Fight Aging! Newsletter, February 27th 2017

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • The Media Meanders on the Topic of Enhanced Longevity
  • An Interview with Aschwin de Wolf on Cryonics at LongeCity
  • Towards Therapies Capable of Reversing the Progression of Fibrosis
  • Induced Pluripotency as a Tool to Enable Rejuvenation of Blood Production
  • Evidence for Gut Microbes to Speed Amyloid Buildup in Alzheimer's Disease
  • Latest Headlines from Fight Aging!
    • A Diet of Old Tissues Modestly Shortens Life Span
    • SkQ1 Slows Accelerated Aging in Mitochondrial Mutator Mice
    • Identification of a Potential Autophagy Enhancement Drug
    • The Risks of Current Approaches to Rebooting the Immune System
    • Is a Clone Born at Age Zero?
    • Projecting out Current Life Expectancy Trends to 2030
    • Senescent Cells Implicated as a Cause of Idiopathic Pulmonary Fibrosis
    • Working on a Drug to Stimulate Regeneration of Lost Hair Cells in the Inner Ear
    • Arguing that it is Immoral to Object to Longevity Science for Fear of Overpopulation
    • The Basis for an Antibody Therapy to Treat Transthyretin Amyloidosis

The Media Meanders on the Topic of Enhanced Longevity

For various reasons, such as people promoting their books, the mainstream media has been giving more attention than usual these past few weeks to the topic of healthy life extension. The quality of the resulting articles is fairly low, as is usually the case. When given marching orders to cover any particular topic, the average journalist grabs the first few specific items that show up in a search of recent articles, wraps them with some pretty words, and launches the result without any attempt at achieving or conveying real understanding of the subject. When it comes aging and efforts to treat aging as a medical condition, just like any other quite complex topic in science and medicine, that real understanding is absolutely vital in order to distinguish between arrant nonsense, legitimate but poor approaches, and efforts that might do very well indeed if given sufficient support. The media is not the place to search for comprehension, on this or any other subject, sadly. So we see articles in which supplements, calorie restriction mimetic research, senescent cell clearance, and spa treatments are all ranked equally, without judgement or insight - options spanning the gamut of the aforementioned arrant nonsense through to potentially viable rejuvenation therapies.

Does it do the cause of human rejuvenation any good to have the press talk more rather than less, when nine-tenths of what is published is wrong, useless, or outright disinformation? It can be argued that there is no such thing as bad publicity. If these bland articles spur some people into moving from the class of those who do nothing into the class of those who head off to find out more, then some of the more active of those folk will eventually make their way into our community. There are many roads to learning about SENS-like rejuvenation research: from the personal health and fitness world; from time spent in other areas of the life sciences; from a passing interest in living longer acquired via supplement sellers; because it is talked about among members of an otherwise unrelated community, such as in the Bay Area technology circles; and so forth. So long as people arrive and help with meaningful progress in research and development, help to grow the community, I don't think the road taken matters all that much. Even if it starts with a few eye-rollingly terrible articles in the press.

Only Human: Meet the hackers trying to solve the problem of death

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.

Why Do People Want to Live So Long, Anyway?

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.

How Silicon Valley Is Trying to Hack Its Way Into a Longer Life

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."

Should We Die?

"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.

An Interview with Aschwin de Wolf on Cryonics at LongeCity

Aschwin de Wolf of Advanced Neural Biosciences and the Institute for Evidence-Based Cryonics (IEBC) is a noted advocate for cryonics as an industry and area of research. He was recently interviewed by the folk over at LongeCity, and as usual it makes for interesting reading. You might also look at a 2013 interview for more of the same, and in addition you'll find many articles at the IEBC site covering a mix of technical and non-technical topics in the the cryonics field. This is one slice of a great deal of technical writing and advocacy for cryonics published over the course of the past few decades, a fair portion of it by people who are now themselves cryopreserved at Alcor or the Cryonics Institute.

