reasonattlm

Everyone devotes resources to saving themselves from death each and every day. Every time they go to the grocery store, in fact. If you are willing to undertake that action, you should be equally willing to to visit a physician to push back your day of death by a day, each and every day.

There is something about considering alterations in the current trajectory of aging that makes people say strange things. People who exercise to improve their health span, people who visit doctors to prolong their health span, people who put off death in hundreds of small ways, constantly, all the time. But suggest that perhaps aging should be modified, and people who are 100% supportive of ending heart disease and Alzheimer's suddenly develop a deep philosophical attachment to inevitable death on exactly the current schedule for inevitable death. Seems a little suspect.

What really aggravates me about this article is the exceedingly disingenuous dismissal of SENS rejuvenation research programs it puts forward.

The author settles on allotopic expression of mitochondrial genes in the cell nucleus as an example of a project so difficult it is impossible. But allotopic expression is a very poor example to pick for something that is alleged to be "a doomed labor." The work has been accomplished for three of the thirteen genes needed; this is a capability that exists, and is underway towards completion. The allotopic expression of mitochondrial gene ND4 is the basis for a therapy that is currently going through clinical trials in Europe! It exists, it works! Yes, it took effort to get there, effort funded at the early stages by the SENS Research Foundation and those who donated to it, I should note, but so does everything else.

This is one of the things that frustrates me immensely about many of the critics of SENS - they willfully ignore some of the progress that has been made, pretending it doesn't exist.

Yet their behavior for progress that is so compelling they can't ignore it is in many ways worse. Let us look at what is said - and, more importantly, not said - about senescent cell clearance, something that de Grey and other SENS advocates have been promoting as a path to treat aging for the past fifteen years, on the basis of strong evidence, that they assembled from the various groups who created it across the research community, laid out, and made the argument for. It is right there in the SENS outline; hard to miss, and has been from pretty much day one back at the turn of the century. Senescent cell clearance is a core part of the SENS agenda.

Fortunately for all of us, targeted removal of senescent cells has finally taken off these past few years, the evidence for a significant impact on aging has grown to be nigh irrefutable, and near everyone in the research community is enthused. Yet SENS and many researchers' past vocal rejections of senescent cell clearance as a part of SENS is swept under the rug, never to be mentioned. It is unconscionable behavior, and it happens in this article: despite covering UNITY Biotechnology, the senolytics company, no mention of senescent cells is made in connection with the SENS vision. It takes some brass to claim SENS to be a doomed effort and then roll right on in the next paragraph to a discussion with one of the UNITY co-founders on the topic of removing senescent cells to treat aging.

Bear in mind that the evolution of aging is anything but a settled field. It is a battleground of many competing views and theories. The evolution of aging is one of those topics for which the wikipedia page is actually a good place to start, because right from the top it correctly delivers the understanding that this field is (a) complicated, (b) not at all unified, and (c) in flux.

https://en.wikipedia.org/wiki/Evolution_of_ageing

The fellow here is outlining one particular set of views out of something like half a dozen with varying degrees of mainstream support, and that any random selection of evolutionary biologists would take issue with, point by point. He also simplifies down to a level at which some important points are missed, such as the existence of mitochondrially targeted antioxidants and what their ability to slow aging means for various theories of aging and mitochondrial function.

In fact all of the appearances of mitochondria in this article are in that bucket of missing important but subtle points. If you want to chase down more on the viewpoint he discusses in the last section of the article, you should read up on the membrane pacemaker hypothesis:

https://www.google.com/#q=Membrane+Pacemaker+Hypothesis

This is really driven by trying to understand why the outliers on the chart of resting metabolic rate versus species life span are outliers: naked mole rats, birds, microbats, etc.

When it comes to what to do about damaged, bad mitochondria in aging, there are better options than replacement. In fact delivery of good mitochondria as a therapy is probably not useful at all; the bad mitochondria already outcompeted the good mitochondria once, and will quickly do so again. It is so rapid that scientists have never observed this in progress, they only see cells with all bad mitochondria and cells without any bad mitochondria, never the transitional state.

