FIGHT AGING! NEWSLETTER
January 7th 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!
- Looking Back at 2012
- Instructing Scar Tissue to Change Itself into Healthy Tissue
- Why Not Infuse a Person With Many, Many, Many Immune Cells?
- Vision and Efforts Made to Live Longer
- Latest Headlines from Fight Aging!
- Dopamine Receptor Variant Associated With Longevity
- UCP1 Extends Longevity Via Hormesis?
- TFP5 Shows Promise for Treating Alzheimer's Disease
- Does Lichen Age?
- A French Interview with Aubrey de Grey
- Reduced Frataxin Expression Extends Life in Nematodes
- In Search of the Roots of Heat Shock Hormesis
- A New Record For Human Male Longevity
- Early Growth Rate and Aging
- Reviewing the Mechanisms of Muscle Atrophy
LOOKING BACK AT 2012
That was 2012: another year closer to both the grave and the rejuvenation biotechnology to keep us out of it. This is very much a race, but one in which we can all do our part to help the right horse win. Research runs on money and popularity - but mostly money. Every little bit helps.
Follow the link above to read a long Fight Aging! post that reviews the more noteworthy events and research results from the field of longevity science presented this past year, alongside many links to items of interest.
INSTRUCTING SCAR TISSUE TO CHANGE ITSELF INTO HEALTHY TISSUE
A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect. "The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting. The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle."
Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, [researchers] transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material.
The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. [The] hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer.
WHY NOT INFUSE A PERSON WITH MANY, MANY, MANY IMMUNE CELLS?
One of the many things that can be accomplished today, but largely isn't due to regulation, is infusion of a large number of immune cells grown from a patient's own cells. Existing immune cells - or even skin cells - can be reprogrammed to form induced pluripotent stem cells, which can then be then expanded in number and redifferentiated into the hunter killer cells that rove the body in search of things to destroy.
So why not look ahead to a range of treatments that involve temporarily endowing a person with twice as many immune cells as he or she normally possesses? Or five times as many, or ten times as many, or more? There may well be a why not, at least one that lies beyond the concern shared with all stem cell treatments, which is controlling these cells well enough to avoid the risk of pluripotent cells slipping through and generating some form of cancer. That why not hasn't surfaced yet, however, and the fastest way to see whether or not it exists is more research, more clinical trials, and more responsible medical tourism.
VISION AND EFFORTS MADE TO LIVE LONGER
The thesis in a post from last month at Overcoming Bias is that futurists, at least those with the vision to see the golden future ahead better than most folk, don't really do that much more to live longer. Which sounds about right from what I've seen. Do people, even those with vision, really care all that much about living longer? Sometimes it looks like the answer is, on average, not so much. At least not enough to make immediate sacrifices in money and time or hard left turns in the course of life.
One might argue that increasing nihilism with age is something fundamental to the human condition. In order to be successful in our evolutionary role, we have to, on balance, manage to be good worker ants even as the day of our demise looms closer. Whatever benefits we are providing to the propagation of our genes when old, benefits that caused human life span to evolve to be much longer than similarly sized mammals, we can only provide them if staying the course. When young, time preference is on your side: the psychology of discounting the future applies just as much to horrible, terrible things as it does to beneficial events. But later in life something has to take its place, some growing sense of acceptance, one of the many long-standing delusions regarding personal immortality, or disinclination to care one way or another.
People don't tend to break down and run around screaming in later life even though, to my mind at least, it seems that there is every justification for it. I don't think that this is a cultural thing per se, though its exact manifestation might be. Somewhere around the time that most people hit their stride in life, they have every incentive and the evolved wherewithall to stop caring about the fact that life is being stolen from them.
Which is something of a problem. You can only help people who want to help themselves, and those folk serious about building biotechnology and new medicine to intervene in the aging process are a tiny minority. Their entire aggregate yearly funding wouldn't stretch to a large building project in a small city. The world turns, and its population, by their actions, just doesn't seem to care all that greatly about aging to death.
It is a puzzle of our time, given that the very same people would already be taking advantage of these technologies were they in common use, the same way as they go to their annual checkups and brush their teeth.