The term cryonics covers the technology, community, and practice of placing people into a vitrified state as soon as possible following clinical death. Tissues are perfused with cryoprotectant and cooled to liquid nitrogen temperatures in stages, leading to a glass-like state of minimal ice-crystal formation. Under good conditions, this preserves the fine structures of neural tissue, the synapses, dendrites, and dendritic spines within which the data of the mind is thought to be stored. For so long as that data remains intact, and the vitrified individual in low-temperature storage, there is the possibility of future restoration in an era with more proficient technology than our own. In this age of progress, cryonics is a necessary backup plan for those of who may not live long enough to benefit from the near future of rejuvenation therapies after the SENS model. It is a great pity that it remains a small and marginal undertaking, largely non-profit, and unknown to many who would benefit, even as tens of millions march towards their own personal oblivion each and every year.

While higher animals cannot yet be thawed, cleared of cryoprotectant, and brought back to life, that outcome can be achieved with lower animals such as nematode worms. Thawing and transplantation has also been demonstrated in prototype for mammalian organs in recent years. At present there is the makings of a small industry working on reversible cryopreservation for tissue engineering and organ transplantation, where such a technology would greatly reduce costs and simplify logistics. So when we talk about preserving people for the chance at a future restoration, this isn't done in a vacuum, and isn't a flight of fancy; there is good reason to think that there is a chance of success in this endeavor. It certainly beats the odds of revival from the grave, which is to say zero.

Interview with Aschwin de Wolf (February, 2017)

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.

Towards Therapies Capable of Reversing the Progression of Fibrosis

Fibrosis is a significant component of many age-related conditions, a failure of the normal regenerative process that leads to the formation of increasing amounts of scar-like, fibrous connective tissue in organs. This disrupts normal tissue structure and degrades proper function. It features prominently in common forms of heart disease, kidney failure, and liver disease, among others. As is the case for many specific aspects of aging, there is no good treatment for fibrosis, if by this we mean a reliable way to turn back its progression and restore failing tissues to their former state.

The causes of fibrosis lie somewhere downstream of the fundamental forms of cell and tissue damage outlined in the SENS view of aging. Insofar as it is cells that work to produce fibrotic structures, built from the same materials as the normal extracellular matrix, the proximate causes of fibrosis are thus altered cell signaling and behavior, such as that related to the increased chronic inflammation that accompanies aging. The nature of these signals is much debated, and likely varies considerably from tissue to tissue.

Given the importance of fibrosis to the progression of age-related disease, there is considerable interest in finding ways to reverse its progression, not just slow it down. Most such research, as is the case in the paper linked below, is focused on the proximate causes of fibrosis, the altered cellular signaling and behavior. Researchers hope that by forcing a change here, through the use of small molecule drugs and the like, they can change cellular behavior for the better despite the continued existence of underlying damage that causes dysfunction, and set cells to removing fibrosis and correctly regenerating tissue. Or at last tilt the balance somewhat in that direction.

Peptide reverses cardiac fibrosis in a preclinical model of congestive heart failure

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."

Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide

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.

Induced Pluripotency as a Tool to Enable Rejuvenation of Blood Production

It has been a decade or so since the first induced pluripotent stem (iPS) cells were produced. Researchers discovered a recipe by which ordinary, limited, adult somatic cells could be reprogrammed into a state near identical to that of embryonic stem cells, meaning they are pluripotent and can then in principle be used to produce any of the cell types in the body. Doing so in practice requires researchers to establish a suitable methodology to guide cellular differentiation in the right direction, only accomplished at this point for a fraction of all possible cell types. The early attempts at induced pluripotency worked, and were easy to set up, but were also comparatively inefficient. Since then researchers have produced considerable improvement in the methodologies used, and along the way have explored other facets of this reprogramming process. One of the most intriguing aspects of induced pluripotency is that it appears to produce a form of cellular rejuvenation, a sweeping reset and repair of many forms of damage.

