Fight Aging! Newsletter, February 27th 2017

It is tempting to see transhumanism as merely the latest rebranding of a very old desire, for immortality. Aubrey de Grey is a biomedical gerontologist who sees death as a disease to be cured. Anders Sandberg, a neuroscientist working on mind uploading, wishes literally to become an "emotional machine." Zoltan Istvan ran a presidential campaign that saw him travel across the country in a coffin-shaped bus to raise awareness for transhumanism. He campaigned on a pro-technology platform that called for a universal basic income, and promoted a Transhumanist Bill of Rights that would assure, among other things, that "human beings, sentient artificial intelligences, cyborgs, and other advanced sapient life forms" be "entitled to universal rights of ending involuntary suffering."

Then there's Max More, a co-founder of Extropianism, who runs the Alcor Life Extension Foundation in Scottsdale, Arizona. Alcor is a cryopreservation facility that houses the bodies of those hoping to be reanimated as soon as the technology exists. The bodies, "are considered to be suspended, rather than deceased: detained in some liminal stasis between this world and whatever follows it, or does not." Alcor is the largest of the world's four cryopreservation facilities, and houses 149 "patients," nearly 70 percent of whom are male.

Those working on immortality are long-term thinkers and fall, broadly, into two camps: those who want to free the human from the body, and those who aim to keep the body in a healthy condition for as long as possible. Randal Koene, like Max More, is in the first group. Instead of cryonics, he is working toward "mind uploading," the construction of a mind that can exist independent of the body. His nonprofit organization, Carboncopies, aims for "the effective immortality of the digitally duplicated self. Maybe it wouldn't be that much of a shock to the system to be uploaded, because we already exist in this prosthetic relationship to the physical world anyway, where so many things are experienced as extensions of our bodies."

Aubrey de Grey is in the second, body preservationist group, whose efforts tend to be slightly more modest: Rather than solving death, they focus on extending life. His nonprofit, SENS Research Foundation, focuses on research in heart disease and Alzheimer's, and other common illnesses and diseases. (SENS, like many organizations the transhumanists are involved with, has received funding from Peter Thiel.) De Grey's most mainstream contribution is the popularization of the concept of "longevity escape velocity," which is explained as follows: "For every year that passes, the progress of longevity research is such that average human life expectancy increases by more than a year-a situation that would, in theory, lead to our effectively outrunning death." One might dismiss such transhumanist visions as too extreme: so many men, so much hubris. And yet, at a time of great cynicism about humanity - and the future we're all barreling toward - there is something irresistible about transhumanism. Call it magical thinking; call it radical optimism.

Dr. Ezekiel Emanuel is famous for a lot of reasons. He's an acclaimed bioethicist and oncologist and has two very well known brothers, but another thing people always seem to remember about him is that article he wrote in 2014: "Why I Hope to Die at 75." Emanuel's embrace of an early end - one that's only a few years shy of the U.S. life expectancy of 78.8 -is the exact opposite of how most people in America feel about dying. In a survey from the Pew Research Center, nearly 70% of American adults said they wanted to live to be up to 100 years old. But why?

"The quest to live forever, or to live for great expanses of time, has always been part of the human spirit," says Paul Root Wolpe, director of the Emory Center for Ethics. People now seem to have particular reason to be optimistic: in the past century, science and medicine have extended life expectancy, and longevity researchers (not to mention Silicon Valley types) are pushing for a life that lasts at least a couple decades more.

The titans of the tech industry are known for their confidence that they can solve any problem - even, as it turns out, the one that's defeated every other attempt so far. That's why the most far-out strategies to cheat death are being tested in America's playground for the young, deep-pocketed and brilliant: Silicon Valley. Larry Ellison, the co-founder of Oracle, has given more than 330 million to research about aging and age-related diseases. Alphabet CEO and co-founder Larry Page launched Calico, a research company that targets ways to improve the human lifespan. Peter Thiel, co-founder of PayPal, has also invested millions in the cause, including over 7 million to the Methuselah Foundation, a nonprofit focused on life-extension therapies.

Rather than wait years for treatments to be approved by federal officials, many of them are testing ways to modify human biology that fall somewhere on the spectrum between science and entrepreneurialism. It's called biohacking, and it's one of the biggest things happening in the Bay Area. "My goal is to live beyond 180 years," says Dave Asprey, CEO of the supplement company Bulletproof. "I am doing every single thing I can to make it happen for myself."

"So, you don't want to die?" I asked Zoltan Istvan, then the Transhumanist candidate for president, as we sat in the lobby of the University of Baltimore one day last fall. "No," he said, assuredly. "Never." Istvan, an atheist who physically resembles the pure-hearted hero of a Soviet children's book, explained that his life is awesome. In the future, it will grow awesomer still, and he wants to be the one to decide when it ends. Defying aging was the point of his presidential campaign. He knew he'd lose, of course, but he wanted his candidacy to promote the cause of transhumanism - the idea that technology will allow humans to break free of their physical and mental limitations. His platform included, in part, declaring aging a disease.