The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
DOPAMINE RECEPTOR VARIANT ASSOCIATED WITH LONGEVITY
Friday, January 4, 2013
This research illustrates one of the many challenges associated with untangling genetic contributions to longevity; some of those genes affect personality traits that are also known to correlate with longevity: "A variant of a gene associated with active personality traits in humans seems to also be involved with living a longer life. [This] derivative of a dopamine-receptor gene - called the DRD4 7R allele - appears in significantly higher rates in people more than 90 years old and is linked to lifespan increases in mouse studies. The variant gene is part of the dopamine system, which facilitates the transmission of signals among neurons and plays a major role in the brain network responsible for attention and reward-driven learning. The DRD4 7R allele blunts dopamine signaling, which enhances individuals' reactivity to their environment. People who carry this variant gene [seem] to be more motivated to pursue social, intellectual and physical activities. The variant is also linked to attention-deficit/hyperactivity disorder and addictive and risky behaviors. "While the genetic variant may not directly influence longevity, it is associated with personality traits that have been shown to be important for living a longer, healthier life. It's been well documented that the more you're involved with social and physical activities, the more likely you'll live longer. It could be as simple as that.""
UCP1 EXTENDS LONGEVITY VIA HORMESIS?
Friday, January 4, 2013
Uncoupling proteins affect mitochondrial function, altering the balance of energy going to heat versus building ATP molecules to store it for use elsewhere. Like a range of other mitochondrial manipulations, altering levels of uncoupling proteins can extend life in laboratory animals, and here researchers suggest this works via hormesis, causing just enough damage to spur repair mechanisms to greater ongoing effects for a net overall gain: "Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria considerably increases lifespan in high fat diet fed UCP1 transgenic (TG) mice in comparison to wildtype (WT). In order to clarify the underlying mechanisms we investigated substrate metabolism as well as oxidative stress damage and antioxidant defense in SM of low fat and high fat fed mice. TG mice [showed] elevated lipid peroxidative protein modifications with no changes in glycoxidation or direct protein oxidation. This was paralleled by an induction of catalase and superoxide dismutase activity, an increased redox signaling (MAPK signaling pathway), and increased expression of stress protective heat shock protein 25. We conclude that increased skeletal muscle mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell. Moreover it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. All together our data argue for an adaptive role of reactive species as essential signaling molecules for health and longevity."
TFP5 SHOWS PROMISE FOR TREATING ALZHEIMER'S DISEASE
Thursday, January 3, 2013
A new candidate for building an Alzheimer's therapy shows promise in mice: "When a molecule called TFP5 is injected into mice with disease that is the equivalent of human Alzheimer's, symptoms are reversed and memory is restored - without obvious toxic side effects. "We hope that clinical trial studies in AD patients should yield an extended and a better quality of life as observed in mice upon TFP5 treatment. Therefore, we suggest that TFP5 should be an effective therapeutic compound." To make this discovery, [researchers] used mice with a disease considered the equivalent of Alzheimer's. One set of these mice were injected with the small molecule TFP5, while the other was injected with saline as placebo. The mice, after a series of intraperitoneal injections of TFP5, displayed a substantial reduction in the various disease symptoms along with restoration of memory loss. In addition, the mice receiving TFP5 injections experienced no weight loss, neurological stress (anxiety) or signs of toxicity. The disease in the placebo mice, however, progressed normally as expected. TFP5 was derived from the regulator of a key brain enzyme, called Cdk5. The over activation of Cdk5 is implicated in the formation of plaques and tangles, the major hallmark of Alzheimer's disease."
DOES LICHEN AGE?
