present in a 30-something adult can be repeated as needed and can in principle completely remove this contribution to the aging process.
Given all this it is interesting to see one of the modes of autophagy and initiation of cellular senescence linked as described below, though the researchers' ideas for turning their work into potential treatments sound a lot more complicated and less likely to succeed than the easier target of simply destroying senescent cells every so often. One of the great advantages of senescent cell clearance as an approach is that it sidesteps an awful lot of work; figuring out exactly how and why senescent cells are produced and cause harm becomes an optional nice-to-have if you can just get rid of them.
Autophagy Works in Cell Nucleus to Guard Against Start of Cancer
The material that autophagy can digest ranges from a single molecule to a whole bacterium. Previously, all known substances consumed by autophagy took place outside the nucleus in the cell's cytoplasm. In the new study autophagy is shown, for the first time, to digest nuclear material in mammalian cells. "We found that the molecular machinery of autophagy guides the degradation of components of the nuclear lamina in mammals." The nuclear lamina is a network of protein filaments lining the inside of the membrane of the nucleus. It is a crucial network in the nucleus, providing mechanical support to the nucleus and also regulating gene expression by making some areas of the genome less or more available to be transcribed into messenger RNA.
In response to cellular stress that can cause cancer, the team found that LC3, chromatin, and laminB1 migrate from the nucleus - via nuclear blebs - into the cytoplasm and are eventually targeted for disposal. This breakdown of laminB1 and other nuclear material leads to a cellular state called senescence. Human cells have complicated ways to protect themselves from becoming cancerous, and one way is to drive themselves to become senescent, so that the cells can no longer replicate.
The team showed that when a cell's DNA is damaged or an oncogene is activated (both of which can cause cancer), a normal cell triggers the digestion of nuclear lamina by autophagy, which promotes senescence. Inhibiting this digestion of nuclear material weakens the senescence program and leads to cancerous growth of cells. "The nucleus is the headquarters of a cell. When a cell receives a danger alarm, amazingly, it deliberately messes up its headquarters, with the consequence that many functions are completely stopped for the cell. Our study suggests this new function of autophagy as a guarding mechanism that protects cells from becoming cancerous."
Although senescence suppresses cancer, which is the good side of this physiological balance, there is also a dark side. Senescence is associated with normal aging, and senescent cells accumulate in aged tissues, which impair the normal functions of the tissue and contribute to age-related diseases. The team noted that while autophagy digestion of the nucleus is able to restrain cancer, this machinery is improperly turned on during normal aging. "There is a short term 'tactical' advantage, but a long term 'strategic' defeat. This mechanism makes a normal cell, even without cancer stress, get old much faster, and in a detrimental way."
In support of this notion, the team found that in late middle-aged normal cells, blocking the autophagy-driven breakdown of the nuclear lamina can make cells live 60 percent longer. Looking toward the future, the team reasons that specific manipulation of the nuclear digestion by autophagy holds promise to intervene in age-related diseases. The team showed that a blocking peptide, which inhibits LC3-laminB1 interaction, is able to slow cell aging. The implications are that a small molecule could be made to stop the long-term dark side of the senescence pathway, and to treat age-related diseases, especially those related to chronic inflammation as seen in human aging.
Autophagy mediates degradation of nuclear lamina
Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.
ARTICLES ON NEURODEGENERATION FROM ALZFORUM
ALZFORUM is a long-running, industry-supported site covering Alzheimer's research, and the staff there turn out a good line in explanatory and popular science articles on the topic. This is something that we need a lot more of in the field of aging research, and especially for those portions of the field focused on SENS or SENS-like strategies of damage repair. Efforts like LIFEmag, the Longevity Reporter, the Rejuvenation Biotechnology Update quarterly emails to supporters of the Methuselah Foundation and SENS Research Foundation, and the publications of the Healthspan Campaign and similar are steps in the right direction, but there is still a sizable gap to be filled here.