(There are two separate things going on in aging vis a vis mitochondria. Firstly the type of damage to mitochondria that results in bad mitochondria, under discussion here. Secondly changes in cell signaling and environment that leads to a sort of general malaise in mitochondrial function and replication thoughout a tissue without this damage or formation of bad mitochondria, and that is not really under discussion here or in the article. It is probably a secondary consequence of other forms of damage and change in aging).

The SENS approach of allotopic expression, moving mitochondrial genes into the cell nucleus, currently demonstrated for three of the necessary thirteen genes, is the best and most permanent of solutions to prevent mitochondrial damage, being a one-time therapy. If something else is used, such as periodic delivery of replacement mitochondria, it would have to coupled with some kind of targeted destruction of bad mitochondria. That is a thorny problem, as anything less than complete destruction is just a short postponement. These things replicate quickly, and bad mitochondria of the aging-causing sort have a replication advantage over normal, good mitochondria. I'm not aware of anyone with a credible approach to that selective destruction yet, however.

There is a long and proud history of writers promptly losing all common sense whenever asked to take on the topic of changing the current situation for aging, age-related disease, and death.

If you take a utilitarian view, every problem other than aging is secondary to some degree, usually a very large degree, just by looking at the number of people negatively affected, and the level of suffering involved.

Not that people who don't write for a living appear much better than the writers on this topic. If you ask most people, they proudly declaim their willingness to age to death on the same schedule as their parents. Not that they'd follow through on that declaration were the technologies of rejuvenation available when needed, since they go to the doctor when sick, or when suffering age-related disease, and do all they can with what is available.

People in general are, for the most part, profoundly irrational and/or hypocritical when it comes to aging and the near future of real, working rejuvenation treatments. They won't help to make these technologies a reality, they decry the idea, and they will run in their multitudes to use the therapies when they arrive.

We'll find out in the next 12-24 months. UNITY is starting trials this year, and Oisin won't be too far behind.

If they don't work in humans it will be a great surprise given the science to date - an unlikely outcome. The open question is the degree to which specific diseases are rolled back and life extended, given that this is only one of a number of mechanisms causing aging.

Yes, the cells can be replaced. In old people, with their declining stem cell populations, that replacement will be slower and less effective. So give them lower doses over longer periods of time.

Stem cell replacement is something that should be developed for use in old people anyway; the more of that going on the better.

Or you could try navitoclax, dasatinib, fisetin, piperlongumine, or any of the others tested so far in animal models and human cancer trials with well-understood pharmacology and that are easily purchased.

The trick here is that the current state of assays for senescent cell presence in samples is pretty terrible if you're outside a lab, and there is little point in doing this without measuring the outcome.

Many of the current methods of killing senescent cells hinge on apoptosis in some way.

UNITY Biotechnology: using repurposed chemotherapeutic drugs like navitoclax to selectively drive senescent cells into apoptosis by suppressing on the mechanisms that prevents that fate. They also have antibodies and immunotherapies in their backlog of patents, but if they haven't got it to work by now, not likely to be a direction they take in favor of the drugs.

Oisin Biotechnologies: programmed gene therapy that assesses p16 levels in the cell and then induces caspase expression and apoptosis if it looks senescent.

SIWA Therapeutics: monoclonal antibodies.

Everon Biosciences: small molecule drugs and related immunotherapies.

There is a lot of money sloshing into the field of senescent cell clearance at the moment, and given that the target market is ultimately every adult human for a treatment undertaken every few years, I think there is plenty of room for more players.

That we are actually quite close to the development of a panoply of working rejuvenation therapies capable of significantly extending human life spans, were the right lines of research and development just more aggressively funded than is the case at present.

My thoughts on Kurzweil's predictions from 12 years ago:

My own two cents thrown into the ring say that the class of future portrayed in the Singularity is Near (TSiN) is something of a foregone conclusion. It's quite likely that we'll all be wildly, humorously wrong about the details of implementation, culture and usage, but - barring existential catastrophe or disaster - the technological capabilities discussed in TSiN will come to pass. The human brain will be reverse engineered, simulated and improved upon. The same goes for the human body; radical life extension is one desirable outcome of this engineering process. We will merge with our machines as nanotechnology and molecular manufacturing become mature technologies. Recursively self-improving general artificial intelligence will develop, and then life will really get interesting very quickly. And so forth ... the question is not whether these things will happen, but rather when they will happen - and more importantly, are we going to be alive and in good health to see this wondrous future?

