Aubrey de Grey AMA Held at /r/futurology Today
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Aubrey de Grey of the SENS Research Foundation is an advocate and scientist focused on advancing the state of rejuvenation research, progress towards therapies capable of repairing the cell and tissue damage that causes degenerative aging. He put forward the Strategies for Engineered Negligible Senescence (SENS) research proposals some fifteen years ago, and since then has raised funding, organized research programs, cofounded the Methuselah Foundation and SENS Research Foundation, and traveled the world to speak at scientific conferences and meetings of supporters.

Back when this all began, members of the scientific community were very reluctant to speak openly about treating aging as a medical condition, the press treated the prospect of therapies for aging as a joke, and the public at large gave no attention to the topic. Yet the potential was there, with many disparate branches of research into age-related diseases demonstrating even then that scientists understood more than enough to get started on meaningful therapies to repair the damage of aging. The problem has always been cultural: that no-one cares, that funding is non-existent, that few are willing to step up and speak out on the issue, that the status quo of suffering and disease is accepted. With the help of people like de Grey and his allies the last decade has seen a real sea change in the research community and the media, however, as well as in the actuarial and the futurist communities, and the years ahead will see that change in attitudes spread to the population at large. If we keep working at this by the mid 2020s I expect the average individual in the street to think of aging in the same way as he or she thinks of cancer today: a fearsome medical condition that causes great suffering, researchers need to work harder at fixing it, and charities raising funds for research are a worthy cause.

Over at the Reddit /r/futurology community today de Grey was answering questions in an AMA (Ask Me Anything) event. It is worth remembering that every Reddit community of any size is a collection of widely divergent interests. Thus /r/futurology is a mix of folk who follow progress in computing technology, basic income advocates, popular science buffs, futurists of all stripes, both for and against longevity enhancement, and various other less categorizable groups. So the forum can host a respectful AMA for de Grey packed by people who look forward to progress in rejuvenation research just a day after an long discussion on a recent aging research paper in which most of those involved were opposed to human life extension. It is a big world, communication is making it smaller, and we're all rubbing shoulders these days.

Ask Aubrey de Grey anything!

Buck-Nasty: I'm curious about how the advent of CRISPR affects the development of SENS therapies?

Aubrey de Grey: It's huge. It will be central to the delivery of the many SENS components that involve somatic gene therapy.

Buck-Nasty: Does it speed up the development timeline at all?

Aubrey de Grey: A lot, yes.

Jay27: Kind of a shame, because it looks to me like deep learning algorithms will be plowing their way through a million genomes in 2020. You'd think they'd yield some valuable genemod insights which can then be applied with CRISPR.

Aubrey de Grey: We don't need insights right now - we need implementation of what we already know or are developing. That's why CRISPR is so important.

Senf71: s it fair for me to be telling my friends and others I tell about this stuff, that considering the $25 a month I donate to SENS and the many dozens of people I have educated about SENS and curing aging in general, many quiet successfully educated, that I may have personally saved the lives of 100,000 people at this point? Along that line is this something it would be good for you and your people to really emphasize during talks? To tell people that they can feel good about them selves for going out and advocating and donating even a meager amount of money because doing so means they are very truthfully saving the lives or 10s or 100s of thousands of people?

Aubrey de Grey: This is by far the best question yet on this AMA. Thank you! First: I think you can say something like that (depending on how long it's been that you've been sending us $25). I believe that $1 billion right now would hasten the achievement of LEV by about 10 years; you can do the rest of the maths, but it comes out to about $2 per life - and of course "saving" means a great deal more in terms of extra years than it does for other ways of saving lives, so arguably it's more like a few cents per life. And yes, I think I should emphasise this more. I probably will.

Spats_Mgee: Several aspects of your SENS proposal are essentially destructive in nature (removing intra/extracellular junk, killing errant cells, etc). Your proposal to deal with these problems involves utilizing enzymes found in other species to break down these molecular structures. I'm curious if you've weighed the pros and cons of this (let's say "organic") approach to the "inorganic" approach of using gold nanoparticles for targeted photothermal ablation of these cellular/molecular structures.

Aubrey de Grey: We've looked at this approach and we haven't rejected it out of hand. A big issue is penetration: how does one irradiate deep within the body?

Lavio00: I watched a video from you back in 2013 where you commented the announcement from Larry Page about Calico. You mentioned that Calico - if they're focused on early stage research - might highly benefit the battle against aging. What is your comment regarding Calico's research now that a couple of years have passed? More/less excited about their potential?

Aubrey de Grey: Cautious. They are structured perfectly: they are doing a bunch of highly lucrative irrelevant short-term stuff that lets them get on with unlucrative critical long-term stuff without distraction. But the latter may be getting too curiosity-driven and insufficiently translational. We'll see. Here "highly lucrative irrelevant stuff" = drugs for specific diseases of aging, "unlucrative critical stuff" = work leading to actual LEV.