Some of that gap is, I think, conceptual. People who are developing the symptoms of Alzheimer's - and their supporters and their caregivers - will do exactly what everyone else faced with currently intractable medical issues does: go online, network, find a community, read up on research. People suffering from aging, which is to say everyone, don't really exhibit all that much of the same behavior, however. Convincing the rest of the world to think of aging itself as a medical condition, amenable to near-future treatment, rather than a fact of life is perhaps still a hurdle to be overcome. In any case, today I'll point out a couple of articles recently published at ALZFORUM; see what you think:
Does the Blood-Brain Barrier Stand Up to Alzheimer's? Study Finds No Breach
The blood-brain barrier shields the brain from potentially harmful things, and some findings have suggested that this protective border weakens with age or disease. However, a study now reports that the barrier remains largely intact in multiple mouse models of neurodegenerative disease. The researchers also found that brains from healthy aging people bore the scars of just as many barrier breaches as those from Alzheimer's disease (AD) patients. This study contradicts previous work that has called disruption of the blood-brain barrier (BBB) both a cause and a consequence of AD pathology.
Researchers wanted to formally test the idea that AD disrupts the BBB. They are developing a strategy to smuggle therapeutic antibodies across the brain's border, hence evidence of an intact barrier would further support the need for such a trafficking route. The researchers previously developed bispecific antibodies, which recognize a different target with each of their two arms. While one arm recognizes BACE1, the other latches on to the transferrin receptor (TfR) expressed on endothelial cells lining the barrier, which then transport the antibody across via transcytosis. In plaque-ridden, 10- to 13-month-old PS2-APP mice, the researchers found that, as in wild-type mice, only the bispecific TfR antibody crossed the barrier efficiently, while BACE1 or control antibodies remained largely outside. This indicated that a barrier disruption large enough to let antibodies across did not occur in these AD mice. The same held true for two transgenic mouse models expressing disease-associated forms of human tau despite extensive tauopathy and neurodegeneration.
The authors' conclusion that the blood-brain barrier remains largely intact across models of neurodegenerative disease and in humans with AD contradicts many studies using differing techniques that say otherwise. What do results from AD mouse models say about the state of the BBB in human disease? Maybe the import of antibodies is limited because one big difference between animal models and human AD is the presence of cerebral amyloid angiopathy (CAA). In some people, the vascular amyloid deposits of CAA cause vessels to bleed, but most mouse models have no CAA.
Reinforcement, or Replacement? Stem Cell Strategies Divide to Conquer
Behind every successful neuron, there is a support crew of glia. Stem cell researchers are aiming to replace both types of cell in an effort to slow neurodegenerative disease. The defining characteristic of neurodegenerative disease is the death of neurons, and researchers have long searched for ways to either replace the fallen cells or bolster support for those that remain. Stem cell therapy offers opportunities to try both. Scientists have developed protocols to transform stem cells or induced pluripotent stem cells (iPSCs) into neurons of various persuasions, or into the glial cells that support them.
Another approach is to skip the complexity of the stem cell altogether and directly deliver trophins such as brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF). The latter has a long history. In 2001, researchers delivered NGF to people with probable AD by injecting directly into the striatum either patient-derived fibroblasts engineered to pump out NGF, or adeno-associated virus (AAV) expressing NGF. Recently, the scientists reported postmortem results from 10 patients who died between one and 10 years later. The researchers observed neurons undergoing a growth spurt - putting out axonal projections and expressing key signaling molecules - in the areas near the injection. In the viral gene therapy recipients, both healthy neurons and degenerating cells riddled with tau tangles expressed NGF, indicating that even sickly neurons retain the capacity to produce trophic factors. While the results did not reveal whether the trophic support slowed the pace of AD in these patients, they suggest that when such therapy is delivered, neurons respond.
Viral delivery of BDNF has shown promise in rodent models of neurodegenerative disease as well as in aging primates. However, the treatment is still in its preclinical stages as researchers grapple with the challenge of efficiently delivering the trophin to specific regions in the brain. Some researchers believe that the factors might work best when delivered by professionals (i.e., by glial cells that normally produce them). This was tried this in ASO mice, a model of dementia with Lewy bodies (DLB) that overexpresses human α-synuclein. These animals are riddled with Lewy bodies and develop both motor and cognitive deficits. The researchers transplanted neural stem cells (NSCs) derived from normal mice directly into the striata of 12-month-old ASO mice. They found that the transplanted cells differentiated into astrocytes and oligodendrocytes, and six weeks after the injection had migrated throughout the striatum and even into the neighboring cortex and amygdala. The transplanted cells restored the animals' deteriorating motor function, as well as learning and memory.
