Fight Aging! Newsletter, March 28th 2016

The Vascular Tissue Challenge rules are currently open for public comment. If interested in this challenge, please provide your feedback.

The ability to provide oxygen and nutrients to thick human tissue by adequate vascularization of layers of cells to ensure metabolic functions similar to native in-vivo tissues has not been reliably demonstrated. Developing this capability will enable new research initiatives that may bring real solutions to organ disease, skin burns and other medical concerns. NASA's objective for this challenge is to produce viable thick-tissue assays above and beyond the current state of the art technology.

Competitors will be asked to produce an in-vitro vascularized tissue that is more than 1 centimeter in thickness in all dimensions at the launch of the trial and maintains greater than 85% survival of the required parenchymal cells throughout a 30-day period. Tissues must provide adequate blood perfusion without uncontrolled leakage into the bulk tissue to maintain metabolic functionality similar to their in-vivo native cells. Histological measurement of the quality and amount of functional performance will be required to determine survival of parenchymal tissue. Teams must demonstrate 3 successful trials with at least a 75% trial success rate to win an award. In addition to the in-vitro trials, teams must also submit a Spaceflight Experiment Concept that details how they would further advance some aspect of their tissue vascularization research through a microgravity experiment that could be conducted in the U.S. National Laboratory (ISS-NL) onboard the International Space Station.

Even if the first clinical methods for slowing ageing arrive a few decades ahead, that is still good news for the majority of people living today. Especially since slowed ageing gives you more years of medical progress. While nothing is certain, it looks like in the long run ageing may become just another treatable chronic disease. Some would argue that slowing ageing is all about achieving immortality. But treating ageing directly makes sense simply in terms of health: ageing is a direct contributor to heart disease, diabetes, weakened immune system, Alzheimer's and many other maladies. Life extension cannot give us eternal life: besides ageing, we are killed by diseases, accidents and violence. And if we fix those, we are still finite beings in a universe ruled by probability. Sooner or later we will be unlucky and perish. But we can maybe make this probability so low that it does not matter much in practice. The real issue might be what we would do if we had indefinite lifespans.

Every time someone dies, a library burns. The experiences, skills, and relationships painstakingly built across a lifetime disappear forever. We cannot prevent any particular library from eventually having a fire, but we can make sure the fires are rare. Humans are precious, and that is why we should not wish them to age. Some might say we need a change of generations to keep our culture youthful. Yet, to continue the library metaphor, few people think the way of maintaining a successful culture is to burn the archives and art museums. There are better ways of changing things than killing the old guard. The physicist Max Planck said that science advances one funeral at a time, but in practice many radical new ideas do sweep the scientific world faster than scientists are being replaced. In the social arena we have seen struggles to extend human rights succeeding faster and faster, despite people living longer: compare the time it took for female suffrage to go from academic idea to political practice with the time it took gay rights to make the leap from unthinkable to orthodox. At any rate, if long lives actually do slow social changes there are still better ways of speeding it up than letting people die prematurely. We have term limits in politics: maybe we should have them for professors and CEOs too.

I have met 18 year olds claiming they do not want to live beyond 20 because they will be old and decrepit, while my 105 year old grandmother still potters on since dying is simply not done. Some people find new meaning again and again, others feel suicidal about Sunday afternoons. It is not uncommon to envision one's life as a book, and then assume it must have a beginning, a middle and an end. This is reasonable since we tend to construct our identities as narratives: we often tell stories about who we are, what we have done, and where we are going, so thinking of a life this way comes naturally to us. But a book can be a short pamphlet, a thick epic, or maybe a never-ending fantasy series ... which one would we want to be like?

Many people who wish for radical life extension are afraid of dying. This is a bad motivation: sooner or later they will run out of time anyway, and living just to avoid something is a diminished way of life. They are not hoping for something of value, merely the avoidance of loss. The problem with death is not just that it can be painful, but that it also irreversibly prevents any more experience, any more action. Our social bonds are broken. Pain can be dealt with, but these other factors point at what makes life worth living. We should seek to live longer because we love life. We should wish to experience good things, gain wisdom, and interact with people in important ways. A long and healthy life is quite useful for this.