SirT6: One thing that has always struck me about your vision for extending human lifespan is that you don't seem particularly interested in attempting to leverage the molecular genetics of aging. Numerous animal studies have implicated a number of genes which may serve as pharmacological targets for ameliorating aging and age-related pathologies. Studies of human centenarians have also validated the idea that modulation of these genes or their protein products may be a viable option for extending lifespan. And from an evolutionary perspective, this seems to make sense - many genes exhibit antagonistic pleiotropy (good when young, bad when old), so inhibiting these genes/proteins as people age is likely to reduce the burden of age-related disease. I suppose you could argue that this won't drastically increase human lifespan, but it seems to be a far more tractable approach in the near term (clear molecular targets, easier biomarkers, simplified drug development etc.). I would be curious to hear your thoughts on the issue. Thanks!

Aubrey de Grey: You put your finger on it - tractability versus magnitude of effect. As I think you know, I subscribe to the school of thought that CR-mimicking genetic or pharmacological manipulations cannot to much in long-lived species. I don't want to suppress such research, but I do think that the field has been immensely harmed over the past 20 years by overoptimism concerning the CR-mimicking approach and consequent lack of interest in alternatives. Antagonistic pleiotropy has very little to do with this.

akerenyi: I believe that the distinction you make between SENS-type of research focusing on damage from ageing and research on age-related diseases (ARDs) is purely arbitrary and misleading. For example you correctly claim that ageing and ARDs are pretty much the same thing, but than go on the criticize research on ARDs for not focusing on the right thing, while even further you plan to use therapeutics coming from this research, like Alzheimer's vaccines for rejuvenation (correctly so). I think the reality is that research on ARDs does involve more basic, mechanistic work as well as more later-stage, symptomatic approaches, compared to your engineering approach. However, I think the former gave and will give the targets for SENS, like beta-amyloid or tau, while the latter gave us drugs like levadopa, which while being crude and non-definitive, did improve the quality of life of millions of patients, while stem-cell therapy or gene therapy is being developed. Please clarify whether you still think such a distinction is desirable or meaningful.

Aubrey de Grey: The issue is relative funding. Illustration: it is absolutely accepted that atherosclerosis, the #1 killer in the western world, starts with the inactivation of macrophage lysosomes by oxidised cholesterol. Yet, about two labs in the world are focused on that step. I'm very satisfied indeed with the amyloid-beta vaccine results - they eliminate plaques. Same with gene therapy.

jimofoz: Can you give us any updates on the research towards allotopically expressing all 13 protein coding mitochondrial DNA genes?

Aubrey de Grey: It's going really well. We've made big breakthroughs this year and we'll be publishing something soon.

jimofoz: How pleased are you that Gensight is now taking the allotopic mtDNA expression technology whose development SENS partially funded into stage III clinical trials?

Aubrey de Grey: Overjoyed. We funded the Corral-Debrinski lab early on. Our work is leaning heavily on their early discoveries.

Rdapt85: I haven't heard any development in GlycoSENS since the discovery of synthesizing glucosepane in the lab 2 years ago. How is it going?

Aubrey de Grey: It's tough as hell but yes, we are plugging away. Watch this space.

Cell Spreading and Mitochondrial DNA Deletions
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Researchers here argue for decreased cell spreading in old skin to be a cause of higher levels of mitochondrial DNA deletions in longer-lived skin cells. Their methodology leaves open the possibility of other possible causes for the data they have gathered, however. I don't believe that they have convincingly demonstrated causality at this point. Nonetheless worth reading, I think.

Why is this interesting? Because mitochondrial DNA damage is strongly implicated as a contributing cause of degenerative aging, but there is considerable debate over how and why this damage occurs and accumulates with age. The SENS rejuvenation research viewpoint is to skip the debate over causes and just repair the damage and measure the benefits that result, but this is not a popular viewpoint in the scientific community, where most participants are aiming for complete understanding at some indefinite future date rather than the production of useful therapies as soon as possible. So we are going to see much more research in the future exploring this aspect of biochemistry.

Mitochondria are the power plants of the cell, each cell containing a swarm of hundreds of these descendants of symbiotic bacteria, each of which contains at least one copy of the remnant DNA left over from that of their ancestors. Evolution has moved much of this DNA to the cell nucleus, or it has atrophied, leaving just a small number of genes that are passed from mother to child. Mitochondrial populations are very dynamic, constantly dividing and fusing, passing chunks of protein machinery between one another, and culled by cell quality control mechanisms when damaged. Damage occurs to cellular machinery all the time, and near all of it is repaired. Mitochondrial DNA (mtDNA) deletions can be a real problem, however: DNA encodes for the proteins needed for correct function, and there is a way in which a mitochondrion with just the right type of damage can fall into a malfunctioning state that provides it an advantage in replication and resistance to quality control. When that happens the whole cell is quickly taken over by the descendants of that dysfunctional mitochondrion. The cell itself becomes broken, exporting harmful reactive molecules into surrounding tissues. A small but influential population of cells are in this state by the time old age rolls around, and they cause significant harm.