Thursday, January 3, 2013
There are many candidates for ageless organisms, such as the hydra or the lobster, and some that have been revealed to in fact age in recent years as research costs fall far enough to allow these niche questions to be answered. Bacteria, for example, do age, but that was only conclusively established comparatively recently. Aging is not a large field in comparison to the life science mainstream, which is one of the reasons why there are so many unanswered questions relating to aging in various species. Here is a fairly typical example - a collection of lower species that may or may not age, probably does so in a very different way to higher organisms, and where the process is largely unstudied. "Pale green and vaguely ruffled, like calcified doilies, lichens grow all over the tombstones and the old stone walls that fringe properties in this part of the world. Most people barely notice them. But Dr. Pringle, a mycologist at Harvard, believes they may help answer one of science's greatest questions: Is immortality biologically possible? For eight years, Dr. Pringle, 42, has been returning to this cemetery each fall, to measure, sketch and scrutinize the lichens, which belong to the genus Xanthoparmelia. She wants to know whether they deteriorate with the passage of time, leaving them more susceptible to death. Lichens are not individuals but tiny ecosystems, composed of one main fungus, a group of algae and an assortment of smaller fungi and bacteria. [While] lichens are communities, Dr. Pringle is largely interested in the fungi. Mycologists, the scientists who study fungi - not the most glamorous corridor of biology - have long assumed that many of these organisms don't age.The clear exception is yeast, a single-cell fungus that does senesce and that researchers use as a model to study aging. But most multicellular fungi, the assumption goes, don't senesce. No one has ever proved that, though, or even collected much data."
A FRENCH INTERVIEW WITH AUBREY DE GREY
Wednesday, January 2, 2013
In the French language press, translated via machine: "[JOL Press]: You are often described as "the man who tries to make us immortal." Immortality, do you believe? [Aubrey de Grey]: I do not agree with this presentation of my research. Sensationalism and this annoys me a lot because it undermines our credibility and affects, therefore, the money we can raise for [the research that] we finance. [JOL Press]: In this case, how would you describe your work? [Aubrey de Grey]: SENS is an association with a research center in California. We drive medical research whose goal is to prevent people from getting sick. One of our projects which we hope to make public soon, revolutionary advances, is to insert a gene [derived from bacteria] in our patients and prevent them from dying from cardiovascular disease - the No. 1 cause of death today. [JOL Press]: You say "soon", you hope when? [Aubrey de Grey]: In time ... there are different approaches to deal with - and destroy - the effects of aging on an individual and we are progressing slowly. We are continuing our experiments. If all goes as we hope, we expect significant gains in the rats of 8 to 10 years, then apply to humans in 20 or 40 years. [JOL Press]: Specifically, what do you mean by "treating aging"? [Aubrey de Grey]: Humans can live healthier, longer. Our approach is to transform the aging process. [JOL Press]: How do you get there? [Aubrey de Grey]: Regenerative medicine aims to repair the effects of damage, to prevent their recurrence. Our goal is to reverse the process, rather than just stop it or slow it down."
REDUCED FRATAXIN EXPRESSION EXTENDS LIFE IN NEMATODES
Wednesday, January 2, 2013
Many of the methods of extending life in laboratory animals involve boosting levels of autophagy, the cellular housekeeping processes that remove damaged components and unwanted proteins. Here is another of them: "Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans, can have pro-longevity effects. This apparent paradox indicates that cellular adaptation to partial mitochondrial stress can induce beneficial responses, but how this is achieved is largely unknown. Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich ataxia, is lethal in C. elegans, while its partial deficiency extends animal lifespan in a p53 dependent manner. In this paper we provide further insight into frataxin control of C. elegans longevity by showing that a substantial reduction of frataxin protein expression is required to extend lifespan, affect sensory neurons functionality, remodel lipid metabolism and trigger autophagy. We find that Beclin and p53 genes are required to induce autophagy and concurrently reduce lipid storages and extend animal lifespan in response to frataxin suppression. Reciprocally, frataxin expression modulates autophagy in the absence of p53. Human Friedreich ataxia-derived lymphoblasts also display increased autophagy, indicating an evolutionarily conserved response to reduced frataxin expression. In sum, we demonstrate a causal connection between induction of autophagy and lifespan extension following reduced frataxin expression."