There are many open questions regarding this incompletely explored cellular rejuvenation achieved through induced pluripotency: how it works at the detail level; exactly which types of damage are repaired and which are not; how it relates to the equivalent process that occurs in the early development of the embryo. How do old gamete cells, laden with the molecular damage of aging, produce young offspring who lack that damage? Somewhere in there, rejuvenation happens. Is there any way to adapt this process of rejuvenation for use in therapies? It seems unwise to, for example, apply pluripotency reprogramming methods directly to a patient. This sounds a lot like opening the door to a high risk of uncontrolled cellular replication, or cancer in other words. Nonetheless, that experiment was recently carried out in mice, more or less, so we'll likely hear more about the risks in the years ahead. It is possible that such an approach will in the end fall into the same ballpark as stem cell therapies when it comes to overall degree of risk, though it is worth noting that, when performed improperly, stem cell therapies can also result in cancer, and considerable amount of work has gone into minimizing that outcome in those therapies that have made it to widespread clinical availability.

There are other possibilities when it comes to using the rejuvenation that occurs during the induced pluripotency process, however. Take a population of cells that are damaged and dysfunctional in an old individual, for example. Obtain a sample, create an induced pluripotent lineage from that sample, and then apply a suitable recipe to differentiate the pluripotent cells back into the original cell type. Do these recreated cells now behave as though they are younger, and can thus form the basis for a cell therapy to replace the old cells in the patient? Researchers here demonstrate that this is in fact the case for the stem cells responsible for generating blood:

How blood can be rejuvenated

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.

Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate

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.

Evidence for Gut Microbes to Speed Amyloid Buildup in Alzheimer's Disease

A great diversity of microbial life dwells inside us all, largely in the gut, and these microbes interact with our tissues and immune system in ways that the research community has only recently started to map in earnest. There are a handful of obvious and sometimes very serious medical conditions caused by the presence and inappropriate behavior of forms of microbe in the gut, but beyond this even the more common species are clearly an important component of the body as a whole. They play as great a role as many individual organs in determining health and pace of aging, one slice of the myriad complex interactions that take place constantly between the surrounding environment and various bodily systems.

One of the more direct paths by which the microbiome of the gut can affect long-term health is via its interactions with the immune system. The degree to which the immune system declines with age is in part a function of its exposure to pathogens and other, similar circumstances, and the more of that taking place the worse off you'll be by the time old age rolls around. It is also a matter of the degree to which the immune system is constantly active, however, due to the rising levels of chronic inflammation that accompany old age. Gut microbes can certainly trigger greater inflammation at any age, to some degree, and over time that is thought to add up. Most age-related conditions are accelerated in their progression by inflammation, both via its impact on immune function and via other mechanisms. Among these is Alzheimer's disease and its association with misfolded protein aggregates in the brain: amyloid and tau. Levels of amyloid and tau in the brain are at least somewhat determined by the efficiency with which the immune system can dispose of the unwanted excess, but other links with the inflammatory state of the brain's immune system are also well demonstrated.

So all that said, the open access paper linked below fits into the bigger picture fairly well. Working with mice, the authors provide evidence for differing constituents of the gut microbiome to contribute to the progression of Alzheimer's disease, or at least to the observed levels of amyloid in the brain. While interesting, I think that the likely outcome of applying this knowledge to human medicine is probably incremental at best, let us say along the lines of the impact of excess fat tissue, or poor diet, and probably overlapping with both of those in the mechanisms involved. Tinkering with gut microbes isn't the path to a cure for Alzheimer's disease or other conditions involving the accumulation of damaged proteins in the brain. A cure must, by necessity, involve clearing out the damage comprehensively, which will require a more sophisticated approach to therapies.

Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota

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.