A BRIEF LOOK AT RETROTOPE
Today, I'll point out the early stage company Retrotope, more out of curiosity than as an example of a research and development strategy that I'd favor pursuing. They don't make it terribly easy to see exactly what they're up to, as seems to be the trend for the online presence of young biotech companies these days, but the digest is that the staff there are trying to build therapies based on substituting deuterium for hydrogen in some of the molecules employed in cellular structure and machinery.
As long-time readers will no doubt recall, a slow trickle of evidence has arrived over the past decade to suggest that replacing a small fraction of hydrogen atoms with deuterium atoms in the proteins and other molecular machinery of a living organism produces a slight beneficial outcome to health and longevity. Deuterium is an isotope of hydrogen, with a nucleus containing a proton and a neutron rather than just a proton. So it is twice as heavy, but with the same single electron as hydrogen it has similar chemical properties. Molecules in which this substitution has been made have broadly similar characteristics, but there is enough of a difference to ensure that, for example, heavy water is toxic, more so to lower animals than to mammals, and, apparently, that a low level of deuterium substitution in cellular machinery can be slightly beneficial. In studies of deuterium substitution a common methodology is to culture worms, flies, and so forth, with a diluted dose of heavy water and then observe the results. You'll find examples back in the Fight Aging! archives.
This exploration has to date been anemic and far from conclusive, for all that it is a fascinating topic, and this is why I point out Retrotope. I imagine that the efforts to run a potential isotope substitution treatment through a clinical trial, currently in the recruitment phase, may prove to be the sharp edge of work that advances the state of knowledge regarding the effects of isotope substitution on cellular biology. It is undeniably interesting stuff from a life science perspective, regardless of its likely poor best possible outcome in comparison to damage repair approaches to treating aging. Even the current trial is for the inherited condition Friedreich's ataxia, with only vaguely similar mechanisms to aging involved in its pathology.
In any case, the basic plot here is based on the view that the presence of heavier isotopes helps to resist the effects of oxidative stress, the damage to molecular machinery caused by the presence of free radicals, whether produced by disease processes, aging processes, or less common issues such as radiation exposure. Somewhere between an absence of deuterium and enough deuterium to be toxic lies a level at which enough of a benefit is produced to be worth turning it into a treatment. This, at least, is the hope. Various other strategies aimed at ameliorating oxidative stress should give us some idea as to the plausible range of expected outcomes for this sort of approach. For example, you might look at the results from gene therapies to boost levels of the antioxidant catalase in cells. These are not large positive effects in the grand scheme of things, I'm sorry to say.
Pill of superprotective 'heavy' fat
Mikhail Shchepinov, director of Retrotope, a biotech company based in Los Altos, California, wants eventually to slow down the ageing process. But he is starting with a related problem - treating the inherited movement disorder Friedreich's ataxia, with which ageing shares a mechanism. They are both caused, in part, by a molecular attack on our cells. Shchepinov's idea is to counteract this assault by reinforcing our cells' defences, slowing the progression of this incurable disease. If it works, it should demonstrate that the approach is also suitable for tackling ageing.
He reckons we can protect our cells from free radicals simply by strengthening the bonds between molecules that make up our cell membranes. This can be done by swapping the hydrogen in the fatty acids for a different form known as deuterium. Because deuterium has an extra neutron, it is heavier than hydrogen and forms stronger bonds.
Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia
Oxidative stress can be the cause and/or the consequence of mitochondrial energy imbalance, leading to cell death. Fibroblasts from two mouse models were used to analyse two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers. The former have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger the well-known Nrf2 antioxidant pathway. Our results show that the sensitivity to oxidative stress of mouse fibroblasts, resulting in cell death and lipid peroxidation, can be prevented by d4-PUFA and Nrf2-inducers.
Retrotope is currently assessing technical proof of principle, regulatory requirements, and viability of several products in multiple market segments. The company has a pipeline of products, including single agent and multiple stabilized polyunsaturated fatty acids (PUFAs), stabilized amino acids, each in a variety of indications. Pharmaceutical candidates include:
1) Fortified lysine: Anti-metastatic agent against cancer proliferation and fibrotic disease, downregulating the effects of LOX, a well documented target for pathological collagen crosslinking.
2) Stabilized fatty acids: Treatment and high risk mitigation of diseases involving oxidative mitochondrial membrane damage. Anti-proliferative for protein damage and aggregation in Parkinson's and other orphan central nervous system diseases, using stabilized fatty acid mimetics.