We humans are in the process of building tools that enable us to create or meaningfully interact with ever-greater complexity. There is one important area of complexity management in which we seem to be making little headway, however: the organization of humans in business and research. For all that we can now accomplish with faster computers and enormous leaps in telecommunications, we don't seem to have made significant inroads in getting large numbers of humans to cooperate efficiently. I am prepared to go out on a limb here, as I have done before, and say that business and research cycles that involve standard-issue humans are incompressible beneath a certain duration - they cannot be made to happen much faster than is possible today.

This is not to say that they cannot be made cheaper. But cheaper doesn't equate to faster business and research cycles; rather, it means that any given problem will be tackled by many more parallel attempts. Expensive projects mean conservative funding organizations, which means organizational matters proceed at a slow pace. This is a defining characteristic of our time: we have blindingly fast rates of research and technological advances once the money is on the table, but the cycles of business, fundraising and research are still chained to the old human timetable.

Kurzweil's Singularity is a Vingean slow burn across a decade, driven by recursively self-improving AI, enhanced human intelligence and the merger of the two. Interestingly, Kurzweil employs much the same arguments against a hard takeoff scenario - in which these processes of self-improvement in AI occur in a matter of hours or days - as I am employing against his proposed timescale: complexity must be managed and there are limits as to how fast this can happen. But artificial intelligence, or improved human intelligence, most likely through machine enhancement, is at the heart of the process. Intelligence can be thought of as the capacity for dealing with complexity; if we improve this capacity, then all the old limits we worked within can be pushed outwards. We don't need to search for keys to complexity if we can manage the complexity directly. Once the process of intelligence enhancement begins in earnest, then we can start to talk about compressing business cycles that existed due to the limits of present day human workers, individually and collectively.

Until we start pushing these limits, we're still stuck with the slow human organizational friction, limits on complexity management, and a limit on exponential growth. Couple this with slow progress towards both organizational efficiency and the development of general artificial intelligence, and this is why I believe that Kurzweil is optimistic by at least a decade or two.

Near complete ablation of all immune cells in circulation is proving to be pretty effective as a way to put autoimmunity into long-lasting remission. It can be done with high dose immunosuppressants at the cost of much the same symptoms as cancer chemotherapy - these are harsh drugs - plus a few day period of vulnerability to infection while the immune system rebuilds. But the cures are demonstrated, for type 1 diabetes and multiple sclerosis over the past five to ten years.

All automimmunities should be amenable to cure this way, as the malfunctioning is based on bad data that is stored in the immune cells, nowhere else. Newly created immune cells do not have this malware; they acquire it from the existing population. (It would be interesting and novel to find an autoimmunity where this is not the case).

Unfortunately, the cost-benefit equation for this current form of ablation doesn't work for things that don't kill patients. No-one undergoes chemotherapy for a condition that merely shortens your life expectancy by a decade and makes you miserable, as chemotherapy has a significant risk of death and shortens your life expectancy by a decade.

So what is needed are better forms of ablation, those with no side-effects. The programmable gene therapy cell killer produced by Oisin Biotechnologies is one possible class of approach, as are other targeted cell killing approaches such as that demonstrated last year to selectively kill blood stem cells.

Then an application of cell therapies is needed, creating immune cells from a patient tissue sample, and infusing them in bulk immediately following ablation, to remove the period of vulnerability.

These are very feasible targets. A company could be founded today, right now, to do this, and have something ready for human trials by 2019. Sadly, here as elsewhere in medicine, there seems to be no hurry to change the world.

Slows glaucoma: https://dx.doi.org/10.1038/srep33950

Effects in long-lived mice: https://doi.org/10.1016/j.exger.2013.06.009

Protective of the aging heart: https://doi.org/10.1016/j.freeradbiomed.2009.10.003

Benefits without calorie reduction: https://dx.doi.org/10.1073/pnas.1035720100

In nematodes, looking at signaling: http://dx.doi.org/10.1038/nature07583

And so on. There is a lot more out there on this topic:

https://www.ncbi.nlm.nih.gov/pubmed/?term=alternate+day+fast...