Astrocytes have been found to have a much more active role that the one predicted by the earlier guessers. Particularly, they are involved in the ions exchange with neurons, they are organized as a syncytium that allows them to interchange information with other astrocytes residing in a defined net through different types of Ca+++ signals while regulating the release of signaling molecules involved in the production of trophic factors, transmitters and transporters that when released to the extracellular medium will modulate the synaptic activity synchronizing the neuronal functions. Also they are involved in the extracellular K+ uptake, in synaptogenesis and gene expression; adapting, at the same time, the permeability of the blood-brain barrier to the neuronal and synaptic needs.

Slowly but relentlessly, the results of several studies have confirmed the existence of an active role played not only by the astrocytes but also by microglia. Mounting evidence suggests that astrocytes modulate microglial response, through the establishment of a complex cross-talk between both types of cells mediated by the production of different chemokines and cytokines. Therefore, we think that the broader term primary degenerative disorders of the central nervous system (PDD CNS) alludes to the complex pathology of these diseases (in contrast to the classic term neurodegeneration). An early astrocytic dysfunction in the PDDs of the CNS has been broadly observed. We advocate that these observations obtained from different degenerative pathologies, but mostly from experimental animal studies, may be the trees from a forest characterized by primary astrocytic dysfunction as the main process starting them.

I spoke to experts who foresee a coming revolution in medicine, where we treat age instead of disease. To do this, they are trying to figure out how aging works at the molecular level. The goal isn't exactly immortality. Instead, these scientists have noticed that a variety of diseases, from cancers to Alzheimer's, share aging as a major risk factor. Rather than spending a lot of money to treat each disease individually, why not tackle the root cause? What if there was a pill that slowed how our cells age, letting us avoid age-related illnesses - and also likely extending our lives? It's a safe bet that when most of us contemplate the gaping abyss of mortality, we decide we'd like to postpone that fate as long as possible, while remaining mobile, independent, and mentally sharp. If we must die, let us go peacefully in our sleep, at home, when we're at least 100.

But how might such a revolution ripple across society? Life expectancy already varies greatly. It's tied to education, wealth, and even where you live. According to Alexander Capron, an expert in health policy and ethics at the University of Southern California Gould School of Law, life-extending therapies could exacerbate these differences. For example, if these treatments are expensive, or aren't covered by affordable health care plans, only people with disposable cash will have access. This means people with money and resources will have the choice to live longer. Those who don't, won't.

"We can't cherry-pick the costs or savings to focus on," says Patrick Lin, director of the Ethics + Emerging Sciences Group at California Polytechnic State University. Instead, he says,to fairly examine the ethics involved, we should consider impacts both on the individual and society level. "Yes, healthier people may mean lower health costs and more productivity, but that's a partial picture at best. We'd also have to consider the impact of extended lives on, say, Social Security, pensions, job openings given fewer retirements, crime from unemployment, natural resources, urban density, copyright durations, prison sentences, and many, many other effects."

Another effect to consider is how families pass on their legacies, says Nigel Cameron, president of the Center for Policy on Emerging Technologies. Life extension would mean more time with extended family. But it will also mean that inheritance and property will transfer later and less often, which could put more pressure on younger generations to acquire property independently. Lifespan extension could also influence politics and social change, with different age groups pushing for different policies. "There are big generational differences in economic and social interests," Cameron says. "The whole thing becomes much more extended if people live longer, much more competitive."

Still, the research that could lead to life extension is happening, so the conversation about its implications should, too. "Personally, I'm cautiously optimistic about life extension research, but we need to be careful to manage the hype and not ignore the risks," says Lin. "Will we ever become immortal? I don't know, and no one else can see that far, either. But even extending our lives another 20-100 years or more, to start with, is a game-changer."

In other words, what we think of as "dead" actually means "doomed, under the current circumstances." Someone fifty years ago who suffered from cardiac arrest wasn't dead, they were doomed to die because the medical technology at the time couldn't save them. Today, that person wouldn't be considered dead yet because they wouldn't be doomed yet. Instead, someone today "dies" 4-6 minutes after cardiac arrest, because that happens to be how long someone can currently go before modern technology can no longer help them. Cryonicists view death not as a singular event, but as a process - one that starts when the heart stops beating and ends later at a point called "the information-theoretic criterion for death" when the brain has become so damaged that no amount of present or future technology could restore it to its original state or have any way to retrieve its information.

Here's an interesting way to think about it: Imagine a patient arriving in an ambulance to Hospital A, a typical modern hospital. The patient's heart stopped 15 minutes before the EMTs arrived and he is immediately pronounced dead at the hospital. What if, though, the doctors at Hospital A learned that Hospital B across the street had developed a radical new technology that could revive a patient anytime within 60 minutes after cardiac arrest with no long-term damage? What would the people at Hospital A do? Of course, they would rush the patient across the street to Hospital B to save him. If Hospital B did save the patient, then by definition the patient wouldn't actually have been dead in Hospital A, just pronounced dead because Hospital A viewed him as entirely and without exception doomed.

What cryonicists suggest is that in many cases where today a patient is pronounced dead, they're not dead but rather doomed, and that there is a Hospital B that can save the day - but instead of being in a different place, it's in a different time. It's in the future. That's why cryonicists adamantly assert that cryonics does not deal with dead people - it deals with living people who simply need to be transferred to a future hospital to be saved.

Today, brain death, rather than cardiac death, is considered the stamp of finality. But even this, it might be argued, is not entirely infallible. For instance, in 1955, James Lovelock cooled a rat to just above 0°C. Its brain completely stopped its normal business. However, Lovelock managed to reanimate the rodent by warming it back up. Even in a real life situation - cold water drowning - similar findings have been described. A young girl was resuscitated after an astonishing 66 minutes of total submersion in freezing water. After an hour under water, most people would consider the individual irreversibly dead. We now know this is not always the case. Importantly, her memories and personality were still intact. This is not the only case of people "surviving clinical death." Cases like these have spawned a saying in some emergency rooms: "Nobody is dead until warm and dead."

"In our new study, we show that long-term dietary supplementation with pyruvate increases the energy reserves in the brain, at least in mice, in the form of the molecules glycogen, creatine, and lactate. The mice became more energetic and increased their explorative activity. It appears that these behavioral changes are directly due to the effect of pyruvate on brain function, since we didn't find that these mice had developed greater muscle force or endurance. For example, chronic supplementation with pyruvate facilitated the spatial learning of middle-aged (6- to 12-months-old) mice, made them more interested in the odor of unfamiliar mice, and stimulated them to perform so-called "rearing", an exploratory behavior where mice stand on their hind legs and investigate their surroundings. The dose necessary to achieve these effects was about 800 mg pyruvate per day - which corresponds to about 10 g per day in humans - given to the mice in normal chow over a period of 2.5 to 6 months. A single large dose of pyruvate injected directly into the blood stream had no detectable effect.

An enriched environment (EE) is characterized by sensory, motor and social stimulation relative to standard housing conditions. The incorporation of exercise is an important component of an EE and its benefits have been shown to be a powerful mediator of brain function and behaviour. To determine whether the D2R gene is involved in the mechanism of environmental enrichment, different housing conditions were examined in mice. This study hypothesized that the D2 gene, in the presence of an EE, significantly influenced lifespan, body weight, and locomotor activity.

Results supported the hypothesis. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.