IN SEARCH OF THE ROOTS OF HEAT SHOCK HORMESIS
Tuesday, January 1, 2013
The heat shock response can induce hormetic benefits: repair and maintenance systems are spurred to greater activity for some time, leading to a healthier, longer-lived organism. Researchers are in search of the pivotal mechanisms of this process, with an eye to targeting them in therapies: ""That which does not kill us, makes us stronger" This famous quote by Friedrich Nietzsche is exemplified by the phenomenon of "hormesis". Exposure of organisms to mild stress fortifies them against subsequent, more severe insults. Yet, the relevant molecular mechanisms remain poorly understood. [Small heat shock proteins, or sHSPs] constitute a diverse family of proteins with multiple roles. Several ageing theories suggest that longevity positively correlates with the ability of the cell and the organism to resist stress. Ageing influences both general and organelle-specific stress response pathways. Distinct experimental approaches have identified proteins that are abundant in long-lived worms. Intriguingly, the most consistently represented subset is the sHSP group, including the HSP-16 family. We propose that HSP-16.1 mediates its protective effect partly by preserving cellular ionic homeostasis, which is perturbed in the stressful context of ageing. How could sHSPs protect under unfavorable conditions? In stressed cells, ATP levels drop significantly leading to fatal aggregation of damaged proteins. sHSPs protect proteins from thermal denaturation and irreversible aggregation in an ATP-independent manner. We propose that sHSPs constitute one of the cell's first lines of defense against cell death."
A NEW RECORD FOR HUMAN MALE LONGEVITY
Tuesday, January 1, 2013
One of the expected signs of an upward trend in longevity is the setting of new records in maximum human life span, and an increase in the number of people getting closer to that record. The longest documented human life, that of Jeanne Calment, was an unusual statistical outlier, however, so despite progress that record will stand for a while at the current rate of increase in elder life expectancy. On the male side of the house there is no such unusually long-lived individual in the verified records, and the age of the oldest male supercentenarians is indeed inching upward: "[On December 28th] Jiroemon Kiruma has set a world record. At 115 years 253 days he has become the oldest living man in history. The record was previously held by Christian Mortensen who lived to 115 years 252 days. Among supercentenarians being a male is particularly rare. The oldest living person in history was a woman named Jeanne Calment who lived to be 122. Currently there are 64 supercentenarians in the world (those 110 years and old) and only 4 of them are males. Kiruma is also the oldest living person in the world, a record he achieved when Dina Mafredini of Iowa passed away ten days ago. Kiruma has a strong will to live per family members, though presently he is in a hospital suffering from an illness of 10 days duration. His condition is noted to be improving. "His condition has improved, and we're not worried, but the doctors said it would be best if he stayed in the hospital into the new year," said Yasuhiro Kawato a hospital spokesperson. Kimura lives with his grandson's widow Eiko Kimura, and continues to eat three small meals per day, a strategy he has maintained for life. He is conversant and generally cheerful though now spends most of his time in bed. He has also escaped disease."
EARLY GROWTH RATE AND AGING
Monday, December 31, 2012
From earlier this month, something to think about in the context of reliability theory and life span: "Manipulating growth rates in stickleback fish can extend their lifespan by nearly a third or reduce it by 15 percent. [Researchers] altered the growth rate of 240 fish by exposing them to brief cold or warm spells, which put them behind or ahead their normal growth schedule. Once the environmental temperature was returned to normal, the fish got back on track by accelerating or slowing their growth accordingly. However, the change in growth rate also affected their rate of ageing. While the normal lifespan of sticklebacks is around two years, the slow-growth fish lived for more than 30 percent longer, with an average lifespan of nearly 1000 days. In contrast, the accelerated-growth fish had a lifespan that was 15% shorter than normal. These effects occurred despite all fish reaching the same adult size, and were even stronger when the rate of growth was increased by artificially manipulating the length of daylight the fish were exposed to, 'tricking' their bodies into growing faster to reach their target size before the start of the breeding season. The results of the study are striking. It appears that bodies which grow quickly accumulate greater tissue damage than those that grow more slowly and their lifespan is substantially reduced as a result. The study also demonstrates the surprising ways in which a slight change in environmental conditions in early life can have long-term consequences. These findings are likely to apply to many other species, including humans, since the manner in which organs and tissues grow and age is similar across very different kinds of animal. It has already been documented in humans, for example, that rapid growth in early childhood is associated with a greater risk of developing ailments later in life such as cardiovascular disease in middle or old age, possibly because of the way in which the tissues of a fast-grown heart are laid down."
REVIEWING THE MECHANISMS OF MUSCLE ATROPHY
Monday, December 31, 2012
Muscle mass and strength diminish with age, and researchers are making steady progress into understanding exactly why this is the case. Rejuvenation biotechnologies of the sort proposed in the SENS plan should reverse this decline, but most researchers are looking more narrowly at intervening in secondary mechanisms - patching the problem rather than attacking aging at its roots. "Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases."