Fight Aging!

DRACO, double-stranded RNA activated caspase oligomerizer, is a broadly applicable antiviral technology that has been under development at a slow pace for quite some time now. You might recall some publicity back in 2011, for example, but that marked the results of years of earlier work. DRACO attacks infected cells, not the viruses themselves, following the principle of finding a common vulnerability to target rather than trying to tailor therapies to every different variety of attacker. Despite technology demonstrations to show effectiveness against a broad range of very different types of virus, and the fact that this technology can in principle be applied to near any type of virus, there is next to no ongoing funding for DRACO. It stands as an example of the fact that you can build a better mousetrap and still have the world ignore you. In this case DRACO is languishing despite grave concerns regarding spreading viral resistance to existing drugs, and billions devoted to constructing new drugs that are just more of the same.

Advocacy and philanthropy are often the only ways forward for a new medical technology that is a radical departure from the present status quo. This is a lesson to keep in mind when we talk about the various branches of longevity science. It is hard to obtain funding in the life sciences in any meaningful fashion, and the organization of funding for any ongoing serious effort has become a baroque effort involving many players, all of whom are operating with perverse incentives that only serve to slow down progress and make funding less effective on a dollar for dollar basis. For example the large funding bodies are extremely risk-averse, and thus almost never fund the most important early-stage and high-risk projects, the science that is actually science, at the forefront and involving new discoveries. These funding bodies only ever put money into ongoing development wherein which the researchers can already demonstrate proof of concept and an understanding of the mechanisms involved. Getting to that point for any new line of research requires creative accounting and the help of philanthropic donations, and even so there is far too little actual science taking place in major laboratories.

I noticed a recent paper, one of the few for DRACO of late, in which the authors provide evidence to show that DRACO is a worthwhile avenue for antiviral therapies in pigs, targeting diseases for which there are no presently adequate therapies. Another of the draws here is that DRACO isn't just an approach for near all viruses but also an approach that should work for near all mammals as well.

DRACO inhibits porcine reproductive and respiratory syndrome virus replication in vitro

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Current vaccination strategies and antiviral drugs against PRRSV are still inadequate. Therefore, there is an urgent need for new antiviral strategies to control PRRSV.

Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) is a synthetic construct consisting of a dsRNA detection domain, an apoptosis induction domain, and a transduction tag. It has been shown to have broad-spectrum antiviral activity, but there have been no reports regarding its effect on PRRSV. Here, we demonstrate that DRACO exhibits robust antiviral activity against PRRSV infection by suppressing virus RNA and protein synthesis in both Marc-145 cells and porcine alveolar macrophages (PAMs). In addition, DRACO still exhibited strong anti-PRRSV activity when viral replication was enhanced by knockdown of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in Marc-145 cells. Furthermore, in PAMs, DRACO was capable of inducing IL-6 expression and reducing Hsp70 expression, which might contribute to the inhibition of PRRSV infection.

Collectively, our results imply that DRACO holds promise as a novel anti-PRRSV therapeutic drug.

Yet there is insufficient funding for any meaningful ongoing development of DRACO. Some people have been trying to put together a foundation to raise philanthropic funds, and of late some of their advocacy efforts can be seen at Facebook, but so far there is little progress towards gathering broader support. It is most frustrating; yet another example of the way in which our world is far from ideal.

The first stage for commercially useful tissue engineering is testing and further research, and that is actually well underway. Tissue sections for test and research purposes don't have to be large, and therefore the big problem of how to generate suitable blood vessel networks doesn't have to be solved yet. So researchers have been building organoids and other small sections of tissue, gaining experience and refining techniques. The first tissue types were being sold years ago by companies such as Organovo, and these days many more are being added at an accelerating pace by competing research and development groups. This is a staging ground for the near future construction of organs to order, built from scratch from a patient's own cells:

Efforts to grow stem cells into rudimentary organs have taken off. Using carefully timed chemical cues, researchers around the world have produced three-dimensional structures that resemble tissue from the eye, gut, liver, kidney, pancreas, prostate, lung, stomach and breast. These bits of tissue, called organoids because they mimic some of the structure and function of real organs, are furthering knowledge of human development, serving as disease models and drug-screening platforms, and might eventually be used to rescue damaged organs. "It's probably the most significant development in the stem-cell field in the last five or six years."

The current crop of organoids isn't perfect. Some lack key cell types; others imitate only the earliest stages of organ development or vary from batch to batch. So researchers are toiling to refine their organoids -- to make them more complex, more mature and more reproducible. Still, biologists have been amazed at how little encouragement cells need to self-assemble into elaborate structures. "It doesn't require any super-sophisticated bioengineering. We just let the cells do what they want to do."

Biologists know that their mini-organs are still a crude mimic of their life-sized counterparts. But that gives them something to aim for. "The long-term goal is that you will be able to replicate more and more of the functionality of a human organ." Already, the field has brought together developmental biologists, stem-cell biologists and clinical scientists. Now the aim is to build more-elaborate organs -- ones that are larger and that integrate more cell types. Even today's rudimentary organoids are facilitating discoveries that would have been difficult to make in an animal model, in which the molecular signals are hard to manipulate.

Link: http://www.nature.com/news/the-boom-in-mini-stomachs-brains-breasts-kidneys-and-more-1.18064

Researchers have demonstrated slower aging in yeast by increasing H3K36 methylation, which has the effect of restricting certain forms of transcription, the first step in the process of gene expression whereby proteins are generated from their genetic blueprints. It is worth noting that many ways to slow aging in laboratory species, including calorie restriction, have broad effects on observed patterns of transcription, and there is a still a long way to go towards a complete understanding of everything that is taking place in these portions of cellular biochemistry.

Gene expression is regulated by chemical modifications on chromatin - histone proteins tightly associated with DNA. Certain chemical groups on histones allow DNA to open up, and others to tighten it. These groups alter how compact DNA is in certain regions of the genome, which in turn, affect which genes are available to be made into RNA (a process called transcription) and eventually proteins. Researchers have pinpointed specific histone modifications that not only are altered during aging, but also directly determine longevity. "In this study, we found that a type of abnormal transcription dramatically increases in aged cells and that its reduction can prolong lifespan. This longevity effect is mediated through an evolutionarily conserved chemical modification on histones. This is the first demonstration that such a mechanism exists to regulate aging."

In yeast, aging is measured by the number of times a mother cell divides to form daughters before it stops. This number - a mean of 25 divisions - is under tight control and can be either reduced or increased by altering histone modifications, as the researchers found. They showed that when fewer chemical groups of a certain type attach to yeast histones, the abnormal transcription greatly increases in old cells. In contrast, the team found that in yeast strains with a certain enzyme deletion, this abnormal transcription is reduced and lifespan is extended by about 30 percent.

The results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. "We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity. We have started investigating whether such a longevity pathway can also be demonstrated in mammalian cells. However, these investigations are confounded by the complexity of the genome in more advanced organisms. One of our long-term goals is to design drugs that can help retain these beneficial histone modifications and extend healthy lifespan in humans."

Link: http://www.uphs.upenn.edu/news/News_Releases/2015/07/berger/

Today I stumbled over a popular press article on the topic of longevity science, in which a fair amount of attention is given to Aubrey de Grey and the SENS Research Foundation vision for rejuvenation biotechnology. Like most such articles it is a view from an individual who, though a scientist himself, stands far outside the field of aging research - just like much of the world he is looking in with limited knowledge, trying to make sense of it all, in search of truth from a position of ignorance.

This struggle, the search for truth in a field in which you will never personally know enough to verify any significant detail for yourself, is one of the defining characteristics of the human condition. We have the urge to know in the moment that we encounter a new assertion, but we cannot justify spending the years it would take to know ourselves, versus accepting a secondhand truth that may or may not in fact be correct. It is frequently a challenge even to understand how great or little is the uncertainty of any claim we come across. This has always been the case, but now that we are all connected in a vast web of communications, superficial summaries of every aspect of human knowledge at our fingertips, the quest for truth is a mouse click away every moment of the day, and we accept all too much of what we see simply because we do not have the time to do otherwise.

This is compounded by the fact that some fields of science are in tumult, experienced researchers in public dispute over vital theories. It is a sign of the times, of accelerating progress. Astrophysics and cosmology were some of the first to benefit from the computational revolution and haven't stood still for long enough to catch a breath in decades; what a student learns in school is out of date within a few years. The life sciences are now in much the same boat, and the study of aging in fact has a great in common with the study of astrophysics in that (a) technology now enables theorizing to proceed far more rapidly than the collection of new and useful data, (b) the problem space is vast, the existing volume of data huge, and the unknown details yet to be filled in even larger, which means that (c) many theories can be made to fit the data that we do have, these theories are multiplying rapidly, and proving or disproving them is a slow process indeed. The junk builds up alongside the specks of gold, and sifting becomes an ever more laborious process.

This all matters far more for aging than for the study of the observable universe beyond the Earth because we are operating under a deadline. We're all aging, and if the research community chases the wrong theories for the next decade or two, meaning those that require expensive work for marginal benefits, that will make the difference between a good life and a painful death in old age for most of us. Pure science is all well and good, but therapies are needed, and pushing for meaningful development as fast as possible requires a slightly different focus from that of the standard scientific model of learning everything there is to know about the system in question before taking action. One other way in which aging research is similar to astrophysics is that very little of it has any connection with development of new technologies: most aging research groups are entirely happy with their focus on gathering data and nothing more.

In any case, the author of this article is some places self-aware of the issue of ignorance and truth, while in others he hasn't looked deeply enough. He could have looked at the scientific advisory board of the SENS Research Foundation today to see the heavy-hitters in the scientific community who are on board rather than simply quoting some of those who opposed SENS as a research strategy in public a decade ago, to pick one example. How do you sift for truth? You look for networks of people who have taken the time to run the analysis, who have the specialized knowledge to say one way or another. There are few who steadfastly claim SENS is the wrong road these days, and they are largely in the programmed aging community, not the same folk as those who turned up their noses more than ten years ago, long before SENS and SENS-like programs had produced numerous confirmations of the potential of this research strategy.

Since then we've seen examples of senescent cell clearance, mitochondrial repair through allotopic expression is in late stage development for the treatment of mitochondrial disease, work on therapies for senile systemic amyloidosis is moving ahead, and so forth. It's a different world now. All this information is out there if you care to look, or ask those who have been following along all this time:

The God quest: why humans long for immortality

Myths live on by disguising themselves in the apparel of modernity. So it is fully to be expected that immortality today is a business offering to tailor clients' diet regimes, that it is expounded at conferences in PowerPoint presentations, that it announces itself with words such as "telomere extension" and "immune regulation". This is distressing to serious biogerontologists, who worry that funding of their careful work on age-related disease and infirmity will seem boring in comparison to supporting folks who promise to let us live for ever. They are right to be concerned but sadly theirs will ever be the fate of scientists working in a field that touches on fabled and legendary themes, where both calculating opportunists and well-meaning fantasists can thrive. Age-related research until recently has been rather marginalised in medicine, and the gerontologist Richard Miller of the University of Michigan suggests one reason for this: "Most gerontologists who are widely known to the public are unscrupulous purveyors of useless nostrums."

It is surprising, perhaps alarming, that we know so little about ageing. We get old in many ways. For instance, some of our cells just stop dividing - they senesce. While this shutdown stops them becoming cancerous, the senescent cells are a waste of space and may create problems for the immune system. Cell senescence may be related to a process called telomere shortening: repeated cell division wears away the end caps, called telomeres, on the chromosomes that contain our genes. Although shortened telomeres seem to be related to the early onset of age-related disease, the ­relationship is complex. It is partly because cancer cells are good at regenerating their telomeres that they can divide and proliferate out of control. Cells also suffer general wear and tear because of so-called oxidative damage, in which reactive forms of oxygen - an inevitable by-product of respiration - attack and disrupt the molecules that sustain life. This has made "antioxidants" such as Vitamins C and E, and the compound resveratrol, found in red wine, buzzwords in nutrition. But the effects of oxidative damage and antioxidants are still poorly understood.

These factors and others can interact with each other in complex ways. A group of UK experts called the Longevity Science Panel, funded by the insurers Legal & General, concluded in a 2014 report: "There is little consensus on which mechanisms of ageing are the most important in humans." Biogerontologists don't even agree about whether the ageing process itself is best considered as a single effect, or many.

Aubrey de Grey genuinely seems to believe not only that he is on to something but that his ideas are of humanitarian importance. He is nothing if not sincere in thinking that to slow and ultimately reverse ageing is an obligation that science is failing dismally to fulfil. He regards old age as a disease like any other: it is scandalous, he says, that it kills 90 per cent of all human beings and yet we are doing so little about it. De Grey calls his quest a "crusade to defeat ageing", which he regards as "the single most urgent imperative for humanity". Death, he says, "is quite simply repugnant", and he equates our acceptance of it in elderly people with our past casual acceptance of the slaughter of other races.

How does de Grey think we will stop our bodies from ageing? He proposes a seven-point plan called SENS (Strategies for Engineered Negligible Senescence) that, in his view, picks off all the processes by which our cells decline, one by one. We can get rid of unwanted cells, such as excess fat cells and senescent cells, by training the immune system or triggering the cells into eliminating themselves. We can suppress cancer by silencing the genes that enable cancer cells to repair their telomeres. We can avoid harmful mutations in the handful of genes housed in our energy-generating cell compartments called mitochondria by making back-up copies, to be housed in the better-protected confines of the cell's nucleus, where the chromosomes reside. We can find drugs that inhibit the degradation of tissues at the molecular level. And so on.

His detractors point out that almost all of these plans amount to saying, "Here's the problem, and we'll find a magic ingredient that fixes it." If you think there are such ingredients, they say, then please find just one. He is looking. With inherited wealth and venture capital backing from the likes of PayPal's co-founder Peter Thiel, de Grey maintains an institution in Mountain View, California, called the SENS Research Foundation, with laboratories to investigate his proposals. But he insists that the criterion of success isn't a steadily increasing longevity in model organisms, because SENS is a ­package, not a series of incremental steps. No one criticised Henry Ford, de Grey says, because the individual components of his cars didn't move if burning petrol was poured on them.

The hope of medical immortality may be false but it raises moral and philosophical questions. Is there something fundamental to human experience in our mortality, or is de Grey right to see that as a defeatist betrayal of future generations? Do we value life precisely because it passes? And is there an optimal span to our time on earth? These are pertinent questions for even the most sober gerontologists, because the truth is that the ageing process can be slowed, and we can expect to have longer lives in the future and to remain well and active for more of that time.

For instance, it has been known for decades that rats and mice live longer, and stay healthy for longer, when given only the quantities of a well-balanced diet that they need and no more. This so-called caloric restriction seems to slow down ageing in a wide range of tissues. No one knows why, but it seems to point to a common mechanism of ageing that extends between species. Some researchers think that with caloric restriction it might be possible to extend mean human lifespans to roughly 110 years. Others aren't persuaded that caloric restriction would be effective at all for slowing ageing in human beings - studies on rhesus monkeys have been inconclusive - and they point out that it is a bad idea for elderly people.

Couldn't we just make an anti-ageing pill? There are candidates. The drug rapamycin, which is used to suppress immune rejection in organ transplants and as an anti-cancer agent, also has effects on ageing. It stops cells dividing and suppresses the immune system - and increases the lifespan of fruit flies and small mammals such as mice. But it has nasty side effects, including urinary-tract infections, anaemia, nausea, even skin cancer. Other researchers think that the answer lies with genetics. The genomics pioneer Craig Venter, whose company Celera privately sequenced the human genome in the early 2000s, recently launched Human Longevity, Inc together with the spaceflight entrepreneur Peter Diamand. It aims to compile a database of genomes to identify the genetic characteristics of long-lived individuals. Whether Venter will find genes responsible for the exceptional longevity of some individuals, and whether they would be of any use for extending average lifespan, is another matter. "His approach has some serious conceptual limitations," the Michigan gerontologist Richard Miller tells me. "I think he's radically overestimating the degree to which the ageing process is modulated by genetic variation."

To read one script, we are on the cusp of a revolution in ageing research. Google has recently created the California Life Company, or CALICO, which seems to be seeking life-extending drugs. The hedge-fund billionaire Joon Yun has launched the $1m Palo Alto Longevity Prize to bring about the "end of ageing", so that "human capacity would finally be fully unleashed". But the Longevity Science Panel, composed of scientists rather than venture capitalists, had a much more sobering message. To get a substantial increase in lifespan - an extra decade or so, say - we would need to find ways of slowing the ageing rate by half (which the panel deemed barely plausible given the current knowledge) and apply that treatment throughout a person's life from an early age. If you're already middle-aged today, even major breakthroughs are barely going to make any difference to how long you will live.

Researcher Richard Miller is a good example for the complexity of positions in aging research. He is an outspoken opponent of SENS research, yet he and I are basically on the same page when it comes to the poor value of genetic research into variations in human longevity. When you look at a given researcher's position, it isn't just a matter of for and against, or a few large camps of opinion, but rather in a field this complex you really have to make a list of twenty or so nuanced opinions and run through them all to check boxes. Everyone has a slightly different overall take, and while many overlap to a considerable degree, there is always something to disagree on. This state of affairs will continue until good data arrives to support one course forward above the others - which I would expect to happen when the first robust SENS-like repair therapies in mice demonstrate unequivocal extension of healthy life span. We're somewhere near that point for senescent cell clearance, I think, but there is much more to come yet.

A range of research efforts aim at finding ways to improve or enhance the activity of cellular maintenance mechanisms involved in ensuring quality control. Proteins are the building blocks of cell machinery but constantly become damaged or misfolded, which can then cause harm through incorrect function. Thus cells work hard to clear out, break down, and recycle these problem molecules, but all of these mechanisms decline with aging; based on what we know to date, this happens because the repair machinery itself is vulnerable to forms of damage or can be negatively impacted by reactions to damage taking place in other processes, just like the rest of a cell.

So far there is little concrete progress towards therapies based on enhanced protein quality control, though a variety of genetic alterations that extend life in laboratory animals are shown to include enhanced quality control as a part of their effects. I would expect some candidate therapies to emerge in the years ahead, however, as the interest in moving in that direction certainly exists:

Impairment of "protein quality control" in neurons is associated with the etiology and pathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy.

The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, Pick disease, Frontotemporal dementia, Huntington disease, Amyotrophic lateral sclerosis and many others. Although the primary events in etiology and pathogenesis of sporadic forms of these diseases are still unknown, it is clear that aging, in connection with decreased activity of ubiquitin proteasome system, is the most significant risk factor.

We discuss the pathogenic role and intracellular fate of the candidate molecules associated with onset and progression of AD and PD, the protein tau and α-synuclein in context with the function of ubiquitin proteasome system. We also discuss the possibility whether or not the strategies focused to re-establishment of neuroproteostasis via accelerated clearance of damaged proteins in proteasome could be a promising therapeutic approach for treatment of major neurodegenerative diseases.

Link: http://www.ncbi.nlm.nih.gov/pubmed/26221742

A number of ongoing research programs aim to collect more data on the biochemistry and genetics of the oldest of old people, and here is an example of one of them. I don't believe that these efforts contribute greatly towards building meaningful treatments for aging, for all the same reasons that trying to build calorie restriction mimetic drugs is a dead end: the underlying causes of aging are known, the damage that produces degeneration and loss of function, and researchers should be focused on repairing it to extend healthy life by decades, not on exploring comparatively small differences in how the body adapts to high levels of damage, or how to eke out a few more years while in a diminished and dysfunctional state. From a purely academic perspective, the study of natural variations in human aging is a good way to learn more about the fine details of how exactly aging progresses at the cellular level, however. Just don't expect this to have practical results beyond the production of new knowledge.

Supercentenarians are very rare, very precious individuals, who have lived to at least 110 years of age. Surviving decades longer than their peers -- often in far better health -- supercentenarians may hold the keys to protection from disease, decline, and early death. Our researchers are engaged in an extensive, international study of individuals demonstrating increased or extreme resistance to devastating, age-related diseases -- such as cancer, cardiovascular disease, diabetes, Alzheimer's disease, Parkinson's disease, organ failure, immune system failure, and neurodegeneration -- as well as the illness and injury caused by bone and muscle deterioration, dementia, loss of mobility, and cognitive decline. Supercentenarians have avoided the vast majority of these age-related illnesses, and the study of the protective mechanisms that have ensured their survival may lead to the discovery and development of new treatments and therapies, bringing the good health and great longevity of supercentenarians to the rest of us.

There is a great deal of research to support the theory that supercentenarians' longevity is hereditary. The siblings of supercentenarians are up to 17 times more likely to survive to age 100 than the siblings of non-supercentenarians. Many of these individuals also enjoy increased and lifelong resistance to disease, suffering far less age-related morbidity. Studies reveal a strong link between inherited traits and healthy longevity, as well as mechanisms that protect against a wide variety of illnesses. The careful study of supercentenarians and their families can provide unparalleled insights into the mechanisms of health, aging, and disease.

Link: http://www.supercentenarianstudy.com/

A group of US researchers have demonstrated the potential to induce greater regeneration in heart tissue through overexpression of PIM-1. This is one of many varied approaches to generating greater repair and maintenance of tissues presently under development or in the clinic, ranging from stem cell transplants to the search for signal molecules that spur old tissues into greater activity. The researchers working on PIM-1 have been involved in this program for a number of years now: if you look back in the Fight Aging! archives, you'll find a report from 2012, for example. Sadly, from an outsider's perspective there is little visible difference between the state of this project then and now. The high level outline is the much the same and the expected course ahead is much the same. Benefits have been demonstrated in laboratory animals and human tissues, and the researchers would like to move to clinical trials, but lack the funding needed to take that step.

This is the situation for a lot of medical research these days, stuck at the level of gathering more data and creating more variants on the basic technology demonstration, seeking sufficient funding to enter the path to clinical trials. Thanks to the modern regulatory straitjacket for medical technology it is the case that moving beyond the laboratory has become so enormously and unnecessarily expensive in comparison to building a proof of concept that potential therapies can languish indefinitely in this state of demonstrated promise but lack of meaningful progress. I think this will be a growing class of research program in the future, absent some sort of sweeping change, as the cost of early stage research is falling precipitously while the cost of regulatory compliance for clinical development is steadily rising. Something has to give eventually.

Can We Restart the Heart?

The heart in particular seems to be resistant to developing cancerous cells. "When's the last time you heard of anyone having heart cancer? It's almost unheard of." That's not surprising from an evolutionary standpoint. If heart cells make a grave transcription error during cell division and your ticker ticks its last tock, there's no fixing the problem. So it makes sense that heart cells are incredibly careful when it comes to proliferating. But it's this very meticulousness that makes heart disease such an intractable problem. Over time, the cells burn themselves out. Their ability to repair themselves and generate fresh replacements gets progressively worse. By the time you reach old age and start experiencing symptoms of age-related heart disease, your cardiac cells are running on fumes and aren't able to properly divide into new cells.

Researchers are exploring the results of taking an enzyme, Pim, known to be associated with growth and survival of certain types of cancer cells, and causing it to be overexpressed in cardiac progenitor cells in mice. In healthy cells, Pim helps facilitate chromosome splitting, a key part of the cellular division process. The gene that encodes the production of this enzyme, PIM1, is what's known as a proto-oncogene. That means that by itself, the gene doesn't cause cancer. But when it teams up with another gene, Myc, tumors are likely to form. Fortunately, the Pim/Myc combination isn't an issue in heart progenitor cells, meaning you could tweak those cells to overexpress the PIM1 gene without raising the risk of cancer.

Researchers modified mouse heart progenitor cells to overexpress PIM1 in specific locations within the cell, targeting specific locations with more of the critical Pim enzyme in hopes that it would protect against aging-related heart disease. And it worked. Compared to controls, the mice with overexpressed PIM1 lived longer and showed stronger cell proliferation. But interestingly, the way it worked was different depending on where in the cell the gene was overexpressed. If the researchers caused PIM1 to be overexpressed in the progenitor cell's nucleus, they saw increased proliferation into new cells. If they overexpressed the gene in a different region of the cell, the mitochondria, they found that the enzyme inhibited the cell's natural self-destruct signals, causing them to live longer.

Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells

Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of this kinase in hCPCs to increase proliferation and survival, and antagonize cellular senescence.

Below find an interesting discussion of one research program aimed at producing a better class of cryoprotectant that enables tissue thawing without damage. The organ storage and cryonics industries have many of the same technical goals: how to preserve complex tissues for the long term at low temperatures while enabling a safe thaw at the far side of storage. Some research companies straddle both industries, such as 21st Century Medicine. The enemy here is ice, as it is crystallization that destroys cells and structures in straight freezing. If near-future thawing is not a concern, then many varieties of cryoprotectant compounds are useful. When infused into tissue the result is vitrification rather than freezing, with minimal ice crystal formation and preservation of even very fine-scale cellular structures, such as synapses and other aspects of brain structure thought to hold the data of the mind.

To date there are very few examples of the successful thaw and use of a vitrified organ, even in the laboratory. It is research programs such as the one noted here that may help to change this state of affairs. Given better cryoprotectants and significant use of long-term organ storage in medicine, one would hope that the public will become more accepting of cryonics as an end of life choice, a shot at living again to see a better future for those who will age to death prior to the advent of rejuvenation therapies.

Researchers have synthesised a polymer that limits ice crystal growth in frozen red blood cells as they thaw. The polymer is set to pave the way for similar synthetic structures that mimic the properties of natural antifreeze proteins. During cryopreservation, cells and tissues are stored at sub-zero temperatures and thawed before use. However, frozen cells can be damaged as they defrost. When ice melts, it can refreeze into larger crystals that puncture cells from the outside. This process, called recrystallisation, is especially damaging for organs and blood bags, which defrost over a long time. "'If you directly freeze cells they don't survive due to ice-induced damage, and the traditional solution is to add antifreeze solvents. Although these work, they involve complex preparation procedures, and transfusing large volumes of solvent is not desirable. Alternatives to the conventional cryoprotectants are urgently required as the fields of regenerative medicine and tissue engineering continue to advance."

Unlike proteins, which need to be extracted or expressed in microorganisms, polymers are more accessible, processable, tunable and cheaper. Researchers modified an already available polymer called a polyampholyte, which is composed of monomers with both positively and negatively charged groups. The polymer functions outside the cells, so it can be washed-off after thawing. This may explain its good compatibility with red blood cells. Up to 60% red blood cell recovery after freezing was observed during slow thawing when the new polymer was used, and this increased to 80% when the cells were thawed quickly. Notably, the polymer was capable of inhibiting ice recrystallisation by 50%.