These data provide the first evidence of the role of D2R gene on lifespan in mammals. Mice with normal or reduced expression of the D2 gene and housed in an EE showed significant increases in lifespan. However, mice deficient in D2 failed to benefit from an EE. The D2 gene function appears to be a critical mediator linked to the behavior and lifespan effects associated with an EE. D2's mediating role, however is environment-dependent and was not observed in mice raised in DE conditions. The anti-aging and neuroprotective factors associated with exercise may be the key factor as to why Drd2 +/+ and Drd2 +/- EE mice showed increased lifespan in comparison to their DE cohorts.

A topic highly debated in the field is the role that mitochondrial ROS play in age related and non-age related pathological processes with a mitochondrial component. Are ROS a cause or a consequence of mitochondrial dysfunction? This is a very important question, which needs to be addressed, since it will affect the treatment of those pathologies. Considering all the available evidence, it is plausible to suggest that ROS can have both positive and negative roles depending on the type of the ROS, when, where and how much is produced. Therefore, we can talk about "Good" and "Bad" ROS. "Good" ROS being low reactivity ROS (i.e. superoxide or hydrogen peroxide) produced at specific places, at specific times and in moderate amounts and "Bad" ROS being highly reactive ROS (or low reactive ROS as hydrogen peroxide or superoxide produced at high concentrations) generated continuously and unspecifically. Experimental evidence suggests that boosting ROS production can contribute to the maintenance of cellular homeostasis and positively affect lifespan when induced correctly, whereas if produced in excess or in an unspecific way, they shorten survival and accelerate the onset of age-related disease.

The researchers found that having more ideal cardiovascular health factors was associated with better brain processing speed at the initial assessment. The association was strongest for being a non-smoker, having ideal fasting glucose and ideal weight. Having more cardiovascular health factors was associated with less decline over time in processing speed, memory and executive functioning. Executive function in the brain is associated with focusing, time management and other cognitive skills. While this study suggests achieving ideal cardiovascular health measures is beneficial to brain function, future studies are needed to determine the value of routinely assessing and treating risk factors, such as high blood pressure, in order to reduce brain function decline.

The team then investigated whether it might be possible to create a biobank of potential organs for transplant. Large organs cannot be frozen to prevent decay because water in them turns to ice as they freeze, destroying delicate call structures. But the embryonic precursor kidneys are much smaller, enabling them to use a cryopreservation process called vitrification that can prevent ice formation by pumping antifreeze into an organ before cooling it to -196 °C. This technique is normally only used to freeze small tissues such as human eggs because it is difficult to get the antifreeze around larger, more complicated organs. The team managed to successfully vitrify and store the precursor kidneys for three months in liquid nitrogen. They then warmed the tissue and transplanted it into adult rabbits. Some 25 per cent of the transplants grew into healthy adult organs in the host - not as high as the 50 per cent success rate they achieved with fresh embryonic tissue, but still good.

The results suggest we may one day be able to create a long-term biobank of animal kidneys that provides an unlimited source of organs for transplanting in people. The team is now trialing a similar experiment between rabbits and goats. More than one kidney could potentially be transplanted into larger animals to make up the mass needed for them to act as a native kidney.

In the observational study, 59 participants with mild to moderate Alzheimer's disease were cognitively assessed and a blood sample was taken to measure inflammatory markers in their blood. The majority of participants were followed-up at six months when all assessments were repeated. The presence of gum disease at baseline was associated with a six-fold increase in the rate of cognitive decline in participants over the six-month follow-up period of the study. Periodontitis at baseline was also associated with a relative increase in the pro-inflammatory state over the six-month follow-up period. The authors conclude that gum disease is associated with an increase in cognitive decline in Alzheimer's disease, possibly via mechanisms linked to the body's inflammatory response.