3) Episodic or regular intervention for radiation exposure events or at high radiation- risk populations (e.g. security personnel, military, etc).
LATEST HEADLINES FROM FIGHT AGING!
SUPPLYING YOUNG CELLS TO AN INVOLUTED THYMUS PRODUCES GROWTH AND INCREASED T CELL PRODUCTION
Monday, October 26, 2015
Several distinct lines of ongoing (but unfortunately poorly funded) research aim to restore at least some degree of youthful activity to the thymus in old individuals, and researchers here demonstrate one of them: a process of introducing young thymus cells into an old thymus. The thymus plays a vital role in the generation of immune cells, and during childhood the rate of production is high. In early adulthood the thymus atrophies in a process known as involution, however, and the supply of new immune cells diminishes to a trickle. This is one of the important limiting constraints that determine the way in which the immune system ages. Restoring an old thymus should improve immune function in adults, and given that the degeneration of immune function in the old is a large component of the frailty of old age, this is an important and much underrated goal.
The thymus reaches its maximum size early in life and then begins to shrink, producing fewer T cells with increasing age. This thymic decline is thought to contribute to age-related T cell lymphopenias and hinder T cell recovery after bone marrow transplantation. Although several cellular and molecular processes have been implicated in age-related thymic involution, their relative contributions are not known.
Using heterochronic parabiosis, we observe that young circulating factors are not sufficient to drive regeneration of the aged thymus. In contrast, we find that resupplying young, engraftable thymic epithelial cells (TECs) to a middle-aged or defective thymus leads to thymic growth and increased T cell production. Intrathymic transplantation and in vitro colony-forming assays reveal that the engraftment and proliferative capacities of TECs diminish early in life, whereas the receptivity of the thymus to TEC engraftment remains relatively constant with age. These results support a model in which thymic growth and subsequent involution are driven by cell-intrinsic changes in the proliferative capacity of TECs, and further show that young TECs can engraft and directly drive the growth of involuted thymuses.
MORE WORK ON GENE EXPRESSION CHANGES AS A BIOMARKER OF AGING
Monday, October 26, 2015
A range of research groups are presently working on the development of biomarkers based on gene expression changes that occur with aging. Insofar as everyone suffers the same forms of cell and tissue damage that causes aging, it should be expected that cellular reactions to rising levels of that damage have similar patterns, albeit mixed in with environment effects and individual differences. A robust biomarker of aging would be a very useful thing to have to hand, as without it the only way to prove that a potential rejuvenation therapy in fact extends healthy life is to wait and see. That is slow and expensive, even in mouse studies, and this cost is a ball and chain holding back the pace of progress.
Researchers examined expression of genes in blood samples from 15,000 people across the world. They found 1,450 genes that are linked to ageing, and also uncovered a link between these genes and factors such as diet, smoking and exercise. The research team specifically looked for changes in gene expression, a process in which the information contained in genes is 'expressed' by reading the DNA sequence and creating RNA, and subsequently proteins. By looking in blood, the researchers aimed to find easy to measure markers of human ageing. This technique allowed them to develop a new method to predict people's 'biological age' and show that people with a biological age older than their actual age were more likely to have conditions such as high blood pressure or cholesterol. Many of the genes work together in pathways such as generating the energy supply of the cells (mitochondrial function), metabolic processes, and the stability and flexibility of the cells.
"This study has discovered many genes that change in their patterns of expression with age. This study has not only given insights into ageing mechanisms - such as mitochondrial function - but these techniques have potential use in prediction and treatment. Large, observational, and collaborative projects such as these provide a great platform to focus ageing research in the future, with the hope that predictive tests can be developed, and treatment strategies for age-related conditions improved."
HEALTHSPAN, NOT LIFESPAN
Tuesday, October 27, 2015
In this paper the author looks ar the oucomes of past efforts to modestly extend life, mostly in the laboratory only, via the traditional drug discovery and development process, or pharmacology. I'd argue that any debate over targeting lifespan versus healthspan is an artifact of focusing on strategies that can do very little in the grand scheme of things, either slightly slowing aging or slightly compensating for one or more aspects of aging without addressing its causes. Only in this realm is it possible to produce therapies that could extend life without extending health to match. It becomes moot for true rejuvenation therapies that repair the underlying cell and tissue damage that causes aging, and are capable in principle of extending life by decades if made effective enough at that repair. At that scale of life extension, and by that methodology of damage repair, healthspan and lifespan are extended in tandem - it isn't possibly to move one independently of the other. Present damage determines both current health and future trajectory of health and mortality absent future repair.