The mechanism by which the synthesised polymer inhibits ice recrystallisation is still not clear. Although it has been assumed for many years that macromolecules had to bind directly to ice crystal faces to inhibit growth, their work supports the idea that binding to ice crystals is not essential. "It seems that they somehow disrupt the rate exchange of water molecules between ice crystals, via the quasi liquid layer, although we do not have direct evidence for this at the moment. As to why the ampholyte structure works, we are not sure, but we are thinking that it might be a semi-rigid polymer due to charged interactions along the backbone, which helps. Cheap, non-toxic, degradable polymers that inhibit ice recrystallisation may become attractive non-permeating additives for cryopreservation of red blood cells if these boost cell recovery by more than 80% and allow for prolonged post-thaw storage."

Link: http://www.rsc.org/chemistryworld/2015/07/antifreeze-polymer-cryopreservation-red-blood-cells

Researchers building on twin study data are suggesting that the well-known correlation between greater intelligence and a little additional longevity is mostly genetic in nature, not a matter of more intelligent people making better lifestyle choices, or tending to be wealthier, or any of the other social or economic factors that are associated with both intelligence and longevity. The size of the effect due to intelligence is small, but a demonstration of it being due to genetics is not the result I would have expected based on past data on human longevity. To date I'm aware of little other research to back this point of view. For one of them, you might look at a paper from a few years back that suggests learning and longevity in bees are both influenced by the same underlying mechanisms of robustness in biological systems, their resistance to stress.

The tendency of more intelligent people to live longer has been shown, for the first time, to be mainly down to their genes. By analysing data from twins, researchers found that 95 per cent of the link between intelligence and lifespan is genetic. They found that, within twin pairs, the brighter twin tends to live longer than the less bright twin and this was much more pronounced in fraternal (non identical) twins than in identical twins. Studies that compare genetically identical twins with fraternal twins - who only share half of their twin's DNA - help distinguish the effects of genes from the effects of shared environmental factors such as housing, schooling and childhood nutrition.

"We know that children who score higher in IQ-type tests are prone to living longer. Also, people at the top of an employment hierarchy, such as senior civil servants, tend to be long-lived. But, in both cases, we have not understood why. Our research shows that the link between intelligence and longer life is mostly genetic. So, to the extent that being smarter plays a role in doing a top job, the association between top jobs and longer lifespans is more a result of genes than having a big desk. However, it's important to emphasise that the association between intelligence and lifespan is small. So you can't, for example, deduce your child's likely lifespan from how he or she does in their exams this summer. It could be that people whose genes make them brighter also have genes for a healthy body. Or intelligence and lifespan may both be sensitive to overall mutations, with people with fewer genetic mutations being more intelligent and living longer. We need to continue to test these ideas to understand what processes are in play."

Link: http://www.lse.ac.uk/newsAndMedia/news/archives/2015/07/Link-between-intelligence-and-longevity-is-mostly-genetic.aspx

The public echo chamber is often crowded by class warfare sentiments, and they are rarely absent from any discussion of progress in medicine. The green-eyed monster of jealousy dons its best suit and those without power denounce those who have more of it because of their greater wealth. Many believe that the wealthy have greater access to medical technology, while the truth is that those who complain, sitting in the first world, are in exactly the same tier as their wealthier counterparts, with access to exactly the same forms of medicine. The yawning gulf is that which exists between the complainants and the genuine poor in the third world, while the only thing that being first world wealthy buys you is a more handsome, well-dressed set of doctors than the average American will see. Under the hood the drugs are the same, the heart surgery the same, the cancer treatments the same, the outcomes the same. We are all aging to death, and the demographic studies tell us that massive wealth doesn't buy you all that much of an advantage at all.

That is unless the wealthy choose to spend that massive wealth on research and development, the production of entirely new capabilities in medicine. In which case they and everyone else might win together - provided the right research programs are funded. The wealthy who choose to fund medicine with the goal of extended health longevity are, with only a few exceptions, doing it not for their own benefit for but the population as a whole. Most of them believe that they will not live long enough to enjoy more than the first tentative results, as they are either not aware of the potential of SENS-like rejuvenation research programs if fully funded, or not yet convinced by those who advocate that work.

A truly wealthy individual is primarily a figurehead for a process, a life consumed by the demands of maintaining a vast amount of property and business interests. He or she cannot also be a citizen scientist, taking the years to become knowledgeable enough to make their own call about what is the best path forward in research. These high net worth individuals are each the leader of a tribe, beholden to advisers and interests, insulated from views and truth by a layer of people regardless of their desires on that front, and with many ongoing responsibilities that have little to do with philanthropy. Almost all philanthropists in the modern mold of successful businessmen are philanthropists in their snatched spare time, a minute here and a minute there taken hastily around the edges of the all-consuming job of steering their ventures. The exceptions are rare and usually older, retired, focused on spending down their fortunes to get things done: Paul Allen, Bill Gates, Paul Glenn, for example.

The class war voices would have us believe that the evil modern rich have turned to selfishly building longevity technologies for their own use, and to hell with the result of the world. That is simply untrue, not to mention impossible. It takes thousands of people, an entire industry, to build any entirely new class of medical technology. No-one can keep that to themselves: there are no secrets in business and science, and competitors always arise close on the heels of success. Further, the rejuvenation therapies of tomorrow will be infusions, mass-produced, and cheap as today's immune-altering biologics, taken every few years at a cost that after the first few years will settle to a couple of thousand dollars a shot or thereabouts if today's medicines are any guide. A few decades after that and these will be cheap enough for the third world, one step removed from free, like the simpler medicines of past years are today. In the matter of treating aging as a medical condition, we all win together or we all lose together. This is a collaborative game, not a competitive one.

Given this why do we not see the world's wealthy falling over themselves to change the world? Not just in the way we care about, to eliminate aging, but in general? I think it is that many simply do not know how to even begin to do this. Wealth doesn't grant vision, and becoming wealthy only gives you experience in managing your particular process for becoming wealthy. Most people don't look beyond their immediate surroundings, don't think far to the future, and that is just as true of high net worth individuals as it is of the rest of us. They have followed their particular passion, whatever it was that happened - as a side-effect - to mint money. That doesn't give a person any particular insight into how to use that money to change the world for the better. Look at the number of wealthy individuals who go into politics, for example. That is the ultimate public declaration of a lack of vision: it is an admission that you have no ideas on to how to change the world; you can see no further than ordering people around and rearranging the deck chairs that exist today.

So don't snipe at those who are actually trying to use their wealth to make the world a better place. They're figuring it out as they go along, just the same as everyone else has to, new entrants to areas of interest such as aging research and human longevity. Remember when you were first learning about this field of science and the present state of research? A wealthy individual will have just the same issues as you did; it's no easier for them to figure things out. The best that we can do is to help make the signposts better, more clear, and put forward sensible position statements on how newcomers can help to make a revolutionary difference in this field. (Such as by funding SENS research). This is just the same as we'd do for everyone else, as, after all, we're all in this together.

Why are all the tech billionaires chasing 'immortality'?

Although undoubtedly motivated by financial reward, for some investors who have proclaimed their wish to radically extend human lifespan there are also personal factors which can explain each individual's contributions. In this regard, those investing in radical life extension of course want to see the benefits of it themselves. But is it so hard to believe that billionaires really seek to do good with their money? Perhaps these investments can actually be explained as a desire to genuinely improve society by leading the cause of prolonging healthy lifespan.

When Page and Brin formed Calico Labs, Missy Krasner, a Google Health employee declared: "Larry and Sergey have always had this grand vision about how to help society and improve public health." For Sergey Brin this mission has so far manifested itself in over $150 million of personal investments, given primarily to companies that use data to understand DNA. Together with Mark Zuckerberg, he also co-sponsors the $33 million Breakthrough Prize for Life Sciences, awarded to scientists engaged in curing age-related diseases.

Peter Thiel is also driven by the desire to improve public health in the US, a system which he is openly critical of, and one which is increasingly burdened by an aging population. In a Reddit AMA Peter Thiel declared: "We would never design a system like this if we were to start from scratch." As a result, through his $2 billion capital Founders Fund, Thiel regularly provides money for biotechnology companies and researchers looking at different ways to slow down or stop aging. He has provided Aubrey de Grey's SENS Research Foundation with over $6 million to help with their mission to find drugs to cure age-related damage.

Similarly Bill Maris has long insisted on a more meaningful purpose for Google Ventures' investments, and moving into the field of healthcare represents a chance for Google money to be used towards developing a more optimistic scenario where people are given the chance to live longer healthier lives. In exclaiming "medicine needs to come out of the dark ages", he plans to use Google Ventures as a primary vehicle for making this happen.

For the newest tech billionaire to enter the arena, Facebook's Mark Zuckerberg the intentions particularly appear to be altruistic and humanitarian. To Stephen Hawking's question in a recent Facebook Q&A on which of the biggest mysteries in science he would like to have an answer to, Zuckerberg wrote an entire list, including "how to cure all diseases" and "what could enable us to live forever?" Also, in 2013, in a status update, the Facebook chief executive wrote: "Our society needs more heroes who are scientists, researchers, and engineers," and "we need to celebrate and reward the people who cure diseases, expand our understanding of humanity, and work to improve people's lives."

Thus, judging by the amounts of money and time these investors are devoting to supporting a range of innovations designed to improve both the human condition and healthcare, one can easily determine that there is genuine interest in making a positive impact on society.

Here is recent news of another team working to engineer salivary gland tissue, one of many parts of the body typically given little thought until it stops working. This team doesn't seem to be as close to a functional end result as the Japanese group I pointed out last month, but a diversity of approaches is always a good sign:

Saliva is critical to good health. It helps with speaking, swallowing, washing food off teeth, initial food digestion and preventing oral infections. Insufficient saliva can cause chronic bad breath, cavities, gum disease, as well as systemic infections. There is no treatment for low-producing or nonfunctioning salivary glands, and the glands have little regenerative capability.

A research team is the first to use silk fibers as a framework to grow stem cells into salivary gland cells. Silk is a good choice for stem cell scaffolding because it is natural, biodegradable, flexible and porous, providing the developing cells easy access to oxygen and nutrition. It also does not cause inflammation, as other scaffold materials have. The researchers' new process is the first major step toward helping more than 4 million people in the U.S. with a degenerative autoimmune disease called Sjögren's syndrome, in which the body attacks its own tear ducts and salivary glands. Low saliva production also is a devastating problem for thousands of patients who have had radiation treatment for head and neck cancer, as well as about 50 percent of older Americans whose medications can cause dry mouth, also known as xerostomia.

"Salivary gland stem cells are some of the most difficult cells to grow in culture and retain their function. In our process, we purified the silk fibers by removing a number of contaminants. We put stem cells from rat salivary glands on the silk framework with a media to nourish them. After several weeks in culture, the cells produced a 3-D matrix covering the silk scaffolds. The cells had many of the same characteristics as salivary gland cells that grow in the mouth. Until now, retention of salivary gland cell properties has not been possible using other tissue culture techniques. This unique culture system has great potential for future salivary gland research and for the development of new cell-based therapeutics."

Because there are few salivary gland stem cells in the human mouth, the scientists plan to continue using rat salivary glands to refine the process, but eventually hope to use stem cells derived from human bone marrow or umbilical cord blood to regenerate salivary glands for humans.

Link: http://uthscsa.edu/hscnews/singleformat2.asp?newID=5099

Evidence suggests that transthyretin (TTR) amyloidosis, also known as senile systemic amyloidosis, is the condition that kills the oldest people, those who have survived every other aspect of aging to reach ages of 110 and greater. Here, I'll note a review paper in which the authors point out that TTR amyloidosis in aging is very likely much more prevalent than this: not a condition only seen in the oldest old, but rather also the cause of a small but sizable fraction of some varieties of heart failure across the entire elderly population. It has been misdiagnosed due to lack of adequate testing for the condition, and thus the development of treatments has not been prioritized highly enough.

Numerous types of amyloid appear in tissues with aging, each consisting of a specific misfolded protein that precipitates to form form clumps and fibrils. In the case of transthyretin amyloid, these deposits clog blood vessels and lead to hypertrophy of the heart, ending with something that looks a lot like congestive heart failure.

The obvious path to dealing with amyloids and their contribution to aging and age-related disease is to periodically remove them. This is the approach taken by much of the Alzheimer's research community, but in that case has proven unexpectedly challenging to date even though a large amount of funding is devoted to, for example, the development of immune therapies to achieve this goal. In the case of TTR amyloidosis there is very little work under way, but the SENS Research Foundation has funded a so far successful program into the use of catabodies to degrade transthyretin amyloid. As this paper notes, the need for therapies is there, even if under-appreciated by the medical community at present:

Transthyretin (TTR) amyloidosis is a disease caused by systemic deposition of wild-type (WT) or mutant TTR fibrils, resulting in heart failure when deposition occurs in the heart. Mutant TTR deposition leads to familial TTR amyloid. Accumulation of the normal TTR protein causes WT cardiac amyloidosis (also known as senile amyloidosis).

In recent years, heart failure with preserved ejection fraction (HFpEF) has become increasingly prevalent among individuals hospitalized for acute decompensated heart failure. A recent autopsy series provided pivotal evidence that TTR amyloidosis is more prevalent among HFpEF population. Of the 109 Caucasian patients seen at Mayo Clinic hospitals between 1986 and 2001 with subsequent autopsy, 5% were found to have moderate or severe WT TTR deposits in the left ventricle, consistent with WT systemic amyloidosis as the primary etiology of heart failure. In addition, mild interstitial and/or variable severity of intramural coronary vascular WT TTR deposition occurred in 12% of this cohort. None of these patients carried an antemortem diagnosis of cardiac amyloid.

How TTR amyloidosis contributes to the development of HFpEF is not known. We can only hypothesize that the accumulation of dense TTR amyloid likely worsens diastolic function. Slow accumulation of pathologic TTR amyloid deposits in the heart may initially cause asymptomatic left ventricular (LV) hypertrophy, with relatively late diagnosis because of its gradual progression. The diagnosis of TTR cardiac amyloidosis is often missed until very late in the disease course, as it is an indolent illness affecting the same elderly population with HFpEF. Unlike light chain (AL) amyloidosis, there is no readily available blood test for misfolded TTR protein. Diagnostic algorithms, including non-invasive imaging modalities and endomyocardial biopsy, have been published elsewhere. Yet these algorithms can only be applied if cardiac amyloid is suspected.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284988/

In the paper quoted below, researchers review the links between immune system dysfunction in aging and pulmonary diseases - diseases of the lungs, ranging from infections to fibrosis. This is just one of many classes of medical condition that are much more serious and frequent in the elderly.

We all know that the immune system fails in its duties with aging. The elderly are frail in large part because they have little resistance to infection, their healing is impaired, and other functions depending on components of the immune system are similarly diminished. This is partially the result of high levels of various forms of cell and tissue damage, and partially the result of the immune system having evolved into a form that cannot continue to adapt to new threats indefinitely. To oversimplify somewhat, parts of it run out of space, too many cells devoted to memory of pathogens and too few to devoted to the destruction of those pathogens and potentially harmful cells.

The immune system is an enormously complex array of specialized cell populations, and so its progressive failure is similarly complicated. Beyond the disarray within the immune system, we must also consider that immune cells have intricate parts to play in the proper function of many different organs and tissue types, all of which are impacted as the immune system as a whole runs down. Wound healing, for example, falters in the old in part because of dysregulation in the macrophage population. One of the consequences of immune aging is a rising level of chronic inflammation, and it is known that inflammation contributes meaningfully to the development of many age-related conditions. Inflammation grows troublesome in lung tissues for example, the result of changing behavior on the part of immune cells.

The good news is that there are numerous potential ways to adjust the old immune system for more youthful performance, some of which could be realized quite soon, even though none are as yet comprehensive. Any engineering effort that results in more active, useful immune cells in circulation should be beneficial, however. This could be achieved through, for example, restoration of thymic function, or by destroying the clutter of memory cells or other unwanted sections of an experienced immune cell population, or even by using the techniques of stem cell medicine to grow a supply of immune cells and infuse large numbers of them on a regular basis.

The Impact of Immunosenescence on Pulmonary Disease

The shift in global demographics as a consequence of increased life expectancies has given greater clinical and research focus to the physiological process of aging and its impact on chronic disease. Morbidity and mortality from pulmonary illness have interestingly increased while those from other prevalent diseases such as cardiovascular or neurological have remained stable or in some cases decreased. This has led to recognition of the importance of age-related changes to the development and progression of lung disease.

While a multitude of cellular and molecular changes occur with age, their specific impact on the respiratory system, pulmonary physiology, and disease susceptibility remains undetermined. Age-related declines in immune function, termed "immunosenescence," likely play a critical role in the manifestation of age-related pulmonary diseases. Influencing both innate and adaptive components of the immune system, immunosenescence shapes the clinical phenotype observed in many chronic respiratory diseases including asthma and pulmonary fibrosis. This importantly differs from the same disease observed in younger cohorts. Age-related change in immunity additionally predisposes the elderly to pulmonary infection such as influenza and pneumococcus while a poorer vaccine response contributes to poorer outcomes.

Immunosenescence causes age-related declines in immune function at both cellular and serologic levels. Specific responses to foreign and self-antigens ensue promoting an increased susceptibility of the elderly to diseases including infection, cancer, autoimmune, and other chronic processes in addition to a poorer vaccine response. Both innate and adaptive arms of immune function are affected. Autoimmunity, immunodeficiency, and immune-dysregulation are some of the theories put forward to account for this physiological phenomenon; however it is likely that a combination of these takes place in vivo. Aging is associated with a chronic low grade inflammatory state. As such, proinflammatory cytokines including TNF-α, IL-1, and IL-6 are systemically elevated. Such "inflamm-aging" may be part of the aging process itself; however it has been proposed in the pathogenesis of several age-related inflammatory diseases including atherosclerosis, diabetes, and Alzheimer's.

Asthma and Allergy

While the asthmatic phenotype in children is well defined, "late-onset" asthma has lagged behind. This is largely explained by the heterogeneous nature of disease despite the similar treatment approaches. Until recently, phenotypes of "late-onset asthma" were based on aetiology, for instance, aspirin sensitivity, toxic exposures, or occupational influence or alternatively clinical disease characteristics such as mild, moderate, or severe. Consequently, mechanisms associated with late-onset asthma are incompletely understood. Suggestions are that it may occur as a consequence to viral infection that promotes persistent inflammatory change when coupled to the effects of immunosenescence.

Pulmonary Infection

Respiratory infections remain a leading cause of morbidity and mortality worldwide especially in older adults. The increased risk of community-acquired pneumonia in elderly patients ranges from 15 to 30% independent of socioeconomic status or comorbidities. Despite advances in molecular based detection techniques, there is limited evidence addressing specific mechanisms by which immunosenescence predisposes to pneumococcal associated disease. It is very likely that immunosenescence plays a role in increasing susceptibility to respiratory infection in the elderly population. This is likely facilitated by an impaired mucosal barrier, reduced mucociliary clearance, and blunted airway immune and inflammatory responses on exposure to potentially pathogenic microorganisms.

Pulmonary Fibrosis

Several of the affected cellular and molecular mechanisms associated with the aging process are implicated in idiopathic pulmonary fibrosis (IPF). Patients with IPF also demonstrate increased markers of oxidative stress both within the airway and systemically. Abnormal cellular senescence is demonstrated in patients with IPF, particularly from bone marrow derived stem cells such as fibrocytes. Fibrocytes have been shown to traffic into the lungs and to contribute to IPF pathogenesis. Additionally, high levels of circulating fibrocytes have been shown to herald a poor prognosis in IPF. A chronic background inflammatory state occurs in IPF that compares with immunosenescence associated "inflamm-aging."

Autoimmune Disease, Vasculitis, and Other Respiratory Diseases

The elderly have a higher rate of autoimmunity but lower prevalence of autoimmune disease. The explanation for this is uncertain; however, it is postulated to be due to the increased expansion of peripheral regulatory T-cells. Autoimmunity may increase the affinity of T-cells to self-antigens or latent viruses promoting an autoimmune process. Older adults have been shown to possess increased amounts of circulating autoantibodies due to the increased amount of tissue and cell damage coupled with apoptosis. Importantly however higher levels of autoimmunity do not equate with increased autoimmune disease. Thymic T-regulatory cells (Tregs) increase autoimmunity and reduce the CD4 and CD8 response which in turn increases susceptibility to infection and cancers. Recurrent bacterial and viral infections stimulate the release of proinflammatory cytokines which in turn are further expanded by activation of Tregs. Treg expansion is associated with T-helper 17 (Th17) cells and the persistence of chronic inflammation, a phenomenon that occurs during the physiological aging process.

Below find linked a popular science article on some of the strands of research that aim at safely altering the operation of cellular metabolism to either (a) gently slow aging by reducing the pace at which underlying cell and tissue damage accumulates or (b) override some of the reactions to cellular damage that cause declines in tissue maintenance. Neither strategy aims at repair of that damage, unfortunately, and so is ultimately limited in the quality of results that can be achieved: no true rejuvenation, no indefinite healthspan, just a slowing of the inevitable. Nonetheless, overriding natural mechanisms to restore age-related declines in stem cell activity seems to be on track to produce benefits despite the continued presence of unrepaired cell and tissue damage. The evolved balance between cancer risk and stem cell decline appears to leave more room for action than anticipated.

The majority of older Americans live out their final years with at least one or two chronic ailments, such as arthritis, diabetes, heart disease or stroke. The longer their body clock ticks, the more disabling conditions they face. Doctors and drug companies traditionally treat each of these aging-related diseases as it arises. But a small group of scientists have begun championing a bold new approach. They think it is possible to stop or even rewind the body's internal chronometer so that all these diseases will arrive later or not at all. Studies of centenarians suggest the feat is achievable. Most of these individuals live that long because they have somehow avoided most of the diseases that burden other folks in their 70s and 80s. Nor does a centenarian's unusual longevity result in an end-of-life decline that lasts longer than anyone else's. In fact, research on hundreds of "super agers" suggests exactly the opposite. For them, illness typically starts later and arrives closer to the end.

Living longer may come with trade-offs. Making old cells young again will mean they will start dividing again. Controlled cell division equals youthfulness; uncontrolled cell division equals cancer. But at the moment, scientists are not sure if they can do one without the other. Figuring out the right timing for treatment is also complicated. If the goal is to prevent multiple diseases of aging, do you start your antiaging therapies when the first disease hits? The second? "Once you're broken, it's really hard to put you back together. It's going to be easier to keep people healthy." So it probably makes more sense to start treatment years earlier, during a healthy middle age. But the research needed to prove that supposition would take decades.

If various diseases can be pushed off, the next obvious question is by how long. It will take at least another 20 years of study to answer that question. Scientists have successfully extended the life span of worms eightfold and added a year of life to three-year-old lab mice. Would these advances translate into an 80-year-old person living five or six centuries or even an extra 30 years? Or would they get just one more year? Life extension in people is likely to be more modest than in yeast, worms, flies or mice. Previous research has suggested that lower-order creatures benefit the most from longevity efforts - with yeast, for instance, deriving a greater benefit in caloric-restriction experiments than mammals. The closer you get to humans, the smaller the effect on life span. And what magnitude of benefit would someone need to justify taking - and paying for - such a treatment? "Do you take a drug your whole life hoping to live 4 percent longer or 7 percent longer?"

I would hope that question never arises in any practical sense for the population at large, as efforts to alter metabolism to slow aging should be quickly overtaken and discarded in the near future by the far better results I'd expect to see achieved through damage repair therapies, such as those proposed in the SENS programs. SENS-like rejuvenation approaches based on repair of cell and tissue damage are slowly advancing to the point of generating meaningful results. That is already the case for senescent cell clearance, but there are numerous other lines of rejuvenation research still at far earlier stages. The sooner this transition happens, the better off we all are.

Link: http://www.scientificamerican.com/article/researchers-study-3-promising-anti-aging-therapies/

Some types of cancer produce cells that are not as picky as ordinary, correctly functioning cells in the nucleosides they are willing to incorporate into their DNA during repair and replication. Researchers here propose that by introducing a suitably altered nucleosides into tissues it should be possible to produce DNA in cancer cells that will cause them to destroy themselves. Other cells in the body will be unharmed by the treatment. This is still in the early conceptual stage of development, however; it remains to be seen what hurdles lie ahead in the development of a practical therapy built on the idea:

Normal cells have highly selective mechanisms to ensure that nucleosides - the chemical blocks used to make new strands of DNA - don't carry extra, unwanted chemical changes. But some types of cancer cells aren't so selective. These cells incorporate chemically modified nucleosides into their DNA, which is toxic to them. The findings indicate that it might be possible to use modified nucleotides for specific killing of cancer cells.

Cells are thrifty when it comes to synthesizing new DNA. In addition to making new nucleotides, they recycle chemical parts from the DNA of dying cells, or DNA that we ingest in our diets. However, one of the four types of nucleotides in DNA - the 'C' in genetic sequences - is often chemically modified. These chemical modifications, which are called epigenetic changes, are important for controlling genes and need to be in the correct places in DNA for cells to function normally. If the epigenetic modifications are on the wrong C nucleotides, they could make cells cancerous or kill them.

The enzymes that recycle nucleotides are highly specific. They don't use the modified nucleosides, so the new DNA is epigenetically 'clean.' However, when they looked at the recycling process in cancer cell lines, researchers discovered that some of the cancer cells are able to transform these nucleosides, allowing incorporation into new DNA. This process often kills the cells. It was the cancer cell lines that expressed unusually high levels of a protein called cytidine deaminase (CDA) that made this mistake in recycling. CDA is often overexpressed in certain tumor types, including pancreatic cancer. "It has been suggested that CDA inactivates cytidine analogues that are already used in the clinic to treat some blood and pancreatic cancers. In a strikingly reverse scenario, the nucleosides that we used in our study are relatively harmless until they encounter CDA, which converts them into hostile cytotoxic agents." The researchers will likely continue to investigate this new avenue for 'epigenetic' drugs as cancer therapies.

Link: http://www.ludwigcancerresearch.org/news/modified-dna-building-blocks-are-cancers-achilles-heel

Today I thought I'd point out an interesting and very readable open access paper on immune system aging and the contribution of cytomegalovirus to that process. The authors outline the generation of a large set of data on immune aging, sampling a few hundred healthy individuals to obtain a range of measures of immune function, and discuss the results. It makes for interesting reading if you've been following research into cytomegalovirus in immune aging, and there are even online data visualization tools for the results published in this paper.

The immune system grows simultaneously overactive and ineffective in old age, generating chronic inflammation while failing to respond adequately to threats such as pathogens and potentially cancerous cells. A growing consensus in the researcher community sees exposure to cytomegalovirus (CMV) as an important contribution to this dysfunction. CMV is a very prevalent herpesvirus; near everyone has it in their system by the time they are old, and like all herpesviruses it resists clearance, reemerging from hiding to challenge the immune system repeatedly. In the old immune system there is an expansion of memory T cells, and especially memory T cells devoted to CMV. This expansion takes place at the expense of naive T cells needed to respond to new threats.

There is more than just this one form of dysfunction in the aged immune system, but this particular problem might be addressed in the near future in a variety of ways: clear out the useless duplicated memory T cells to free up space, or deliver a much larger supply of new T cells, such as by rejuvenating the thymus, the organ responsible for T cell maturation, or simply culturing new immune cells from a patient's own tissues and periodically delivering them. It is also possible to work towards a reliable way to clear CMV permanently - better ways to treat all herpesviruses are certainly needed. Even if completely successful this won't undo the damage done to the immune system's balance of cell populations, however. It only prevents the accumulation of more damage.

This paper can be taken as one of many that illustrates the magnitude of the effect of CMV on immune aging. It also makes some other interesting points regarding the scale of variations between individuals as compared to variations over the course of aging. It is possible to be old and still have a comparatively effective immune system by some measures: there is considerable overlap in the range of values across a given age and the range across all ages. The trend is still downhill and we need the development of rejuvenation treatments to reverse that, but all is not hopeless.

Large-Scale and Comprehensive Immune Profiling and Functional Analysis of Normal Human Aging

In this study, we describe a large immunological data set based on about 240 individuals from a clinical cohort of 740 healthy aging adults. Data from cellular, protein, and genomic assays are described, with particular emphasis on stimulation-response assays (analysis of cytokine signaling, and cytokine production and gene expression from stimulated peripheral blood mononuclear cells). Our emphasis in this paper was to describe the features of each assay with regard to discovering differences based on age, sex, and CMV status. Further analysis of the data is welcomed, via a parallel coordinates visualization tool.

One common theme among nearly all our immunological readouts is that there is considerable heterogeneity at every age, which is generally greater than the mean change across ages. This is exemplified by the CD27+CD8+ subset of T cells. While the downward trend with age is highly significant, the breadth of values at every age is very high. In this regard, there are essentially no "clock" analytes, which would accurately and independently predict age, since there is so much overlap in the distributions among young and old individuals. The corollary to this is that many, if not most, elderly individuals still fall within the range of the younger adults. In fact, we often observed a broadening of the distribution with age.

In this regard, it is important to note that this study had strict exclusion criteria, such that overt diseases of aging were not clinically present. Although our data provide a relatively clean description of the range of immunological values associated with healthy aging, they represent a cross sectional analysis and as such may include individuals at risk for or developing disease.

As a result of quantifying significant readouts by age, sex, and CMV status, one can pose the question, "Which of these three variables has the greatest impact on the immune system as we measured it?" From our data, it seems reasonable to conclude that age, then sex and CMV status, show the greatest effects. Taken another way, it is impressive to see that the changes in the immune system brought about by a single pathogen, CMV, rival the differences seen between the sexes, in terms of the number of significantly affected analytes. Another conclusion from our data is that there is a clear interaction of age, sex, and CMV status. For example, T cell subsets are highly influenced by all three. In this case, the effect of CMV appears to be a downward broadening of the distribution, such that a subset of CMV positive individuals shows markedly lower levels of these cells.

Given the potential for producing effective treatments in near all areas of medicine brought about by the ongoing revolution in biotechnology, a growing number of people are coming to see that the present established systems of funding, both public and private, are essentially broken. They are far too conservative, funding next to none of the most important early stage research. All of the most important and risky early stage research programs are funded by either administrative sleight of hand or by visionary philanthropy: established funding sources as a rule never offer grants unless the new science has already been discovered and mapped out with a fair degree of certainty. Thus they fund the process of fleshing out and developing a discovery, not the work needed to create and validate that discovery in the first place. If we want real progress and radical new directions in medicine, it is exactly the early stage and risky research that must be funded with greater confidence, however.

The difference between science and engineering is that scientific research starts without understanding and tries out various hypotheses until one seems to work; while an engineer works with a paradigm that she knows to be reliable enough to be a basis for results of her innovations in advance. A high failure rate is inseparable from good science. But the National Science Foundation (NSF) prefers to fund low-risk work, which is really engineering. One irony is that capitalism is pretty good at allocating funds for engineering. Once the science is well developed, the marketplace isn't a bad model for deciding where to invest engineering resources. We probably don't need NSF to fund the "D" half of "R&D". But the reason that we need NSF (and NIH and NIA) as public funding institutions is that the rewards of science are difficult to predict.

I venture to propose that the more unpredictable the result, the more important the experiment. The best prospects for future scientific breakthroughs lie in the direction of things that we already know but don't understand - things that don't make sense. Most of these will turn out to be mistakes in experimental technique or interpretation; but there are some that have such broad corroboration from diverse laboratories that this is unlikely. I could say that "professional scientist" is already a oxymoron. Scientists work best when they are driven by curiosity and a passion to find out, when they are doing what they love. How can that be consistent with centralized decision-making and bureaucratic control of research priorities? If we pay a scientist to do science, we should not make the payment contingent on studying anything in particular. No one in a government bureaucracy has the wisdom to predict next year's breakthroughs, or to single out the scientists most likely to achieve them.

In the late 1970s, when I was a low-level researcher at a government contract research house, we always worked one year ahead of our funding. By the time a proposal was written, we had worked out the science in sufficient detail that we knew the results. If the proposal was funded, we would use the proceeds to support us while we worked on next year's proposal. We may be outraged at 70% overhead rates for administration, and think of this as "slush money" that is ripe for abuse. I agree that bureaucrats receive too big a share of the pie, and scientists too little. But there is some portion of the overhead money that finds its way back through departments to the researchers themselves, and offers them some slack between contracts, their only real freedom to think and to innovate. I asked my collaborator at Prominent Midwestern U whether he had funding for the exploratory, groundbreaking work on population dynamics that he was doing with me, but I already knew the answer. He was doing it with soft funding for a follow-on to previously successful research. He had prudently kept the funders in the dark about this specific project. There's plenty of time to tell them about it if we succeed.

Link: http://joshmitteldorf.scienceblog.com/2015/07/23/funding-policies-distort-science/

Researchers here present a fairly compelling case that the characteristic decline in the protective heat shock response with age is an evolved program. Compelling but not airtight: one could still argue that the rapid transition from effective to less effective observed in nematode worms is, along with other changes that occur at the same time, a response to rising levels of cellular damage rather than something that will occur regardless of circumstances. It is not too hard to envisage further studies that might add evidence to either side of the argument, and I will be very interested to see the outcome of similar investigations in mammals, but for now the primary point of interest is to see if the signaling that causes this decline can be usefully interfered with. The expectation is that increased levels of heat shock activity should result in more active maintenance and damage repair in cellular machinery, leading to slower aging and longer healthspan, and thus there is some interest in the research community in finding potential approaches to achieve this end.

Knowing more about how the quality control system works in cells could help researchers one day figure out how to provide humans with a better cellular quality of life and therefore delay degenerative diseases related to aging, such as neurodegenerative diseases. "Wouldn't it be better for society if people could be healthy and productive for a longer period during their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress."

A genetic switch starts the aging process by turning off cell stress responses that protect the cell by keeping important proteins folded and functional. In C. elegans, the decline begins eight hours into adulthood - all the switches get thrown to shut off an animal's cell stress protective mechanisms. Researchers found it is the germline stem cells responsible for making eggs and sperm that control the switch. In animals, including C. elegans and humans, the heat shock response is essential for proper protein folding and cellular health. Aging is associated with a decline in quality control, so researchers looked specifically at the heat shock response in the life of C. elegans. "We saw a dramatic collapse of the protective heat shock response beginning in early adulthood." Once the germline has completed its job and produced eggs and sperm - necessary for the next generation of animals - it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal. "All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses."

Using a combination of genetic and biochemical approaches, researchers found the protective heat shock response declines steeply over a four-hour period in early adulthood, precisely at the onset of reproductive maturity. Repression of the heat shock response occurred due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This resulted in a repressed chromatin state that interfered with HSF-1 binding and suppresses transcription initiation in response to stress. The animals still appeared normal in behavior, but the scientists could see molecular changes and the decline of protein quality control. In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.

Link: http://www.sciencedaily.com/releases/2015/07/150723125244.htm

In the research noted here, scientists have identified a potential treatment for cataracts based on the details of a rare human mutation that causes cataracts to form in young children. These patients lack lanosterol, and for reasons not yet fully understood that causes cataract formation in the lens of the eye. Following on from that finding researchers demonstrated that providing greater than usual levels of lanosterol in tissues and animals causes cataracts to shrink. The initial results are promising, but it remains to be seen how well it does outside the laboratory: too little is yet understood of the underlying mechanism to be sure that it will do well. Still, this is a good example of the very positive side of genetic studies: using mutational differences between individuals to gain enough insight into poorly understood disease mechanisms to enable the production of better treatments.

Most cataracts are age-related, with no meaningful genetic contribution to their progression, at least not to outweigh the damage you do to yourself through becoming overweight or smoking. In later life cataracts of several varieties can form in the lens of the eye to cause progressively worsening blindness. Some types result from changing structural properties of the lens that lead to damage and loss of transparency, while others involve deposition of opaque waste products or damaged and misplaced versions of the proteins that make up the lens. The present state of the art in treating cataracts is surgery to remove the damaged portions and replace them with prosthetic lens material, but some form of drug-like treatment - as proposed here - to clear out the unwanted compounds blocking vision would be a great improvement for some types of cataract.

Looking at the broader picture, a great deal of aging is a matter of the wrong proteins showing up in the wrong places. Protein aggregates feature prominently in neurodegenerative conditions such as Alzheimer's disease, for example. A large segment of the near future of medical science will involve finding ever more sophisticated methods of safely removing specific proteins from specific locations in our tissues. Many of these errant proteins come into existence as a side-effect of the normal operation of cellular metabolism, so it is perfectly feasible to look to periodic clearance as the basis for rejuvenation treatments. Provided that the level of these proteins is kept fairly low, as it is in young people, they should not cause further damage at a pace high enough to cause the emergence of age-related disease, as is the case today.

Eye drops could dissolve cataracts

Though scientists don't fully understand how cataracts form, they do know that the "fog" often seen by patients is a glob of broken proteins, stuck together in a malfunctioning clump. When healthy, these proteins, called crystallins, help the eye's lens keep its structure and transparency. But as humans and animals alike get older, these crystallin proteins start to come unglued and lose their ability to function. Then they clump together and form a sheathlike obstruction in the lens, causing the signature "steamy glass" vision that accompanies cataracts. Researchers came up with the eye drop idea after finding that children with a genetically inherited form of cataracts shared a mutation that stopped the production of lanosterol, an important steroid in the body. When their parents did not have the same mutation, the adults produced lanosterol and had no cataracts.

So the researchers wondered: What if lanosterol helped prevent or reduce cataracts? The team tested a lanosterol-laden solution in three separate experiments. First, they used human lens cells to test how effectively lanosterol shrank lab models of cataracts. They saw a significant decrease. Then, they progressed to rabbits suffering from cataracts. At the end of the 6-day experiment, 11 of 13 rabbits had gone from having severe or significant cataracts to mild cataracts or no cataracts at all. Finally, the team moved on to dogs with naturally occurring cataracts. The dogs responded just as the researchers hoped to the lanosterol solution, which was given in the form of both eye injections and eye drops. The dogs' lenses showed the same type of dissolving pattern as the human and rabbit lens cells. The improvement was remarkable - researchers could tell just by looking at the dogs' eyes that the cataracts had decreased. But the exact mechanism of how lanosterol manages to disperse the mass of proteins remains unknown.

Lanosterol reverses protein aggregation in cataracts

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses.

The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs.

Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

This is the third in a recent series of local news articles on the work of the Buck Institute for Aging Research in California. Sadly very little of that work is relevant to the SENS vision of rejuvenation biotechnology, targeted repair of the damage that causes aging with the ultimate goal of entirely preventing degeneration and disease. Like much of the field, research at the Buck Institute is almost entirely focused on modest goals; better understanding of the fine cellular details of how aging progresses, and manipulating the operation of cellular metabolism so as to slightly slow the accumulation of damage that causes frailty, suffering, and disease:

Simon Melov, a founding faculty member of the Buck Institute in 1999, trained in molecular biology. Before the 1990s, scientists shunned research on aging as too difficult. "You couldn't do anything about it," Melov said. That attitude persisted for years. "Gordon Lithgow and I would go to conferences. and people would say we were stupid for working on aging. Everyone knows it's ridiculous." A future Nobel prize winner came up to them at a podium where Lithgow was presenting, Melov recalls. "He said we should get out of this and go do something worthwhile. Nothing will ever come of this."

In about 1990, Tom Johnson, in whose University of Colorado lab Lithgow and Melov worked, discovered that aging in worms could be changed by modifying a gene. A few years later, Cynthia Kenyon's paper on her similar research drew acclaim. "When her paper came out, the floodgates opened. It was the aha moment. Cynthia (now at Calico, Buck Institute's Google-funded partner) was a big name." The 2000s brought a shift toward finding drugs that manipulate lifespan. Now the emphasis is on healthspan. "Function is more important than lifespan. The elderly complain about living too long in poor health. Is it easy to put your clothes on every day, reach the top shelf in your kitchen? Is it painful to walk, carry loads? Can you get in and out of the shower easily?"

Melov looks for interventions that improve gene-expression profiling, for instance. In people, he studied resistance exercise as a means to stress bones and help preserve their integrity. "In the mouse, you argue with it for an hour before it goes anywhere. In people, you get a good degree of compliance. We found that repeated resistance exercise over six months reversed many gene expression profiles -- a genetic fingerprint of cellular function in muscle -- associated with aging, back to a more youthful profile. Exercise rejuvenates the tissue." Exercise in the future will be viewed as essential to functioning. "If you don't exercise, you're going to add to the health-care burden. You have to make the time or end up subtracting years from your life." He used to take supplements then realized there's little data to support such intake. "If you exercise and have a good diet. you don't need supplements. It's a very different matter if you have a bad diet and don't exercise."

Lack of substantial federal funding for aging research confounds Melov. "Look at the NIH," he said. "There was an expectation that legislative bodies would recognize that baby boomers were aging," that this is a serious health care crisis "with large-scale financial ramifications for the economy. Unless that investment happens rapidly over the next five years. we are going to be in big trouble. This is a slow-motion train wreck. We're not going to be able to reach into the back pocket of our scientific lab coats and pull out a solution on demand. We need time and money. I'm still optimistic that reality will rear its ugly head."

Link: http://www.northbaybusinessjournal.com/northbay/marincounty/4206440-181/buck-research-mice-clues-on

Here researchers propose an interesting approach to destroying cancer stem cells via targeted antibiotics. Cancer stem cells have been shown to be the driving force behind many types of cancer: without their presence, tumors would halt their growth or wither. At this point cancer research as a whole is far too slow and expensive. Faster progress towards meaningful treatments will arise from identifying and focusing on common points of attack that are essentially the same in many different types of cancer. However all too many of today's expensive and time-consuming research programs are entirely specific to the genetics and cell metabolism of one very narrow subtype of cancer, and even then individual tumors of that subtype can evolve to remove the vulnerability in question. So it is worth keeping an eye on programs that might blossom into classes of therapy applicable to a broad swathe of cancers:

We propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect".

Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy.

Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467100/

There's a lot more going on out there these days in terms of advocacy for longevity science. People are finding it easier to raise funds from the broader community for acts of pure persuasion, which I think is a good sign on the whole. It is one metric by which we can measure support for the cause. Here I'll point out a couple of recent and ongoing projects, the Longevity Cookbook by Maria Konovalenko and allies, and Zoltan Istvan's use of the US presidential election as a platform for raising awareness of long-standing futurist and transhumanist goals such as the defeat of aging.

While you're looking through the materials below, here is something to consider: is it better to fund research or is it better to fund publicity? I suspect that both are needed, striking some sort of balance between (a) science that is within striking distance but effectively invisible to the world and large funding sources, which has been the state for SENS rejuvenation research for quite some time, and (b) advocacy that is so far ahead of technological plausibility that the snake-oil salesmen sneak in and corrupt an entire generation with their nonsense, which is the story of the last quarter of the last century. An argument for the "fund research" side is that meaningful progress in medical science tends to generate its own news. An argument for the "more publicity efforts" side is that there are plenty of historical examples of important scientific progress languishing at the verge of completion for a lifetime or longer. Personally, I'm in favor of funding the research at this time, and one of my main reasons for that is that early stage research has become very cheap over the course of the modern biotechnology revolution, while publicity remains stubbornly expensive. Yes, it is far easier to send your message out into the world, but there is now such a sea of content that making yourself heard is harder than ever.

The Longevity Cookbook managed to raise more than $50,000 via crowdfunding last month, and congratulations to those involved: that certainly surprised me given how much of a challenge it is to pull in that much money for research over at this end of the pool. So far as I can see this will produce a book analogous to Kurzweil and Grossman's Fantastic Voyage from a decade ago: a mix of old school thoughts on diet and health, which will have very little to no determination on the future of your health and longevity, but which are ever popular with the public, merging into discussions of the latest life science research that may lead to therapies to treat aging as a medical condition. I wasn't all that happy with the way in which Fantastic Voyage dwelled upon diet and supplements, things that won't matter in the slightest in comparison to the consequences of success or failure in building SENS rejuvenation therapies or something very similar, and I expect I'll have similar complaints about the Longevity Cookbook. But then I'm not the audience, and there is always an argument for steering people into the topic of a cure for aging softly and by degrees.

Longevity Cookbook

Aging steals away your most valuable resource: time. The Longevity Cookbook is a strategy guide to help you get more time to experience the joy from everything that you like in life. Take yourself on a journey starting with nutrients and exercise regimes that goes on to explore the usage of genetically modified symbiotic organisms and using gene therapy to boost your own longevity.

Most importantly, we want to draw attention to an overlooked problem whose time has come: aging. In recent decades, we have begun to understand how to use changes in nutrition and lifestyle to extend the healthiest years of life. At the same time, findings in the lab have shown that it may someday be possible to greatly extend our maximum lifespan, and our quality of life as we age. This could happen sooner than you might think!

Any ambition to live longer than the historical human maximum lifespan of ~120 years will require a complex approach, that is not yet fully understood. It's possible that by modestly improving our health, and rolling back the clock using improvements to nutrition and lifestyle, such as those to be outlined in the Longevity Cookbook, we may live long enough to reap the benefits of revolutionary interventions that are currently still in the lab. With this thinking in mind, in the book we'll outline some of the most promising experiments that are currently underway or being proposed.

Zoltan Istvan is a character, and an outspoken transhumanist in a time when it is becoming perhaps a trifle unfashionable to refer to oneself as a transhumanist. Of course we are all transhumanists together here, reading this post while hoping and planning for a future in which fundamental limits of the human condition will be overcome through technological progress, such as this business of aging, suffering, and dying. Istvan has been publishing and speaking relentlessly on the topic of transhumanism for years now, and of late has settled upon the forthcoming presidential race as one of the few opportunities for an activist to make use of the US political system to promote a cause. In Europe starting single issue parties is a viable approach, but not in the US. So Istvan plans a tour and is already attracting attention and giving interviews:

This US presidential candidate doesn't want to be president - he wants to live forever

Zoltan Istvan was among the earliest candidates to declare his bid for the 2016 US presidential elections. But most Americans still won't know about this writer and Transhumanist philosopher by the time they head to the polls. Istvan knows that. Yet, his platform is refreshing: put science first. His ideas are radical, which is not uncommon for third-party candidates, but they are also appealing: make college education mandatory and free; create policies so that everyone can have designer babies, not just the rich; and discover immortality in the next 15-20 years.

Istvan represents the Transhumanist Party, which claims to have its root in philosophical thoughts going back centuries, and has the core aim of building technologies that will give us superhuman powers. The total number of members of Humanity+, the biggest such membership organization, is only 10,000. His campaign - which includes a bus shaped to represent a coffin - is run with help of a group of volunteers in California.

"The reception in the media has been better than anticipated. I think that's because people are really interested in the kinds of questions we ask, such as those about designer babies, artificial intelligence, exoskeleton suits. The big disappointment so far has been the funding."

I have just donated $10,000 to the Immortality Bus, which was the most rational decision of my life

I have non-zero probability to die next year. In my age of 42 it is not less than 1 per cent, and probably more. I could do many investment which will slightly lower my chance of dying - from healthy life style to cryonics contract. And I did many of them. Me and Exponential Technologies Institute donated $10,000 for Immortality bus project. This bus will be the start of Presidential campaign for the writer of "Transhumanist wager". 7 film crews agreed to cover the event. It will create high publicity and cover all topics of immortality, aging research, Friendly AI and extinction risks prevention. It will help to raise more funds for such type of research.

Researchers have found a way to induce complete regrowth of the liver in mice, which intriguing involves inducing far greater cellular senescence than is normally the case. The liver is normally the most regenerative of organs in mammals, capable of regrowing sections of tissue following injury, but this result is somewhat more impressive than that.

Cellular senescence is known to be involved in and promote wound healing, and researchers have shown in past years that senescence in liver cells is both flexible and amenable to manipulation. However clearance of senescent cells is of general interest in the prospective treatment of aging: senescent cells accumulate in all tissues with age and contribute to damage and loss of function through a variety of mechanisms. A more sophisticated control of cellular senescence in tissues may well lead to a range of therapies that alternately encourage it and suppress it at various times and under various circumstances.

Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution.

HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.

Link: http://dx.doi.org/10.1038/ncb3203

Researchers here investigate the transplant of induced pluripotent stem cells-derived progenitor cells produced from the recipient's tissues as a possible way to spur regeneration of kidney damage, such as the fibrosis characteristic of chronic kidney disease. Like many forms of stem cell therapy, this appears to produce benefits due to the signal molecules generated by the transplanted cells. That in turn suggests that near future therapies emerging from stem cell research will largely involve providing the signals directly, not via cells, in ever more sophisticated efforts to control the behavior of native cells. This present phase of cell transplant development will be used to gain the knowledge needed to build therapies lacking cells but which have the same beneficial effects.

One promising way to treat diseased or damaged kidneys is cell therapies that include the transplantation of renal progenitor cells, which can then develop into the cells needed for full recovery. Acquiring a sufficient number of progenitor cells has been difficult, however, which is why scientists have considered induced pluripotent stem cells (iPSCs), since they can be expanded at significantly high levels and then differentiated into the progenitors.

Researchers transplanted iPSC-derived renal progenitors into the kidney subcapsule, which is at the kidney surface of a mouse model with acute kidney injury. Even though the transplanted cells never integrated with the host, mice that received this transplant showed better recovery, including less necrosis and fibrosis, compared with mice that received transplants of other cell types. One reason attributed to this improvement was the use of cells that expressed Osr1 and Six2. Although these two factors are known markers of renal progenitors, until now researchers had not exclusively used cells that expressed both for cell therapies.

Another conclusion from the study was that because the cells did not integrate into the kidney, their therapeutic effects were the result of paracrine actions that included the secretion of key renoprotective factors. While most stem cell therapies aim for integration, these findings could have important clinical implications. Foremost is that it is one of the first to show the benefits of using human iPS cell-derived renal lineage cells for cell therapy. Second, fibrosis is a marker of progression to chronic kidney disease, suggesting that the paracrine effects could act as preventative therapy for other serious ailments. Finally, these effects could give clues for drug discovery. "There is no medication for acute kidney injury. If we can identify the paracrine factor, maybe it will lead to a drug."

Link: http://www.eurekalert.org/pub_releases/2015-07/cfic-isp072115.php

The UK mortality risk study I point out below doesn't provide any real surprises when it comes to the risk factors associated with higher mortality rates at a given age, but taken as a whole it is a good example of the present trend towards much more data and far larger study sizes in epidemiology. In this age of databases, with the cost of storage and computation falling rapidly towards numbers barely distinguishable from zero, the quality of epidemiological analysis is increasing. More data and larger study populations bring the possibility of ever better statistical measures, the ability to identify more subtle correlations, and - perhaps of greatest interest for those of us not in the science business - online databases that allow everyone to jump and and look at the results.

So you should head over to the UK Longevity Explorer and take a look at the Association Explorer; it's an interesting tool to tinker with, especially once you start digging down into the weeds of smaller associations. It is a nice view of all the things we'd like to render entirely irrelevant by producing rejuvenation biotechnologies capable of repair of cell and tissue damage. In a world in which the causes of aging can be meaningfully addressed, it no longer matters that you have minor gene variants, or had more or less exposure to infectious diseases in youth, or experienced other circumstances that presently swing life expectancy a year or a few years in either direction. The benefits provided by repair therapies will vastly outweigh all of that when it comes to long term health and life expectancy.

On a slightly different topic, and unlike the study below, I suspect that the largest datasets of interest to aging research that emerge in the decades ahead will be obtained without the consent of study participants. The incentives align with this outcome: (a) all groups with the capability to gather large amounts of data are presently doing so rapaciously, since they can use that data to generate profits in many ways; (b) few organizations are any good at defending large databases from attackers; (c) a dataset released into the wild from legal jurisdiction A is a dataset that researchers in legal jurisdiction B don't have to do the work to assemble or otherwise pay to use.

Given these points, I think that we will see continuing theft and release of large sets of medically relevant data, and that researchers and their boards will concoct ethical justifications for using this data as becomes more widely available. For example, researchers might pay a third party to anonymize stolen datasets available online in a way that prevents records from being associated with individuals without disturbing statistical associations, and then never officially view the original data themselves. There will be a sense that it is a shame to let this all go to waste since it is out there.

5 year mortality predictors in 498,103 UK Biobank participants: a prospective population-based study

Participants were enrolled in the UK Biobank from April, 2007, to July, 2010, from 21 assessment centres across England, Wales, and Scotland with standardised procedures. In this prospective population-based study, we assessed sex-specific associations of 655 measurements of demographics, health, and lifestyle with all-cause mortality and six cause-specific mortality categories in UK Biobank participants using the Cox proportional hazard model. We excluded variables that were missing in more than 80% of the participants and all cardiorespiratory fitness test measurements because summary data were not available. Validation of the prediction score was done in participants enrolled at the Scottish centres. UK life tables and census information were used to calibrate the score to the overall UK population.

Of 498,103 UK Biobank participants included (54% of whom were women) aged 37-73 years, 8532 (39% of whom were women) died during a median follow-up of 4·9 years. Self-reported health was the strongest predictor of all-cause mortality in men and a previous cancer diagnosis was the strongest predictor of all-cause mortality in women. When excluding individuals with major diseases or disorders (Charlson comorbidity index greater than 0; n=355 043), measures of smoking habits were the strongest predictors of all-cause mortality. The prognostic score including 13 self-reported predictors for men and 11 for women achieved good discrimination and significantly outperformed the Charlson comorbidity index.

Measures that can simply be obtained by questionnaires and without physical examination were the strongest predictors of all-cause mortality in the UK Biobank population. The prediction score we have developed accurately predicts 5 year all-cause mortality and can be used by individuals to improve health awareness, and by health professionals and organisations to identify high-risk individuals and guide public policy.