Researchers still have a very long way to go in order to understand the calorie restriction and intermittent fasting responses completely. In order to do that one pretty much as to have a complete map of cellular biochemistry. Don't hold your breath waiting for that to happen; decades is a very reasonable expectation, I think, based on watching progress in understanding sirtuins over more than a decade, which is just one very thin slice of a very large problem. Practical rejuvenation based on repair of damage after the SENS vision (such as via clearing senescent cells) will be a going concern well before researchers can fully explain calorie restriction in the context of age-related changes and cause and effect in the operation of mammalian biochemistry.

The fascinating thing about water intake is that there is no scientific consensus regarding the optimal point or how to determine it, or how it varies between individuals. It is one of those items that you think would have a good answer, given where we are in the development of the medical life sciences, but apparently not.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908954/

"Little work has been done to measure total fluid intake systematically and there is no understanding of measurement error and best methods of understanding fluid intake. The most definitive US and European documents on total water requirements as based on these extant intake data. We feel that absence of validation of methods for water consumption intake levels and patterns represents a major gap. Little exploration of even varying methods of probing to collect better water recall data have been conducted.

"Of course, the other half of the issue is the need for understanding total hydration status. We have no acceptable biomarkers of hydration status at the population level. Controversy exists about current knowledge of hydration status among older Americans. This represents a topic understudied at the population level though certainly scholars are focused on attempting to create biomarkers for measurement of hydration status."

The price is zero, because the necessary information to do exactly the same thing yourself with plain old food is available in the papers and in the vast number of calorie/micronutrient information sites out there online, and it is really, really easy to just go and do that.

The point of Prolon is that it is a way to obtain money from the regulatory/Big Pharma system in order to do more research into quantifying the benefits fasting and calorie restriction. Not that it is anything special in and of itself. It is just food, less of it.

If this area of research interests you, here are some other resources from recent years:

Will calorie restriction work in humans? http://dx.doi.org/10.18632/aging.100581

Diet that mimics fasting appears to slow aging http://news.usc.edu/82959/diet-that-mimics-fasting-appears-t...

Fasting mimicking diet reduces risk factors for aging and multiple age-related disease https://www.eurekalert.org/pub_releases/2017-02/cci-fm020717...

Diet that mimics fasting may also reduce multiple sclerosis symptoms http://news.usc.edu/101187/diet-that-mimics-fasting-may-also...

Fasting Therapy for Treating and Preventing Disease - Current State of Evidence http://dx.doi.org/10.1159/000357765

And so forth. There's a lot of information out there.

Journalists as a rule exhibit next to no ability to analyze or distinguish varieties of what is going on in the areas of (a) meaningful longevity science that can plausibly produce large gains in life span at some point, (b) dumb "anti-aging" industry nonsense, and (c) longevity science that is not in principle capable of useful gains in life span.

They are given the instruction from above to write something about efforts to live longer in order to fill today's news hole, grab the first five things they come across in a quick search of recent news, rank them all equally, and throw them into the blender. Out pops a popular science article. Little to no attempt is made to gain or convey insight or understanding.

A first guess would be that these diets are passing over aggregate compounds and compatible metabolic waste: misfolded proteins, lipfuscin, oxidized lipids, and so forth, and enough of those escape the stomach to be incorporated into tissues to do harm.

That said, 10% for mice is well within the "try it again in a different lab, get a different result" margin of error for this sort of study.

Some of the more interesting recent research, from the perspective of evidence for meaningful health benefits, and some degree of additional longevity in our long-lived species.

Caloric restriction improves health and survival of rhesus monkeys https://dx.doi.org/10.1038/ncomms14063

Will calorie restriction work in humans? http://dx.doi.org/10.18632/aging.100581

Rate of living theories are more or less thrown out as not useful at this point in time.

https://en.wikipedia.org/wiki/Rate-of-living_theory

These correlations probably have more to do with the membrane pacemaker view of resistance to oxidative damage, and how lipid composition of membranes varies with metabolic demands. Look at birds and bats, for example: tiny, with rapid heart rates, and very long lived in comparison to other species of similar size.

https://dx.doi.org/10.1016/j.chemphyslip.2015.08.008

Of note, Geroscience is a new popular science of aging online magazine supported by the Apollo Ventures investment fund, devoted to longevity science startups. You should absolutely take a look at their site to see the sort of sea change that has occurred for the perception of aging research in the funding community:

http://apollo.vc

They take a very Hallmarks of Aging view of the causes of aging, which I can quibble with around the edges, but it is good to seem more people putting their money into the game of building ways to treat the causes of aging.

