reasonattlm

Animal studies show that isocaloric intermittent fasting, altering eating schedules, to e.g. alternate day, while still ingesting the same amount of calories, do have benefits. Those benefits hit many of the same areas of metabolism as calorie restriction, but are still significantly different in their overall operation. They are also not as effective at extending life.

Time spent being hungry might be a good metric, but even that is overly simplistic. Grehlin has all sorts of regulatory connections throughout metabolism, but you can't point to any one thing. All of these dietary changes, less calories or more hunger, cause sweeping changes throughout metabolism that are not well understood as a whole. Cause and effect and which parts are important versus not is very much open for debate for any part of this system.

Further, fasting (or fasting mimicking) for longer periods is clearly a different beast from just rescheduling a few meals. In humans fasting for 72 hours or more results in very different outcomes for immune health than anything less than 72 hours. The longer fast kills up to a third of the immune system, which then repopulates when the individual starts eating again, and thus has very beneficial effects in people whose immune system is damaged or dysfunctional in some way (e.g. as the results of chemotherapy).

Similarly these longer fasts produce changes to insulin metabolism that last for months after the fasting is done, which is not the case for fasting in the rearranging a few meals sense.

But you are right; next to no-one cares. The thing that is driving anti-amyloid work in this case is inherited disease in which there is excessive amyloid formation at younger ages, and the growing realization that 10% or more of people who die from heart disease in the 60+ age range are doing so because of normal levels of transthyretin amyloid deposition.

Reading the scientific literature is reading the moment to moment output of a noisy search algorithm. Any given publication is near meaningless on its own.

This business of reading the context for a specific item of research isn't that hard. If as a layperson you feel up to having an opinion on a specific paper, then you are certainly equipped to do more reading in the field.

Start with review papers, which tend to be a gentler uphill slope, and then fit other papers into what you see there. Take note of the disagreements between reviews, the different emphasis placed on different aspects of the topic. In most scientific fields review papers are usually pretty good at explicitly covering the unknowns and debates of interest. The subtexts and unwritten stuff, such as funding-driven conflicts of research strategy, take longer to figure out. But one has to start somewhere.

https://www.fightaging.org/archives/2009/05/how-to-read-the-...

"The scientific community doesn't produce an output of nice, neat tablets of truth, pronouncements come down from the mountain. It produces theories that are then backed by varying weights of evidence: a theory with a lot of support stands until deposed by new results. But it's not that neat in practice either. The array of theories presently in the making is a vastly complex and shifting edifice of debate, contradictory research results, and opinion. You might compare the output of the scientific community in this sense with the output of a financial market: a staggeringly varied torrent of data that is confusing and overwhelming to the layperson, but which - when considered in aggregate - more clearly shows the way to someone who has learned to read the ticker tape."

https://www.fightaging.org/archives/2014/06/fasting-can-be-u...

The other problem is that there are people with high levels of of amyloid who don't get Alzheimer's, so you need other factors as well. That may be obesity / metabolic dysfunction, hence the view of Alzheimer's informed by metabolic syndrome, diabetes, insulin.

The further challenge is that chronic inflammation in immune aging is clearly an important factor, as is vascular aging. A third of Alzheimer's patients also have some degree of vascular dementia, and the decline in blood flow and capillary networks are clearly significant in neurodegeneration considered as a whole.

Another point to consider is that a competing hypothesis for the microbial increase in amyloid levels is the progressive age-related failure of cerebrospinal fluid drainage to remove buildup of aggregates as it does in youth. This has just as compelling a set of supporting evidence at the present time.

Alzheimer's is a condition with many significant contributing causes. The amyloid cascade (with the various reasons as to why there might be more amyloid), immune aging, vascular aging. All the causes may be real, and about as important as one another. It is a condition that results from many discrete items, most of which may have to be addressed to produce significant gains in the patient population.

Validation of the above educated guess, and some form of dose optimization, will arrive sometime after the introduction of good senescence assays that don't involve staining tissue samples, something that isn't viable for everyday human medicine.