UK Longevity Explorer

Interest into the causes of death and disease is growing, as is our knowledge and understanding. Individuals, healthcare professionals, researchers, health organisations and governments all want to understand more about what might improve or reduce life expectancy, particularly in the middle-aged and elderly.

A large-scale project called UK Biobank was set up, and between 2006 and 2010, it collected 655 measurements from nearly half a million UK volunteers (498,103) aged 40-70. This website presents the two main parts of the researchers' work: the Association Explorer and the Risk Calculator. These are closely connected - the Risk Calculator is based on findings from the Association Explorer.

The Association Explorer is an interactive graph where you can explore how closely 655 measurements (variables) from the UK Biobank study are associated with different causes of death. The results for different associations are presented separately for women and men, and illustrate the ability of each variable to predict mortality. For more detailed results for each specific measurement, you can click on each dot (data point). You can also select groups of measurements, different causes of death, as well as search for a particular variable of interest using the search bar.

As questionnaire-based variables were found to be the strongest predictors, the researchers created a calculator that could use questionnaire answers to predict an individual's risk of dying within five years ('five-year risk'). To do this, they used a computer-based approach to automatically select the combination of questions from UK Biobank that gave the most accurate prediction of death within five years.

Smoking is an effective way to both shorten your life span and suffer ugly medical complications in later life, as this epidemiological study illustrates. Along with being overweight and sedentary it produces one of the larger negative effects on life span that you can achieve through common lifestyle choices. Interestingly, the effects on life expectancy and mortality are about the same size as those resulting from being obese.

Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. Therefore, we aimed to estimate the influence of smoking and smoking cessation on all-cause mortality in people aged ≥60 years. Relative mortality and mortality rate advancement periods (RAPs) were estimated by Cox proportional hazards models for the population-based prospective cohort studies from Europe and the U.S. (CHANCES [Consortium on Health and Ageing: Network of Cohorts in Europe and the U.S.]), and subsequently pooled by individual participant meta-analysis. Statistical analyses were performed from June 2013 to March 2014.

A total of 489,056 participants aged ≥60 years at baseline from 22 population-based cohort studies were included. Overall, 99,298 deaths were recorded. Current smokers had 2-fold and former smokers had 1.3-fold increased mortality compared with never smokers. These increases in mortality translated to RAPs of 6.4 and 2.4 years, respectively. A clear positive dose-response relationship was observed between number of currently smoked cigarettes and mortality. For former smokers, excess mortality and RAPs decreased with time since cessation, with RAPs of 3.9, 2.7, and 0.7 for those who had quit less than 10, 10 to 19, and more than 20 years ago, respectively.

Smoking remains as a strong risk factor for premature mortality in older individuals and cessation remains beneficial even at advanced ages. Efforts to support smoking abstinence at all ages should be a public health priority.

Link: http://dx.doi.org/10.1016/j.amepre.2015.04.004

Here researchers show, once more, that the process of creating a line of induced pluripotent stem cells from ordinary cells and then differentiating the pluripotent cells back into the original cell types will repair and reverse measures of cell damage along the way. It makes sense that mechanisms of this nature must exist somewhere in the cellular repertoire, since parents are old but children are young: an embryo undergos a period of intense repair and restoration very early in its development process.

Now that numerous research teams having confirmed this aspect of induced pluripotency and are cataloging the details, the real question is what can be done with this? Producing less damaged patient-matched cells for cell therapies in the old is one immediate possibility, but evidence to date suggests that the problem is the tissue environment as much as the cells - even young and undamaged cells struggle once introduced back into old tissues. So how best to use damage repair via induced pluripotency in therapies remains an open question, I think:

Most neurodegenerative diseases are late-onset and aging-related, and no effective treatments have been developed. The successful generation of induced pluripotent stem cells (iPSCs) and the direct conversion of neurons from patients' specific somatic cells have offered cell resources for disease modeling and potential cell transplantation therapy. However, to date no systematic studies have investigated which approach is more suitable for future cell therapy. Here, using the two approaches mentioned above in parallel we successfully obtained functional neurons from tail-tip fibroblasts (TTFs) of a 1-year-old mouse, which were characterized by specialized morphologies, neuronal marker expressions and electrophysiological properties.

Genome-wide expression analysis revealed that a set of genes related to the stress response and DNA damage were expressed at a much higher level in iNs than in diNs derived from 1-year-old TTFs. Subsequently, significant decreases in mitochondrial dysfunction and DNA damage were observed in diNs compared with iNs derived from aged TTFs. Moreover, the levels of epigenetic markers such as 5hmC, H3K4me3, H3K9me3 and H3K27me3 in iNs were more similar to those in the old TTFs compared with those in diNs, indicating that the iNs converted directly from TTFs may retain some residual epigenetic memories. By contrast, reprogramming to iPSCs not only rejuvenated the cell stages but also erased such epigenetic memories obtained along the aging process. Taken together, the results of our study are instructive and meaningful for future clinical applications.

Link: http://dx.doi.org/10.1089/scd.2015.0137

The folk behind Heales and the International Longevity Alliance are running a short film contest with a 3,000 € first prize. The topic is longevity for all: that progress towards therapies to enable longer and healthier lives is good thing for everyone. The submission deadline is September 21st 2015, so if you or anyone you know is a budding filmmaker, here is your chance to make a statement on the future of rejuvenation biotechnology and the prospects for bringing an end to all of the ills and frailties of aging.

Competition for Best Short Film on Life Extension and Promoting A Longer, Healthier Life (PDF)

Dear citizen, Dear artist, Dear activist,

The scientific community and the media are increasingly telling us that we might enjoy healthier and longer lives thanks to medical progress. This is great and we want more people to be involved to promote longevity. The future can be bright and healthy. However describing something potentially beautiful is not always easy. We think you can help.

You could make a (very) short movie making clear that a longer and healthier life thanks to sustainable medical interventions will be positive for citizens and society alike. Do you want to reach immortality by being famous or by avoiding death? By taking part in this competition, you have a small chance to succeed in both goals :­)

Alexander, Daria, Didier, Sven and Peter.

Rules of the "Longevity for all" Competition 1. The submitted film should show that medical progress for a healthier and longer life is generally a good thing for citizens and society alike. The length of the film should be a minimum of 1 to a maximum 10 minutes (minimum 60 seconds, maximum 600 seconds). The link to the file should be sent, together with the mention of the last name and first name of the competitor and the proposed title of the work, to the address info@heales.org. Videos may also be posted online. The submission deadline is 23:59GMT on 21 September, 2015.

2. Everything is allowed: films, comics, succession of pictures,... It can be science, fiction or science-­fiction, a story, sad or funny, a docufiction or a documentary. However, you cannot use copyrighted documents for which you don't have the rights and of course, you cannot use unlawful documents.

3. The members of the international jury will be Alexander Tietz (Germany), Darya Khaltourina (Russia), Didier Coeurnelle (French speaking Belgium), Peter Wickx (United Kingdom), and Sven Bulterijs (Dutch speaking Belgium). They will communicate their decision the 1st of October 2015 (international day of older persons also often seen as the International Day of Longevity).

4. The language of the video will be English, French or Dutch. Subtitled submissions will be accepted.

5. If your submission is selected for a prize, you agree that Heales and the International Longevity Alliance (ILA) use your movie without restriction to promote life extension. Heales and the ILA can show your work on the internet or by all other means. However, it is prohibited for Heales and the ILA to earn any money with this work and compulsory to mention the authors of the work. Should some organization/person want to pay to have the right to use your work, Heales and the ILA engage themselves to inform you and the possible benefit would be for you.

6. The first prize is 3,000 €. If the members of the jury unanimously decide to give the first prize to 2 competitors, each competitor will receive 2,000 €. If the members of the jury unanimously decide so, they can prolong the competition for 3 months. If the work of the winner is a collective work, each person mentioned as a competitor will receive a proportionate part of the prize. If the winner lives in a country where the € is not the current currency, there will be a conversion of the prize in the local currency. The second prize is a stay for 2 persons for two nights in a Spa of the country where the person lives, travel included up to 150 €. (value 400 €). The third prize is a selection of books related to longevity (value 100 €).

7. For all issues not mentioned above, the members of the jury will decide. They must decide in equity and with the same rules for all competitors. The competent courts in the event of litigation will be those of Brussels.

Here, recently published research adds to the weight of evidence to show that firstly even modest levels of reduced calorie intake produce measurable health benefits over the long term, and secondly it is possible to have a high degree of compliance in the study population. The knee-jerk reaction in many quarters to the practice of calorie restriction with optimal nutrition, meaning fewer calories consumed without reducing the intake of vital micronutrients, is that it is too hard. It is certainly true that most people in this age of cheap calories and ever more enticing foods choose not restrict their intake, but that isn't the same thing as "too hard." If you actually take the time to try it out and experiment with dietary options, you'll find that modest calorie restriction is not all that challenging at all.

Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR. To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change ("RMR residual") and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures.

Body mass index averaged 25.1 (range: 21.9-28.0). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7%CR and maintained 10.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at 12 and 24 months, while tumor necrosis factor-α decreased significantly more only at 24 months. CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life.

We conclude that sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.

Link: http://biomedgerontology.oxfordjournals.org/content/early/2015/07/17/gerona.glv057.abstract

Every so often along comes a new over-hyped drug candidate with studies showing it extends life in laboratory animals. People throw away common sense and buy the stuff for a few years until the hype wears off in the face of more scientific evidence that throws doubt upon the early claims, and the realization that, like all the preceding drug candidates, this latest one also does next to nothing to impact the progression of aging in humans.

It helps greatly to realize that life span and health are much more plastic in short-lived species than in comparatively long-lived species such as we humans. All sorts of things extend life in lower animals by a large amount yet have no such result in humans. Consider calorie restriction for example, which extends life by 40% in mice, but certainly doesn't do as much in humans. Did you know that ibuprofen use meaningfully extends life in a number of species to a an equal or greater level than metformin, a currently hyped drug candidate to slow aging? Or that aspirin has sizable effects on life span in short-lived species as well? Yet clearly neither of those extends human life span to anywhere near the same degree, despite decades of use and a great deal of data on its effects.

Chasing meaningful effects from drug candidates such as metformin is irrational based on what is known to date. It is not where the research community should be putting time and money. When people point to the effects in animal studies, noting that in some of these metformin is shown to extend life, you can say "but so does aspirin, and that certainly doesn't have the same effect on life span in people."

We examined the impacts of aspirin and metformin on the life history of the cricket Acheta domesticus (growth rate, maturation time, mature body size, survivorship, and maximal longevity). Both drugs significantly increased survivorship and maximal life span. Maximal longevity was 136 days for controls, 188 days (138% of controls) for metformin, and 194 days (143% of controls) for aspirin. Metformin and aspirin in combination extended longevity to a lesser degree (163 days, 120% of controls). Increases in general survivorship were even more pronounced, with low-dose aspirin yielding mean longevity 234% of controls (i.e., health span).

Metformin strongly reduced growth rates of both genders (less than 60% of controls), whereas aspirin only slightly reduced the growth rate of females and slightly increased that of males. Both drugs delayed maturation age relative to controls, but metformin had a much greater impact (more than 140 % of controls) than aspirin (~118 % of controls). Crickets maturing on low aspirin showed no evidence of a trade-off between maturation mass and life extension. Remarkably, by 100 days of age, aspirin-treated females were significantly larger than controls (largely reflecting egg complement). Unlike the reigning dietary restriction paradigm, low aspirin conformed to a paradigm of "eat more, live longer." In contrast, metformin-treated females were only ~67 % of the mass of controls.

Our results suggest that hormetic agents like metformin may derive significant trade-offs with life extension, whereas health and longevity benefits may be obtained with less cost by agents like aspirin that regulate geroprotective pathways.

Link: http://dx.doi.org/10.1007/s11357-015-9769-x

We stand at the dawn of a new age of medicine, an era in which the causes of aging will be treated and reversed, leading ultimately to indefinite healthy life spans, as many years as want. The transition from where we are today to the availability of effective therapies to prevent and cure the manifestations of degenerative aging will be very rapid in the context of the overall history of medicine, but still a matter of years and decades of hard work and persuasion for those of us living through it. At the large scale funding and progress in medicine follows popular support for the end goal, and at the present time we're still in the late opening stages of persuading the world that, yes, treating aging is a good thing and we should get right on with it. It remains the case that the average fellow in the street is suspicious, indifferent, or even hostile to the idea of living longer through medical science.

This will no doubt be seen as inexplicable by our exceedingly long-lived descendants, who will never suffer age-related disease and look back on our era in the same way as we look back on the poverty, disease, and suffering of Dickensian London. But we must play the hand we are dealt, and we are faced with a task of persuasion in order to bring enough people around to the idea that we should be treating aging. Given the number of deaths caused by aging, far more than any other medical condition, treating it should in fact be the primary purpose of the medical community rather than a field that receives little funding and notice - but again, all too few people agree. The more that we speak out in favor of greater funding and more effective approaches to treating aging as a medical condition, the faster we move towards that end goal.

Every cultural movement is a tapestry of efforts, woven from the initiatives at the grassroots to the backroom conversations of venture capitalists, and ideas flow here and there very freely in our highly connected society: a diffuse conversation about medicine and aging that anyone can join to have their say. The more that we talk about this topic, the more that people will think on it. Some of them will also join in. Over the past decade I have seen an acceleration in the number of new faces and new initiatives: the size of the community of people in favor of medicine to treat aging is increasing, and a tipping point lies somewhere ahead, much closer than when I first had this notion of writing about the science of aging and the prospects for healthy longevity.

We can all write, we can all talk to our friends, and we can all distribute our thoughts on the matter far and wide thanks to the internet. As ever more of us choose to do this, we help to build the future consensus on the treatment of aging. One day not so far from today, it will be obvious to the fellow in the street that aging itself falls into the same category as cancer and Alzheimer's disease, and of course it is a good thing that researchers are working towards a cure for aging, and it won't be unexpected to see people raising funds for those research programs in exactly the same way that they do for cancer today. So keep right on helping: talk to your friends, write online, say something about aging and longevity. It makes a difference.

Transhumanism Is Booming and Big Business Is Noticing

I recently had the privilege of being the opening keynote speaker at the Financial Times Camp Alphaville 2015 conference in London. One thing I noticed at the conference was the increasing interest in longevity science--the transhumanist field that aims to control and hopefully even eliminate aging in the near future. Naturally, everyone has a vested interest in some type of control over their aging and biological mortality. We are, at the core, mammals primarily interested in our health, the health of our loved ones, and the health of our species. But the feeling at the conference - and in the media these days too - was more pronounced than before.

As a transhumanist, my number one goal has always been to use science and technology to live in optimum health indefinitely. Until the last few years, this idea was seen mostly as something fringe. But now with the business community getting involved and supporting longevity science, this attitude is inevitably going to go mainstream. I am thrilled with this. Business has always spurred new industry and quickened the rise of civilization.

A matter of chance

Rejuvenation biotechnologies wouldn't just cure billions of people of age-related diseases, but would prevent the life of severely injured, sick and disabled people from getting considerably worse with age; and on top of that, anti-ageing therapies have the potential to enable them to live long enough to see the day when the condition that has been afflicting them for so long can be cured. They could see the day they can walk again, and undo the damage done to their only chance, which will hopefully last for yet very long. In the end, it isn't all that wrong to say that we have only one chance; that's exactly the reason why we shouldn't take any chances with it.

For Life's Sake, Join the Movement for Indefinite Life Extension

The number of demonstrations and rallies designed to drive awareness of the cause have been increasing. These brave and vital showings of leadership are pivotal in reaching the next levels of awareness and willingness to step forward for this cause. Because of these people, more around the world find the courage to take their first steps in support of this cause. To find a hero in this cause, you need not look far; there are whole groups of them, and you can take your pick.

We don't want to die. Sitting it out and letting others handle it will get us all killed. Time is ticking. This isn't about seeing if we can reach a goal; this is about having it within us to understand that we can achieve this in time for us and the people we know. Achieving indefinitely healthy longevity is about the expedition of this goal as a movement.

For those who haven't yet got the message, the article linked here points out just how little came of resveratrol as a drug candidate and sirtuin research as a whole from the past decade. Resveratrol and the study of sirtuins were hyped up at the time, as I'm sure many of you recall, and yet nothing came of it beyond a little more knowledge of cellular metabolism. Sirtuins do not have any meaningful influence on aging from the perspective of producing therapies and neither does resveratrol. The hype resulted from a confluence of the tendency for venture investment to talk up a position (in the company Sirtris, acquired for more than $700 million in the end, money written off by the acquirer since nothing of practical use ever came from it), and the "anti-aging" marketplace finding yet another set of potions its members could market to the gullible. A lot of resveratrol was sold, and many people who really should have known better bought some.

Whenever a new drug candidate emerges with claims that it allegedly slightly slows the aging process, the first thing you should think of is resveratrol, and be wary of hype driven by the profit motive. Resveratrol was just the latest in a line of hyped products allegedly providing benefits to health in aging, and in fact doing nothing of any significance other than helping some people to find profits. Mining the natural world for compounds that can alter the operation of metabolism has shown itself incapable of reliably producing results that matter when it comes to aging: decades of work on this and nothing to show for it but the continued ability to sell useless products to people who hope for something that works.

There is only one useful road ahead here when it comes to aging and health. It is the construction of new biotechnologies that deliberately and usefully repair the cellular damage that causes aging. Don't alter metabolism, instead fix it by removing the dysfunction that causes it to run awry in a careful, targeted way. The future is clearance of damaged cells, gene therapies to repair mitochondrial DNA, manufactured enzymes that break down specific forms of persistent metabolic waste, and so on - a world away from screening random compounds from plants in the hope that they will do more good than harm.

Resveratrol is a compound that gained a lot of notoriety in the mid-2000's as sort of a multipurpose pro-health molecule. In its heyday, it spawned companies and a plethora of enthusiastic articles that recommended binging on resveratrol-containing foods as an all-purpose health enhancement. Interest has since waned on this compound, but it's worth revisiting the story to see how an exciting, trendy scientific discovery can lose steam when scientists better understand its limitations. A first hint of Resveratrol's pro-health effects came in 2003 out of the lab of David Sinclair, a young investigator at Harvard. Sinclair's lab found that resveratrol could extend lifespan in yeast. The extension was thought to be dependent on the protein Sir2, the founding member of a family of related proteins called sirtuins. The idea that small molecules could be used to extend healthspan was gaining excitement and attracting funding. A year later, Sirtris went public, eventually being bought up by pharma giant GlaxoSmithKline. The resveratrol supplement industry grew.

However, later reports led to questioning resveratrol's benefits. Work out of the lab of Linda Partridge, a well-respected Drosophila researcher, was unable to reproduce earlier findings of lifespan extension in Drosophila and produced only variable effects in C. elegans. There has also been a broader controversy over the role of resveratrol's reported target SIRT1. A major stain on the field came in 2012, when resveratrol researcher Dipak Das was fired from UConn for allegedly committing 145 instances of scientific fraud including "fabrication and falsification of data". Much of Das' work formed the basis for supposed cardioprotective benefits of resveratrol. As a result, resveratrol's efficacy for this application is now in serious doubt.

But even before the Das controversy, there were indications that people in the know had cooled on resveratrol related formulations as therapeutics, possibly due to inherent limitations with the compound. One of the co-founders of Sirtris left the company in 2011, and GlaxoSmithKline eventually shut down Sirtris and folded it into its broader business. This diminished industry interest in resveratrol may stem from two unfortunate issues: 1) research suggesting resveratrol does not act via SIRT1 makes it difficult to develop resveratrol into a drug; and 2) resveratrol is rapidly degraded by the liver after ingestion, making it naturally a poor drug. The first is an even bigger problem than it seems because FDA approval of new drugs requires knowing their mechanism of action. The second is a problem because it means it's difficult to increase the levels of resveratrol in the body by taking a pill, and medicines usually need to be administered by pill for average patients to be able to use them.

Link: http://sage.buckinstitute.org/resveratrol-placebo-or-youth-in-a-pill/

Here is a second in a series of popular press articles on the work of the Buck Institute for Aging Research, this one focused on studies of the mechanisms of aging in nematode worms:

The genes of Caenorhabditis elegans, a 1 millimeter-long, soil-dwelling roundworm or nematode, resemble those of people. Its genome - complete set of DNA with about 19,000 protein-coding genes - differs from ours in architecture but has some 60 percent protein conservation, where proteins expressed by the genes have similar shapes and functions. With a normal lifespan of just 20 days, C. elegans offer scientists at Novato-based Buck Institute for Research on Aging a keen glimpse of the aging process. A C. elegans worm has only 959 cells, each conveniently transparent when viewed through a microscope.

In 1993, Cynthia Kenyon, a biochemist and former faculty member at University of California, San Francisco with a Ph.D. from MIT, discovered that partially disabling the daf-2 gene which encodes the insulin-like growth factor receptor in C. elegans doubled its healthspan. It was a breakthrough. Like worms, humans have genes that control insulin-like growth factor. Since then she genetically tinkered further to give some worms a sixfold lifespan.

Scientists in laboratories at Buck continue to push C. elegans for answers to human aging, drawing on Kenyon's lead. Kathleen Dumas, post-doctoral research fellow for the past two years in Buck's Lithgow lab, also studies the worms. Dumas explores protein homeostasis in the worms. "With age, we have a breakdown in the normal maintenance of cells," Dumas said. "Protein folding can change with age." She is looking for genetic tools or drug molecules that can be used to shift protein misfolding. "We don't know that protein misfolding is causing aging. It could be the other way," that aging causes misfolding. "We see that it correlates. This is one of the bad things. If we can prevent protein misfolding, that could be one way to improve cellular functioning with age."

Cellular cleanup mechanisms and gene expression such as synthesizing protein change with age, Dumas said. Both processes relate to protein homeostasis inside cells. "Parkinson's and Alzheimer's are probably directly caused by aggregates of proteins that no longer do what they should," she said. "Proteins are the machines doing everything in our cells. If we have faulty parts or the wrong number of parts, those machines will break down. You get chaos - functional decline."

Link: http://www.northbaybusinessjournal.com/northbay/marincounty/4166497-181/research-worms-glimmer-of-hope

The White House Conference on Aging was held a few days ago, but you didn't need to pay any attention. The event related to matters that have absolutely no bearing on the future of aging research or the future of aging itself: it focused on entitlements and organization of the process of dying, and had nothing to do with treating aging or medical research in any meaningful sense. There is a way to go yet before the ripples of revolution in scientific circles make their way to be seen by the majority of politicians and bureaucrats.

Representative governments are in essence an expression of conservatism, in the sense of seeking stasis, pursuing the preservation of the present situation. This is more or less human nature; it is the way groups of people react. There is resistance to change, even obviously beneficial change, and a desire to decorate and sustain the present status quo, no matter how terrible that status quo, no matter how it came about, and no matter how long it has been around. The inner ape seeks assurance that present circumstances have a permanence to them, that tomorrow will be the same as today. The possibility of change equates to a threat in this instinctive view of the world. We should be better than that, but put any hundred of us in a room together and we are not. The crowd is even more the ape than the individual.

Given that we live in an era of radical change, far greater than in any past age, there is considerable tension between what we can achieve with technology and instinctive conservatism. People organize to resist every prospective change that they later take full advantage of and approve of, and the acts of government employees are just one of the better reported parts of this urge to stasis. All meaningful progress happens against the will of the grumbling masses and their elected leaders, yet is instantly adopted as the new stasis the moment that people can buy the products, or the therapies, or the activities. In advocacy for rejuvenation research and the medical control of aging it is quite frustrating to listen to opponents who, were they lucky enough to be born later, would be uncritically accepting of the medicine they oppose. Were they unlucky enough to be born earlier, they would have railed against gene therapy, or heart surgery, or other important past advances that are now proudly accepted as proof of prowess in technology. It has everything to do with change and nothing to do with the matter at hand.

Moving away from opposition to progress, the flip side of the urge to stasis is support for the present situation, even if absolutely untenable. In the case of aging we are faced with a medical condition that kills 100,000 people every day, while hundreds of millions are unable to support themselves, or in chronic pain, or possessed of a heart or a mind no longer fully functional. The conservative response to that is to do nothing other than try to better organize this vast and ongoing dying: to accept it as-is, to accept the enormous waste and expenditure, pain and suffering. It is all about coping, not fixing. You'll find no sign of anything involving change for the better, or change at all for that matter, in the story presented by the government here:

White House Conference on Aging (WHCOA)

As expected, there was next to nothing at the WHCOA about aging research. At an early (April) local WHCOA meeting in Phoenix, the director of the National Institute on Aging - Dr. Richard Hodes - spoke a few minutes about the genetics of Alzheimer's, and the possibility and need for its early detection. But apparently that was about it.

Fact Sheet: The White House Conference on Aging

The HHS Health Resources and Services Administration announced that it will develop an Alzheimer's Disease and Related Dementias training curriculum next year to build a health care workforce with the necessary skills to provide high quality dementia care and ensure timely and accurate detection and diagnosis of dementia.

Care, detection, diagnosis. No mention of treatment. This is representative of all of the documents resulting from this initiative. You'll see the same in the health sections of aging.gov if you care to look. The lesson to take away here is that change for the better will never emerge from the normal machinations of government. Change comes from outside the system. If you are one of those who wants the government to participate and lead, then you have to accept that the only way to make that happen is for the research strategies you favor to become the mainstream of research or a popular cause for millions. The people who guide the direction of resources in representative governments are the very last to turn their eyes to any sort of new project.

Today I thought I'd point out an interesting take on advocacy for faster progress in research from an organization called The Cure is Now. There is a great deal of frustration with the slow pace of medical research, the consequence of excessive regulation in that field. The regulatory cost of developing treatments has far less new medicine is actually making it out of the labs, despite the enormous and rapid progress in biotechnology taking place. One manifestation of this frustration is the existence of organizations such as Faster Cures, Tomorrow's Cures Today, and Breakout Labs, all of which take somewhat different approaches to trying to break the logjam, ranging from straightforward lobbying to venture philanthropy.

The Cure is Now has yet another view on the best way forward to speed up the development of better therapies and new cures, its focus being on accelerating the coming technological convergence in fields such as genetics, computing, and molecular nanotechnology. Once further along present trends in this direction will result in entirely new paradigms and platforms for medicine based on complete control over cells and the replacement of biological components at all scales with more effective and more robust machinery. These are explicitly transhumanist goals, and more people are thinking in those terms these days, given the popularizing of modern variants of the technological singularity concept, now having more to do with accelerating progress and next generation technology than the original ideas from Vinge specifically related to artificial intelligence.