The principals at Apollo became involved in this space and raised a fund both because they are enthused by the field of therapeutics to treat aging and want to see it succeed, but also because they recognize the tremendous potential for profit here. The size of the market for enhancement biotechnologies such as rejuvenation treatments is half the human race, every adult individual.

Publishing a magazine on aging research is a way to help broaden their reach within the community, find more prospective investments, talk up their positions, and raise the profile of the field as a whole, all of which aligns fairly well with the broader goals of advocacy for longevity science. Many hands make light work, and we could certainly use more help to speed up the growth of this field of research and development.

Revaccination, yes, definitely necessary in the idealized case of a complete wipe of immune cells. But that's a small problem in comparison to having a broken immune system. Just get all the vaccinations done following immune repopulation.

Part of the problem in old people is that they have too much memory in the immune system, especially of pervasive herpesviruses like cytomegalovirus. Those memory cells take up immunological space that should for preference be occupied by aggressive cells capable of action.

Another point: in old people, as a treatment for immunosenescence, immune destruction would probably need to be paired with some form of cell therapy to repopulate the immune system. In young people, not needed, but in the old there is a reduced rate of cell creation - loss of stem cell function, thymic involution, etc. That again, isn't a big challenge at this time, and is something that can already be done.

At present sweeping immune destruction is only used for people with fatal autoimmunities like multiple sclerosis because the clearance via chemotherapy isn't something you'd do if you had any better options - it's pretty unpleasant, and produces lasting harm to some degree. Those people who are now five or more years into sustained remission of the disease have functional immunity and are definitely much better off for the procedure, even with its present downsides, given where they were before. If the condition is rhematoid arthritis, however, it becomes much less of an obvious cost-benefit equation, which is why there needs to be a safe, side-effect free method of cell destruction.

From one of the companies working with an implementation:

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"Our approach is quite different from most other attempts to clear these cells. We have two components to our potential therapy. First, there is a gene sequence consisting of a promoter that is active in the cells we want to kill and a suicide gene that encodes a protein that triggers apoptosis. This gene sequence can be simple, like the one that kills p16-expressing cells, or more complicated, for example, incorporating logic to make it more cell type specific. The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses."

"There's a subtle but profound distinction between our approach and others. The targeting of the cells is done with the gene sequence, not the vector. The liposomal vector doesn't have any preference for the target cells. It delivers the gene sequence to both healthy and targeted cells. We don't target based on surface markers or other external phenotypic features. We like to say "we kill cells based on what they are thinking, not based on surface markers." So if the promoter used in our gene sequence (say, p16) is active in any given cell at the time of treatment, the next part of our gene sequence - the suicide gene - will be transcribed and drive the cell to apoptosis. However, if p16 isn't active in a given cell, then nothing happens, and shortly afterwards the gene sequence we delivered would simply be degraded by the body. This behavior allows our therapy to be highly specific and importantly, transient. Since we don't use a virus to deliver our gene sequence, and our liposomal vector isn't immunogenic, our hope is that we should be able to use it multiple times in the same patient."

Safe selective destruction of cells via their internal chemistry, not surface markers, via uptake of lipid-encapsulated programmable suicide gene arrangements.

With the right program and a distinctive chemistry to target in the unwanted cell population, this flexible technology has next to no side-effects, and enables rapid development of therapies such as:

1) senescent cell clearance with resorting to chemotherapeutics, something shown to extend life in mice, reduce age-related inflammation, reverse measures of aging in various tissues, and slow the progression of vascular disease.

2) killing cancer cells without chemotherapeutics or immunotherapies.

3) destroying all mature immune cells without chemotherapeutics, an approach that should cure all common forms of autoimmunity (or it would be surprising to find one where it doesn't), and also could be used to reverse a sizable fraction of age-related immune decline, that part of it caused by malfunctioning and incorrectly specialized immune cells.

And so forth. It turns out that low-impact selective cell destruction has a great many profoundly important uses in medicine.

There are several competing lines of technology:

1) humanized organs in animals such as pigs.