The main goal of this paper is to present the case for shifting the focus of research on aging and anti-aging from lifespan pharmacology to what I like to call healthspan pharmacology, in which the desired outcome is the extension of healthy years of life rather than lifespan alone. Lifespan could be influenced by both genetic and epigenetic factors but a long lifespan may not be a good indicator of an optimal healthspan. Without improving healthspan, prolonging longevity would have enormous negative socioeconomic outcomes for humans. The goal of aging and anti-aging research should therefore be to add healthy years to life and not to merely increase the chronological age.
This paper summarizes and compares two categories of pharmacologically induced lifespan extension studies in animal model systems from the last two decades: those reporting the effects of pharmacological interventions on lifespan extension alone, versus others that include their effects on both lifespan and healthspan in the analysis. The conclusion is that the extrapolation of pharmacological results from animal studies to humans is likely to be more relevant when both lifespan and healthspan extension properties of the pharmacological intervention are taken into account.
LIFE EXTENSION IN OLD MICE VIA TRANSPLANT OF BONE MARROW CELLS FROM YOUNG MICE
Tuesday, October 27, 2015
The research noted here, in which scientists transplant young stem cells into old mice, is a logical exploration of the bounds of the possible along the lines of parabiosis studies, in which the circulatory systems of old and young individuals are linked. The results demonstrate that regular cell transplants incorporating young bone marrow stem cells can extend life when provided to older individuals, provided there is a close genetic match between donor and recipient. Without that match there was no effect on life span:
The method of lifespan extension that is a practical application of the informational theory of aging is proposed. In this theory, the degradation (error accumulation) of the genetic information in cells is considered a main cause of aging. According to it, our method is based on the transplantation of genetically identical (or similar) stem cells with the lower number of genomic errors to the old recipients. For humans and large mammals, this method can be realized by cryopreservation of their own stem cells, taken in a young age, for the later autologous transplantation in old age.
To test this method experimentally, we chose laboratory animals of relatively short lifespan (mouse). Because it is difficult to isolate the required amount of the stem cells (e.g., bone marrow) without significant damage for animals, we used the bone marrow transplantation from sacrificed inbred young donors, males and females of 1.5-3 months. Bone marrow transplantation (2 × 10^6 cells) was performed with the intervals of 3 months to the death of the animal. Experiments were started at age of 7-8 months for the recipients of the first and the second experimental groups and at age of 6-10 months for those of the third group.
It is shown that the lifespan extension of recipients depends on level of their genetic similarity (syngeneity) with donors. We have achieved the lifespan increase of the experimental mice by 34% when the transplantation of the bone marrow with high level of genetic similarity was used. The value of lifespan increase in our experiments varies from 34% for high-level syngeneic transplantation to 0% for allogeneic transplantation.
A PERSPECTIVE ON STEM CELL AGING AND REJUVENATION
Wednesday, October 28, 2015
This open access paper from some of the researchers involved in parabiosis research, aiming for at least partial restoration of youthful stem cell activity and tissue maintenance in old individuals, is a reminder that there is a lot of politics and happenstance in research, as in every other human endeavor:
It has been 10 years since the paradigm-shifting observations that in heterochronic parabiosis, the young systemic milieu rapidly and broadly rejuvenates organ stem cells in muscle, brain/hippocampus and liver, while the old systemic milieu rapidly and broadly ages myogenesis, liver regeneration and neurogenesis, with the responsible biochemical pathways being re-set to their young or old states. Before this work, the prevalent theories of tissue decline in aging focused on cumulative cell intrinsic changes as culprits: telomere attrition, DNA damage, oxidative damage, mitochondrial dysfunction, etc.). While all of the above continue to be true for differentiated cells, it is important to realize that organ stem cells age "extrinsically", and maintain a relative "youth" that could be due to the state of quiescence, which is default for most if not all postnatal stem cells. As such, stem cell regenerative capacity persists throughout life, but sadly, the biochemical cues regulating organ stem cells change with age in ways that preclude productive regenerative responses, causing the abandonment of tissue maintenance and repair in the old.