But his central goal-pushing the human lifespan far beyond the record 122 years and possibly into eternity - is one shared by many futurists in Silicon Valley and beyond. Investor Peter Thiel, who sees death as "the great enemy" of man, is writing checks to researchers like Cynthia Kenyon, who doubled the life-spans of worms through gene-hacking. Oracle founder Larry Ellison has thrown hundreds of millions toward anti-aging research, according to Inc magazine, and Google founders Larry Page and Sergey Brin launched the Google subsidiary Calico specifically with the goal of "curing death."

But let's assume, for the sake of argument, that it can be. Let's say human lives will soon get radically longer - or even become unending. The billionaires will get their way, and death will become optional. If we really are on the doorstep of radical longevity, it's worth considering how it will change human society. With no deadline, will we still be motivated to finish things? Or will we while away our endless days, amusing ourselves to - well, the Process Formerly Known as Death - while we overpopulate the planet? Will Earth become a paradise of eternally youthful artists, or a hellish, depleted nursing home? The answers depend on, well, one's opinion about the meaning of life.

How has the cryopreservation procedure evolved since the first human was placed in cryostasis?

The most important element in the progress of cryopreservation procedures in cryonics is the progressive elimination of ice formation. When cryonics started, patients were often cryopreserved without any cryoprotection or very low concentrations of cryoprotectant. In the 1980's and 1990's organizations such as Alcor started adapting mainstream perfusion technologies to introduce high concentrations of cryoprotectants (such as glycerol) to mitigate ice formation. In 2000 Alcor formally introduced vitrification with the aim of eliminating freezing altogether.

The elimination of ice formation, which can be achieved in good cases, removes one major form of mechanical damage in the cryopreserved brain. One very attractive feature of a low-toxicity vitrification agent like M22 is that it does not require rapid cooling to prevent ice formation. Under good circumstances (no prior ischemia) it can also be used in whole-body patients without edema - a problem that seemed to plague prior DMSO-based cryoprotectants in cryonics. Elimination of ice formation and reduced toxicity has substantially reduced the degree of damage associated with cryopreservation.

Which foreseeable advances in the field of cryobiology do you believe will lead to improvements in cryonics?

I foresee further advances in two areas; a more detailed understanding of the nature of cryoprotectant toxicity and the design of brain-optimized cryoprotectants. Cryoprotectant toxicity is currently the most formidable obstacle preventing reversible cryopreservation of complex mammalian organs. With the exception of the work of Dr. Greg Fahy and his colleagues at 21st Century Medicine, it is rather surprising how little theoretical and experimental research has been done to illuminate the mechanisms of cryoprotectant toxicity. It is also increasingly recognized that the poor penetration of cryoprotectants across the blood-brain barrier causes dehydration of the brain. We need to develop brain-optimized vitrification solutions and/or identify better methods to deliver cryoprotectants to the brain without such significant changes in brain volume. Resolving these two issues will bring us much closer to reversible brain cryopreservation.

What evidence is there that the brain is not damaged by the cryopreservation process to such an extent that the information in it may be lost forever?

To start with, if we can eliminate ice formation in the brain, the damage associated with cryoprotectant toxicity is assumed to be mostly of a biochemical nature (i.e. denatured proteins) and does not alter the ultrastructure of the brain in a way that precludes inferring the original state. Cryoprotectant-induced dehydration of the brain is a little more of a wild card because we do not have much detailed information about the kind of ultrastructural changes associated with it. Hence, the priority to avoid the brain shrinking that is routinely observed in "good" cases. Ultimately, our incomplete knowledge of the neuroanatomical basis of identity, and about the exact capabilities and limits of future medicine, prompt us to be agnostic about the degree of damage that is still compatible with meaningful revival. Advocates of cryonics are sometimes accused of being too optimistic about future science, but perhaps skeptics are too pessimistic.

To our knowledge (which is based on cryobiological studies and theoretical calculations), deterioration of patients stored at cryogenic temperatures should be non-existent or negligible. Things get a little bit more complicated when we store patients at intermediate temperatures instead of liquid nitrogen temperatures. It has been suggested that nucleation may still occur slightly below the temperature where the vitrification solution turns into a glass (-123 degrees Celsius). At that temperature, however, nucleation does not translate into ice formation but it might create more challenging repair and revival scenarios.

Do you have any hypotheses on how the cryoprotectant could be removed from the body during the reanimation procedure and how hypoxic injury during this removal procedure could be prevented?

In the vision of researchers such as Robert Freitas and Ralph Merkle, a mature form of mechanical nanotechnology will be used to conduct the initial stages of repair and cryoprotectant removal at cryogenic temperatures. If this vision of nanotechnology is plausible, cryoprotectant can be removed while providing (local) metabolic and structural support to prevent damage or freezing. An alternative vision of nanomedicine will involve the use of biological repair machines such as modified viruses or modified white blood cells that operate using conventional diffusion-driven chemistry rather than molecular mechanical nanotechnology. Repair is more challenging in this biological scenario because tissue first needs to be warmed to temperatures at which the cryoprotectant solution inside cells and tissue becomes liquid. This risks movement of damaged structures, possible growth of ice, and cryoprotectant toxicity accumulation occurring at the same time as repairs are being made.