2) decellularization of animal organs, such as from pigs, followed by replacement with the patient's cells.

3) outright creation of organs from scratch, from a patient's cells (e.g. https://www.neworgan.org )

4) repair of existing organs in situ.

It will be interesting to see how it shakes out; #1 and #2 are only in the running instead of #3 because no-one yet has a good solution for creating the blood vessel networks needed for full size tissue engineering. At the moment only organoids or other thin tissues (e.g. trachea, esophageal lining) can be constructed reliably. #3 is only a goal to the extent that #4 isn't figured out: how to spur regeneration and change cell behavior for the tissues that exist.

Telomere length as presently measured in white blood cells is a measure of immune health before all other factors: how often are new cells turning up with long telomeres (thus how well is the thymus and bone marrow stem cell population doing), how often are existing cells dividing and shortening their telomeres while doing it (how much stress is the immune system under, how much war is it waging), how many senescent cells are hanging around lowering the average, that sort of thing.

Exercise is very well associated with better immune function. So not a surprising result beyond the fact that they actually managed to get a result at all, as telomere length measured this way is actually a pretty terrible metric of aging. The correlations with aging only show up in large populations, and even there you'll find as many failures to identify associations as successes in the literature. For an individual knowing your immune cell telomere length won't tell you a great deal that you don't already know, and nor will changes over time. The numbers will be all over the map, and won't compare usefully at all with other individuals in your circumstances, unless you have a few thousand of them to compare with.

If you want a decent biomarker that might actually prove to be actionable, DNA methylation patterns after the model pioneered by Horvath et al look fairly promising. (There's even a Florida company offering an implementation as a service these days).

The sitting question is generating a lot of ink in the research community. All sorts of large epidemiological studies have tackled the topic. I think it remains unsettled as to whether it is the sitting or whether it is the inactivity: decent arguments from data could be made either way. If pulling in data from the broader context, however, the inactivity looks more compelling. Accelerometer studies are becoming more common since the miniaturization and cost reduction that came with cell phones, and these are showing that even very low levels of exercise appear to make noticeable differences to outcomes in later life - at the level of housework and puttering around the garden.

As I've been saying for the past couple of years, gene therapies are straightforward enough and cheap enough to carry out that people are doing it, usually quietly, but it is happening. You only have to be connected enough to know a biotechnologist or two with the right skills, as the example here shows. The stage of the adventurous and the self-experimenters is an important part of the development of any new medical technology, helping to overcome institutional reluctance while gathering initial data on how best to approach such treatments in practice. The next part of the process, something that does requires much greater funding and participation from the research and development community, will happen over the next few years; it involves making the therapies more robust, the outcomes more reliable, and assembling the suite of tools and clinics needed for those tasks. That is certainly the goal of BioViva, and as they move forward, others will join them.

There is more than enough evidence for the potential utility of enhancement gene therapies based on producing greater muscle growth and improved metabolism via increased follistatin or myostatin knockout, ranging from numerous animal studies to existing natural human and animal mutants to myostatin antibody trials. There is also considerable interest in telomerase gene therapies, though I'd like to wait for more data on that front before diving in myself, given the potential cancer risk. Once these initial approaches are out there, available, and the methodologies of gene therapy have progressed to the point at which there is reliably comprehensive cell coverage - especially in stem cells, as that will determine how lasting the effect is - then a score of other genes bear further investigation and consideration as targets for enhancement therapies.

While I applaud those who set out to undergo gene therapy today, as their work is necessary to move matters along in this age of overabundant caution and oppressive regulation of every activity, I can't say as I think the fellow here made a good choice of gene. This has the look of a more sophisticated form of the hormone therapies practiced over the past few decades, approaches that really don't have a good impact on aging, and outside of correcting deficiencies are not something that should benefit or is expected to benefit someone in normal health for their age. Increased growth hormone, if anything, is exactly the opposite of what animal and human studies suggest is good for longevity.

Original publicity materials: http://www.salk.edu/news-release/turning-back-time-salk-scie...

As I've said in the past, it has always been pretty random as to what the popular press picks up versus what they ignore in the output of the aging research community. Possibly it doesn't much matter, as they'll horribly mangle the significance and meaning regardless.