As to what "partially reversed" means, the answer is "read the literature". It is all out there. Search PubMed for "senolytic". Use Sci-Hub to read papers. The comparison pictures of treated and untreated mice in papers that have them are particularly telling, but no substitute for the raw data on arthritis, cardiovascular function, inflammation, neural function, tissue elasticity, etc.

For side effects, a single dose dasatinib pharmacokinetics study in volunteers with lots of references to start you off: https://doi.org/10.1124/dmd.107.018267

The dasatinib + quercetin combination for clearance of senescent cells is an excellent candidate on the basis of cost, evidence, and amount of information on these compounds, as well as a clear, low-cost, legal path for companies to bring it to patients. The eventual size of the market is every human being much over the age of 50.

1) Senescent cell accumulation is one of the root causes of aging, supported by decades of scientific evidence [1]. In lab mice, removal of senescent cells has partially reversed progression of osteoarthritis, lung disease, kidney disease, tauopathies such as Alzheimer’s disease, and a long and growing list of other age-related conditions.

2) A single treatment of dasatinib + quercetin clears a fraction of senescent cells in aged mice, leading to lasting improvement in health as a result [2]. Monthly treatment of dasatinib + quercetin starting in late old age reverses measures of age-related decline and extends life by 36% in mice [3].

3) Dasatinib is a generic chemotherapy drug, originally approved for the treatment of cancer in 2006 as Sprycel. Pharmacology and side-effects in humans are well characterized [4]. Quercetin is a widely used flavonoid supplement. Quercetin is not effective versus senescent cells when used on its own [5].

4) The non-profit Betterhumans is running human trials of dasatinib + quercetin, as is the Kogod Center at the Mayo Clinic.

5) Dasatinib costs less than US$100 per dose if obtained from manufacturers, deriving a human dose from the mouse studies. Perhaps US$200 per dose in the form of Sprycel via the pharmaceutical market. Quercetin costs less than a dollar per dose.

6) A drug approved by the FDA for one use can be prescribed by physicians for other uses, if in their professional judgment it is safe and effective. This is known as off-label use, and is commonplace for many medications.

[1]: https://doi.org/10.1111/j.1749-6632.2002.tb02115.x

[2]: https://doi.org/10.1111/acel.12344

[3]: https://doi.org/10.1038/s41591-018-0092-9

[4]: https://doi.org/10.1124/dmd.107.018267

[5]: https://doi.org/10.1371/journal.pone.0190374

Technological progress will not freeze. Past increases in life expectancy due to slowing of aging (versus control over infectious disease to reduce early life mortality) have been incidental, not intentional. They arguably largely arise from that control over infectious disease. But the research and development community are now transitioning into a deliberate targeting of the mechanisms of aging. The difference will be night and day. Great discontinuities in the curve of life expectancy lie in the near future, upward leaps of five years here and ten years there as therapies that repair the root causes of aging become available. Senolytics will be the first of these - already something that the adventurous can get out there and try. There will be many more.

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I will be 85 somewhere in the mid 2050s. It seems like a mirage, an impossible thing, but the future eventually arrives regardless of whatever you or I might think about it. We all have a vision of what it is to be 85 today, informed by our interactions with elder family members, if nothing else. People at that age are greatly impacted by aging. They falter, their minds are often slowed. They are physically weak, in need of aid. Perhaps that is why we find it hard to put ourselves into that position; it isn't a pleasant topic to think about. Four decades out into the future may as well be a science fiction novel, a far away land, a tale told to children, for all the influence it has on our present considerations. There is no weight to it.

When I am 85, there have been next to no senescent cells in my body for going on thirty years. I bear only a small fraction of the inflammatory burden of older people of past generations. I paid for the products of companies descended from Oisin Biotechnologies and Unity Biotechnology, every few years wiping away the accumulation of senescent cells, each new approach more effective than the last. Eventually, I took one of the permanent gene therapy options, made possible by biochemical discrimination between short-term beneficial senescence and long-term harmful senescence, and then there was little need for ongoing treatments. Artificial DNA machinery floats in every cell, a backup for the normal mechanisms of apoptosis, triggered by lingering senescence.