Cryogenic storage of genetic mutants is already a common procedure in the roundworm C. elegans. Are you aware of any research taking place that tries to expand cryogenic storage to other model organisms?

Natasha Vita-Moore, who conducted recent studies on the effects of vitrification on memory in C. elegans, has suggested that the next step would be a slightly more complex organism such as the Greenland Woolly Bear Caterpillar or the ozobranchid leech. One of the most common suggestions I get is to attempt suspended animation on a mouse or rat. This would definitely provide powerful proof of principle for the feasibility of human suspended animation, but I do not think that the challenges in achieving reversible biostasis in a small mammal are that much smaller than in humans. We would need to overcome the same obstacles: minimizing cryoprotectant toxicity, chilling injury, dehydration of the brain, ischemia during cooling, and cryoprotective perfusion, etc. The majority opinion in cryonics is to solve these individual problems more thoroughly before attempting reversible cryopreservation of a complete animal.

Cardiac fibrosis, an abnormal thickening of the heart wall leading to congestive heart failure, was not only halted but also reversed by a caveolin-1 surrogate peptide (CSD) in a preclinical model, report researchers. CSD was able to decrease the fibrotic ventricular wall thickness and improve heart function, all with apparently no toxicity and minimal off-target effects. More than a decade ago, researchers noted that the skin and lung cells producing excess collagen in scleroderma, leading to fibrosis, were deficient in caveolin-1. Supplementing these cells with a caveolin-1 surrogate peptide (CSD; caveolin-1 scaffolding domain peptide), a truncated version of the original compound, showed a reversal of fibrosis.

Hypertrophic overgrowth and profibrogenic signaling of the cardiac muscle occurs under pressure overload. Fibrosis that develops under these conditions is detrimental to the heart's pumping efficiency as it causes a stiffer and less compliant cardiac muscle, leading to the progression of congestive heart failure. To mimic the cardiac fibrosis typical of heart failure, researchers used a transverse aortic constriction mouse model to create pressure overload hypertrophy that then led to the development of fibrosis. Treatment with CSD not only halted the progression of the cardiac fibrosis but also led to its reversal with improved ventricular function.

Although promising, these findings are preliminary - only reflecting outcomes in mice. The researchers plan to run larger preclinical studies using the same approach to generate more definitive data, and if all goes as expected, to move forward to the large-animal studies necessary to take a compound forward into clinical trial. They also note that they are testing CSD in a different congestive heart failure model, the angiotensin II infusion model, which also affects the kidneys. CSD is showing promising anti-fibrotic effects on both the heart and the kidneys in this model. "Fibrotic diseases are related to each other no matter the affected organ. In our case, we were studying lung and skin fibrosis. We had the opportunity to test the same reagent in heart fibrosis and, lo and behold, it worked even better than in lung and skin fibrosis models. And there are plenty of other diseases with a fibrotic element to them where we think the CSD peptide might be useful."

Chronic ventricular pressure overload (PO) results in congestive heart failure (CHF) in which myocardial fibrosis develops in concert with ventricular dysfunction. Caveolin-1 is important in fibrosis in various tissues due to its decreased expression in fibroblasts and monocytes. The profibrotic effects of low caveolin-1 can be blocked with the caveolin-1 scaffolding domain peptide (CSD, a caveolin-1 surrogate) using both mouse models and human cells.

We have studied the beneficial effects of CSD on mice in which PO was induced by trans-aortic constriction (TAC). Beneficial effects observed in TAC mice receiving CSD injections daily included: improved ventricular function (increased ejection fraction, stroke volume, and cardiac output; reduced wall thickness); decreased collagen I, collagen chaperone HSP47, fibronectin, and CTGF levels; decreased activation of non-receptor tyrosine kinases Pyk2 and Src; and decreased activation of eNOS. To determine the source of cells that contribute to fibrosis in CHF, flow cytometric studies were performed that suggested that myofibroblasts in the heart are in large part bone marrow-derived. Two CD45+ cell populations were observed. One (Zone 1) contained CD45+/HSP47-/macrophage marker+ cells (macrophages). The second (Zone 2) contained CD45moderate/HSP47+/macrophage marker- cells often defined as fibrocytes. TAC increased the number of cells in Zones 1 and 2 and the level of HSP47 in Zone 2. These studies are a first step in elucidating the mechanism of action of CSD in heart fibrosis and promoting the development of CSD as a novel treatment to reduce fibrosis and improve ventricular function in CHF patients.

When we are young, our blood stem cells produce an even and well-balanced number of red and white blood cells according to need. As we age, however, the capacity of the blood stem cells to produce the number of blood cells we need declines. "This type of age-related change can have major consequences as it can lead to an imbalance in stem cell production. For example, a reduced production of immune cells or excessive production of other types of cells can be a precursor to leukaemia."