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A Diet of Old Tissues Modestly Shortens Life Span

In an interesting series of experiments, researchers found evidence for a diet of old tissues to modestly reduce life span in flies and mice. If speculating on specific mechanisms, we might look to the various forms of metabolic waste and damaged proteins that accumulate with age; some of that might find its way past the digestive process to be incorporated into tissues and thereby accelerate the aging process. This sort of dietary influence on aging is already a much-debated topic regarding advanced glycation end-products, for example. The results of the studies here offer reinforcement for the SENS approach of damage repair to create rejuvenation, but sadly that is not the conclusion reached by the researchers involved. They instead look ahead to a much harder task with the prospect of only marginal benefits, which is to say safely altering cellular metabolism in order to slow down damage accumulation. This is an inferior approach to periodic damage repair, requiring far more research to realize, and capable of producing only lesser gains in health and life span.

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?"

SkQ1 Slows Accelerated Aging in Mitochondrial Mutator Mice

Mice engineered to generate a high level of deletion mutations in mitochondrial DNA exhibit accelerated aging. As in most cases of accelerated aging, we can debate whether or not it is correct to call it accelerated aging. The important point is whether or not the type of cellular damage involved provides a significant contribution to the normal aging process, which in this case it does. The normal lower levels of mitochondrial DNA damage are implicated as a cause of aging and age-related disease. Then the question becomes whether or not it is acceptable to continue to call it aging given a vastly greater presence of just one of the types of age-related damage, or is it now some other form of pathology?

Putting this to one side, here researchers show that SkQ1, a mitochondrially targeted antioxidant shown to modestly slow aging in laboratory species, helps to ameliorate the harm done by high levels of mitochondrial deletion mutations. To my eyes, at least, it would have been unexpected to find another outcome, given what is known of the mechanisms involved here. This class of targeted antioxidant compounds come with a good deal of evidence backing their impact on mitochondrial metabolism; to the degree that deletions occur due to oxidative damage, and to the degree that they in turn cause greater levels of oxidative damage throughout the cell through disarrayed mitochondrial function, the presence of antioxidants in the mitochondria should reduce the harmful outcomes. This class of compound is currently being developed as a treatment for inflammatory eye conditions, as this is one of the areas in which the benefits are both reliable and large, and the regulatory path to market is comparatively smooth.

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.

Identification of a Potential Autophagy Enhancement Drug

Researchers here note the identification of a drug candidate to enhance autophagy, a process of cellular housekeeping responsible for removing damaged proteins and structures in the cell. Enhanced autophagy is associated with many of the interventions known to slow aging in laboratory species, and in at least some cases, such as for calorie restriction, the correct operation of autophagy has been shown to be necessary for extension of life span to take place. Consequently, the research community has for some time shown interest in the development of therapies based on the enhancement of autophagy, but there has been surprisingly little progress on this front to date.

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.

The Risks of Current Approaches to Rebooting the Immune System

The present approaches to rebooting the immune system have shown considerable promise in treatment of autoimmune diseases such as multiple sclerosis. Unfortunately the current methods of immune destruction involve chemotherapy, which is a damaging process in and of itself, and there is as yet too little attention being given to protection against infection in the period while the immune system is absent or near-completely suppressed. The risks are significant, and until addressed mean that this remains useful only for patients who will suffer worse absent the therapy.

Both of the major risks noted above could be addressed in the near future, however. Firstly through the development of targeted cell destruction methods with minimal side-effects, such as that currently pioneered by Oisin Biotechnologies, and secondly through delivery of new immune cells generated from the patient's own cells. It is in all our interests to see a broadening of immune reboot work, as this class of therapy could help clear out the malfunctioning and misconfigured cells from an age-damaged immune system, producing a partial rejuvenation of immune function in the elderly.

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."

Is a Clone Born at Age Zero?