When I am 85, the senolytic DNA machinery are far from the only addition to my cells. I underwent a half dozen gene therapies over the years. I picked the most useful of the many more that were available, starting once the price fell into the affordable-but-painful range, after the initial frenzy of high-cost treatments subsided into business as usual. My cholesterol transport system is enhanced to attack atherosclerotic lesions, my muscle maintenance and neurogenesis operate at levels far above what was once a normal range for my age, and my mitochondria are both enhanced in operation and well-protected against damage by additional copies of mitochondrial genes backed up elsewhere in the cell. Some of these additions were rendered moot by later advances in medicine, but they get the job done.

When I am 85, my thymus is as active as that of a 10-year-old child. Gene and cell therapies were applied over the past few decades, and as a result my immune system is well gardened, in good shape. A combination of replacement hematopoietic stem cells, applied once a decade, the enhanced thymus, and periodic targeted destruction of problem immune cells keeps at bay most of the age-related decline in immune function, most of the growth in inflammation. The downside is that age-related autoimmunity has now become a whole lot more complex when it does occur, but even that can be dealt with by destroying and recreating the immune system. By the 2030s this was a day-long procedure with little accompanying risk, and the price fell thereafter.

When I am 85, atherosclerosis is curable, preventable, and reversable, and that has been the case for a few decades. There are five or six different viable approaches in the marketplace, all of which basically work. I used several of their predecessors back in the day, as well. Most people in the wealthier parts of the world have arteries nearly free from the buildup of fat and calcification. Cardiovascular disease with age now has a very different character, focused more failure of tissue maintenance and muscle strength and the remaining small portions of hypertension that are still problematic for some individuals. But that too can be effectively postponed through a variety of regenerative therapies.

When I am 85, there is an insignificant level of cross-linking in most of my tissues, as was the case since my early 60s. My skin has the old-young look of someone who went a fair way down the path before being rescued. Not that I care much about that - I'm much more interested in the state of my blood vessels, the degree to which they are stiff and dysfunctional. That is why removal of cross-links is valuable. That is the reason to keep on taking the yearly treatments of cross-link breakers, or undergo one of the permanent gene therapies to have your cells produce protective enzymes as needed.

When I am 85, I have a three decade patchwork history of treatments to partially clear this form of amyloid or that component of lipofuscin. Modified enzymes are delivered here, a gene therapy applied there. I will not suffer Alzheimer's disease. I will not suffer any of the common forms of amyloidosis that degrade heart muscle performance or disrupt function in other organs. The potential for such conditions is controlled, shut down with the removal of the protein aggregates that cause cellular dysfunction. There is such a breadth of molecular waste, however: while the important ones are addressed, plenty more remain. This is one of the continuing serious impacts to the health of older individuals, and a highly active area of research and development.

When I am 85, I am the experienced veteran of several potentially serious incidences of cancer, all of which were identified early and eradicated by a targeted therapy that produced minimal side-effects. The therapies evolve rapidly over the years: a bewildering range of hyper-efficient immunotherapies, as well as treatments that sabotage telomere lengthening or other commonalities shared by all cancer cells. They were outpatient procedures, simple and quick, with a few follow-up visits, so routine that they obscured the point that I would be dead several times over without them. The individual rejuvenation technologies I availed myself of over the years were narrowly focused, not perfect, and not available as early as I would have liked. Cancer is an inevitable side-effect of decades of a mix of greater tissue maintenance and unrepaired damage.

Do we know today what the state of health of a well-kept 85-year-old will be in the 2050s? No. It is next to impossible to say how the differences noted above will perform in the real world. They are all on the near horizon, however. The major causes of age-related death today will be largely controlled and cured in the 2050s, at least for those in wealthier regions. If you are in your 40s today, and fortunate enough to live in one of those wealthier region, then it is a given that you will not die from Alzheimer's disease. You will not suffer from other common age-related amyloidosis conditions. Atherosclerosis will be reliably controlled before it might kill you. Inflammatory conditions of aging will be a shadow of what they once were, because of senolytic therapies presently under development. Your immune system will be restored and bolstered. The stem cells in at least your bone marrow and muscles will be periodically augmented. The cross-links that cause stiffening of tissues will be removed. Scores of other issues in aging process, both large and small, will have useful solutions available in the broader medical marketplace. We will all live longer and in better health as a result, but no-one will be able to say for just how long until this all is tried.