A fundamental question was whether blood stem cells age differently within a single individual or whether all blood stem cells are equally affected by advancing age. In an initial stage, it was therefore important to genetically mark old blood stem cells, to enable the identification and tracking of those most affected by age. In the next step, these traceable cells were reprogrammed to another type of stem cell - known as iPS cells, which can generate all cells in an individual and not only blood cells. When the cells are reprogrammed, their identity is "re-set"; when these reprogrammed iPS cells formed new blood stem cells, the researchers observed that the re-set had entailed a rejuvenation of the cells. "We found that there was no difference in blood-generating capacity when we compared the reprogrammed blood stem cells with healthy blood stem cells from a young mouse. This is, as far as we know, the first time someone has directly succeeded in proving that it is possible to recreate the function of young stem cells from a functionally old cell.ˮ

The research team's studies have also thereby shown that many age-related changes in the blood system cannot be explained by mutations in the cells' DNA. If the changes depended on permanent damage at the DNA level, the damage would still be present after the re-set. Instead, epigenetic changes appear to underlie the decline in function associated with advancing age.

While age-related diseases evidently can arise due to changes that compromise or alter the function of mature effector cells, this is harder to reconcile with organs such as the blood, that rely on inherently short-lived effector cells in need of continuous replenishment. Rather, accumulating data have suggested that the de novo production of subclasses of haematopoietic cells shifts in an age-dependent manner, akin to that seen during more narrow time windows in early development. These findings have to a large extent also challenged the classically defining criteria of haematopoietic stem cells (HSCs) as a homogenous population of cells with differentiation capacity for all haematopoietic lineages. Rather, the differentiation capacity of HSCs might be more appropriately defined by a continuous multilineage haematopoietic output, but which might not necessarily include the production of all types of blood cells at all points in time.

The mechanisms that drive ageing at both the organismal and cellular level have attracted significant attention as they represent prime targets for intervention. An increased function of aged cells by 'young'-associated systemic factors has been proposed. Whether such approaches indeed reflect rejuvenation at a cellular level or rather stimulate cells less affected by age is mostly unclear. This concern applies also to previous studies approaching the prospects of reversing cellular ageing by somatic cell reprogramming, which have typically failed to distinguish between functionally versus merely chronologically aged cells.

Here we approach these issues by genetic barcoding of young and aged HSCs that allows for evaluations, at a clonal level, of their regenerative capacities following transplantation. This allows us to establish that ageing associates with a decrease of HSC clones with lymphoid potential and an increase of clones with myeloid potential. We generate induced pluripotent stem (iPS) lines from functionally defined aged HSC clones, which we next evaluate from the perspective of their blood-forming capacity following re-differentiation into HSCs by blastocyst/morula complementation. Our experiments reveal that all tested iPS clones, including such that were originally completely devoid of T-cell and/or B-cell potential, perform similar to young HSCs both in steady-state and when forced to regenerate lymphomyeloid haematopoiesis in secondary transplantations. This regain in function coincides with transcriptional features shared with young rather than aged HSCs. Thereby, we provide direct support to the notion that several functional aspects of HSC ageing can be reversed to a young-like state.

According to the amyloid cascade hypothesis of Alzheimer's disease (AD) pathogenesis, the aggregation and cerebral deposition of amyloid-β (Aβ) peptides into extracellular amyloid plaques is an early and critical event triggering a cascade of pathological incidents that finally lead to dementia. Thus, arguing in favor of this hypothesis, the most rational strategy for an AD therapy would be to retard, halt and even reverse Aβ aggregation. However, despite all research efforts there is currently no treatment for AD, and currently approved therapies only provide symptomatic treatments for this disease.

Numerous studies indicate that microbial communities represent an essential factor for many physiological processes including nutrition, inflammation, and protection against pathogens. The microbial community is largely composed of bacteria that colonize all mucosal surfaces, with the highest bacterial densities found in the gastrointestinal tract. Increasing evidence suggests the gastro-intestinal tract is the bridge between microbiota and the central nervous system. Clinical and experimental evidence suggests that gut microbiota may contribute to aging and influence brain disorders. Recently, a study revealed an association of brain amyloidosis with pro-inflammatory gut bacteria of cognitively impaired patients. Furthermore, a recent study showed that antibiotic-mediated perturbations in the gut microbiome modulates amyloid deposition in an AD mouse model. While such findings strongly suggest that the gut microbiota may impact a wide range of brain disorders including AD, the impact of complete depletion of intestinal microbes on AD pathogenesis is unknown.

Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

Our results showing reduced microgliosis and changes in the brain cytokine profile are in line with a recent publication demonstrating that germ-free mice show immature microglia and reduced pro-inflammatory cytokine production. Importantly, caspase-1 knockout (which prevents the production of IL-1β) has been shown to be sufficient to strongly reduce plaque load in APPPS1 animals through altering the microglial activation state and enhancing microglial phagocytosis of Aβ plaques. Therefore, a change in microglial responses in germ-free APPPS1 animals could contribute to the reduction of amyloid load observed in germ-free animals. Several in vitro and in vivo studies have shown that neprilysin (NPE) and insulin degrading enzymes (IDE) can degrade Aβ. Most notably, NPE and IDE levels were increased in germ free APPPS1 mice, indicating that increased levels of these Aβ degrading enzymes may contribute to decreased cerebral Aβ amyloidosis in germ free animals. Altogether, these results indicate that Aß degrading enzymes may partially play a role in decreasing Aβ levels and cerebral Aß amyloidosis in germ free animals.

A study offers evidence bolstering one long-held theory: that aging is caused, at least in part, by molecular damage accumulating in the cells. This damage is generated by nearly every cellular process by the work of enzymes and proteins and the life-sustaining metabolic processes that occur at every level of complexity, from simple molecules and cell components to whole cells and entire organs. Over time we have many, many damage forms, byproducts of enzyme function, for example, or of protein-to-protein interactions, errors in DNA transcription or translation. As a function of age, they accumulate, and eventually, it's more than the body can cope with.

Researchers found that feeding a diet of "old" organisms to yeast, fruit flies, and mice shortened their lifespans by roughly 10 percent. Here's how it worked: for yeast, the researchers formulated one cell-culture medium composed of extracts from young yeast cells and another of extracts from old ones. They then grew new yeast cells on each medium and watched to see which set would live longer. "Our hypothesis was that as yeast ages, it accumulates certain damage forms, and we wanted to test that specific damage and find out if it is deleterious for yeast."­­­­ The team replicated the same basic procedure in fruit flies and mice: they collected 5,000 freshly dead flies that had lived an average of 45 days, and sacrificed 5,000 others that were three to five days old. Then they prepared two homogenized diets, one composed of young flies and the other using the old ones. They fed these diets to young female fruit flies. The mice were fed diets of skeletal muscle from young and old farmed red deer (three years old versus 25) that replaced the animal-product components (insects, carrion, worms, etc.) of a normal mouse diet. Using mouse tissue was not feasible because of the large quantities needed for the experiment; deer meat was a suitably close match.

The experiments raise new questions - in a field that's full of them - and some of the results were a little unexpected. The researchers had expected to see larger differences in the test organisms' relative lifespans. The effect was consistent, however, across all three species. In the study, the authors interpret the minor-but-consistent effect to mean that damage accumulation may be only one contributing factor in aging, and also that damage caused by internal molecular changes may have a stronger effect than damage introduced through the diet. It's also likely that the damage arises from many processes. "And they all work together in a deleterious way. So the question is, how do we slow down this process? How do we restructure cellular metabolism so that this damage accumulates at a slower rate?"

As a cause for the decreasing health status that accompanies aging, mitochondrial deterioration has been repeatedly suggested. Particularly, it has been discussed that an accumulation of errors in mitochondrial DNA (mtDNA) replication would lead to mitochondrial dysfunction, including increased production of reactive oxygen species (ROS) that may both further deteriorate the mitochondria and affect the function of the rest of the cell. However, the significance of ROS for the aging process has been doubted, particularly based on observations in the mtDNA mutator mice. These mice accumulate errors in their mtDNA and demonstrate subsequent alterations in their respiratory chain composition. They also demonstrate an early occurrence of characteristics normally associated with aging, and they die at a young age. However, there has been no convincing evidence that oxidative damage causes these problems.

Experimentally, an alternative avenue to examine the possible involvement of ROS in the development of aging characteristics would be to examine the ability of mitochondrially targeted antioxidants to ameliorate the health problems associated with experimentally induced aging. In this paper, we find that the mitochondrially targeted antioxidant 10-(6'-plastoquinonyl)decyltri-phenylphosphonium cation (SkQ1) substantially counteracts the acquisition of aging characteristics in the mtDNA mutator mice. We also find that parameters for oxidative damage not earlier examined (cardiolipin depletion and accumulation of hydroxynonenal protein adducts) are diminished by SkQ1 treatment. These data clearly indicate that ROS production and oxidative damage are substantial factors in the development of aging characteristics in the mtDNA mutator mice.

As the presently reluctance to associate mitochondrial dysfunction with aging through ROS and oxidative damage are largely based on the notion that these phenomena were apparently not involved in aging in mtDNA mutator mice, and as our present data indicate the opposite to be the case, our observations may also be of significance for discussions of the nature of aging and the possibility to ameliorate the aging process therapeutically.

Autophagy functions as a main route for the degradation of superfluous and damaged constituents of the cytoplasm. Defects in autophagy are implicated in the development of various age-dependent degenerative disorders such as cancer, neurodegeneration and tissue atrophy, and in accelerated aging. To promote basal levels of the process in pathological settings, we previously screened a small molecule library for novel autophagy-enhancing factors that inhibit the myotubularin-related phosphatase MTMR14/Jumpy, a negative regulator of autophagic membrane formation.