If all this has been known for 10 years, why is there still no therapeutics? One reason is that instead of reporting broad rejuvenation of aging in three germ layer derivatives, muscle, liver, and brain by the systemic milieu, the impact of the study published in 2005 became narrower. The review and editorial process forced the removal of the neurogenesis data from the original manuscript. Originally, some neurogenesis data were included in the manuscript but, while the findings were solid, it would require months to years to address the reviewer's comments, and the brain data were removed from the 2005 paper as an editorial compromise. The phenomenon and its magnitude were replicated, expanded and elegantly described in a 2011 paper, but if the friendly neighbor of the original lab had not been interested in this project after learning of our findings, this important result could have been lost or remained on a "back-burner" indefinitely. While it is certainly better late than never and even if the data are more elaborated than in the original manuscript, one can argue that the scientific community could already have been working on the extrapolation of these results and translating them into therapeutics against neuro-degeneration for 10 years.
Another reason for the slow pace in developing therapies to broadly combat age-related tissue degenerative pathologies is that defined strategies, which are "beyond parabiosis", for the rejuvenation of multiple old organs have been very difficult to publish in high impact journals; only the magic of "heterochronic parabiosis" seems to keep the editors' and reviewers' attention. As the result, in the current dynamically raging scientific waters, significant work that is directly relevant to attenuation or even reversal of human tissue aging (e.g., molecules that work in mice and are FDA approved or in clinical trials for human applications) can sadly get washed over, particularly, when relevant publications from lower impact journals are not always noticed or cited.
RISK AND CONSEQUENCES OF STROKE IN DECLINE, WHILE OVERALL INCIDENCE INCREASES
Wednesday, October 28, 2015
Recent historical data for the harm done due to the incidence of stroke in the old is similar to that gathered for many age-related diseases. With progress in medicine the risk of suffering a stroke is falling, and the following consequences are becoming less severe. To be clear, it is still a life-threatening, potentially fatal, crippling biological structural failure. Yet your odds are better today than they were last year, and continue to improve. Because there are more people in the world, and more of those people are living longer, the overall incidence and cost of stroke is increasing, however. An optimist might see this as a spur that will lead to more interest in treating the causes of aging, the collection of processes that are the underlying reason for stroke and all of the other catastrophic age-related failures of the cardiovascular system.
The objective of this study is to show geographic patterns of incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke and hemorrhagic stroke in the world for 1990-2013. Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated following the general approach of the Global Burden of Disease (GBD) 2010 with several important improvements in methods. Data were updated for mortality (through April 2014) and stroke incidence, prevalence, case fatality and severity through 2013. Death was estimated using an ensemble modeling approach. All rates were age-standardized to new GBD estimates of global population.
Age-standardized incidence, mortality, prevalence and DALYs/YLDs declined over the period from 1990 to 2013. However, the absolute number of people affected by stroke has substantially increased across all countries in the world over the same time period, suggesting that the global stroke burden continues to increase. There were significant geographical (country and regional) differences in stroke burden in the world, with the majority of the burden borne by low- and middle-income countries. Global burden of stroke has continued to increase in spite of dramatic declines in age-standardized incidence, prevalence, mortality rates and disability. Population growth and aging have played an important role in the observed increase in stroke burden.
A POSSIBLE WAY TO TARGET EXHAUSTED T-CELLS FOR DESTRUCTION
Thursday, October 29, 2015
Researchers here identify a possible way to identify and target T-cells that clutter up the aged immune system, impacting its effectiveness. A sizable part of immune decline in aging seems to result from the accumulation of large numbers of memory T-cells and exhausted or anergic T-cells at the expensive of naive T-cells capable of attacking threats. This may be due to the presence of cytomegalovirus, CMV, which is very prevalent and largely harmless, except for the fact that it cannot be cleared from the body and over the years the immune system devotes ever more of its limited resources to the problem.
This issue has a blunt solution: destroy the useless and the excess T cells, freeing up space for new competent immune cells to be generated as replacements. The basic concept has been demonstrated for other parts of the immune system; destruction of old, bad B cells led to the creation of fresh new B cells in animal studies, for example. A range of targeted cell destruction technologies are at various stages of development in the cancer research community, many of which can be coupled to arbitrary detection and delivery mechanisms. A whole field of research revolves around building future standards for platforms that can join a cell-killer to a sensor and delivery mechanism that discriminates targets by their particular surface chemistry. The first step on this road is finding a useful characterization of the target:
In acute infections, antigen-specific T cells differentiate into activated effector cells and then into memory T cells which rapidly gain effector functions and re-expand on subsequent encounter with the same pathogen. In contrast, during chronic infections, pathogen-specific T cells gradually lose effector functions, fail to expand, and can eventually become physically deleted. These traits are collectively termed T cell exhaustion, and have been described both in animal models of chronic viral infection as well as in human infections with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Identifying reversible mechanisms of T cell exhaustion is therefore a major goal in medicine.