Mitochondrially targeted antioxidants such as SkQ1 were first approved for use against inflammatory eye conditions. They act to dampen the consequences / amount of inflammation, and do this by cutting down on oxidizing molecules produced within mitochondria. They were first developed out of an interest to slow aging through this sort of modulation of mitochondrial oxidative stress and damage. They do slow aging to some degree, but don't do anywhere near as well as calorie restriction - say 10% in flies, something less than that in mice, which isn't impressive.

The first earnest human trials for mitochondrially targeted antioxidants such as MitoQ (which from the studies is actually less effective than SkQ1) suggest it can reduce the impact of oxidative stress or inflammation on the smooth muscle cells in blood vessel walls. Their dysfunction produces some fraction of the stiffening of blood vessels with age. That stiffening causes raised blood pressure, which in turn causes too many bad things to list here.

So these are not massive effects. You can probably do as well as MitoQ by bumping up your exercise level to the next tier. But then you can always both exercise and take a mitochondrially targeted antioxidant. The costs are not high, so it may be worth it based on the preliminary data.

Not a cure for aging, and thus not worth spilling immense amounts of ink and effort over it. Just something to think about doing and then get on with better development projects with better expected outcomes.

Many means of breaking cell biology can produce things that look superficially like accelerated aging in at least some ways. That doesn't mean it is aging: given that aging is widespread tissue dysfunction, anything that causes widespread tissue dysfunction can have overlapping phenotypes, but that doesn't mean it has anything to do with normal aging. DNA repair deficiency is the usual example - something that isn't all that apparent in normal aging, in comparison to the models in which DNA repair machinery is missing or broken.

So, similarly, pulling the rug out from under mitochondrial function can be done in countless ways that have very little to do with what happens in aging. I think the onus is still on these researchers to demonstrate that the method they have chosen has much of anything to do with aging per se.

In the case of aging, everyone ages for the same reasons. A few types of underlying molecular damage that are comparatively straightforward to investigate and address, when compared to the enormous complexity of metabolism. Look at senolytic drugs: remove senescent cells, life span increases, aspects of aging are reversed in old individuals. Aging is like rust in a complex metal structure; the failure modes appear varied and complex because the structure is complex. But rust isn't complicated. Aging is the same story.

Genetic variation is not particularly meaningful for the vast majority of age-related disease. It isn't important for most of the life span. It only becomes even somewhat influential in very late life where there is variation in resistance to damage and consequences of damage. But why care thing one about that when the right strategy is to repair the underlying damage in order to ensure that people either never enter or are removed from the situation in which genetics start to matter a little?

Another problem is that too many of today's medical technologies are horribly marginal in their benefits. Marginal benefits have a way of smoothing out to nothing as the patient population broadens. The industry isn't approaching medicine for age-related disease in the right way. If you are actually addressing a useful mechanism, the effect won't be marginal. Science managed that shift from marginal to effective for infectious disease. There is now a pending transition for the diseases of aging - from marginal messing with the disease state to actually addressing the root causes.

Here is a phase 3 that succeeded and failed. Clearly it works. But the study design is such that they had an unexpected result:

https://www.gensight-biologics.com/2018/04/03/gensight-biolo...

They show a good effect in the treated eye, and their gene therapy also produces benefits in the untreated eye. Since they don't know how that could happen, no approval.

Part of this is that researchers don't know how to launch it, and most are not entrepreneurial. Part of it is that many technology transfer groups are like dogs in a manger, toads squatting atop things they'll never put any effort into helping along, and whose job in life is to make it slow, expensive, and hard to deal with their IP. Part of it is that funds, VCs, and to some degree entrepreneurs sit around waiting for something to be handed to them, nicely packaged.

I think most of the fault is with the funds and the incubators. They have the money to craft a solution, to make a landing pad for scientist outreach, to give them a beacon to aim at. They can reach back into the research community to a much greater extend. They can build BDCs that increase the ratio of projects:entrepreneurs that can be tackled profitably. But very little of this actually happens.