Growing evidence from a number of studies links the body's inflammatory response to increased rates of cognitive decline, suggesting that it would be worth exploring whether the treatment of gum disease might also benefit the treatment of dementia and Alzheimer's disease. In the UK in 2009, around 80% of adults over 55 had evidence of gum disease, whilst 40% of adults aged over 65-74 (and 60% of those aged over 75) had less than 21 of their original 32 teeth, with half of them reporting gum disease before they lost teeth. "A number of studies have shown that having few teeth, possibly as a consequence of earlier gum disease, is associated with a greater risk of developing dementia. We also believe, based on various research findings, that the presence of teeth with active gum disease results in higher body-wide levels of the sorts of inflammatory molecules which have also been associated with an elevated risk of other outcomes such as cognitive decline or cardiovascular disease."

Aggregates of amyloid proteins form and deposit in different tissues which can affect the normal function. As the disease progresses and amyloid deposits grow, tissues become irreversibly damaged. Amyloid deposits can be found in many different organs leading to a wide range of possible symptoms and making diagnosis challenging. To date, the primary mode of diagnosis for amyloidosis has been the Congo red stain. However, evidence from the team shows that their new probe is much more sensitive, being able to detect small amyloid deposits in samples that were previously determined to be amyloid-free.

According to the U.S. Office of Rare Diseases (ORD) amyloidosis is a rare disease, affecting less than 200,000 people in the U.S.. However, the Amyloidosis Foundation suspects that the figures are underreported and that amyloidosis is not that rare - just rarely diagnosed. A more sensitive diagnostic method would help to uncover the reality of the situation. "Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement. It could also be used to identify new types of amyloids and presymptomatic patients who are at risk of developing the disease."

The results of the analysis showed that increasing physical activity was correlated with larger brain volumes in the frontal, temporal, and parietal lobes including the hippocampus. Individuals experiencing this brain benefit from increasing their physical activity experienced a 50% reduction in their risk of Alzheimer's dementia. Of the roughly 25% in the sample who had mild cognitive impairment associated with Alzheimer's, increasing physical activity also benefitted their brain volumes.

We chose to search for such a 'Smurf transition' in two other Drosophila species, Drosophila mojavensis and Drosophila virilis whose last common ancestor with Drosophila melanogaster existed approximately 50 million years ago, the nematode Caenorhabditis elegans whose divergence time with D. melanogaster is around 750 million years, and finally the vertebrate zebrafish Danio rerio, which diverged from D. melanogaster around 850-950 million years ago. We investigated whether Smurf-like animals could be observed in individuals from populations of these evolutionarily distant organisms. For each tested species, we could identify individuals showing extended dye coloration throughout their bodies. Moreover, we observed heterogeneity in a given population with only a fraction of the individuals exhibiting increased dye level outside the intestine. Thus, at least in old animals, it is possible to identify individuals with increased intestinal permeability.

One of the most striking characteristic of Smurf individuals previously described in Drosophila is the high risk of impending death they exhibit compared to their age-matched counterparts in a given population. So we decided to verify whether Smurf individuals were also committed to die in the other organisms we studied in this article. We showed that the proportion of individuals showing increased intestinal permeability grows linearly - or quasi-linearly - as a function of chronological age in these different organisms as it was previously reported in Drosophila melanogaster. Finally, we validated that, similar to what has been shown in D. melanogaster, the Smurf phenotype is a strong indicator of physiological age since it is a harbinger of natural death occurring during normal aging.

Intestinal dysfunction, as measured by the smurf assay in different species, associated to sharp transitions in gene expression and behavior appears to be a conserved hallmark of impending death. If this phase of aging is as broadly present in living organisms as our present study suggests, highly stereotyped molecularly and physiologically as well as sufficient to explain longevity curves, then we think that identifying the very events responsible for entering into this phase or those characterizing the high risk of impending death associated with that phase could answer fundamental questions about aging and lead to treatments able to significantly improve lifespan/healthspan across a broad range of species.

Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the pre-senescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the pre-senescent state results from loss of autophagy, leading to increased reactive oxygen species (ROS) and epigenetic modification at the CDKN2A locus due to decreased H2Aub, up-regulating cell senescence biomarker p16ink4a. However, the pre-senescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells.

Other work suggests that in humans loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus down regulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to pre-senescence in the very old.