Discovering surface markers of exhausted T cells is important for both to identify exhausted T cells as well as to develop potential therapies. We report that the ectonucleotidase CD39 is expressed by T cells specific for chronic viral infections in humans and a mouse model, but is rare in T cells following clearance of acute infections. In the mouse model of chronic viral infection, CD39 demarcates a subpopulation of dysfunctional, exhausted CD8+ T cells with the phenotype of irreversible exhaustion.
In this study, we demonstrate that, in contrast to CD8+ T cells from healthy donors, antigen-specific CD8+ T cells responding to chronic viral infection in humans and a mouse model express high levels of biochemically active CD39. CD39+ CD8+ T cells co-express PD-1 and are enriched for a gene signature of T cell exhaustion. In the mouse model of chronic LCMV infection, high levels of CD39 expression demarcate terminally differentiated virus-specific CD8+ T cells within the pool of exhausted CD8+ T cells. Thus, CD39 provides a specific, pathological marker of exhausted CD8+ T cells in chronic viral infection in humans and mouse models of chronic viral infection.
MORE ON FOXN1 IN THE AGING THYMUS
Thursday, October 29, 2015
Last year, researchers demonstrated restoration of youthful activity of the thymus in old mice via increased levels of FOXN1. Rejuvenation of the thymus is one possible path towards at least partial rejuvenation of the immune system, as its decline in adulthood limits the supply of new immune cells, and that limit is one of the factors that creates dysfunction and dysregulation of the immune system in old people. In this paper researchers further characterize the age-related decline in FOXN1 levels in the thymus:
In human, the thymus-derived naïve T cell repertoire, capable to exert effective protection to foreign antigens, is established during early embryonic life and it reaches maximal size in childhood, subsequently, as antigen specific T cells are generated, the naïve T cell pool is gradually depleted. Thus, the limited naïve T-cell repertoire in elderly individuals is a major contributor to age-related immunodeficiency, a frequent cause of death. The immune compromised status results in the lack of effective immune response against pathogenic microrganisms and malignant cells. Because age related immunodeficiency is often life limiting as the cause of frequent nosocomial infections of the elderly, and because current treatment is insufficient, moreover it represents a significant medico-economic burden, there is a strong interest to develop effective and economically sound therapies. One possible strategy is the restoration of the naïve T cell repertoire via therapeutic regeneration of thymic activity.
In humans, as the thymus ages, thymic epithelial mesh is gradually replaced by adipose tissue. The process is thought to start at the first year of life and continues during aging, being accompanied by a decreasing export of naive T cells. The underlying molecular mechanisms responsible for the impairment of thymopoiesis in the aging thymus remains unclear. One possibility is that intrinsic mechanisms related to thymic epithelial cells (TEC) physiology are impaired in old individuals, since bone marrow precursors from old animals are able to colonize the thymus.
Studies in rodent models pointed out that the transcriptional factor forkhead box protein N1 (FOXN1) is both necessary and seemingly sufficient to induce differentiation of functional TEC. For the first time, we report here a striking three-fold decrease of FOXN1 expression over time in the human thymus, when comparing the "Postnatal" group with the "Adult" group. In fact, the decrease of TEC associated expression levels may be markedly higher, as due to the relatively lower lymphocyte content of the aging thymus, the relative abundance of TEC is increasing. We thus suggest that FOXN1 expression may limit thymopoiesis and its reduced expression may be responsible for thymic senescence.
To model age-related changes, we tested a human thymus derived epithelial cell line, hTEC, for expression of FOXN1. One of the most important epigenetic mechanisms that is often involved in transcriptional regulation during development is CpG methylation. To investigate the methylation status of CpG residues in the FOXN1 gene in the hTEC, we tested a candidate regulatory region (we named C20). In the C20 candidate region FOXN1 expressing skin cells show minimal methylation in 8 of the 13 candidate CpGs of the C20 region, while FOXN1 non-expressing leukocyte is highly methylated. Overall methylation is decreasing with age, and hypermethylation of the C20 segment of the hTEC provides a strong clue supporting our hypothesis, namely that hypermethylation may gradually silence the FOXN1 ultimately leading to decreased thymopoesis.