My company, Repair Biotechnologies, has found two immensely promising technologies for human rejuvenation that have been in the first case dropped on the floor at the chasm of death, never carried forward, and in the second case died because the institutions involved couldn't convince their funding sources to back the incredible potential of the work. This happens. Many institutional sources of funding don't want to see biotech barnstorming, don't want to see imaginative, radical new directions. They shut it down.

All of this combines to form a dysfunctional environment in which knowledgable entrepreneurs can pick up truly revolutionary projects, but there really needs to be institutional change that only bigger organizations and wallets can bring to bear.

https://doi.org/10.1371/journal.pone.0190374

Another argument against quercetin on its own having any significant effect is that it is widely used in large enough amounts. It would be well known by now if it had significant senolytic effects, because everyone with arthritis would have found their conditions meaningfully improved. That sort of thing doesn't escape notice for long.

The problem is not that senescent cells exist, it is that there is not 100% coverage of their removal after they do whatever the short-term job at hand happens to be. It is the lingering ones that cause the harm.

The lifespan curves in the paper are very nice: same slope, shifted to the right all the way down to 100% cohort mortality. The 36% increase in remaining life span refers to the difference between 140 days and 190 days to 50% cohort mortality in the control and treated group respectively.

Senolytic approaches that clear some fraction of senescent cells are highly reliable when it comes to extending life span and reversing aspects of aging in mice. The drug combination used here, dasatinib and quercetin, is cheap: $100-200/dose if you are shopping carefully. It is being trialed by the non-profit Betterhumans at the moment in a 65+ year old human group. Dasatinib is a generic, so there is absolutely zero interest in anyone taking this into a development program, which is a shame. None of the later pharmaceuticals have yet demonstrated any better results in terms of percentage of senescent cells killed off, but FOXO4-DRI has essentially no side effects.

(If you are interested, dasatinib pharmacokinetics and side-effects are pretty well described. E.g. https://doi.org/10.1124/dmd.107.018267 )

Based on reporting from the self-experimentation community, and first principles arguments, senolytics are something to take once every few years, and don't expect to see noteworthy effects unless you are into high cancer risk years or have something like obesity or early arthritis going on, in which more than the usual count of senescent cells will be in place. Senescent cell contribution to aging most likely scales in the same way as cancer risk and for the same reason, loss of immunosurveillance.

Or you could wait for the human trial results to be published. Those will start to emerge next year for various senolytic candidates.

An interesting thought: compelling evidence for senescent cells to be an important contribution to aging has existed for 30+ years. The research community deliberately avoided engagement with treatment of aging as a medical condition from the 1970s to a decade or so ago. It took a lot of advocacy and people coming in from outside the research community to make that change. If that cultural black hole for development had not happened, how much sooner could simple pharmaceuticals have been discovered that significantly addressed aspects of aging in humans through selective destruction of senescent cells?

Another thought: there has been the usual foaming at the mouth over the past decade among those who decry rejuvenation therapies as the purview of the ultra-wealthy. Dasatinib and quercetin at $100-200/dose, at one dose every two years or so? That is much closer to the future of longevity science that this wild tale of massively expensive approaches hoarded by the rich.

As a general rule building a new human biology is hard. Even making tiny tweaks to our existing biochemistry, such as calorie restriction mimetics, is proving to be very challenging to do effectively and safely. Reverting to the known good youthful state on the other hand, is less complex. So I'd expect delivery of replacement stem cell populations to be a going concern long before adjustments that produce MRL-like or spiny-mouse-like regeneration in humans.

The feature of aging that proficient regeneration seems most likely to help with is the business of fibrosis (liver, kidney, heart, lungs), where regeneration runs awry into excessive scarring, and damage to organs like the heart that do not repair themselves. Equally, it might have to be controlled very carefully in organs where structure is important, which would limit any early application. Recent experiments with cell therapy in the heart in monkeys produced disruption of heartbeat because of the formation of biological pacemarkers outside the normal parameters, for example.