Here we identify AUTEN-99 (autophagy enhancer-99), which activates autophagy in cell cultures and animal models. AUTEN-99 appears to effectively penetrate through the blood-brain barrier, and impedes the progression of neurodegenerative symptoms in Drosophila models of Parkinson's and Huntington's diseases. Furthermore, the molecule increases the survival of isolated neurons under normal and oxidative stress-induced conditions. Thus, AUTEN-99 serves as a potent neuroprotective drug candidate for preventing and treating diverse neurodegenerative pathologies, and may promote healthy aging.

A type of treatment for multiple sclerosis that 'resets' the immune system may stop progression of the disease in nearly half of patients. In a new study the treatment prevented symptoms of severe disease from worsening for five years, in 46 per cent of patients. However, as the treatment involves aggressive chemotherapy, the researchers stress the procedure carries significant risk. The treatment in the current study, called autologous hematopoietic stem cell transplantation (AHSCT), was given to patients with advanced forms of the disease that had failed to respond to other medications.

The one-off treatment aims to prevent the immune system from attacking the nerve cells. All immune system cells are made from stem cells in the bone marrow. In the treatment, a patient is given a drug that encourages stem cells to move from the bone marrow into the blood stream, and these cells are then removed from the body. The patient then receives high-dose chemotherapy that kills any remaining immune cells. The patient's stem cells are then transfused back into their body to re-grow their immune system. Previous studies have suggested this 'resets' the immune system, and stops it from attacking the nerve cells.

However, because the treatment involves aggressive chemotherapy that inactivates the immune system for a short period of time, some patients died from infections. Out of the 281 patients who received the treatment in the study, eight died in the 100 days following the treatment. Older patients, and those with the most severe forms of the disease, were found to have a higher risk of death. "In this study, which is the largest long-term follow-up study of this procedure, we've shown we can 'freeze' a patient's disease - and stop it from becoming worse, for up to five years. However, we must take into account that the treatment carries a small risk of death, and this is a disease that is not immediately life-threatening."

In 1997, Dolly the sheep was introduced to the world. The implications of cloning animals in our society were self-evident from the start. Our advancing ability to reprogram adult, already-specialized cells and start them over as something new may one day be the key to creating cells and organs that match the immune system of each individual patient in need of replacements. But what somehow got lost was the fact that a clone was born - at day zero - created from the cell of another animal that was 6 years old. Researchers have spent the past 20 years trying to untangle the mysteries of how clones age. How old, biologically, are these animals born from other adult animals' cells?

When Dolly was cloned, she was created using a cell from a 6-year-old sheep. And she died at age 6-and-a-half, a premature death for a breed that lives an average of nine years or more. People assumed that an offspring cloned from an adult was starting at an age disadvantage. Rather than truly being a "newborn," it seemed like a clone's internal age would be more advanced than the length of its own life would suggest. Thus the notion that clones' biological ages and their chronological ones were out of sync, and that "cloned animals will die young."

Some of us were convinced that if the cloning procedure was done properly, the biological clock should be reset - a newborn clone would truly start at age zero. We worked very hard to prove our point. We were not convinced by a single DNA analysis done in Dolly showing slightly shorter telomeres - the repetitive DNA sequences at the end of chromosomes that "count" how many times a cell divides. We presented strong scientific evidence showing that cloned cows had all the same molecular signs of aging as a nonclone, predicting a normal lifespan. Others showed the same in cloned mice. But we couldn't ignore reports from colleagues interpreting biological signs in cloned animals that they attributed to incomplete resetting of the biological clock. So the jury was out.

Aging studies are very hard to do because there are only two data points that really count: date of birth and date of death. If you want to know the lifespan of an individual you have to wait until its natural death. By 2012 that was in fact being accomplished: there were several cloned Dollies, all much older than Dolly at the time she had died, and they looked terrific. This work was finally published last year. "For those clones that survive beyond the perinatal period, the emerging consensus, supported by the current data, is that they are healthy and seem to age normally."

The new Dollies are now telling us that if we take a cell from an animal of any age, and we introduce its nucleus into a nonfertilized mature egg, we can have an individual born with its lifespan fully restored. They confirmed that all signs of biological and chronological age matched between cloned and noncloned sheep. There seems to be a natural built-in mechanism in the eggs that can rejuvenate a cell. We don't know what it is yet, but it is there. Our group as well as others are hard at work, and as soon as someone finds it, the most astonishing legacy of Dolly will be realized.

A new study analysed long-term data on mortality and longevity trends to predict how life expectancy will change in 35 industrialised countries by 2030. Nations in the study included both high-income countries, such as the USA, Canada, UK, Germany, Australia, and emerging economies such as Poland, Mexico and the Czech Republic. The study revealed all nations in the study can expect to see an increase in life expectancy by 2030. The results also found that South Koreans may have the highest life expectancy in the world in 2030. "The increase in average life expectancy in high income countries is due to the over-65s living longer than ever before. In middle-income countries, the number of premature deaths - i.e. people dying in their forties and fifties, will also decline by 2030."