In the overlap between research into aging and research into regeneration there is some interest in what exactly it is that happens between fertilization and later development of a zygote that enables old reproductive cells to produce young children. Some form of reset takes place, a clearing out of damage. This is also seen in induced pluripotency, whereby ordinary somatic cells are reprogrammed into a state very similar to that of embryonic stem cells. It is an open question as to whether any part of this natural rejuvenation mechanism can be safely harnessed and turned into a therapy, though it is worth noting that induction of induced pluripotency in the tissues of adult mice has been tried recently. Animal cloning is another line of research that might help to shed light on what happens in early development, a topic that was covered in some depth last year. Do clones age normally, and are they born with a similar level of molecular damage as their natural peers? Why, if so?

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.

Projecting out Current Life Expectancy Trends to 2030

I think it a given that trend projection at the present time is going to greatly underestimate gains in life expectancy over the next few decades. This present decade and the next encompass a transition from palliative and compensatory medicine that inadequately patches over the causes of aging, and a research community that has no interest in treating aging itself as a medical condition, to a field of rejuvenation treatments that do actually address the forms of cell and tissue damage that cause degenerative aging, and a research community that is now very interested in working towards therapies for aging. Past gains have occurred despite the fact that research and development efforts made no attempt to treat root causes in aging. Future gains, produced by those actually trying to address aging, will be larger and occur more rapidly.

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."

Senescent Cells Implicated as a Cause of Idiopathic Pulmonary Fibrosis

The number of senescent cells in tissues grows with age, and these cells cause harm through forms of signaling that induce inflammation, destructively remodel the extracellular matrix, and alter the behavior of other cells for the worse. Now that clearance of senescent cells has been shown to robustly extend healthy life span in mice, there is a lot more interest in the research community in joining the dots between cellular senescence and specific age-related diseases. The past year has seen a range of publications that directly implicate senescent cells in various age-related diseases, or attempt to quantify exactly how much of the detrimental alterations in aged tissues are caused by these cells. In this particular case, researchers are looking at the lung condition known as idiopathic pulmonary fibrosis, and you might compare these results with another promising study of senescent cells in the lungs carried out last year. We can hope that the various companies developing clearance therapies will bring them to the clinic sooner rather than later.

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."

Working on a Drug to Stimulate Regeneration of Lost Hair Cells in the Inner Ear

One class of the numerous forms of age-related deafness is caused by loss of hair cells in the inner ear. These cells are a necessary part of the chain of systems that leads from sound outside the body to signals passing along nerves into the brain for interpretation. As these hair cells are lost, so is hearing capacity. A range of efforts to reverse this loss are underway at various stages of development, such as reprogramming a cell sample into patient-matched hair cells, or, as in this case, finding ways to provoke regeneration in situ, changing cellular behavior so that they rebuild where they would normally not do so.

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.

Arguing that it is Immoral to Object to Longevity Science for Fear of Overpopulation

Overpopulation is one of the great apocalyptic fears of our era, and like many of the rest of those fears, it is unfounded. If anything, the trajectory is for increased wealth to reduce population as children shift from being a necessary benefit to what is effectively a form of luxury good. Further, the effects of great longevity on population size are generally much smaller than people imagine, as rigorous modeling shows. Lastly, this planet could support more than ten times the current population using present day technologies, were more of the land used efficiently. Yet still, people look at the results of war and kleptocracy and cry overpopulation rather than recognizing the true causes of suffering.

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.

The Basis for an Antibody Therapy to Treat Transthyretin Amyloidosis

Misfolded transthyretin accumulates with age, forming solid amyloid deposits in tissues, particularly in the cardiovascular system. Amyloid disrupts proper function of cells and organs, and this is likely the majority cause of death in supercentenarians, the oldest humans. In recent years evidence has emerged for transthyretin amyloid to be involved in heart failure and a range of other conditions in younger old age, as well. There are a number of different approaches to clearing transthyretin amyloid under development, one of which has had a successful human trial, but progress towards the clinic is nonetheless exceedingly slow. This is disappointing, as this sort of therapy is a form of narrow rejuvenation, beneficial to every adult, and should not be locked up within the regulatory system in this way. Those developing and funding these treatments have to date failed to appreciate the true scope of success, or they would be far more eager to move ahead.

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.


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