The Cure is Now prose is all too breathless, and veers between overly general and too specific, but that is something that improves with organizational growth and experience. I can't say that I was any good when first starting out. Overall this looks like a small group that is doing more than just talking about things, also seeking to fund specific useful areas of research, and that is commendable. You can write however you want to write if you are also delivering money to research efforts. The future is built of many such modest initiatives, a tapestry of individual choices, people trying to make a better future by improving medicine and its support technologies:

The Cure Is Now is a national non-profit organization organized by people who share a common bond. Having their lives personally affected by horrible diseases, this group came together out of desperation over the fact that there does not seem to be a simple answer as to how, when and if there will be reliable, robust, and clear cut cures to the long list of incurable diseases that kill loved ones every day.

There are many incurable diseases that need to be addressed. The Cure Is Now is using what it calls the Root Level Approach to solving the problems by facilitating groups of individuals who will work together to achieve this goal. By employing a Committee on Advanced Technology, Medical Advisory Board and a Science Advisory Board to explore radically advanced, emerging technologies, The Cure Is Now hopes to accelerate speculative and emerging technologies in order to lead to the event known as The Singularity.

The driving forces behind The Cure Is Now are the realization of something known as the technological singularity. There is an event that will change the world more so than major breakthroughs like the Internet, industrialization, democracy, flight, or other paradigm shifting social evolutions. This event known as the technological singularity will bring forth changes for human kind that will address some of our most fundamental needs in ways that have never been before possible.

Research has shown that several groups of thus far so called "incurable" diseases can be potentially addressed in ways that have never before been conceived of. Today The Cure Is Now seeks to address the very concept of attacking these diseases with several new emerging and speculative technologies. So if you're looking for an explanation as to why The Cure Is Now does not target one simple disease but rather several of them, it is precisely because we feel that the way to cure a disease is not necessarily through the conventional pharmaceutical and medical methods used thus far. Rather, a whole slew of new and radically advanced technologies will be converged and applied in order to invent new methods of finding cures. The Cure Is Now subscribes to what we call the root level approach. The root level approach quite simply states that a convergence of several new advanced technologies will address the hurdles in thus far incurable diseases: artificial general intelligence; molecular nanotechnology; biotechnology; brain-machine interfaces and neuroscience, networks and supercomputing; and genomics.

Link: http://www.thecureisnow.org

Here is an example of grassroots advocacy for longevity science in Europe, where single-issue political parties are a viable approach to advancing a cause, unlike the case in the US. It is always heartening to see any one person step out of the crowd to make a stand and say that, yes, it is very important that research into treating aging as a medical condition is funded and supported. Success comes when enough people do this: any movement is just a matter of many individuals making this choice and giving time and money to building the future they want to see.

There are a number of small single-party efforts in various European countries, and many of them collaborate through the International Longevity Alliance, a network of activists looking to make a better future. As of yet this is still a small group, even taken together as a whole, but the fact that it exists at all is a sign that the tide is rising, with ever more people realizing that there are realistic prospects for the treatment of aging and elimination of age-related disease. The efforts of these activists are the seeds of much larger initiatives yet to come, and are to be commended:

In our new LIFEMAG community series, we interview activists throughout the world looking to take life extension ideas from the radical to the mainstream. In this first instalment, Valentina Lencautan speaks to Felix Werth, a biochemistry student at Potsdam University, who has founded Germany's first and only life extension focused political party - the Partei für Gesundheitsforschung (Party for Health Research). At the party's weekly meeting, Felix explains how the party was formed six months ago in the hope of attracting enough members to spread the word about life extension, and increase the German government's investment in aging research.

What made you get into life extension activism?

It was seeing the work of SENS and interviews with Aubrey de Grey among others. I was inspired so much that I decided to study to become a biochemist myself. I was thinking about what I could do for the cause of life extension, and thought starting a political party was a good way to raise awareness, and also encourage the German government to invest more in aging research. The current budget of the German government is over €300bn, so if just one per cent of that was invested in aging research, that would be €3bn.

Is there a big support base for life extension in Berlin?

I am afraid we are still a very small group, but I hope that will change. To be able to participate in the elections, the party needs about 400 members, and we're still some way off achieving that. I try to tell people that this matter concerns their lives, that it's not just about living a healthy lifestyle. Nowadays people are flooded with information about what they should eat and the exercise we should do. Many perceive us as yet another health advisor who is trying to tell them how they should live. Many find it difficult to understand what the SENS concept is, that it is about repairing the body and rejuvenation. Others just do not believe it is possible. It is a matter of convincing people that it can be a reality.

So you are campaigning not for just more funding, but also for the SENS method in research as well?

The SENS method is the best one there is at the moment, but I would leave this kind of decision to the scientists. The party's main purpose is to find the money to be invested into research. It is all about finding therapies for the diseases of old age. If we were to receive more funding, research would evolve so much faster. It is simple logic.

Link: http://www.lifemag.org/article/german-party-for-health-research

The Methuselah Foundation and SENS Research Foundation collaborate to put out a quarterly newsletter on recent scientific advances for members of the 300, people who pledge to donate $25,000 over 25 years to research and development aimed at extending healthy life spans. The earliest members of the 300 collectively gave the first significant funding to the Methuselah Foundation when it launched, providing the resources needed to start the Mprize for longevity science and later the SENS rejuvenation research programs.

SENS research outgrew its roots and spun off into its own non-profit foundation back in 2009, but the staffs of the Methuselah Foundation and SENS Research Foundation continue to collaborate on various ventures. We're all chasing the same goal, after all, meaning the development of therapies that can collectively halt degenerative aging by periodically repairing its root causes. This class of technology can in principle prevent and cure all age-related disease: it is just a matter of building tools that are good enough at the various necessary forms of cell and tissue repair.

This quarter's newsletter turned up in my inbox today alongside a reminder that the Rejuvenation Biotechnology 2015 conference to be held on August 19th in San Francisco is still accepting registrations. Just as last year, this will be a meeting in the middle between industry and academia, building the bridges needed for the near future development of first generation rejuvenation therapies. The times are changing, and this will be just one of a range of well-subscribed events taking place each year, attended by people with a serious focus on the treatment of aging.

Rejuvenation Biotechnology Update, July 2015 (PDF)

Young capillary vessels rejuvenate aged pancreatic islets

The authors showed that in older mice, and in humans, evidence of damage to the pancreatic islet blood vessels could be observed. They took pancreatic islets from old mice and transplanted them into the eyes of young mice whose own β-cells had been destroyed with a drug so that they could produce no insulin on their own (a common model of "type 1" or "juvenile" diabetes). Remarkably, when placed in the environment of the young mouse eye, the islets from the old mice proliferated, developed a healthy blood supply, and were able to completely restore control of blood glucose and function as normal β-cells would in the young, type 1 diabetic mice. As strange as it sounds, these β-cells were able to do this from inside the eye.

This study is very provocative. Similarly to parabiosis experiments, removing aged pancreatic islet cells from their original host and exposing them to the younger host's intact blood vessels was able to restore their normal function. This lends credence to the idea that, at least in the case of pancreatic β-cells and diabetes, the aged tissue environment and not the aged cells themselves is the important determinant of functionality. As the authors point out, this finding provides hope that finding ways of restoring the vasculature of the pancreatic islets to a healthier state could be key in treating age-related type 2 diabetes/glucose homeostasis problems.

Scanning Ultrasound Removes Amyloid-β and Restores Memory in an Alzheimer's Disease Mouse Model

The researchers in this study found a non-pharmaceutical and non-invasive way to stimulate clearance of amyloid-β (Aβ) in the brains of AD mice. Repeated treatments with scanning ultrasound after injecting "microbubbles" of air into the blood of AD mice were able to induce movement of Aβ into the lysosomes (the "cellular incinerator") of microglia (cells that perform cleanup, among other functions, in the brain) in the brains of these mice. Meaningfully, the AD mice who received the ultrasound treatments showed improvements on three different memory tests compared to the control group.

The approach used in this study is very interesting because it does not rely on pharmacological or surgical means, but was able (at least in AD mice) to induce clearance of Aβ from the brain and improvements in memory. The mechanism may lie in the ability of the microbubbles in the blood to vibrate against the lining of the small capillaries in the brain, causing a gentle and temporary disruption of the blood-brain barrier and possibly allowing antibodies or other blood components to access the brain.

There are a few caveats, one of which is how well AD mice accurately model human AD. Many of these mice are genetically altered to produce large amounts of Aβ, and consequently develop symptoms similar to human AD, such as memory decline. But in humans, the majority of cases are not caused by a single genetic mutation. Another caveat: there is always the possibility that brain ultrasound could induce some kind of side effect in humans not observed in the mice, such as microvascular strokes, hemorrhaging, or inflammation - or that it would simply be ineffective because the ultrasound could not penetrate deep enough into the brain tissue of a human as could be done in a mouse with a comparatively tiny cranium and thin skull.

α-Synuclein Inclusions in the Skin of Parkinson's Disease and Parkinsonism

Several degenerative brain diseases (Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy, and others) share the common feature of protein aggregates (clumps) in the brains of patients, made of a protein called α-synuclein. These diseases are sometimes collectively referred to as "synucleinopathies." Since there are two vaccines currently in human clinical trials that are aimed at clearing α-synuclein aggregates (which will hopefully lead to restoration of function), and α-synuclein aggregates are known to be associated with functional impairments in people who have not yet developed full-blown PD or related disease, it would be useful to have a non-invasive test to determine who might need such a treatment, especially if this can be determined before overt disease develops.

There is a hypothesis that while α-synuclein may ultimately aggregate in the brain in PD, it may originate from other sources in the body, such as the gut. The fact that α-synuclein was found in the skin of a majority of PD patients tested is interesting, and it may even provide some basis for speculation that α-synuclein could come from the skin, or from multiple sources, migrate to the brain, and cause Parkinson's Disease. Skin and neural tissue share a common embryonic origin (the ectodermal germ layer), so both cell types may share some genetic program that leads α-synuclein production and accumulation. But this is all just speculation right now, and as is often the case with diseases of aging, it can be very difficult to determine the relationship between various factors and observations.

Not all approaches to changing the behavior of cells so as to spur greater regeneration must necessarily involve drugs. Here researchers demonstrate that ultrasound can partially compensate for age-related deficiency in skin healing, and catalog some of the cellular biochemistry involved. This isn't a case of fixing the proximate cause of faltering wound healing, a decline in one specific type of cell signaling, but rather activating another mechanism that can act as a substitute to some degree. As the publicity materials note, deploying this treatment to the clinic should not be too much of a challenge given the present widespread use of ultrasound for other purposes:

Chronic skin healing defects are one of the leading challenges to lifelong wellbeing, affecting 2-5% of populations. Chronic wound formation is linked to age and diabetes and frequently leads to major limb amputation. Here we identify a strategy to reverse fibroblast senescence and improve healing rates.

In healthy skin, fibronectin activates Rac1 in fibroblasts, causing migration into the wound bed and driving wound contraction. We discover that mechanical stimulation of skin with ultrasound can overturn healing defects by activating a calcium/CamKinaseII/Tiam1/Rac1 pathway that substitutes for fibronectin-dependent signaling and promotes fibroblast migration. Treatment of diabetic and aged mice recruits fibroblasts to the wound bed and reduces healing times by 30%, restoring healing rates to those observed in young, healthy animals. Ultrasound treatment is equally effective in rescuing the healing defects of animals lacking fibronectin receptors, and can be blocked by pharmacological inhibition of the CamKinaseII pathway. Finally, we discover that the migration defects of fibroblasts from human venous leg ulcer patients can be reversed by ultrasound, demonstrating that the approach is applicable to human chronic samples.

By demonstrating that this alternative Rac1 pathway can substitute for that normally operating in skin, we identify future opportunities for management of chronic wounds.

Link: http://dx.doi.org/10.1038/jid.2015.224

There are always those who try to argue that increasing human healthy life span would be an economic disaster. I would have thought this a hard view to justify to oneself given centuries of economic growth walking hand in hand with greater life expectancy, but many people prioritize the present unsustainable structure of economic entitlements in Western societies more highly than any number of lost and crippled lives. In their eyes the machine must continue exactly as it is, regardless of the deaths and suffering that pays for it. This is the small-c conservative impulse at work, the tendency for people to support and defend the present status quo, no matter how ridiculous it might be, and no matter how or when it came into being. But the world will change in response to new capabilities in medicine, and political and economic systems that cannot possibly work will fall. They are far less important than better and longer lives for ordinary people.

Change is not disaster. It is progress. Why receive entitlements if you are old but not frail? Why retire if you don't have to? Why think of someone in their 60s and 70s as less capable than someone in their 30s when that is no longer the case? The purpose of research into extended longevity is to prevent the frailty and illness that stops people from being able to support themselves. Entitlements and forced wealth transfers have no place in that near future world, regardless of what you might think of them today.

Most of us think of longevity as a gift, a blessing, a sign of social progress. Gordon Woo thinks of it as a catastrophe. Woo is one of the world's best-respected "catastrophists," and helps insurers and reinsurers calculate the likelihood of disastrous earthquakes, hurricanes, droughts, terrorist attacks, financial crises, and other hazards. Woo's major preoccupation these days is the risks posed by people living longer. Unlike some futurists, Woo does not believe the aging of the population is going to plateau any time soon - not in an era when you'll be able to replace more of your spare parts and take the drugs that work best for your personal genome. And that could have huge implications in the coming decades, as civilizations struggle to meet the medical and financial needs of their elders.

MG: Can you explain why longevity is bad?

GW: We're focusing on the pension retirement sector, and it's really underfunded in terms of its provision for increasing lifespan in the decades ahead. One reason is that when it comes to making provisions for longevity instead of ecological or geological catastrophes, regulators tend to be fairly light of touch. There's good reason for this. If a corporation seems to have a black hole in its pension fund, it may not be a good policy to force the corporation to pump more money into the fund while it's going through hard times, because that very act could draw the corporation into insolvency. That's why regulators, even if they spot the problem with the pension fund, are often reluctant to force measures to remedy the situation. Often the thinking is, times will get better, corporations will get out of trouble, hopefully everything will be rosy in the future. But that will not be the case.

MG: How much longer are people living? Is this trend going to accelerate going forward?

GW: There is one view within the actuarial community that it might be leveling out - medical discovery is plateauing, it's getting harder to discover new drugs, there are diminishing returns, that kind of thing. But that perspective doesn't allow for the expansion of research into whole new territories such as regenerative medicine and anti-aging.

Link: http://www.politico.com/agenda/story/2015/07/americans-are-living-longer-what-if-thats-a-disaster-000144

Here I'll point you to a discussion paper published last month on the topic of whether or not aging is a disease: it is on the whole eminently sensible and well worth reading, and it is a pity that the vast majority of the people who would most benefit from looking over this paper will never even notice that it exists.

In recent years a large amount of ink has been spilled in the debate over whether or not aging should be either colloquially or formally defined as a disease, although this is a discussion almost entirely restricted to the scientific community, invisible to the world at large. As I've noted in the past this really wouldn't matter all that much, save for the fact that medical development and provision of medicine is heavily regulated. In countries like the US it is literally the case that everything to do with medicine that is not explicitly permitted and on a list somewhere at the FDA is by default forbidden and illegal. Treating aging is at present not on that list - and even some conditions of aging such as sarcopenia are not yet on the list, despite years of lobbying. The wheels move exceedingly slowly.

Thus underlying any debate over what exactly we mean by disease and what exactly we mean by aging is the fact that funding and the pace of progress in aging research rests on which boxes are checked by various bureaucrats. Powerful incentives steer those who work within the regulatory straitjacket, and changing the use of language to better move with the imposed limits is almost the least of harmful outcomes. Still, there are other reasons to argue for aging to be called a disease, such as clarifying the position of the research community for the layperson, and aiming for greater support for the goal of bringing aging under medical control.

The aging-disease false dichotomy: understanding senescence as pathology

Is our understanding of aging still in the dark ages? Over the course of the last centuries a gradual process of enlightenment has taken place in many different areas of human understanding, in which traditional views have been overturned by new knowledge borne of reason and the results of scientific investigation. A more realistic view of things, though it can initially cause controversy by upsetting traditional views and practices, ultimately enables more effective and more ethical action. Such a process of rationalization has profoundly affected the field of medicine, and the way we view many health-related issues. Yet when it comes to aging this salutary process of rationalization is still in its early stages. Here a salient example is the widespread and, arguably, false view that aging is distinct from disease and therefore not appropriate for medical attention - and even something benign and wholesome.

I have encountered many erroneous views during my 20 years working as a biogerontologist, often from members of the public but also from clinicians, gerontologists, and academics of various other specialities. A particular source of error is the false dichotomy drawn between aging and disease. When biogerontologists speak of aging they usually mean senescence. Is senescence a disease? The very word senescence, denoting deterioration leading to death, certainly carries that implication. If senescence is an evolutionary adaptation, this would to some extent support the idea that aging is non-pathological. But this reasoning would also involve a fallacious appeal to nature, a false equation of human evolutionary fitness with well being. If human aging did in fact evolve to benefit the species by ridding it of worn out elderly people, this should not deter us from looking for treatments for Alzheimer's disease and cancer.

Is aging distinguishable from pathology? Given the similarity in meaning between disease and pathology, asking this is similar to asking whether aging is a disease. It has been concluded that there is no clear distinction between aging and pathology, and this is supported by accumulating evidence from biology. Treatments that extend lifespan in animal models typically delay age-related pathology and extend youth span: life extension only occurs as the result of prevention of pathology, whether the pathology is caused by aging or by something else. Life extending treatments in the laboratory invariably decelerate aging (rather than stopping or reversing it); this results in a delay in the appearance of age-related pathology (extending youthspan), but then such pathologies still eventually appear, causing illness, and death.

A goal of preventing diseases of aging without altering aging itself makes little sense if aging itself is pathological, though it certainly makes sense to prioritize action against the more lethal pathologies. In a similar vein, the likelihood of recapitulating Tithonus's dreadful fate is very remote; in fact, to my knowledge no biogerontologist has ever generated a worm or fruitfly Tithonus in which life in a state of advanced senescence is greatly extended. Finally, the goal of enabling people to die without pathology, or of pure aging, is untenable if non-pathological senescence does not exist. In fact, the idea of elderly people dying of aging without pathology is plainly nonsense; among the defining properties of pathology, causing death is surely a sine qua non. (Yet I recently discussed with a former director of a major medical research funding agency the idea that elderly people can die without pathology, and found that they agreed with it).

It seems likely that advances in biogerontology will contribute to geroprotective interventions which hold back the pathologies of human aging; such interventions may well increase lifespan. A recurrent feature of arguments against treating aging is an over-emphasis on increased lifespan as an outcome, and neglect of alleviation of illness. Thus, to say: "I would like a longer life" may be presented as egoism or folly, but not "I would like to remain free of cancer." Likewise, one would not hold against someone infected with, say, malaria their wish not to die from the disease - and one would certainly not accuse them of egotism for wishing to extend their life. The point here is that, in the end, senescence is in many ways just like other severe diseases: it causes illness and death, and treating it results in a longer life. Critics of treating aging are often guilty of double standards, and of undervaluing the well being - and life - of older people.

To act ethically a realistic grasp of relevant facts is critical. This is particularly important for aging, the main cause of chronic disease and death in the world today. Yet traditional ideas about aging include some major misconceptions, including the aging-disease false dichotomy. It is to be hoped that such ideas do not misguide those responsible for the healthcare interests of older people, including those responsible for setting medical research priorities. Neglect resulting from misunderstanding aging may cause harm by allowing preventable illness, both now and in the future - given that geroprotection is most efficacious in the form of prevention. To achieve the best outcomes in terms of the future health of older people, it is vital to adopt a frank and rational attitude to aging. We must draw aside the rosy veil of tradition and face aging for what it is, and in all its horror: the greatest disease of them all.

Researchers here uncover a novel mechanism that contributes to age-related hearing loss, involving changes in nerve cell communication in older animals. At the present time, much of the work on potential ways to treat loss of hearing with age is focused on hair cells and their regeneration. Some progress has been made on this front, with mouse studies demonstrating partial recovery of hearing through restoration of hair cell populations. It will be unfortunate if it turns out that this approach isn't sufficient on its own to form an effective therapy, but the presence of another important mechanism would explain the partial results seen to date:

Conventional wisdom has long blamed age-related hearing loss almost entirely on the death of sensory hair cells in the inner ear, but new information about the workings of nerve cells suggests otherwise. Researchers have verified an increased number of connections between certain sensory cells and nerve cells in the inner ear of aging mice. Because these connections normally tamp down hearing when an animal is exposed to loud sound, the scientists think these new connections could also be contributing to age-related hearing loss in the mice, and possibly in humans. "The nerve cells that connect to the sensory cells of the inner ear are known to inhibit hearing, and although it's not yet clear whether that's their function in older mice, it's quite likely. If confirmed, our findings give us new ideas for how physicians may someday treat or prevent age-related hearing loss."

The new research builds on the knowledge that inside the ear lies a coiled row of sensory cells responsible for converting sound waves into electrical signals sent through nerve cells to the brain, which processes and tells animals what they "hear." Each of those nerve cells is like a one-way street, taking signals either from the ear to the brain or vice versa. The nerve cells that take signals to the ear are known to turn down the amplification provided by outer hair cells when an animal is, for example, exposed to a noisy environment for an extended period of time. But studies over the last decade have suggested that changes over time also occur in the connections between hair cells and the nerve cells to which they are attached.

The researchers painstakingly recorded electrical signals from within the inner hair cells of young and old mice. They found that the incoming nerve cells were indeed active and that their activity levels correlated with the animals' hearing abilities: The harder of hearing an animal was, the higher the activity of its incoming nerve cells. "These nerve cell connections seem to be reverting back to the way they worked during early development before the animals' sense of hearing was operating. We don't know why the new connections form, but it might be as simple as a lack of competition for space once the outgoing nerve cells have retracted."

Link: http://www.eurekalert.org/pub_releases/2015-07/jhm-fal071015.php

A recent interview with Aubrey de Grey of the SENS Research Foundation touches on a range of topics relevant to progress in the development of rejuvenation therapies:

I got involved in gerontology about 20 years ago when I discovered that hardly any biologists were trying to do anything about aging. Until then I had always assumed that everyone understood that aging is the world's worst problem and that defeating it was a major focus of biology. I co-founded SENS Research Foundation (and the Methuselah Foundation before it) because I saw that the most promising source of funding for this sort of long-term translational work was philanthropy, rather than government funding or the private sector. We have about a dozen different projects going on, which span most of the areas that have been described in my publications, out of the $5 million that we spend each year, most goes on these research projects, two of them in our center in California, and the rest in various institutes and universities across the USA (plus one in the UK). We also spend some money on outreach and education.

To me, gerontology is the study of aging as a basic science - the quest to understand aging better and better. But what SENS Research Foundation does is to try to manipulate aging - to postpone it better and better. And promising advances in one of those quests are not necessarily promising in the other one. So the most promising developments in gerontology would include things like the finding that calorie restriction doesn't work much in monkeys, or that naked mole rats protect themselves from cancer using long-chain hyaluronic acid; the most promising advances in engineering negligible senescence would include things like the removal of amyloid in Alzheimer's patients using vaccination, or the protection of cells from oxidised cholesterol by giving them a bacterial enzyme that breaks it down.

Everyone in the field knows that longevity is a side-effect of health: if you increase healthspan (i.e. you postpone the ill-health of old age), you will similarly increase lifespan. Everyone in the field also knows that there is no good age to die - that however much we succeed in postponing age-related disease and disability, we will always want to postpone it more. But they also know that politicians and the general public are petrified of thinking rationally about all this, because aging has them in such a tight psychological stranglehold that all they want to do is put it out of their minds - so they feel forced into this downright dishonest kind of language that implicitly deprecates those few people who dare to be honest about the fact that the longevity side-effect of postponing ill-health is a side-effect that we should welcome. They feel that if they were to endorse the desirability of much longer lifespans, they would cause a backlash in political circles and a reduction in research funding. I'm quite sure they are wrong, and that if the whole field were as honest about all this as I've always been then it would have far more money by now - but there seems to be no way to persuade most of my colleagues of that.

Link: http://www.planettechnews.com/interviews/ptn-interviews-dr-aubrey-de-grey-researcher-and-a-thought-leader-in-anti-aging-regenerative-medicine

Beginning on October 1st and lasting though to the end of the year we'll be running our latest grassroots fundraiser to support the work of the SENS Research Foundation. This remains perhaps the only charitable organization in the world devoted to removing all the hurdles standing in the way of progress in rejuvenation research: halting and reversing all age-related disease by repairing the known common root causes. Most of this work involves funding and cultivating research programs in vital areas overlooked by the scientific mainstream, wherein a modest investment in capital, networking, and persuasion over a few years can get things moving. There is a well-oiled, massive infrastructure already in place that picks up and develops medical research that reaches a certain point of maturity and demonstrable results, and the principal challenge for potential rejuvenation therapies at the present time largely lies in reaching that point.

Help Us to Build a Matching Fund: $70,000 and Counting

This year, just as in 2014, we are preparing for the October fundraiser by building a matching fund. I kicked things off with a $25,000 contribution from Fight Aging! and called for people to match as much as they can. So far, Josh Triplett, Christophe and Dominique Cornuejols, and forever-healthy.org have stepped up to swell the fund to $70,000. Can you help us make this a bigger round number? All pledges are tax-deductible and go to fund SENS Research Foundation programs.

We Raise Funds to Start the Avalanche

We raise funds for rejuvenation research because our contributions make a difference, because no-one other than philanthropists funds very early-stage medical research, and because as little as a few tens of thousands or hundreds of thousands of dollars is enough to start the avalanche. You probably think of medicine as one of the most expensive undertakings in the world today. That's certainly true of bringing therapies from the lab into the clinic, when a single clinical trial can cost tens of millions of dollars, but the business of actually making the initial prototypes in the lab? The cost of that work is startlingly low in this age of biotechnology: a grad student with $10,000 to spend can do more today in a semester than an entire laboratory staff with a budget of millions could have achieved twenty years ago. Building the prototypes of tomorrow's therapies is something that is well within our means when we collaborate.

A Proven Method: In 2008 Philanthropic Funding for SENS Started an Avalanche

So this is a golden age for medicine, in which people of modest means, you and I, can fund the first proof of concept for a rejuvenation treatment based on repair of cellular and molecular damage. The SENS research programs themselves have been underway for long enough that we can already see the signs of success, modest funding and collaboration carried out years ago blossoming into an active development program with a large budget. Started in 2008, the SENS programs at the Methuselah Foundation and then at the SENS Research Foundation funded collaborative early stage work on mitochondrial repair technologies with the lab of Marison Corral-Debrinksi in Paris, moving that work into animal models and demonstrating success in repairing specific mitochondrial DNA mutations associated with the hereditary blindness condition LHON. This was far enough for other funding sources and collaborators to join in and reinforce this success.