The team calculated life expectancy at birth, and predicted a baby girl born in South Korea in 2030 will expect to live 90.8 years. Life expectancy at birth for South Korean men will be 84.1 years. The researchers also calculated how long a 65-year-old person may expect to live in 2030. The results revealed that the average 65-year-old woman in South Korea in 2030 may live an additional 27.5 years. Scientists once thought an average life expectancy of over 90 was impossible. "We repeatedly hear that improvements in human longevity are about to come to an end. Many people used to believe that 90 years is the upper limit for life expectancy, but this research suggests we will break the 90-year-barrier. I don't believe we're anywhere near the upper limit of life expectancy - if there even is one."

French women and Swiss men were predicted to have the highest life expectancies at birth in Europe in 2030, with an average life expectancy of 88.6 years for French women and nearly 84 years for Swiss men. The results also revealed that the USA is likely to have the lowest life expectancy at birth in 2030 among high-income countries. The nation's average life expectancy at birth of men and women in 2030 (79.5 years and 83.3 years), will be similar to that of middle-income countries like Croatia and Mexico. The team also predicted a 65-year-old UK man in 2030 could expect to live an additional 20.9 years (12th in the table of countries), while a 65-year-old woman in the UK could expect to live an additional 22.7 years, up (22nd in the table of countries). The research also suggested the gap in life expectancy between women and men is closing. "Men traditionally had unhealthier lifestyles, and so shorter life expectancies. They smoked and drank more, and had more road traffic accidents and homicides. However as lifestyles become more similar between men and women, so does their longevity."

A study has shown evidence linking the biology of aging with idiopathic pulmonary fibrosis, a disease that impairs lung function and causes shortness of breath, fatigue, declining quality of life, and, ultimately, death. Researchers believe that these findings are the next step toward a possible therapy for individuals suffering from idiopathic pulmonary fibrosis. "Idiopathic pulmonary fibrosis is a poorly understood disease, and its effects are devastating. Individuals with idiopathic pulmonary fibrosis express difficulty completing routine activities. There are currently no effective treatment options, and the disease leads to a dramatic decrease in health span and life span, with life expectancy after diagnosis between three to five years."

Researchers studied the lung tissue of healthy individuals and of persons with mild, moderate and severe idiopathic pulmonary fibrosis. Researchers found that the markers of cellular senescence, a process triggered by damage to cells and linked to aging, were higher in individuals with idiopathic pulmonary fibrosis, and senescent cell burden increased with the progression of the disease. Then, they demonstrated that factors secreted by senescent cells could drive inflammation and aberrant tissue remodeling and fibrosis, which are hallmarks of idiopathic pulmonary fibrosis. "Up to this point, research efforts have largely focused on understanding the unique elements that contribute to idiopathic pulmonary fibrosis. Here, we are considering whether the biology of aging is accelerated in this aggressive disease. What we've found is that senescent cells are prevalent, secreting toxic molecules that affect healthy cells in that environment and are essentially promoting tissue fibrosis."

Equipped with the findings from their studies of human lung tissue, researchers then replicated the process in mice. They found that, much like in humans, mice with clinical features of idiopathic pulmonary fibrosis also demonstrated increased amounts of senescent cells. Researchers used a genetic model programmed to make senescent cells self-destruct and a drug combination of dasatinib and quercetin which, in previous studies, was shown to eliminate senescent cells. Results showed that clearing senescent cells from unhealthy mice improved measures of lung function and physical health, such as exercise capacity on a treadmill. "We are exploring whether senolytic drugs, or drugs that can selectively kill senescent cells, can be used for the treatment of aging-associated conditions, including idiopathic pulmonary fibrosis. More research is needed to validate this, and our goal is to move quickly from discovery to translation to application, and, ultimately, meet the unmet needs of our patients."

Within the inner ear, thousands of hair cells detect sound waves and translate them into nerve signals. Each of us is born with about 15,000 hair cells per ear, and once damaged, these cells cannot regrow. Noise exposure, aging, and some antibiotics and chemotherapy drugs can lead to hair cell death. In some animals, those cells naturally regenerate, but not in humans. However, researchers have now discovered a combination of drugs that expands the population of progenitor cells (also called supporting cells) in the ear and induces them to become hair cells, offering a potential new way to treat hearing loss.

The research team began investigating the possibility of regenerating hair cells during an earlier study on cells of the intestinal lining. In that study, researchers reported that they could generate large quantities of immature intestinal cells and then stimulate them to differentiate, by exposing them to certain molecules. During that study, the team became aware that cells that provide structural support in the cochlea of the ear express some of the same surface proteins as intestinal stem cells. The researchers decided to explore whether the same approach would work in those supporting cells.