[1]: https://www.ucsf.edu/news/2015/11/251746/human-gene-prevents...

[2]: https://uknow.uky.edu/research/uk-researchers-identify-macro...

[3]: http://dx.doi.org/10.7554/eLife.05505

The challenge in Alzheimer's disease is most likely that it has several mechanisms that are all of similar importance to degeneration. Get rid of one of them and benefits are obscured by the others.

The most likely list is amyloid aggregation, tau aggregation, neuroinflammation (covering microglial dysfunction, persistent infection), energy metabolism issues (covering mitochondrial aging, loss of capillary density, etc), and vascular dementia.

So therapies are needed that can address many of these issues at once. An example is the approach of restoring drainage of cerebrospinal fluid, e.g. at Leucadia Therapeutics. That should reduce all metabolic waste in the brain by restoring a normal sink for amyloid, tau, and anything else that might be an issue along the way.

The amyloid hypothesis seems unlikely to be wrong; there is extensive evidence for amyloid aggregation to cause tau aggegation to cause neurodegeneration. It just isn't the only problem: certainly vascular dementia (present to a clinical level in 30%+ of Alzheimer's patients) is severe enough to question whether it is a major problem in those trials that reduced amyloid and failed to greatly improve dementia. The other big plausible issue is that amyloid is the early stage of Alzheimer's, while tau is the later stage - so messing with amyloid levels is not the way to go for late stage, severely impacted patients. Still has to be done, but it if picking only one, then tau clearance is a better bet.

It does in flies, and there is very clear evidence for that. The evidence in humans to date is very sparse, and where people have done good work on the numbers, they have not seen signs of a plateau. So in that sense, that people have found a larger data set that shows it, that is fuel for the fire.

No-one has the slightest idea as to how you can balance the fundamentals of reliability theory with a late life mortality plateau. If damage is accumulating, and no-one really believes it stops accumulating, then your risk of mortality should keep on going up. What sort of mechanisms in a highly damaged biology could buffer that underlying reality? And why in very late life versus other times?

None of this, of course, has anything to do with efforts to treat aging or extend human life. It is an academic debate that will likely fade out before answers are found, made irrelevant by the advent of ways to treat aging and its causes. Methods of extending life will work by putting off or repairing the very damaged state. There will likely never be a large multiple of the present count of exceptionally physiologically aged individuals. Rejuvenation therapies are just around the corner.

One might argue that the interaction between the need for hierarchy and need for conformity is also at the root of the essential conservatism in human nature: the urge to preserve the present state of the world, to change it as little as possible. Given a teacup, ambition is restrained to the safe, conformist goal of two teacups - rather than, say, the disruptive change of a tea set factory, a house, an end to aging, the colonization of Mars, the cure for cancer. We live in an age of radical change, a revolution in the capabilities of biotechnology presently underway, but when you ask people what they want for their health, they'll claim nothing more than ten more years. That is the least of what might be achieved soon in the medical sciences, but without the desire for more than that, the rejuvenation research projects capable of providing far more will continue to struggle to find funding.

At the same time as the potential has arisen for a future in which the suffering and death of aging is banished, all disease controlled through advanced medicine, the vast majority of people still march stolidly towards what they assume to be the same fate as their grandparents [2]. They are conforming. They expect to live a life that is the same in shape as it was for those born in the early to mid 1900s, somehow holding this idea in their minds at the same time as retaining the memory of living through the computing and internet revolutions, alongside any number of other sweeping changes in the nature of the human experience. How do we change this story that people are telling themselves? That is the fundamental question for all advocacy for radical change, such as the radical change of bringing an end to aging.

[1]: http://www.pewforum.org/2013/08/06/living-to-120-and-beyond-...

[2]: https://www.exratione.com/2017/04/blind-upon-the-eve-of-apot...

Small molecule development, in the sense of changing the parameters of your candidate in a desired direction in a class of molecules, is slow and expensive and to a certain extent reliant on good fortune. You can't just reliably and cheaply dial up the effectiveness or adjust with tissue specificity.