By 2013 Gensight was founded to commercialize this technology, and today that company devotes tens of millions of dollars to finalizing and bringing to the clinic a SENS vision for mitochondrial repair technologies, with an initially limited application to cure inherited mitochondrial disease. Every advance in the state of the art hammered out by this well-funded effort can later be adapted for therapies capable of repairing the forms of mitochondrial mutation that contribute to degenerative aging. Gensight is building one of the robust technology platforms needed for near future rejuvenation treatments.

Those of us who made charitable contributions to the very limited SENS budget as it was all the way back in 2008 had a hand in setting this avalanche in motion. This is how the model works: support early research and the scientists performing that work sufficiently well, by donating to an organization that has great experience in doing just that, and a few years later the funding flowing into ongoing development will expand far beyond your contribution.

By Helping Now, You Start the Avalanches Leading into the Early 2020s

This is a long game we're playing here. By helping the Fight Aging! fundraiser for the SENS Research Foundation this year, you support and expand research programs that will lead to the Gensights of the 2020s, companies yet to exist whose backers will pour tens of millions of dollars into creating medical technologies needed for human rejuvenation therapies. Join us in helping to create the next stage in this journey towards a better world, one in which aging and all of its pains and frailties and medical conditions are banished to the history books.

Spread the Word!

Point a friend to the Fight Aging! FAQ. Tell someone you know about the SENS Research Foundation and what it is they do. Pass around one of this year's fundraising posters, or dare I ask, improve upon them. The grand tapestry of success is built of small choices to help, and all of us can choose to make a difference.

mTOR is a hot topic in aging research these days, at least for those parts of the community seeking to develop drugs capable of modestly slowing the aging process. As a goal this is something that I think isn't really worth the time and money poured into it, not when there are other paths ahead based on repairing the causes of aging, capable of producing the far better outcome of rejuvenation and restored health. Persuading the research community on this topic is an ongoing project, led by organizations such as the SENS Research Foundation.

Rapamycin is one drug candidate shown to slow aging in laboratory species, but it affects both mTORC1 and mTORC2 to cause beneficial and harmful effects in equal measure - it isn't something you'd want to take if you had any choice in the matter. Thus researchers focus on intervening in mTORC1, and rapamycin should probably be considered a tool for investigation rather than an actual drug candidate. Like many areas of research into metabolism and aging, this is also relevant to cancer research:

mTOR is a serine/threonine kinase found in two complexes, mTORC1 and mTORC2. mTORC1 coordinates cell growth and metabolism in response to environmental stresses, nutrient and energy levels, growth factors and other conditions. Rapamycin extends life span of wild type mice, possibly through cancer suppression since mTORC1 signaling is often dysregulated in cancer cells. Dietary rapamycin also ameliorated general aging in wild type mice for most, but not all studies. Rapamycin also extended life span for lower organisms that do not die from cancer suggesting that rapamycin suppresses general aging in addition to cancer. Thus, rapamycin appears to suppress mTORC1-mediated oncogenesis and possibly general aging.

p53 is a transcription factor with broad biological function that is best known for suppressing tumors in humans and mice by inducing cell cycle arrest, apoptosis and senescence in response to a variety of stresses. p53 inhibits mTORC1 and thus suppresses mTORC1-driven cell growth in response to cellular stresses like DNA damage.

We provide three lines of evidence that support the notion that p53 and rapamycin are additive. First, p53 enabled enterically targeted rapamycin to extend life span in mice. Second, p53 facilitated the ability of rapamycin to suppress radiation-induced amino acid and citric acid levels in mouse embryonic stem cells. Thus, there appears to be an augmentative relationship between p53 and rapamycin.
We suggest that p53 and rapamycin blunt mTORC1 activity through different pathways to result in this additive relationship.

This contention is relevant to the use of mTORC1 inhibitors as anti-cancer therapeutics since p53 is mutated or dysfunctional in most cancers. mTORC1 inhibitors might be most effective early in the oncogenic process, before p53 is mutated. Our previous results support this possibility since we found that rapamycin suppressed the development of tumors with wild type p53. High levels of mTORC1 inhibitor might be needed to overcome cancer with p53-null mutations. Yet for those p53-dysfunctional cancers that have a functional p53 protein, mTORC1 inhibitors coupled with p53 enablers such as nutlin could be a powerful combination allowing a lower dose for each.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=4602&path%5B%5D=10532

A great deal of early stage research into the mechanisms of aging takes place in very short-lived species such as the nematode worm Caenorhabditis elegans, and here researchers review the use of this species in the laboratory. Why research aging in species very different to our own? Because the economic advantages of being able to study a full life span of many individuals in a short time and at a low cost, coupled with a mature technology platform for genetic manipulation and analysis, more than offset the hurdles and dead ends that arise due to biological differences between nematodes and mammals. The fundamental mechanisms of metabolism and their relationship with aging are in fact surprisingly similar between very diverse species, a fortunate happenstance that speeds exploratory research.

Over a century ago, the zoologist Emile Maupas first identified the nematode, Rhabditis elegans, in the soil in Algiers. Subsequent work and phylogenic studies renamed the species Caenorhabditis elegans or more commonly referred to as C. elegans; (Caeno meaning recent; rhabditis meaning rod; elegans meaning nice). However, it was not until 1963, when Sydney Brenner, already successful from his work on DNA, RNA, and the genetic code, suggested the future of biological research lay in model organisms. Brenner believed that biological research required a model system that could grow in vast quantities in the lab, were cheap to maintain and had a simple body plan, and he chose the nematode C. elegans to fulfill such a role.

Why has C. elegans been used so successfully for aging research? What would make an organism suitable for aging research? The ability to easily and cheaply grow large quantities of worms in the lab is very helpful for aging research, especially when identifying long-lived mutants. C. elegans also have a relatively short lifespan (average approximately 17 days at 20 °C), and the lifespan is largely invariant. The latter allows for identification of mutants that shorten or lengthen average lifespan by as little as 10-15% and still be of statistical significance. Additional benefits of using C. elegans include that the entire genome is sequenced and annotated, the availability of an RNAi library comprising approx. 80% of the genes in the genome, the ease of generating transgenic strains and the recent development of gene-targeting approaches. This has allowed for extensive forward and reverse genetic screens for genes that modulate lifespan.

Another advantage working with C. elegans for studying the aging process is that the lifespan assay is straightforward, which allows for large numbers of worms to be assayed in a single experiment. Therefore, statistical significance can be tested in addition to the analysis of mortality rates. Together, these techniques allow one to comprehensively survey the worm genome for genes that modulate lifespan. This has led to the identification of more than 200 genes and regimens that modulate lifespan in C. elegans and revealed evolutionarily conserved pathways that modulate lifespan. Therefore, the combination of the short, invariant lifespan, ease of assays, ample genetic, molecular and genomic tools, and evolutionary conservation has allowed C. elegans to develop into a premiere model system for aging research.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464094/

Glial cells perform many vital tasks in the brain and other nervous system tissues, and age-related changes in their behavior are a part of the progression of neurodegenerative conditions. In the last couple of months a fair number of very readable review papers on this topic have been published. If you are interested in learning more about this aspect of the brain, now is your chance; take a look at the reviews referenced below.

There are many varied types of glia, each with a different role. Some provide structure and nutrients so as to support neurons, others appear essential to activities such as the formation of synaptic connections, or undertake immune system functions such as the destruction of invading pathogens. Much of the focus in the study of glia falls upon microglia, which carry out immune functions, and astrocytes, which have a very broad portfolio of responsibilities and contributions: near every aspect of the brain's operation is influenced by or dependent upon their activities. In the study of the aging brain, rising levels of chronic inflammation and dysfunction of specific mechanisms are both topics of interest. Microglia mediate inflammation, while many neural mechanisms disrupted in the progression of neurodegenerative disorders involve astrocytes in one way or another.

Neuroinflammation: good, bad, or indifferent?

Under non-diseased conditions, central nervous system (CNS) homeostasis is maintained by an intricate crosstalk between glia and neurons. For example, astrocytes play a key role in neurogenesis, metabolism, and regulating neuronal activity at the tripartite synapse. Microglia are continuously surveying their microenvironments for foreign antigens and are important phagocytes, playing roles in synaptic pruning and clearance of apoptotic debris. However, in response to CNS infection or injury, these glial cells become activated and contribute to ensuing inflammatory processes, in either a beneficial or detrimental manner, depending on the nature, intensity, and duration of the insult. Yet, another wrinkle to this paradigm is the fact that many immune-related molecules can possess secondary functions in the CNS, which expands their portfolio of action.

It is now evident that many diseases affecting the CNS have some inflammatory component, either as a primary cause or secondary outcome of tissue damage. Much work remains to be done to identify the critical mediators and cell types involved; however, this will prove to be a challenging task given the complexities already uncovered with regard to the timing, context, and crosstalk between individual inflammatory molecules. Nonetheless, harnessing inflammation to promote CNS healing/regeneration remains an area of active investigation.

New advances on glial activation in health and disease

In addition to being the support cells of the central nervous system (CNS), astrocytes are now recognized as active players in the regulation of synaptic function, neural repair, and CNS immunity. Astrocytes are among the most structurally complex cells in the brain, and activation of these cells has been shown in a wide spectrum of CNS injuries and diseases. Over the past decade, research has begun to elucidate the role of astrocyte activation and changes in astrocyte morphology in the progression of neural pathologies, which has led to glial-specific interventions for drug development. Future therapies for CNS infection, injury, and neurodegenerative disease are now aimed at targeting astrocyte responses to such insults.

Impact of age-related neuroglial cell responses on hippocampal deterioration

Aging is one of the greatest risk factors for the development of sporadic age-related neurodegenerative diseases and neuroinflammation is a common feature of this disease phenotype. In the immunoprivileged brain, neuroglial cells, which mediate neuroinflammatory responses, are influenced by the physiological factors in the microenvironment of the central nervous system (CNS). These physiological factors include but are not limited to cell-to-cell communication involving cell adhesion molecules, neuronal electrical activity and neurotransmitter and neuromodulator action. However, despite this dynamic control of neuroglial activity, in the healthy aged brain there is an alteration in the underlying neuroinflammatory response notably seen in the hippocampus, typified by astrocyte/microglia activation and increased pro-inflammatory cytokine production and signaling. These changes may occur without any overt concurrent pathology, however, they typically correlate with deteriorations in hippocamapal or cognitive function.

Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.

Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity?

An emerging aspect of neuronal-glial interactions is the connection glial cells have to synapses. Mounting research now suggests a far more intimate relationship than previously recognized. Moreover, the current evidence implicating synapse loss in neurodegenerative disease is overwhelming, but the role of glia in the process of synaptic degeneration has only recently been considered in earnest. Each main class of glial cell, including astrocytes, oligodendrocytes, and microglia, performs crucial and multifaceted roles in the maintenance of synaptic function and excitability. As such, aging and/or neuronal stress from disease-related misfolded proteins may involve disruption of multiple non-cell-autonomous synaptic support systems that are mediated by neighboring glia. In addition, glial cell activation induced by injury, ischemia, or neurodegeneration is thought to greatly alter the behavior of glial cells toward neuronal synapses, suggesting that neuroinflammation potentially contributes to synapse loss primarily mediated by altered glial functions.

Astrocytes in physiological aging and Alzheimer's disease

Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contributes to the aging of the brain and to neurodegenerative diseases. Changes in astroglia in aging and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter the homeostatic reserve of the brain and contribute to early cognitive deficits. At later stages of AD reactive astrocytes are associated with neurite plaques, the feature commonly found in animal models and in human diseased tissue. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at the prevention and cure of neurodegenerative disorders.

Microglia as a critical player in both developmental and late-life CNS pathologies

Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies.

Exercise improves health, but why? Many researchers are digging into the biochemical details, such as the authors of the paper referenced here, who focus on tendon integrity and its deterioration in aging, a degenerative process that is slowed by exercise. Overall regular moderate exercise is comprehensively demonstrated to improve long-term health and raise median life span in animal studies, and is robustly associated with better health, lower medical expenditures, and increased life expectancy in human epidemiological studies.

In recent years, a few studies have been performed to better understand the cellular and molecular mechanisms responsible for the effects of aging on tendons. In general, aging slowly lowers the functional competence of the human body, largely due to the damages in DNA, changes in the cellular microenvironments of the body and epigenetic regulation. In tendons, aging increases the nucleus to cytoplasm ratio and lipid deposition, but decreases vascularization and tendon matrix integrity, and alters tendon cell's response to cellular stimuli. In addition, aging also reduces the number of tendon cells and decreases their activity thereby depleting the resources required to repair injured tendons. Consequently, there is a steady decline in the ability of tendons to repair its injuries over time. Through these changes aging reduces the mechanical strength of tendons and makes them susceptible to injuries, thus lowering the quality of life of the aging population and increasing the healthcare cost.

While aging generally causes detrimental effects on tendons, exercise is known to exert beneficial effects on tendons. Traditionally, tendons were considered to contain only one cell type, the tenocytes, which are resident fibroblast-like cells that maintain tendon integrity, remodeling and repair. However, a new tendon cell type, termed tendon stem/progenitor cells (TSCs), has been identified in recent years in humans, rabbits, mice, and rats. However, the role of TSCs in aging- and exercise-induced changes in tendons is not well understood. Therefore, to explore the TSC-based mechanisms responsible for the beneficial effects of exercise on aging tendons, we tested two hypotheses in this study: i) aging impairs TSC function in tendons, and ii) moderate exercise revives impaired TSC function and thereby exerts beneficial effects on aging tendons.

TSCs derived from aging mice (9 and 24 months) proliferated significantly slower than TSCs obtained from young mice (2.5 and 5 months). In addition, expression of the stem cell markers Oct-4, nucleostemin (NS), Sca-1 and SSEA-1 in TSCs decreased in an age-dependent manner. Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression. In the in vivo study, moderate treadmill running of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons. These findings indicate that while aging impairs the proliferative ability of TSCs and reduces their stemness, moderate exercise can mitigate the deleterious effects of aging on TSCs and therefore may be responsible for decreased aging-induced tendon degeneration.

Link: http://dx.doi.org/10.1371/journal.pone.0130454

Researchers here demonstrate restoration of immune function in mice via transplant of tissue engineered thymus-like organoids, one of a number of lines of research that aims to restore thymic function to boost the aging immune system. A sizable part of the age-related decline of the adaptive immune system arises from a problem of supply: there are no longer enough naive T cells to mount an effective response to new threats.

Some potential approaches to solving this problem involve dealing with issues that reduce the naive T cell population, while others focus on increasing the supply of new T cells. The thymus plays a vital role in the generation of new T cells, and is very active in early life, but withers away upon reaching adulthood in a process known as thymic involution, reducing the supply of immune cells to a trickle. Thus placing new thymic tissue with youthful characteristics into old individuals should be a way to generate more T cells - a straightforward transplant works, for example:

One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering.

Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells.

Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine.

Link: http://www.ncbi.nlm.nih.gov/pubmed/25903472

In the open access paper linked below, researchers outline the proximate cause for one aspect of the characteristic decline in immune function that accompanies aging, in this case the failure to produce sufficient numbers of antibodies in response to the presence of pathogens. Along the way they find an approach that can partially reverse this degeneration, though it remains far from clear as to nature of the root causes and how those root causes lead to the proximate cause.

The progressive failure of the immune system is an important component of age-related frailty, and the more that can be done to turn it back, the better. Here the focus is on humoral immunity and specifically the generation of antibodies by B cells. Portions of the immune system are responsible for digesting the component parts of pathogens such as viruses and microbes, breaking them down into antigens, then presenting those antigens to the antibody manufacturing process. Antibodies are proteins constructed to match and bind to those antigens, let loose in vast numbers so that they can either flag the matching pathogens for destruction by other parts of the immune system, or directly interfere in some vital machinery essential to the pathogen's activities.

It is well known that the aged immune system produces an ever smaller output of antibodies when challenged. This is a part of the reason why vaccinations become ineffective in the elderly, for example. It is worth keeping an eye on research efforts to explain and potentially reverse this decline, but bear in mind that the immune system is enormously complex. Talking about even one narrow portion of the whole - manufacturing antibodies in this case - means considering the roles of many different cell types, mechanisms within cells, and an intricate chain of activities leading from the arrival of a pathogen to matching antibody production, wherein imbalance or failure at any point leads to a worse outcome. You should probably click through and take a look at the diagram that accompanies the abstract before reading on:

Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging

The extent of humoral immunity, or immunity provided by antibodies, decreases with age in both mice and humans. This decrease in humoral immunity translates into increased frequency and severity of infectious diseases in aged individuals. Furthermore, vaccination of the elderly provides inadequate protection against most infectious diseases, leaving these individuals vulnerable to a number of diseases.

The production of antibodies results from a complex interaction of B cells with T follicular helper (TFH) cells in the germinal center (GC) reaction. After differentiation, TFH cells migrate to the B cell follicle and provide help to B cells via costimulation and cytokine production. Mice lacking TFH cells, or their key effector molecules, have severely defective antibody production in response to T-dependent antigens.

T follicular regulatory (TFR) cells are a recently defined specialized subset of effector T regulatory cells (Tregs) that inhibit antibody production. TFR cells originate from natural Tregs in contrast to TFH cells, which develop from naive CD4+ T cell precursors. Programmed cell death protein-1 (PD-1) expression on TFR cells limits both the differentiation and effector function of TFR cells. How TFR cells exert their suppressive effects is not yet clear.

We have demonstrated that the ratio of TFH/TFR cells is an important factor in humoral immunity and that this ratio dictates the magnitude of antibody responses. Therefore, successful humoral immunity is a delicate balance between stimulatory TFH cells and inhibitory TFR cells and not simply a result of the total number of TFH cells. TFR cells appear to be specialized in their suppression of the GC reaction because non-TFR Tregs do not have the same suppressive capacity. We demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. We find increases in both TFH and TFR cells, with a proportionally greater increase in TFR cells. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo.

Together, our studies provide insights into mechanisms for defective antibody production in aging. We find an over-representation of functionally competent suppressive TFR cells in aged mice, most likely resulting from enhanced differentiation of TFR cells. However, expansion of memory TFR cells may also contribute. In addition, we find that TFH cells are generated following immunization of aged mice, but these aged TFH cells fail to elicit strong antigen-specific B cell responses in vivo. Aged TFH cells express higher levels of PD-1 and PD-1 blockade can improve TFH cell function. Thus, the substantial increase in fully suppressive TFR cells, combined with the decrease in antigen-specific responses of TFH cells, results in a significant defect in antibody production in aged mice. Although other mechanisms, such as defects in clonality and/or naive T or B cell numbers also may contribute, our data point to alterations in TFH cell activity and TFR cell proportions as being a key mechanism that impairs antibody production in aging. Therefore, approaches that downmodulate TFR cells may provide a strategy for improving humoral immune responses in the elderly.

Here the Buck Institute blog explains a recent paper on links between mTOR, a focus for research into modestly slowing aging by altering the operation of metabolism, and the bad behavior of senescent cells. Ever more cells become senescent with advancing age, and this contributes to degenerative aging because these cells act in ways that damage surrounding tissue. From where I stand, the best approach is to remove them, however, not modulate their activity. There is a lot left to understand in order to safely change the behavior of senescent cells for the better, while clearing them is a near-term prospect, for example by adapting targeted cell killing technologies developed by the cancer research community.

We showed that the mTOR inhibitor rapamycin blocks the senescence-associated secretory phenotype (SASP) by inhibiting translation of IL-1α, which prevents senescent fibroblasts from promoting cancer tumor growth. What we found is that after chemotherapy or radiotherapy, cancer cells and the cells surrounding them become senescent. That means that the cells surrounding the cancer cells are no longer performing their normal function and they begin to secrete cytokines and growth factors that stimulate cancer growth. We found that a small molecule called rapamycin can prevent this from happening.

So if we extend the findings of that story, this drug may be useful following chemotherapy as an adjuvant. By giving the patient rapamycin after chemotherapy, we might slow down the relapse of the tumor. The next step obvious step is to run a clinical trial with rapamycin or a rapalog. Rapamycin is already FDA approved, so this is exciting for clinical trials, but trials aren't really something that basic scientists are equipped to do. Our paper is showing is that rapamycin would work well as an adjuvant therapy. So after you have received chemotherapy, senescent cells have been induced, and rapamycin can be used to block those otherwise harmful senescent cells. So rapamycin treatment should, in theory, delay relapse.

Half of the people at the Buck Institute work in one way or another with mTOR. So everyone has some connection to translation or mTOR because of how important mTOR is in aging. We have various people working on different aspects of aging. Some are focusing on age-related pathologies, and others are working on aging in general using model organisms. We know that senescent cells accumulate at sites of age-related pathologies and in some pathologies that aren't age related. We are still finding these things out. What is being taught currently is that the deleterious effect that senescent cells have is due to a proinflammatory profile. It is possible that rapamycin extends lifespan because it reduces the low level of chronic inflammation. So if you can think that this is true for aging in general, this could also be true for various age-related pathologies. It will be interesting to see the follow up on rapamycin and modulation of the proinflammatory profile of senescent cells.

Link: http://sage.buckinstitute.org/buck-publication-mtor-regulates-the-pro-tumorigenic-senescence-associated-secretory-phenotype/

Among the sea urchins can be found some of the few species to exhibit negligible senescence, an apparent lack of the obvious features of degenerative aging. By studying negligibly senescent species and the differences in their biochemistry, researchers hope to learn more about the mechanisms that drive aging. As this review notes, the data uncovered to date in sea urchins looks quite similar to the situation for long-lived and negligibly senescent clam species such as Arctica islandica:

Aging in humans and other animals is a well-defined process characterized by a progressive functional decline and increasing mortality over time. However, there are a number of different animals that show negligible senescence, with no increase in mortality rate or decrease in fertility, physiological function, or disease resistance with age. Studying these animals may suggest effective defenses against the degenerative process of aging, and sea urchins provide an ideal model to investigate mechanisms of longevity and negligible senescence.

Different species of sea urchins exhibit very different natural lifespans, and some have extreme longevity and negligible senescence. For example, the red sea urchin Strongylocentrotus franciscanus is one of the earth's longest living animals, living in excess of 100 years with no age-related increase in mortality rate or decline in reproductive capacity. In contrast, Lytechinus variegatus has an estimated lifespan of only 4 years, while the most widely studied species of sea urchin, S. purpuratus, has an estimated maximum lifespan of more than 50 years. Comparisons between long-, intermediate-, and short-lived species may provide insight into mechanisms involved in lifespan determination and negligible senescence. Thus, sea urchins represent an interesting alternative model for aging research.

Studies to date have demonstrated maintenance of telomeres, maintenance of antioxidant and proteasome enzyme activities, and little accumulation of oxidative cellular damage with age in tissues of sea urchin species with different lifespans. Gene expression studies indicate that key cellular pathways involved in energy metabolism, protein homeostasis, and tissue regeneration are maintained with age. Taken together, these studies suggest that long-term maintenance of mechanisms that sustain tissue homeostasis and regenerative capacity is essential for indeterminate growth and negligible senescence, and a better understanding of these processes may suggest effective strategies to mitigate the degenerative decline in human tissues with age.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463994/

In this post I'll point out Gensight, a company creating medical biotechnologies that are relevant to the goal of human rejuvenation, and which is about to undertake an IPO in order to pull in more significant funding for ongoing development. This company has over the past couple of years developed mitochondrial repair technologies based on research at the Corral-Debrinski lab in Paris partly funded by the SENS Research Foundation. This is a great example of what we'd like to see result from the Foundation's intervention in fields of research that need more support in order to move forward.

So the area of interest here is mitochondrial damage and how to remove the consequences of that damage. What does this mean? Mitochondria are the power plants of the cell, working to produce chemical energy stores in the form of adenosine triphosphate (ATP) molecules, though like every cellular component they play a role in many processes beyond their primary function. Evolution likes reuse. Each cell contains a herd of hundreds of mitochondria, which multiply like bacteria, sometimes fuse together, swap component parts of their machinery between one another, and are culled when worn or broken by cellular quality control mechanisms. Mitochondria are the descendants of ancient symbiotic bacteria and carry the remnants of that origin in the form of a small number of genes encoded in mitochondrial DNA. There were originally many more genes, but over evolutionary time they were either lost or migrated to the cell nucleus to reside in the nuclear DNA.

DNA is fragile and a cell is basically a balloon of constant chemical reactions. DNA gets damaged all the time, but the array of repair mechanisms that work to restore that damage are highly efficient: very little slips past. They are far more efficient in the cell nucleus than in mitochondria, however. Further, mitochondrial DNA seems to be more prone to damage for reasons that may include the fairly energetic chemical reactions required to build ATP, or may be an artifact of the way in which mitochondria multiply by division. There is still some debate on this front. What is known is that some forms of mitochondrial DNA damage can bypass quality control, leading very quickly to an entire cell being overtaken by dysfunctional mitochondria with the same broken DNA, unable to properly generate ATP by the usual path, and as a result the cell starts to export harmful, reactive molecules into the surrounding tissue. Enough of these cells and functional damage starts to accrue in tissues and organs: this is one of the contributing causes of degenerative aging.

What to do about this? The strategies are fairly obvious at a high level: replace the broken DNA, or supply new mitochondria, or supply the missing proteins that the broken genes encoded. There are many variants that mix and match between these themes, some are better than others, and some are quite far along in development. The SENS Research Foundation approach is allotopic expression: use gene therapy to put copies of all of the remaining mitochondrial genes into the cell nucleus and then work out how to get the protein produced from that genetic blueprint back to the mitochondria where it is needed - it is that second portion of the work that is the hard part.

Gensight is working on a variant of this approach, but like most groups producing technology of interest to our goals they are not actually focused on aging and longevity at all. Instead Gensight produce their technology to treat inherited mitochondrial disease in which a necessary mitochondrial gene is missing or damaged in wide swathes of a patient's tissues. They are primarily focused on Leber's hereditary optic neuropathy (LHON), a degenerative blindness condition that has been a proving ground for research into mitochondrial repair over the past decade or so. You might recall that the SENS Research Foundation collaborated with Marisol Corral-Debrinski back in the day, helping to fund research on the technology that Gensight is now developing for clinical application.

So the good news here is that a solid, young biotech company with quite a lot of funding is having a serious go at producing a robust platform for repairing the consequences of mitochondrial DNA damage. The next step to follow on from Gensight's progress in reducing this all to practice will be to adapt the core technology to work for all mitochondrial genes of interest, those whose damage is involved in degenerative aging. Given the way companies, business cycles, and intellectual property licensing tend to work out, and allowing some time for the standard confusion and occasional failure, I imagine that start to be underway in earnest somewhere between 2020 and 2025. If we're lucky, someone else will start work on a similar approach to mitochondrial damage in aging before then, however: commercially successful research tends to attract competing scientific programs.