They exposed cells from a mouse cochlea, grown in a lab dish, to molecules that stimulate the Wnt pathway, which makes the cells multiply rapidly. At the same time, to prevent the cells from differentiating too soon, the researchers also exposed the cells to molecules that activate another signaling pathway known as Notch. Once they had a large pool of immature progenitor cells, the researchers added another set of molecules that provoked the cells to differentiate into mature hair cells. This procedure generates about 60 times more mature hair cells than the technique that had previously worked the best, which uses growth factors to induce the supporting cochlea cells to become hair cells without first expanding the population.

The researchers found that their new approach also worked in an intact mouse cochlea removed from the body. In that experiment, the researchers did not need to add the second set of drugs because once the progenitor cells were formed, they were naturally exposed to signals that stimulated them to become mature hair cells. "We only need to promote the proliferation of these supporting cells, and then the natural signaling cascade that exists in the body will drive a portion of those cells to become hair cells." Because this treatment involves a simple drug exposure, the researchers believe it could be easy to administer it to human patients. They envision that the drugs could be injected into the middle ear, from which they would diffuse across a membrane into the inner ear.

In this article, I'll try to show that the overpopulation objection against rejuvenation is morally deplorable, that not developing rejuvenation for the sake of avoiding overpopulation is morally unacceptable, and thus overpopulation doesn't constitute a valid objection to rejuvenation. I'll start with an example. Imagine there's a family of two parents and three children. They're not doing too well financially, and they live packed in a tiny apartment with no chances of moving somewhere larger. Clearly they cannot afford having more children, but they would really like having more anyway. What should they do? The only reasonable answer is that they should not have any more children until they can afford having them. Throwing away the old ones for the sake of some other child to be even conceived yet would be nothing short of sheer madness.

That being said, let's have a look at the overpopulation objection. It can be summarised as follows: If we cured ageing, we would end up having more people than our planet can sustain. Therefore we should not cure ageing. Translation: Curing ageing means eliminating age-related diseases as a cause of death, i.e. eliminating a very effective way to get rid of older people. If we don't get rid of older people, we won't have room for new ones, so we shouldn't cure ageing.

If we were to apply this logic to the small-scale example of the family, we should get rid of the older kids to make room for the new ones, and I'm not talking about kicking them out of the house when they're 18; new people are born all the time in the world, which in our small-scale example translates to the family wanting more kids here and now. Not curing ageing means letting people become sick with horrible age-related diseases and die of them; in the small-scale example, this could be compared to not vaccinating the kids. It goes without saying that, from a merely moral standpoint, if we're afraid that we might end up having more people than we can afford having, the appropriate answer to this problem is 'let's not make more people than we can afford having'.

Still, the idea of present-day people dying for the sake of potential future children who aren't even in their mothers' wombs yet somehow seems perfectly acceptable; however, when applied the example of the family, the very same idea appears to be a clear case of being several sandwiches short of a picnic. Why this double standard? I can think of three reasons. The first, obvious reason is that death by ageing happens 'naturally' and up until now has been inevitable, so by the false equation 'normal'='right', people conclude this is how things should be. The second reason might be that we don't value elderly lives as much as children's. This may be understandable from the cynical survival-of-the-species point of view, but is absolutely undefendable from any humane point of view. The third reason is that we don't really think of humanity as some sort of big family. The children of the family example are much more 'concrete' than the elderly people of the large-scale example. When you think of the former, you identify with one of the parents and are horrified at the thought of throwing away your own children; when you think of the latter, for the most part they're just random elderly people whom you don't know and have no emotional attachment to.

Long story short: You can't use overpopulation as a reason to object to rejuvenation biotechnologies, because you can't ask people to give up on good health and potentially indefinite lifespans for the sake of people who aren't even in the making yet. The only reasonable alternative is that we don't make more people than we can afford having.

Transthyretin amyloidosis (ATTR amyloidosis) is caused by the misfolding and deposition of the transthyretin (TTR) protein and results in progressive multi-organ dysfunction. TTR epitopes exposed by dissociation and misfolding are targets for immunotherapeutic antibodies. We developed and characterized antibodies that selectively bound to misfolded, non-native conformations of TTR. Antibody clones were generated by immunizing mice with an antigenic peptide comprising a cryptotope within the TTR sequence and screened for specific binding to non-native TTR conformations, suppression of in vitro TTR fibrillogenesis, promotion of antibody-dependent phagocytic uptake of misfolded TTR and specific immunolabeling of ATTR amyloidosis patient-derived tissue.

Four identified monoclonal antibodies were characterized. These antibodies selectively bound the target epitope on monomeric and non-native misfolded forms of TTR and strongly suppressed TTR fibril formation in vitro. These antibodies bound fluorescently tagged aggregated TTR, targeting it for phagocytic uptake by macrophage THP-1 cells, and amyloid-positive TTR deposits in heart tissue from patients with ATTR amyloidosis, but did not bind to other types of amyloid deposits or normal tissue. These novel antibodies may be therapeutically useful in preventing deposition and promoting clearance of TTR amyloid and in diagnosing TTR amyloidosis.