EXERCISE SLOWS BLOOD-BRAIN BARRIER DYSFUNCTION IN AGING
Friday, October 30, 2015
Since regular exercise extends healthy life span in mice, it isn't surprising to find it slowing the progression of specific manifestations of damage in aging:
Researchers found that structural changes that make the blood-brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly, so providing a potential explanation for the beneficial effects of exercise on dementia in humans. Old age is the major risk factor for Alzheimer's disease, like many other diseases. Age-related cognitive deficits are due partly to changes in neuronal function, but also correlate with deficiencies in the blood supply to the brain and with low-level inflammation.
Physical activity is already known to ameliorate the cognitive decline and sensorimotor deficits seen in old age in humans as well as in mice. To investigate the impact of long-term physical exercise on the brain changes seen in the aging mice, the researchers provided the animals with a running wheel from 12 months old (equivalent to middle aged in humans) and assessed their brains at 18 months (equivalent to about 60 years in humans, when the risk of Alzheimer's disease is greatly increased).
Young and old mice alike ran about two miles per night, and this physical activity improved the ability and motivation of the old mice to engage in the typical spontaneous behaviors that seem to be affected by aging. This exercise significantly reduced age-related pericyte loss in the brain cortex and improved other indicators of dysfunction of the vascular system and blood-brain barrier. Exercise also decreased the numbers of microglia/monocytes expressing a crucial initiating component of the complement pathway that others have shown previously to play are role in age-related cognitive decline.
LONGEVITY VERSUS FRAILTY
Friday, October 30, 2015
In the most simplistic view, aging is little more than a matter of damage accumulation. The more damage you have, the worse your health, and eventually it kills you. At a very high level, this is in fact the way things are, but living organisms are extremely complex systems, and "damage" is made up of numerous primary causes, direct results of the normal operation of cellular metabolism. These spiral out into hundreds or thousands of secondary and later consequences: further damage, evolved reactions to damage, and so forth. The middle portion of the intricate web of biochemistry that links damage at one side to specific age-related diseases at the other is still comparatively poorly mapped, precisely because it is hugely complex. It is also surprisingly variable from individual to individual, for all that the basic root causes of aging are comparatively simple processes that occur in the same way for everyone.
Thus our situation is that frailty in aging is inevitable in the long run for any individual managing to somehow evade all of the late stage system failures of aging that kill without frailty, but over the present median human life span many people do avoid becoming frail before succumbing to those other ends. So there is some distinction between processes of aging and processes of frailty, for all that the latter is absolutely a function of the former. You might consider this to tie back into the fact that genetic differences have little effect on mortality and health until later in life. The effect of genetic variations on longevity is to a first approximation a matter of how your system manages to cope with being damaged.
Over the next few decades a great deal of effort will be devoted to understanding how exactly all of this works - mapping the middle of the linkage between damage and end results. This is effort that I hope to see side-stepped and evaded via the approach of repairing this fundamental damage, thus creating a toolkit of first generation rejuvenation therapies. How human biology reacts to being very damaged by the causes of aging is a field of research that I would like to live to see become an academic curiosity, along the lines of how human biology reacts to smallpox - something of interest, but neither vital nor important, because it will no longer be the case that people suffer in that state. We have the opportunity to make this happen in the years ahead, but that very much requires greater support and funding for SENS and similar lines of rejuvenation research.
Older people are at risk of developing frailty with advancing age. The prevalence of frailty increases from 2.5-3% in adults aged 65 years to 30-35% in those older than 85 years. These results suggest that an association exists between longevity and frailty. However, at the same time, even at advanced age, the majority of older adults are free of frailty, suggesting that factors different from those contributing to or produced by the life length are involved in producing frailty.
Genetic and epigenetic factors, nutrient-sensing systems, mainly the so-called insulin/insulin-like growth factor-1 signaling pathway, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, inflammation, and some hormonal systems are involved in longevity. However, factors involved in frailty are mainly inflammation and hormones, with an anecdotal role for genetic and other potential factors, but even these two common factors seem to regulate longevity and frailty in different ways. Moreover, their effect on frailty seems to change when they are acting in combination.