Gensight scouts a $100M IPO for its ocular gene therapies

Parisian drug developer Gensight Biologics is swinging for a $100 million U.S. IPO to fund its work on potential one-time treatments for serious retinal diseases, angling to take advantage of a bullish market for biotechs. Gensight's top prospect is GS010, a treatment for certain forms of the rare Leber hereditary optical neuropathy, or LHON, which leads to sudden and irreversible loss of sight in teenagers and young adults. The treatment works by fixing a DNA glitch that leads to LHON, using a harmless virus to deliver a corrective copy of the ND4 gene. Gensight completed a Phase Ib study on GS010 this year, the company said, and plans to push its top prospect straight to Phase III in the second half with data expected in 2017.

Mitochondrial Targeting Sequence (MTS)

Our MTS technology platform enables efficient expression of a mitochondrial gene by nuclear deoxyribonucleic acid, or DNA, and delivery of messenger ribonucleic acid, or mRNA, to polysomes located at the mitochondrial surface. This allows for the synthesis, internalization and proper localization of the mitochondrial protein.

Mitochondrial DNA mutations, whether inherited or acquired, lead to impairment of the electron transport chain functioning. Impaired electron transport, in turn, leads to decreased adenosine triphosphate, or ATP, production, overall reduced energy supply to the cells, formation of damaging free-radicals, and altered calcium metabolism. These toxic consequences lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death. This cycle of increasing oxidative damage insidiously damages neurons, including those in the retina, over a period of years, eventually leading to neuronal cell death.

LHON originates from mutations in three NADH Dehydrogenase mitochondrial genes: ND1, ND4 and ND6. Because ND4 mutations account for more than 75% of the LHON population in North America and Europe, we chose to first focus on this specific mutation. We have demonstrated the feasibility of using the MTS technology platform for the treatment of LHON due to the ND4 gene mutation in animal studies. We plan to use our MTS technology platform to address other LHON mutations and have already initiated a research program for our next potential product candidate, GS011, which targets the ND1 gene mutation. We believe that our MTS technology platform can also be used to address diseases outside of ophthalmology that involve defects of the mitochondrion, such as neurodegenerative disorders.

Women have a longer life expectancy than men, but why is this? There is no definitive answer to that question, but many competing theories exist. It is a good illustration of the point that the biochemistry of aging is, in detail, enormously complex and still poorly understood as a process with definitive causes and consequences at each stage and in each tissue type. There is a mountain of data, but many more mountains to be cataloged yet, and linking together what is known into a coherent picture is another massive task still in the comparatively early stages. In the research noted here, the authors advance a novel theory on the gender longevity gap, painting the comparative longevity of women as a modern phenomenon driven by a combination of improved medical technology and cardiovascular disease rates.

With regards to the complexity of aging, it is fortunately the case that we don't need a full understanding of the progression of aging if researchers just focused on repairing what we know to be the root cause cell and tissue damage. The situation is akin to that of rust in an ornate metal structure: there is a big difference in effort between (a) just rust-proofing the thing and (b) building a complete module of how rust works and interacts at the molecular level and how exactly, in detail, that causes various structural failure modes over decades of exposure to the elements. In aging research, there is a lot more work on (b) than on (a), which is fine from the pure science perspective where the only goal is complete understanding, but not so good from the point of view of producing therapies for aging in time for you and I to benefit.

Across the entire world, women can expect to live longer than men. But why does this occur and was this always the case? According to a new study, significant differences in life expectancies between the sexes first emerged as recently as the turn of the 20th century. As infectious disease prevention, improved diets and other positive health behaviors were adopted by people born during the 1800s and early 1900s, death rates plummeted, but women began reaping the longevity benefits at a much faster rate. In the wake of this massive but uneven decrease in mortality, a review of global data points to heart disease as the culprit behind most of the excess deaths documented in adult men. "We were surprised at how the divergence in mortality between men and women, which originated as early as 1870, was concentrated in the 50-to-70 age range and faded out sharply after age 80."

Focusing on mortality in adults over the age of 40, the team found that in individuals born after 1880, female death rates decreased 70 percent faster than those of males. Even when the researchers controlled for smoking-related illnesses, cardiovascular disease appeared to still be the cause of the vast majority of excess deaths in adult men over 40 for the same time period. Surprisingly, smoking accounted for only 30 percent of the difference in mortality between the sexes after 1890. The uneven impact of cardiovascular illness-related deaths on men, especially during middle and early older age, raises the question of whether men and women face different heart disease risks due to inherent biological risks and/or protective factors at different points in their lives.

Link: https://news.usc.edu/83648/why-dont-men-live-as-long-as-women/

The staff of the Buck Institute for Research on Aging, like most research centers in this field, largely work on things that won't make any meaningful difference to human longevity, such as calorie restriction mimetic drugs and other forms of metabolic manipulation that can only slightly slow the aging process. In among that there are a few useful projects that might form the basis for therapies capable of rejuvenation, repairing and reversing the course of aging, such as efforts to clear senescent cells, but they are a tiny minority of initiatives. Turning the aging research community around to primarily focus on things that actually matter, like senescent cell clearance, is still very much a work in progress, and this isn't helped by the funding situation for all lines of work related to aging:

In April, Novato-based Buck Institute for Research on Aging, with a $32.5 million budget and nearly 300 employees, launched a new partnership with Google-funded Calico Life Sciences, a San Francisco-based startup dedicated to research on aging. Calico's Arthur Levinson strolled the campus of Buck Institute and met with its CEO Brian Kennedy and other top researchers as he explored the emerging partnership. Calico plans to put some of its employees on the Buck site.

Over the past 15 years, government funding has not increased for research on aging such as that done at the Buck Institute, Kennedy said. "We are trying to figure out how to keep the lights on rather than growing. This is ridiculous." Research universities have similar funding struggles, he said. "When I go and argue for more funding I can't say we are going to do science for science's sake. You get put in an insane asylum if you say that. But precisely that spirit of pure inquiry is what drove huge technology advances. People explore and find interesting things. It's a sad indictment in the wealthiest country in the world - you can't make that case anymore. The anti-­intellectual movement in this country is very dangerous. When I go to China, I hear people's imaginations at work. When I talk to scientists in the U.S., I hear, how do I write my grant?"

Their talent for science is diverted to the task of drumming up money and keeping the flow going. "It makes you risk-averse," Kennedy said, yet the most exciting science happens in a risk-embracing environment. "I worry about the long-term state of this culture. We're not investing" even small amounts to drive discovery forward. "We should have a government that isn't afraid to be a little progressive."

About half of Buck Institute's $32.5 million budget comes from the National Institutes of Health. A few years ago, a much larger percentage of NIH funding went to research on aging, Kennedy said. He would like to have 50 investigators exploring the science of aging. He seeks investors in the science or philanthropists to expand the institute. "We need someone to make a $50 million bet" that the research will pay off, he said, a billionaire "to believe in this mission" as a vision, a legacy. "Aging research is an adventure in something completely different," he said. "We know it's going to work. It's time to implement it. We have this huge paradox. The promise of this field is great - the next medical revolution. There's no money. It's a big challenge. Meanwhile we are spending 19 percent of our (federal) budget on health care. It's not even effective." The cost of prevention can be a twentieth of the cost of treatment, he said.

Link: http://www.northbaybusinessjournal.com/northbay/marincounty/4138872-181/quest-to-redefine-aging

A recent open access paper describing efforts to measure degenerative aging in people in their twenties and thirties age bracket has been doing the rounds in the media. It is interesting to see people making an effort to create definitive measurements of aging in earlier age groups. The signs should certainly be there to see, given discriminating enough biotechnologies: the underlying damage that causes aging occurs at all ages. I'm also very much in favor of anything that might make the younger people in the audience feel more like they have skin in the game. In my experience one of the great ironies in persuading people to care about aging, to speak out for the cause and help fund research, is that the young think it isn't their problem, and the old think that there is no point in helping given that meaningful results will only arrive in the decades ahead. Everyone looks to their own lawn and little beyond.

Nonetheless, the young age too. Aging is a process of damage accumulation, accelerating to greater obvious results in later life due to interactions between damage that cause problems greater than the sum of the parts, and also due to declining repair and maintenance mechanisms. Damage feeds on damage in any machine: the more of it there is, the faster it arrives, and old, damaged machines see a rapid decline in mean time to failure. There are numerous types of cellular and molecular damage at the roots of aging, some of which can be repaired by our cells, were they operating at best capacity, and others that cannot. Aging is thus caused by a mix of two types of harm. On the one hand there is a slow and relentless accumulation of some types of defect: consider cross-links in the extracellular matrix that cannot be broken down by any of the enzymes we produce, generated as comparatively rare byproducts of metabolic operation, or mitochondrial mutations that can evade cellular quality control mechanisms and result in a growing population of dysfunctional cells packed with dysfunctional mitochondria. On the other hand there is a constant, ongoing, rapid creation of other types of defect that is matched by an equally rapid and capable set of repair processes. Unfortunately that repair effort itself winds down over time, allowing damage to get ever further ahead. Here you might think of plain old tissue maintenance by stem cell populations, as the decline of stem cell activity in aging is an important concern in medical research these days.

I think that much further work would need to be done in order to validate that the methods of measuring aging used by these researchers hold up well enough, and in fact correlate usefully with outcomes. Telomere length in particular is very flaky as usually measured in white blood cells, prone to all sorts of interesting and apparently contradictory outcomes in various different studies.

Researchers learn to measure aging process in young adults

Researchers introduced a panel of 18 biological measures that may be combined to determine whether people are aging faster or slower than their peers. The data comes from the Dunedin Study, a landmark longitudinal study that has tracked more than a thousand people born in 1972-73 in the same town from birth to the present. Health measures like blood pressure and liver function have been taken regularly, along with interviews and other assessments. "We set out to measure aging in these relatively young people. Most studies of aging look at seniors, but if we want to be able to prevent age-related disease, we're going to have to start studying aging in young people."

The progress of aging shows in human organs just as it does in eyes, joints and hair, but sooner. So as part of their regular reassessment of the study population at age 38 in 2011, the team measured the functions of kidneys, liver, lungs, metabolic and immune systems. They also measured HDL cholesterol, cardiorespiratory fitness, lung function and the length of the telomeres -- protective caps at the end of chromosomes that have been found to shorten with age. The study also measures dental health and the condition of the tiny blood vessels at the back of the eyes, which are a proxy for the brain's blood vessels.

Based on a subset of these biomarkers, the research team set a "biological age" for each participant, which ranged from under 30 to nearly 60 in the 38-year-olds. The researchers then went back into the archival data for each subject and looked at 18 biomarkers that were measured when the participants were age 26, and again when they were 32 and 38. From this, they drew a slope for each variable, and then the 18 slopes were added for each study subject to determine that individual's pace of aging.

Most participants clustered around an aging rate of one year per year, but others were found to be aging as fast as three years per chronological year. Many were aging at zero years per year, in effect staying younger than their age. As the team expected, those who were biologically older at age 38 also appeared to have been aging at a faster pace. A biological age of 40, for example, meant that person was aging at a rate of 1.2 years per year over the 12 years the study examined.

Quantification of biological aging in young adults

At present, much research on aging is being carried out with animals and older humans. Paradoxically, these seemingly sensible strategies pose translational difficulties. The difficulty with studying aging in old humans is that many of them already have age-related diseases. Age-related changes to physiology accumulate from early life, affecting organ systems years before disease diagnosis. Thus, intervention to reverse or delay the march toward age-related diseases must be scheduled while people are still young. Early interventions to slow aging can be tested in model organisms. The difficulty with these nonhuman models is that they do not typically capture the complex multifactorial risks and exposures that shape human aging. Moreover, whereas animals' brief lives make it feasible to study animal aging in the laboratory, humans' lives span many years. A solution is to study human aging in the first half of the life course, when individuals are starting to diverge in their aging trajectories, before most diseases (and regimens to manage them) become established. The main obstacle to studying aging before old age - and before the onset of age-related diseases - is the absence of methods to quantify the Pace of Aging in young humans.

We studied aging in a population-representative 1972-1973 birth cohort of 1,037 young adults followed from birth to age 38 y with 95% retention: the Dunedin Study. When they were 38 y old, we examined their physiologies to test whether this young population would show evidence of individual variation in aging despite remaining free of age-related disease. We next tested the hypothesis that cohort members with "older" physiologies at age 38 had actually been aging faster than their same chronologically aged peers who retained "younger" physiologies; specifically, we tested whether indicators of the integrity of their cardiovascular, metabolic, and immune systems, their kidneys, livers, gums, and lungs, and their DNA had deteriorated more rapidly according to measurements taken repeatedly since a baseline 12 y earlier at age 26. We further tested whether, by midlife, young adults who were aging more rapidly already exhibited deficits in their physical functioning, showed signs of early cognitive decline, and looked older to independent observers.

We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

I absolutely disagree with the author's position that intervention to reverse aging and age-related disease must happen while people are young. It will be certainly be much easier to achieve medical control of aging when people are young, as therapies will then have to successfully repair far less damage and a much smaller variety of damage. But, and this is crucial, the whole point of developing methods of repair for the causes of aging rather than methods of merely slowing it down is so that the old can be rescued - so that we create rejuvenation. This is no small point: it is a core part of the plan for SENS and other repair-based rejuvenation strategies.

It shouldn't be too surprising to find that people with greater levels of minor brain damage are at greater risk of stroke and death, as noted by these researchers. Blood vessel integrity deteriorates with age, and as a result, many tiny areas of damage accumulate in the brain where small blood vessels suffer breakage. This destroyed tissue contributes to cognitive impairment, one small disaster at a time, all of them going individually unnoticed. The amount of this brain damage in any given individual is a reflection of the degree of deterioration that has occurred in blood vessels and other important structures, caused by underlying forms of cellular and molecular damage that accumulate throughout the body. Since aging is a global process, more damage in one location usually correlates well with more damage everywhere:

The researchers analyzed brain magnetic resonance imaging (MRI) data from nearly 1,900 individuals participating in the Atherosclerosis Risk in Communities (ARIC) Study who were 50 to 73 years of age with no prior history of stroke, tracking their health over about 15 years. Risk of stroke or stroke mortality in people with small lesions was three times greater compared with people with no lesions. People with both very small and larger lesions had seven to eight times higher risk of these poor outcomes.

"The lesions on the brain imaging were very small, less than 3 millimeters, and are typically ignored in clinical practice. This is because we have been uncertain as to their meaning; no studies have looked to see if these very small lesions are related to important clinical outcomes. Our findings suggest they are at least as important as 3 millimeter or larger lesions that are typically considered abnormal, even in absence of other lesions. We know that modifiable risk factors like hypertension and diabetes are associated with the larger structural changes in the brain, and those larger lesions are not only associated with stroke risk but with mobility impairments and cognitive impairments as well. Ongoing trials may determine whether treatment of risk factors, like high blood pressure, reduce the incidence of these lesions, stroke and associated death and disability."

Link: http://www.sciencedaily.com/releases/2015/07/150706183247.htm

Over the last few years researchers have gathered data that suggests smooth muscle cells have a more important role in the later stages of atherosclerosis than previously suspected. This new result adds to the evidence:

Until now, doctors have believed that smooth muscle cells - the cells that help blood vessels contract and dilate - were the good guys in the body's battle against atherosclerotic plaque. They were thought to migrate from their normal location in the blood vessel wall into the developing atherosclerotic plaque, where they would attempt to wall off the accumulating fats, dying cells and other nasty components of the plaque. The dogma has been that the more smooth muscle cells in that wall -- particularly in the innermost layer referred to as the "fibrous cap" -- the more stable the plaque is and the less danger it poses.

Recent research reveals those notions are woefully incomplete at best. Scientists have grossly misjudged the number of smooth muscle cells inside the plaques, the work shows, suggesting the cells are not just involved in forming a barrier so much as contributing to the plaque itself. "We suspected there was a small number of smooth muscle cells we were failing to identify using the typical immunostaining detection methods. It wasn't a small number. It was 82 percent. Eighty-two percent of the smooth muscle cells within advanced atherosclerotic lesions cannot be identified using the typical methodology since the lesion cells down-regulate smooth muscle cell markers. As such, we have grossly underestimated how many smooth muscle cells are in the lesion."

The problem is made all the more complicated by the fact that some smooth muscle cells were being misidentified as immune cells called macrophages, while some macrophage-derived cells were masquerading as smooth muscle cells. It's very confusing and it has led to "complete ambiguity as to which cell is which within the lesion." (The research also shows other subsets of smooth muscle cells were transitioning to cells resembling stem cells and myofibroblasts.)

Researchers identified a key gene, Klf4, that appears to regulate these transitions of smooth muscle cells. Remarkably, when Klf4 was selectively knocked out in smooth muscle cells, the atherosclerotic plaques shrank dramatically and exhibited features indicating they were more stable - the ideal therapeutic goal for treating the disease in people. Of major interest, loss of Klf4 in smooth muscle cells did not reduce the number of these cells in lesions but resulted in them undergoing transitions in their functional properties that appear to be beneficial.

Link: http://newsroom.uvahealth.com/about/news-room/archives/fundamental-beliefs-about-atherosclerosis-overturned

Over the past couple of years, researchers have been involved in cataloging differences in signaling molecules in the blood when comparing old and young mice. This is an outgrowth of heterochronic parabiosis studies, in which an old and a young individual have their circulatory systems joined and the results observed. The effects are improved health, regeneration, and aspects of cell biology such as stem cell activity in the old individual, and opposing negative impacts on the young individual. This was in the news recently with a focus on TGF-β signaling and stem cell activity in the brain, but the other part of that research involves β2 microglobulin (B2M), which is front and center in the publicity materials linked below.

The orthodox theory is that stem cell activity declines with age in reaction to growing levels of tissue damage, and this happens because it reduces cancer risk, with life span emerging from the processes of natural selection as a balance between death by cancer on the one hand and death by loss of tissue maintenance and organ function on the other. The evidence to date suggests that in mammals at least this is far from a finely balanced outcome and that there is a in fact a fair amount of room to boost cell activity and regeneration in old age without greatly increasing cancer incidence.

Thus researchers are greatly interested in finding ways to restore stem cell activity in the old, and turn back loss of tissue maintenance. There is a good chance that much of this declining activity is caused, proximately at least, by changes in cell signaling over the course of aging, and especially in levels of signal molecules carried in the blood stream - which comes back to parabiosis as an investigative tool. If specific signals important in age-related decline of function can be identified, then changing their levels can form the basis for therapies.

The root cause of loss of function with age is still cell and tissue damage, however, and the best goal is to repair that damage and thus have the signaling changes revert themselves, not interfere at a higher level, even if it happens to turn out that there are benefits to be had. Even if you can improve greatly on today's medicine by restoring stem cell activity, with a backup provided by next generation targeted cancer therapies, then there is still the harm caused by forms of damage such as mitochondrial dysfunction and waste products such as cross-links and amyloid. That will still kill us if left untreated, stem cells or no stem cells.

Age-related cognitive decline tied to immune-system molecule

Connecting the circulatory system of a young mouse to that of an old mouse can reverse the declines in learning ability that typically emerge as mice age. Over the course of their long-term research on so-called young blood, however, the researchers had noted an opposite effect: blood from older animals appears to contain "pro-aging factors" that suppress neurogenesis - the sprouting of new brain cells in regions important for memory - which in turn can contribute to cognitive decline.

Beta-2 microglobulin, or B2M, levels steadily rise with age in mice, and are also higher in young mice in which the circulatory system is joined to that of an older mouse. B2M is a component of a larger molecule called MHC I (major histocompatibility complex class I), which plays a major role in the adaptive immune system. These findings were confirmed in humans, in whom B2M levels rose with age in both blood and in the cerebrospinal fluid (CSF) that bathes the brain. When B2M was administered to young mice, either via the circulatory system or directly into the brain, the mice performed poorly on tests of learning and memory compared to untreated mice, and neurogenesis was also suppressed in these mice.

These experiments were complemented by genetic manipulations in which some mice were engineered to lack a gene known as Tap1, which is crucial for the MHC I complex to make its way to the cell surface. In these mice, administration of B2M in young mice had no significant effect, either in tests of learning or in assessments of neurogenesis. The group also bred mice missing the gene for B2M itself. These mice performed better than their normal counterparts on learning tests well into old age, and their brains did not exhibit the decline in neurogenesis typically seen in aged mice.

The effects on learning observed in the B2M-administration experiments were reversible: 30 days after the B2M injections, the treated mice performed as well on tests as untreated mice, indicating that B2M-induced cognitive decline in humans could potentially be treated with targeted drugs. "From a translational perspective, we are interested in developing antibodies or small molecules to target this protein late in life. Since B2M goes up with age in blood, CSF, and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically."

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner.

B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

Axons extend from nerve cells, grouped in bundles to form nerves, with the longest axons running for a meter or more. When severed they tend not to regrow, a limitation that researchers are trying to work around. Here is one of a number of instances in which axon regrowth has been demonstrated in the laboratory:

Chronic spinal cord injury (SCI) is a formidable hurdle that prevents a large number of injured axons from crossing the lesion, particularly the corticospinal tract (CST). While physical therapy and rehabilitation would help the patients to cope with the aftermath, axonal regrowth potential of injured neurons was thought to be intractable. Now researchers report that the deletion of the PTEN gene would enhance compensatory sprouting of uninjured CST axons. Furthermore, the deletion up-regulated the activity of another gene, the mammalian target of rapamycin (mTOR), which promoted regeneration of CST axons.

"As one of the long descending tracts controlling voluntary movement, the corticospinal tract (CST) plays an important role for functional recovery after spinal cord injury. The regeneration of CST has been a major challenge in the field, especially after chronic injuries. Here we developed a strategy to modulate PTEN/mTOR signaling in adult corticospinal motor neurons in the post-injury paradigm. It not only promoted the sprouting of uninjured CST axons, but also enabled the regeneration of injured axons past the lesion in a mouse model of spinal cord injury, even when treatment was delayed up to 1 year after the original injury. The results considerably extend the window of opportunity for regenerating CST axons severed in spinal cord injuries. It is interesting to find that chronically injured neurons retain the ability to reform tentative synaptic connections. PTEN inhibition can be targeted on particular neurons, which means that we can apply the procedure specifically on the region of interest as we continue our research."

Link: http://www.eurekalert.org/pub_releases/2015-07/hkuo-hrd070215.php

Targeting antioxidants to the mitochondria inside cells has been shown to produce enough of a benefit to build therapies for a number of conditions, with better outcomes than standard antioxidant treatments. Researchers developing mitochondrially targeted antioxidants based on plastinquinones are still searching for potential clinical applications, however, and in the recent paper referenced here they demonstrate benefits in skin healing for aged mice.

Mitochondria produce reactive oxidizing molecules as a side-effect of their operation. Soaking up some of these molecules at the source has more and better effects on cellular metabolism than the introduction of non-targeted antioxidants, including in some cases extension of healthy life. The reasons for this are complex and still incompletely understood: the emitted reactive molecules are an important signal in addition to being agents that cause damage, cells react to both signals and damage, and among the interventions that slow aging in lower animals some involve greater and some involve lesser generation of reactive molecules in mitochondria. Regarding non-targeted antioxidants, the general consensus at this time is that antioxidant supplementation as a matter of course is probably mildly harmful, as it interferes with hormetic processes based on use of reactive molecules as signals such as those that mediate the beneficial effects of exercise.

The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlier in vitro.

The transforming growth factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.

Link: http://www.impactaging.com/papers/v7/n7/full/100772.html

Many researchers investigate inflammation, but like everything involving the immune system it is a very complex collection of processes, yet to be fully understood, and especially in the role it plays in degenerative aging. The greater the capabilities of modern biotechnology, the more details of molecular biology become visible for scientists to catalog and puzzle over: the deeper they look, the more there is to find. Here I pick one paper out of many - a look at the JAK-STAT signaling pathway in the context of inflammation in nervous system tissues - to illustrate this point.

Numerous age-related diseases count chronic inflammation as a factor contributing to pathology: think of it as a source of cell and tissue damage, even where the link isn't as direct and well understood as is the case for atherosclerosis, to pick an example. Even if you manage to evade all of the common ways to inflict significant additional unnecessary inflammation upon yourself - smoking, chronic injury, a sedentary lifestyle, and perhaps most significantly excess visceral fat tissue - your immune system still steadily malfunctions with advancing age. You're better off for being a fit, thin, non-smoker, but only better off, not immune. Your immune system falls into a state in which it is both ineffective and chronically overactive, and this and its consequences are given the name inflammaging.

If you read around the subject you'll see that enough is known to paint defensible summaries regarding inflammation and the activity of the immune system, but you don't have to wander far beyond the outline to find yourself off the maps and into unknown or hotly debated territory. This is one of the reasons why I favor work on comparatively simple engineering approaches to near-future treatments for immune aging, such as targeted destruction of memory T cells, or complete destruction and recreation of the immune cell population, or regeneration of the thymus. These strategies avoid the need to gain a far greater knowledge of immune system organization before producing new therapies. Gaining that knowledge is proving to be costly and slow, and while it will be needed for meaningful progress in the treatment of some autoimmune conditions such rheumatoid arthritis, the the more direct approaches noted above offer an alternative path with a shorter time to clinical application.

It is interesting that this team has focused on the JAK-STAT pathway in the context of nerve tissue and inflammation, as their research must have overlapped that of another comparatively recent discovery related to this pathway. In that other work, scientists showed that interfering in the JAK-STAT pathways can restore stem cell activity in aged muscle tissue, and via processes that don't immediately seem to be much related to inflammation.

Control of Inflammatory Responses: a New Paradigm for the Treatment of Chronic Neuronal Diseases

The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses.

We identified Janus kinase-signal transducer and activators of transcription (JAK-STAT) as a new inflammatory signal in the brain and showed that its inflammatory signals can be activated by LPS, IFN-γ, gangliosides and thrombin. The receptor activated by these ligands or cytokines phosphorylates JAKs, leading to the phosphorylation (i.e. activation) of STAT molecules. Activated STATs form dimers and translocate to the nucleus, where they act as transcription factors; they induce the expression of inflammatory genes that have STAT-binding sites in their promoter regions, thereby activating subsequent inflammatory responses. Because the JAK-STAT pathways mediate the actions of numerous growth factors and cytokines, their negative feedback pathways are well developed and tightly regulated. The endogenous negative feedback molecules include phosphatases and inhibitory proteins, such as the suppressor of cytokine signaling (SOCS) proteins. Because the individual SOCS family proteins regulate different molecules of the JAK-STAT signaling pathways, we could possibly use them to specifically or synergistically control different JAK-STAT pathways. Indeed, the anti-inflammatory properties of many clinically available drugs, including aspirin, are mediated via SOCS proteins. Thus, it is particularly interesting to consider the development of additional SOCS-targeting drugs.