In a world in which dasatinib/quercetin, which costs ~$100 for a dose you take every year at most, does as well as the Unity candidates, will Unity be able to charge the high costs at a great enough volume required to keep the investors happy? Seems unlikely.

I think Oisin Biotechnologies turning up a year or two later in the clinic with a far superior gene therapy product, clearing near all senescent cells in near all tissues, and which can be adjusted rapidly and at low cost, is less of a threat. The market, every human being much over the age of 40, is truly enormous, and several large companies could operate without bumping into one another all that much.

This is an example of the broad, dominant class of aging research that is purely investigative. Most research into the detailed mechanisms of degenerative aging is very far removed from any thought of application, and it is lucky happenstance when such an opportunity does arise.

Unfortunately, systems very closely tied to cellular housekeeping, or responses to stress, or replication seem unlikely to result in the foundations of truly effective therapies. We can look at calorie restriction or exercise, both of which alter all of the above items quite profoundly and throughout the body, to see the plausible benefits that might be attained through manipulation of these fundamental aspect of cellular behavior. We can also look at the past fifteen years of research into these mechanisms to see just how slow and expensive it is to try to produce therapies to slow aging - there is very little to show for all of the effort invested.

Searching for means to adjust metabolism to modestly slow aging is not a winning strategy; the expected benefits are just not large enough. We must find ways to add decades of vigorous life, not just a few few healthy years.

You cannot age healthily. It is an impossibility. If you are aging, your health is deteriorating.

To say you want to do something about aging by saying that you want to allow it to continue - but "healthily" - is to immediately engineer the defeat of whatever it is you then plan to do, because it won't be anything meaningful. The only way to address aging is to find a piece of it, a cause, and reverse or repair that cause. To attack aging. To oppose it. To try to end it.

Running around trying to figure out why some people have a 1.1% chance of living to 100 rather than a 1% chance of living to 100 isn't helpful. Yes, it will probably tell you something about how our biology works when it is horribly damaged, but why would we care about that, rather than caring about what the damage is and how to repair it?

So very much of aging research is completely irrelevant to progress in human health because it is misdirected in this way.

Welcome to the party!

Transhumanism, make no mistake, is just a fancy name for common sense. Change for the better is good, right? Common sense. It's what we humans do in our scattered finer moments - we work to change things for the better. It's common sense to fetch in the harvest on wheels rather than on foot, and it's common sense to repair the biomolecular damage of Alzheimer's before the mind begins to rot. It's common sense to build perfect immune systems from nanomedical robots, and it's common sense to develop the technologies of regenerative medicine to their logical end.

It takes work, but what is work compared to a world of suffering? Choosing not to attain these goals makes about as much sense as standing out in the rain to spite yourself.

New technology cannot set slaves free, remove poverty brought of corruption, make the willfully blind see, or the unhappy bring themselves to good cheer of their own free will ... but it can remove the limits placed upon us by evolution, and it will one day give us all much, much more time in health and life to work on our other, very human issues. You can't rid the world of poverty when you're sick, decrepit and aged to death. The limits to our lives that we cannot negotiate away by talk and travel are the most confining, don't you agree?

Transhumanism, common sense with a slick name, is really simple humanism - which is also really no more than a name for common sense. It is only humanist to work to give people the choice to live without suffering, and without death. To live, for without life, there is nothing.

The FDA system is the only way to get therapies to large numbers of patients. But it isn't the only way to get therapies to patients period, and it has serious flaws. The FDA is risk averse to the point of suppressing progress. The costs have doubled in the last ten years for no good reason.

There is a desperate need for a less heavy handed, more distributed, faster system that favors pace of progress - but all attempts to build it will run into this problem of incentives. The organizations running trials are targets, and people will respond poorly to being struck by risk no matter what they sign or are given to understand up front.

Non-profits may work for low-cost treatments, such as repurposed cheap-to-manufacture compounds from the drug databases (e.g. senolytics), but some types of therapy genuinely do require an organization with tens of millions in the bank to sustain development. How do they proceed if not via the FDA?

$100-150 to run a sample through LC-MS via any one of dozens of small laboratory groups. Most are willing to explain things to a newcomer who is working his or her way through learning the ropes.