In this case, this is an intervention which falls into the same general area as telomerase gene therapy and stem cell therapies that work via temporarily altering the signaling environment rather than integration of transplanted cells. It is putting damaged cells back to work, getting them to do more than they would otherwise have done.

The question mark on all of these things has been the degree to which they'll produce cancer - and certainly, inducing pluripotency in random cells throughout the body sounds very much like a terrible idea on that front. The decline in tissue maintenance in response to rising levels of cellular damage (e.g. over the course of aging) is thought to be an evolved balance between death by cancer and death by frailty. So far it seems that there may be more leeway than was feared when it comes to putting a thumb on the scales to shift things back to increased cellular activity.

But this isn't rejuvenation. This isn't reversing aging. This is (very) partial compensation for downstream effects of aging, achieved without addressing any of the root causes. The outcomes are going to be limited because root causes are allowed to continue as they are. The outcomes only look good by comparison to present day medicine for age-related conditions because that is even more limited, since it acts on consequences even further along the chain.

This popular science piece is characteristic of a prevalent and hostile view of the growing practice of patient-funded clinical trials. In this model the patient pays a sizable portion of the costs, which certainly makes it a lot easier to gather larger amounts of data, as the trial organizers don't have to seek the funding themselves. On the other hand, it tends to rule out the ability to carry out a blind trial in which not everyone actually gets the treatment, as well as other similar refinements. That is a problem if the goal is to search for and quantify marginal effects, but if the point is to discover or rule out large effects, I'd argue that control groups are not necessary. The control in that case is the established progression for patients who do not get the treatment, or who undergo existing, marginal treatments. We are at the stage in the development of medicine to treat aging in which marginal effects, such as those resulting from the use of metformin as a calorie restriction mimetic, should be discarded as uninteresting. Once at the stage of trying things in human studies, the research community should be filtering for significant effects, such as those obtained by clearance of senescent cells. Given the poor state of funding for aging research in general, methods that can pull in more resources to obtain more data should be applauded.

In the case of the approach being trialed here by Ambrosia, I think our expectations should be low, and the outcome I expect is for there to be no significant benefit. The only ethical question worthy of consideration is whether those involved then do the right thing: publish the data, shut up shop, and move on to the next project - having done the good work of finding out that there is no large effect here. Transfusions of young blood to old individuals are not producing benefits in mice, and there is reason to think that the beneficial outcomes observed in old mice due to parabiosis, the linking of circulatory systems between an old and a young individual, are due to factors or circumstances not replicated by periodic transfusion. It isn't difficult to imagine that beneficial outcomes require the youthful system reacting in a dynamic way to the presence of aged signals, for example, or - as suggested by some researchers recently - that it is nothing more than a consistently maintained dilution of problem signals in the aged environment.

Not as much of a difference as you might think:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192186/

"A common objection against starting a large-scale biomedical war on aging is the fear of catastrophic population consequences (overpopulation). This fear is only exacerbated by the fact that no detailed demographic projections for radical life extension scenario have been conducted so far. This study explores different demographic scenarios and population projections, in order to clarify what could be the demographic consequences of a successful biomedical war on aging. A general conclusion of this study is that population changes are surprisingly slow in their response to a dramatic life extension. For example, we applied the cohort-component method of population projections to 2005 Swedish population for several scenarios of life extension and a fertility schedule observed in 2005. Even for very long 100-year projection horizon, with the most radical life extension scenario (assuming no aging at all after age 60), the total population increases by 22% only (from 9.1 to 11.0 million). Moreover, if some members of society reject to use new anti-aging technologies for some religious or any other reasons (inconvenience, non-compliance, fear of side effects, costs, etc.), then the total population size may even decrease over time. Thus, even in the case of the most radical life extension scenario, population growth could be relatively slow and may not necessarily lead to overpopulation. Therefore, the real concerns should be placed not on the threat of catastrophic population consequences (overpopulation), but rather on such potential obstacles to a success of biomedical war on aging, as scientific, organizational, and financial limitations."

Original publicity materials: https://www.pennmedicine.org/news/news-releases/2017/january...

Paper: https://dx.doi.org/10.1126/science.aai8792

This is somewhat different from earlier lines of research into scarless healing in mammals, such as the work based on the biochemistry of MRL mice ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806350/ ).