Despite years of research, inflammatory responses and the mechanisms underlying the actions of anti-inflammatory drugs remain to be clarified. Current studies in the field of immunology are expected to provide new insights into inflammation responses, inflammation-regulating drugs, and the relevant control mechanisms. Some antibodies and drugs used in clinical practice are capable of directly targeting specific signaling molecules/receptors. In the case of anti-inflammatory drugs, however, most such specific targeting therapeutics have been used only casually or experimentally.

Detailed information is now being obtained regarding the pharmacological actions of typical non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and steroids. If we hope to effectively regulate inflammation for the treatment of diseases, the mechanisms responsible for controlling the inflammatory response need to be firmly established. We should also seek to better understand the cause-and-effect relationships between inflammatory responses and the progression of related human diseases. Given that inflammatory/immune responses are physiological phenomena that can provide protection or cause damage, their therapeutic modulation must be precisely controlled in quantitative, qualitative and temporal terms. Improper control could compound the disease processes or cause a new disease. Thus, additional research is warranted to improve our understanding of the inflammatory response.

If verified by other laboratories, this seems like a meaningful step forward in understanding the physical structure of memory. A greater knowledge of the biological basis for memory storage has important applications in many fields, not just the obvious ones in medicine:

Researchers have shown how how prion-like proteins are critical for maintaining long-term memories in mice, and probably in other mammals. When long-term memories are created in the brain, new connections are made between neurons to store the memory. But those physical connections must be maintained for a memory to persist, or else they will disintegrate and the memory will disappear within days. Many researchers have searched for molecules that maintain long-term memory, but their identity has remained elusive.

Prions - a name derived from the words protein infectious particles - are a unique class of proteins. Unlike other proteins, they are not only able to self-propagate but also to induce other proteins to take on their alternative shape. When prions form in a cell, notably in a neuron, they cause damage by grouping together in sticky aggregates that disrupt cellular processes. In contrast, functional prion proteins can play a physiological role in the cell and do not contribute to disease.

Researchers first identified functional prions in the giant sea slug (Aplysia) and found they contribute to the maintenance of memory storage. More recently, they searched for and found a similar protein in mice, called CPEB3. In one of many experiments, the researchers challenged mice to repeatedly navigate a maze, allowing the animals to create a long-term memory. But when the researchers knocked out the animal's CPEB3 gene two weeks after the memory was made, the memory disappeared.

The researchers then discovered how CPEB3 works inside the neurons to maintain long-term memories. "Like disease-causing prions, functional prions come in two varieties, a soluble form and a form that creates aggregates. When we learn something and form long-term memories, new synaptic connections are made, the soluble prions in those synapses are converted into aggregated prions. The aggregated prions turn on protein synthesis necessary to maintain the memory." As long as these aggregates are present long-term memories persist. Prion aggregates renew themselves by continually recruiting newly made soluble prions into the aggregates. "This ongoing maintenance is crucial."

A similar protein exists in humans, suggesting that the same mechanism is at work in the human brain, but more research is needed. "It's possible that it has the same role in memory, but until this has been examined, we won't know. There are probably other regulatory components involved. Long-term memory is a complicated process, so I doubt this is the only important factor."

Link: http://www.eurekalert.org/pub_releases/2015-07/cumc-lma070215.php

The number of scientific conferences covering the molecular biology of aging seems to be growing. Here is a recently published report from a conference held last year, for example:

Aging is a fundamental problem that the world is currently facing. The population of elderly people is higher than it has ever been before and continues to increase at an even higher rate. Although life expectancy has been dramatically increased in industrialized countries, many elderly people still suffer from serious age-related diseases, and the burden of healthcare costs is increasing steadily because aging is directly related to many illnesses, including cancer, diabetes, and cardiac dysfunction. Therefore, delaying the onset of age-related diseases, improving quality of life, and providing humans with a healthy aging strategy are among the main goals of research on aging. Model organisms have proven to be reliable tools for studying aging and have revealed promising biological foundations for delaying the onset and the progress of age-related human diseases. To address and discuss emerging issues on various aspects of the biology of aging, the International Symposium on the Genetics of Aging and Life History II was held at the campus of the Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea, from May 14 to 16, 2014.

Many leading scientists from all over the world attended the symposium to share their ideas. The scientists at the meeting presented their work, which aims to identify solutions for aging and age-associated diseases. Pharmacological strategies and bioinformatics approaches to understand aging, cellular senescence, sensory and mitochondrial signaling, and the role of microRNAs in the regulation of lifespan were among the wide range of topics covered at the meeting. Interventions that slow aging and delay the onset of age-associated diseases were discussed thoroughly.

There is no doubt that the importance of research on aging has been emphasized in the last few decades. The increasing interest in and demand for aging research is also felt in East Asian countries, including South Korea. Many notable meetings on aging research have been successfully held in Asia, including the Symposium on the Genetics of Aging and Life History (South Korea), the Trinations Aging Symposium (China), a conference on the Molecular Basis of Aging and Disease, Cold Spring Harbor Laboratory Asia (China), and others. Leading scientists in the field are invited from throughout the world, and the number of participants has been increasing at each meeting. We believe that these meetings, including the Symposium on the Genetics of Aging and Life History, substantially bridge different areas of aging research and bring opportunities for collaborations.

Link: http://www.impactaging.com/papers/v7/n6/full/100762.html

Here I'll point out a couple of papers on the topic of energy, metabolism, and natural variations in longevity. One of the many ways of looking at the operation of metabolism is from the point of view of energy consumption and expenditure: how does energy flow around the system, how do these flows vary in different circumstances and between different species, and what can that tell us about the way in which our biology breaks down over the course of aging, or even why we age at all?

It is quite possible to measure a living being in the same way as one can measure an engine as a black box, assessing energy in, energy stored, energy expended. You can put an individual in an enclosed room and measure calorie intake, changes in gas fractions in the air, and so forth. Separately, within cells and tissues it is possible to catalog chemical reactions and the transfers of energy that accompany them, to build a picture of how the energy is ported from, say, food to movement of limbs, at both the high level and the very low level. Some types of model are pretty good and some are pretty sketchy since they depend on incomplete knowledge, but researchers have been working on aspects of this field of research for quite a long time, and both understanding and the quality of the models continues to improve.

One of the other fields tied in to considerations of energy metabolism is the study of calorie restriction, well known to extend healthy life span and improve health in near every species measured to date. Lowered intake of calories causes sweeping changes in the operation of cellular biology, and of course all of that can be considered in terms of energy. The two open access papers linked below both touch upon calorie restriction in the course of their discussion. This first is written from the minority programmed aging point of view, the second from the majority opposition viewpoint of aging as accumulated cell and tissue damage - though of course even with each of these factions there is a great deal of debate and many different theories of aging.

Energy excess is the main cause of accelerated aging of mammals

To date, over 300 theories explaining aging were put forward. Some of them, like the uncritically accepted free radical theory of aging, do not find unequivocal experimental support. Others, like the distinction between mortal soma and immortal germ line or disposable soma theory, can explain only general rules of aging, but are restricted to animals. Those, like antagonistic pleiotropy theory, are informative, but cannot explain the details of mechanisms of senescence and longevity. The closest to ideas presented in this paper is the postulate of hyperfunction.

The analysis of cases of unusually high longevity of naked mole rats and an alternative explanation of the phenomenon of calorie restriction effects in monkeys allowed for postulating that any factor preventing an excess of energy consumed, leads to increased lifespan, both in evolutionary and an individual lifetime scale. It is postulated that in mammals the most destructive processes resulting in shortening of life are not restricted to the phenomena explained by the hyperfunction theory. Hyperfunction, understood as unnecessary or even adverse syntheses of cell components, can be to some extent prevented by lowered intake of nutrients when body growth ceases. We postulate also the contribution of glyco/lipotoxicity to aging, resulting from the excess of energy.

Besides two other factors seem to participate in aging. One of them is lack of telomerase activity in some somatic cells. The second factor concerns epigenetic phenomena. Excessive activity of epigenetic maintenance system probably turns off some crucial organismal functions. Another epigenetic factor playing important role could be the microRNA system deciding on expression of numerous age-related diseases. However, low extrinsic mortality from predation is a conditio sine qua non of the expression of all longevity phenotypes in animals. Among all long-lived animals, naked mole rats are unique in the elimination of neoplasia, which is accompanied by delayed functional symptoms of senescence. The question whether simultaneous disappearance of neoplasia and delayed senescence is accidental or not remains open.

On the complex relationship between energy expenditure and longevity: Reconciling the contradictory empirical results with a simple theoretical model

The relationship between energy expenditure and longevity has been a central theme in aging studies. The oldest theory in the field - the rate of living theory (RLT) suggests that the rate of mass-specific energy expenditure (metabolic rate) is negatively correlated with longevity. The predicted correlation between energy expenditure and lifespan does not hold when comparisons are made across taxons, however. A typical example is that birds have higher metabolic rate than mammals with the same body mass, yet live much longer. The oxidative stress theory of aging (OST), another theory that links energy metabolism and longevity, suggests that the deleterious productions of oxidative metabolism (e.g., reactive oxygen species, ROS) cause various forms of molecular and cellular damage, and the accumulation of the damage is associated with the process of aging. Widely considered by many researchers as a modern version of the RLT at the molecular and cellular level, this theory shares all the supports and challenges of the RLT, as well as a few of its own.

In this paper, we present a simple theoretical model based on first principles of energy conservation and allometric scaling laws. We show that oxidative metabolism can affect cellular damage and longevity in different ways in animals with different life histories and under different experimental conditions. Qualitative data and the linearity between energy expenditure, cellular damage, and lifespan assumed in previous studies are not sufficient to understand the complexity of the relationships. Our model provides a theoretical framework for quantitative analyses and predictions. The model is supported by a variety of empirical studies, including studies on the cellular damage profile during ontogeny; the intra- and inter-specific correlations between body mass, metabolic rate, and lifespan; and the effects on lifespan of (1) diet restriction and genetic modification of growth hormone, (2) the cold and exercise stresses, and (3) manipulations of antioxidant.

The oxidative damage producing process starts from the overall energy expenditure (measured as oxygen consumption rate). Under many circumstances, energy expenditure is proportional to the production rate of ROS, which is in turn proportional to the net oxidative damage. Assuming that the net oxidative damage is the cause of aging and the determinant of lifespan, in these cases there is a direct and simple link between lifespan and metabolic rate. However, two factors, namely antioxidant scavenging and damage repair mechanisms, can alter the damage level (the output of the process) while keeping the energy expenditure rate (the input) roughly unchanged. Enhancing or weakening these two factors can result in a nonlinear correlation between net cellular damage level and oxygen consumption, and therefore a complex relationship between energy expenditure and longevity. The nonlinearity between damage and oxygen consumption may also be partially attributed to the incomplete mitochondrial coupling due to proton leak and electron leak, which causes a fraction of consumed oxygen not to produce ROS.

We need to emphasize that the protective mechanisms of anti-oxidative scavenging and damage repair require energy. So, the overall protective efficacy depends on the amount of energy allocated to these mechanisms and the efficiency of energy utilization for this purpose. Thus, we hypothesize that there are two ways to enhance the protection. The first way is to allocate more energy to protection. More energy for protection does not necessarily require an increase in overall energy expenditure. Some lifespan extension interventions can reshuffle the energy allocation and induce tradeoffs between protection and other life history traits. One of the most important traits that is often manipulated to tradeoff with protection is biosynthesis during growth. For example, when growth is retarded by diet restriction or genetic modification of growth hormone, the energy requirement for biosynthesis is reduced accordingly. The second way is to enhance the protective efficiency, so that one unit of the energy is associated with less molecular damage. Protective efficiency can be altered by experimental manipulations, such as down- or up-regulating genes for antioxidant enzymes, or altering the structures of molecules, such as the fatty acid composition of membranes, to change their vulnerability to oxidative insults.

In the RLT, the overall energy expenditure is the determinant of longevity, whereas in the OST, the determinant is the net cellular damage. As discussed above, because energy allocation and protective efficiency can both change in a variety of situations, these two determinants are not simply proportional to each other, and the link between longevity and energy expenditure is far more complex. Thus, we argue that the OST is not merely the modern version of the RLT at the cellular and molecular level.

Today I thought I'd point out an interesting post from the Buck Institute team on the topic of stem cell aging. The good news here is that the characteristic age-related decline of stem cell function is an issue that the research community has to engage with on the way to developing effective treatments based on their work. It is unavoidable: the majority of regenerative medicine based on the use of stem cells is most applicable to age-related diseases, yet the old and damaged tissue environment disrupts stem cell activity.

What happens to adult stem cells as a person ages? Can they always maintain their regenerative capacity? The answer is no. Adult stem cells maintain tissue homeostasis and differentiate into the cell types that make up the tissue in which they reside, however these processes become less efficient over time. Adult stem cell dysfunction caused by aging has been reported in many organ systems including the heart, muscle, and bone marrow. Some adult stem cell populations like neural stem cells in the brain and melanocyte stem cells in hair follicles actually decline with age. Both adult stem cell dysfunction and a decline in number translate to a reduced regenerative response to tissue or age-related damage.

A few of the culprits: DNA damage occurs in aging stem cells over time because of factors present inside and outside of the cells and because of exposure to genotoxic stress (chemical factors that cause genetic mutations). The machinery that repairs DNA in older stem cells does not function as precisely, and this can cause genomic instability, cell death, or even cancer if a person is really unlucky. Cellular senescence is a term that refers to cells that have entered a state where they can no longer proliferate and divide. Senescence occurs in older stem cells because of elevated cellular stress. Senescent stem cells are bad news because they secrete factors that can cause inflammation and stem cell dysfunction, which further exacerbates symptoms of aging and disease. Then there is mitochondrial dysfunction. Mitochondria are the batteries that power our cells. Mitochondria have their own genome, and in aging stem cells, mitochondrial DNA can be damaged, which impairs mitochondrial function and consequently, adult stem cell function.

So how do we solve the problem of aging stem cells? One obvious approach is to rejuvenate adult stem cells by preventing DNA damage, cellular senescence, and mitochondrial dysfunction. Another strategy is to transplant healthy adult stem cells from a donor into a patient with disease or damaged tissue. However, the issue with adult stem cell transplantation is that the environment (called the niche) into which you transplant healthy stem cells may contain toxic factors (caused by disease or damage) that will kill off the newly transplanted stem cells or impair their function. Thus, a better approach would be to fix or reverse aging phenotypes in the surviving stem cells and other mature cells in that niche, and then transplant healthy donor stem cells into a rejuvenated, healthy environment.

One last thing to consider as one addresses the aging adult stem cell issue is when to intervene therapeutically. Trying to restore adult stem cell function in already diseased or older tissue might not be as effective as preventing damage from accumulating in the same stem cells earlier in life. Prevention of stem cell aging would be a promising strategy to fight aging itself, but that would require the ability to predict or diagnose disease onset in healthy people, which is a huge and complicated endeavor.

Link: http://sage.buckinstitute.org/stem-cells-get-old-too/

Here are a few thoughts on the need for advocacy in longevity science from Rejuvenaction:

People don't think that ageing is a disease because they're used to thinking that it's just a stage of life. They will start to finally accept that this is not the case only when a sufficiently large number of other people in positions of authority, scientists and organizations, will come out and say it out loud. That's one sad truth: people accept things far more quickly than they understand them, and if, at some point, news from the anti-ageing world will frequently populate their TV screens, social media feeds, newspaper articles, and even casual discussions, they will stop ignoring the problem of ageing and cease to oppose its resolution. Nobody likes to advocate for an unpopular cause: it doesn't feel good to be the only person in a group to support a certain claim while being fiercely opposed by all the others, but it does feel nice to be on the winning side of an argument.

Unfortunately, with the exception of the SENS Research Foundation and a few others, researchers of the field are quite hesitant about their goals. I don't see anything wrong with looking for a "fountain of youth". Actually, I don't see how can you want to just "increase health span" without looking for a fountain of youth or eternal life. If they want to increase the current health span it's clearly because they think that the current one isn't enough. So they're not okay with getting sick of the diseases of old age at 80. Now just how much do they want to increase this health span? Till you're 100? 120? When is it okay to get age-related diseases? Unless you increase health-span indefinitely, at some point you are going to get age-related diseases, and they will kill you.

And say that one day they manage to extend health span so that you don't start experiencing age-related decay until you're 120. Then some other researchers come along and say that "they just want to extend health span" so that age-related diseases are delayed until you're 140. Are we saying no to that? Extending your health span up to when you're 120 is fine but up to when you're 140 is not? Why? This game is rather silly, particularly when you think about the obvious fact that unless you have a health problem of some sort, you do not die: yes, being shot, poisoned, electrocuted, eaten by a shark and whatever violent death you can think of counts too, because they all cause you health issues that eventually (rather fast, in fact) kill you. So, if you're not looking for eternal life, it means you're explicitly and intentionally leaving around some health problem of which people can die. In the case of age-related diseases, which ones should we leave around? Which age-related diseases are okay to die of? Alzheimer's? Cancer? Cardiovascular disease? Make your pick - I'm okay without any of those, thank you.

I'm willing to concede that, perhaps, the researchers are playing it safe: they know that if you dare saying that you want to get rid of biological ageing altogether then people will jump down your throat, and thus it's better to slowly get them used to anti-ageing research before making bolder claims. However, I disagree: curing ageing is an urgent humanitarian problem, and there's no time to fool around to please the masses. We need to educate people, get them understand that curing ageing and immortality aren't the same thing at all, that age-related diseases are an extremely serious and compelling problem that needs to be addressed right now, before it goes from bad to worse, and that all the objections to the defeat of ageing make no sense whatsoever.

Link: https://rejuvenaction.wordpress.com/2015/06/22/which-age-related-disease-would-you-like-to-die-of/

It isn't often at all that researchers find an association between longevity and genetic variants in humans that holds up in different study populations. This is quite the contrast with shorter-lived species such as mice, where significant effects on longevity via genetic variants are near commonplace. Nonetheless, here I point out a recent paper in which TXNRD1 variants show longevity associations in two European groups - it is a result of interest purely because of its rarity.

There are as of yet no human single gene manipulations that produce effects on longevity anywhere near as impressive as those achieved in laboratory species such as flies, worms, and mice. In one sense this is a part of a larger theme: approaches to altering the operation of metabolism in short-lived species produce sometimes dramatic extension of healthy life, and the shorter the normal life span the larger the gain. None of these have more than modestly beneficial short-term effects in humans, and nor are they expected to do better than adding just a few years to human life expectancy. Calorie restriction is a great example: it can extend life in mice by 40% or so, but certainly doesn't do that in humans. The rationale for this is that shorter-lived species tend to evolve a much greater plasticity of life span because events that might require a postponement of reproduction until later tend to take place over a much greater proportion of their life span. A seasonal famine is a large fraction of a mouse life span, but not so for humans - and hence only the mouse evolves a large extension of healthy life in response to reduced calorie intake.

It isn't just that there is an absence of large effects from human longevity-related genes, however. It is that there is a near absence of any human longevity-related genes backed by defensible data in multiple study populations. Many studies have found small effects and statistically significant associations between a wide variety of genetic variants and human longevity in one study population, but when following up in a different group of people, even in the same part of the world, researchers find that these correlations cannot be replicated. This strongly suggests that the genetic determinants of natural variations in humans longevity and health in later life are very complex, consisting of the interaction of hundreds or thousands of genes, each producing individually tiny effects, varying widely with environmental circumstances, and the whole network of interactions very different for different groups of people. At this point we probably shouldn't expect the study of genetics in aging to be a good path towards enhanced human longevity, and this simply because we're not finding the same sort of results in people, a plethora of defensible associations between specific genes and longevity, that easily fall out of the data in mice.

So all this said, here is one of the rare small effects and genetic associations with longevity that is replicated in different study populations. There are all too few of these beyond the well known APOE and FOXO3A associations. None have large effects. If you have the beneficial variant, you may have a slightly better chance of reaching extreme old age in the environment of today's medical technology - but in absolute terms your odds are still terrible, and something like three quarters of the people with these beneficial variants are still dead by 90. Improved understanding in biology is always a good thing, but this is not the road to rejuvenation and greatly extended healthy life spans:

Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age

The role of oxidative stress response in the susceptibility to longevity is a hot topic in aging research. Comparisons among species with different rates of aging suggested that long lived species tend to show reduced oxidative damage, reduced mitochondrial free radicals production, increased antioxidant defenses, and increased resistance to oxidative stress. Indeed, centenarians generally show a lower degree of oxidative stress. However, a direct cause-and-effect relationship between the accumulation of oxidative mediated damage and aging has not been strongly established. The overall cellular oxidative stress during aging is determined not only by ROS generation but also by a reduced defense capacity of antioxidant systems.

The thioredoxin system is a most important antioxidant frontier of the cell, able to regulate its reduction/oxidation (redox) status. Thioredoxin (Trx) plays an essential role in the antioxidant defense, both directly, acting as redox regulator of intra- and extracellular signalling pathways and transcription factors, and indirectly, by protein-protein interactions with key signaling molecules such as thioredoxin-interacting protein (TXNIP). Furthermore, Trx protects the cell against lipid and protein peroxidation by controlling the protein folding through the catalysis of sulfur-exchange reactions among protein complexes. Its endogenous regulator, TrxR1, is a key selenoprotein antioxidant enzyme as well, able to reduce Trx (its main substrate) and other compounds, thus detoxifying cells from oxidative injuries. Highly conserved along the evolution, the system has also a pivotal role in growth promotion, neuroprotection, inflammatory modulation, antiapoptosis, immune function, and atherosclerosis.

The variability of encoding gene (TXNRD1) was previously found associated with physical status at old age and extreme survival in a Danish cohort. To further investigate the influence of the gene variability on age-related physiological decline, we analyzed 9 tagging single nucleotide polymorphisms (SNPs) in relation to markers of physical and cognitive status, in a Southern-Italian cohort of 64-107 aged individuals. We replicated the association of TXNRD1 variability with physical performance, with three variants (rs4445711, rs1128446, and rs11111979) associated with physical functioning after 85 years of age. In addition, we found two SNPs borderline influencing longevity (rs4964728 and rs7310505) in our cohort, the last associated with health status and survival in Northern Europeans too. Overall, the evidences of association in a different population here reported extend the proposed role of TXNRD1 gene in modulating physical decline at extreme ages, further supporting the investigation of thioredoxin pathway in relation to the quality of human aging.

The Buck Institute here provides a popular science look at links between cellular senescence and the development of Parkinson's disease. The proximate cause of the symptoms of Parkinson's is the diminishing numbers and function of a small collection of dopamine generating neurons in the brain. This is a process that happens to all of us with aging, but Parkinson's patients have, for a variety of reasons, suffered more of the cell and tissue damage that leads to cell death and dysfunction in this population of neurons.

Parkinson's Disease (PD) is the second most common age-related neurological disorder in the US. Many genetic factors that contribute to an increased risk of developing PD have been identified over the years. These include mutations in the α-synuclein and Parkin genes. Additionally, epidemiology studies show increased risk of PD after exposure to pesticides and organic pollutants, as well as heavy metals. However, recent research shows that aging is a major player in the development of PD.

The motor issues present in PD patients are primarily caused by loss of dopaminergic neurons in the substantia nigra (SN) of the brain, which is a key regulator of motor movement and reward-seeking behavior. As a result, the most widely available PD treatments focus on replacing the neurotransmitter dopamine, which is produced by dopamingergic neurons, in various ways. These treatments do not halt disease progression, since dopaminergic neurons continue to degenerate even with these treatments. Instead, they only treat the symptoms of PD and make everyday life more manageable for PD patients.

Our brains possess the capability to replace lost cells through a process called neurogenesis, or the formation of new neurons. However, it turns out that the ability of the brain to produce new neurons is reduced both with age and in people who have a mutant version of α-synuclein (a major genetic risk factor for PD). This reduced capacity for neurogenesis extends to stem cell transplants in PD patients. Many groups have reported that healthy transplanted stem cells in PD patient brains show pathological characteristics over time. Thus it seems that there is something about the environment in the brain that causes healthy cells to develop the neurodegenerative characteristics of PD.

Here at the Buck Institute, we have found that cellular senescence may play a large role in the pathological neurodegeneration of PD. Cellular senescence is an anti-cancer mechanism intended to irreversibly prevent cell division when a cell is exposed to stress. Senescent cells show distinct biological markers, such as secretion of inflammatory compounds in a phenomenon also referred to as Senescence Associated Secretory Phenotype (SASP). Data suggests that cellular senescence in astrocytes may alter the brain environment to promote disease progression and inhibit neurogenesis. Astrocytes show increased levels of SASP factors, and manipulations that reduce cellular senescence also reduce Parkinsonian phenotypes in mouse models. Since cellular senescence is associated with age, astrocyte senescence may explain the age-dependency of PD onset. We are currently searching for potential treatments that can inhibit cellular senescence in the brain, thereby halting the progress of PD.

While the field of cellular senescence is relatively young in the larger field of neurobiology, it is becoming more evident that cellular senescence is key to explaining age-related disorders. Cellular senescence in the brain may prove to be one of the underlying factors common to multiple age-related neurodegenerative diseases, which would make it an important therapeutic target to pursue.

Link: http://sage.buckinstitute.org/the-parkinsonian-brain-cellular-senescence-and-neurodegeneration/

In past years the Glenn Foundation for Medical Research has reinforced the mainstream of the aging research community with grants of a few million dollars apiece to establish or expand laboratories in many major universities and research centers. Much of this supports work focused on cataloging and then attempting to safely alter the complex details of metabolic operation, such as through potential calorie restriction mimetic drugs, so as to slightly slow the aging process. Here is news of the latest round of grants:

Building on its previous gifts to MIT, the Glenn Foundation for Medical Research has pledged $2 million to establish a new center for the study of aging. The new Paul F. Glenn Center for Science of Aging Research at MIT will be directed by Novartis Professor of Biology Leonard Guarente. "With this generous gift, the Glenn Foundation will enable us to carry out a multitiered approach and leverage the strengths of all three labs to arrive at new and testable conclusions about what pathways and mechanisms govern aging. Behind all of our research is the drive to discover new therapeutic compounds that have the potential to improve the course of the aging process, and hopefully lead the way toward effective treatments for neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease, as well as cancer."

The new center will build upon research that was formerly conducted within the Paul F. Glenn Laboratory for Science of Aging Research, which was established at MIT in 2008 with a $5 million gift from the foundation and expanded with an additional $1 million gift in 2013. These efforts were led by Guarente, a pioneer in the field of aging research who is known for his work to uncover the SIR2 gene, a key regulator of longevity in yeast and worms. Since then, Guarente and his colleagues have continued to explore aging, and key pathways and genes that govern aging in the human brain. A particular focus has been the role of sirtuin activation and nicotinamide adenine dinucleotide supplementation in slowing the aging process and diseases of aging. Their recent work involves the use of bioinformatics to advance their analysis.

Link: http://newsoffice.mit.edu/2015/glenn-foundation-gift-aging-research-initiatives-0625