Why does this DNA damage happen? Some researchers believe it is due to the proximity of mitochondrial DNA to the energetic processes by which mitochondria produce chemical energy stores, coupled with comparatively poor DNA repair processes available in the mitochondria. Other researchers consider that the damage happens during mitochondrial replication, and other changes taking place in cells over the course of aging might explain a rising level of errors that occur during this replication. There are other theories - in biochemistry there are always other theories - and the one described in the following open access paper is one such.

Age-associated reduction of cell spreading induces mitochondrial DNA common deletion by oxidative stress in human skin dermal fibroblasts: implication for human skin connective tissue aging

In human skin, dermal fibroblasts are responsible for collagen homeostasis. Consequently, impaired dermal fibroblast function is a major contributing factor in human skin connective tissue aging. We previously reported that a prominent characteristic of dermal fibroblasts in aged skin is reduced spreading and contact with collagen fibrils, causing cells to lose their typical elongated spindle-like morphology and become shorter with a rounded and collapsed morphology. In young healthy skin, dermal fibroblasts attach to intact collagen fibrils and achieve normal cell spreading and shape. However, in aged dermis the collagen fibrils are fragmented, which impairs fibroblast-collagen interactions. These alterations impair fibroblast spreading and function. While cell shape is known to regulate many cellular functions, the molecular basis of their impact on dermal fibroblast function and skin connective tissue aging are not well understood.

Although dermal fibroblasts are the major cell type responsible for the maintenance of dermal connective tissue homeostasis, little is known about the role of mtDNA common deletion in aging dermal fibroblasts. Dermal fibroblasts have a very low proliferative rate which would allow for an accumulation of mtDNA deletion. Additionally, the relationship between age-related reduced cell spreading, which is a prominent feature of aged dermal fibroblasts, and mtDNA common deletion has been virtually unexplored. Based on this information, we explored the possible connection between age-related reduced cell spreading and mtDNA common deletion in the dermis of human skin. We found that mtDNA common deletion is significantly increased in both naturally aged and photoaged human skin dermis in vivo, and that reduced fibroblast spreading induces the increase in mtDNA common deletion through increased endogenous reactive oxygen species (ROS).

We modulated the shape of dermal fibroblasts by disrupting the actin cytoskeleton with latrunculin-A (Lat-A), which rapidly blocks actin polymerization. As expected, disruption of the actin cytoskeleton impaired fibroblast spreading and resulted in a rounded shape. Reduced cell spreading was associated with a significant elevation of mtDNA common deletion. As mitochondrial morphology is crucial for normal mitochondrial function, we assessed mitochondrial morphology. These data indicated that the gross shape of mitochondria was similar between Lat-A treated cells and control cells. It has been reported that cellular damage from reactive oxygen species (ROS) likely plays an important role in mtDNA deletions as well as in the aging process. We therefore examined the relative oxidant levels in fibroblasts using redox-sensitive fluorescent dye. Normal well-spreading fibroblasts displayed a very low level of oxidant-generated fluorescence. In contrast, reduced-spreading fibroblasts displayed intense oxidant-generated fluorescence.

We next investigated whether boosting cellular antioxidant capacity could protect against mtDNA common deletion associated with reduced cell spreading. We chose N-acetyl-cysteine (NAC), which is an antioxidant and metabolic precursor of glutathione. Reduced cell spreading increased mtDNA common deletion in a time-dependent manner, and that the increase was significantly prevented by NAC treatment. These results indicate that the deleterious effects of endogenous oxidative exposure are responsible, at least in part, for reduced-cell-spreading-associated mtDNA common deletion.

I have to think that the conclusion to be drawn here is that messing with the cell cytoskeleton is a bad thing, not that lack of cell spreading is a bad thing (though it probably is, just not demonstrated to be via this methodology). An item that immediately springs to mind is that progeria involves disruption of cytoskeletal structure in cells, and I'm sure people with more experience than I could come up with other off the cuff examples of cytoskeleton dysfunction producing cellular dysfunction. So here I'd want to see a replication of the mitochondrial DNA deletion data using another completely distinct methodology of preventing cell spreading before giving this too much consideration. It is easy to break things in biochemistry and produce results that look somewhat like aging, since breakage causes damage, and aging is an accumulation of damage. It is, however, hard to prove that any given artificial breakage is relevant to normal aging, and most are not.

To finish up for today I'll again make the point that the research community could skip this painstaking investigative work in order to focus on producing methods of repairing mitochondrial DNA damage, or delivering the proteins via another method, such as the allotopic expression technology funded by the SENS Research Foundation and presently under active development by Gensight. Fix the damage and see what happens, and if the repair is good enough and frequent enough then it doesn't matter how the problem occurs. Then, with the luxury of time, back to the labs to figure out every last detail of what happens if you don't take the treatments. The present status quo seems back to front, given that we're all aging to death.

DRACO Illustrates the Poor Funding Situation for Radical Departures from the Existing Status Quo
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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 Struggle to Find Truth from a Position of Ignorance
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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.

An Update on Spurring Heart Regeneration via PIM-1
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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.