exratione

Vaupel is a respected voice in the field. You might look through his publication history.

I don't think it's particularly controversial at this point that life expectancy at birth is trending upwards at ~2.5 years/decade and adult life expectancy at ~1 year/decade. Vaupel is far from the only researcher publishing studies of life expectancy trends, and the actuarial community is in a state of what passes in their staid halls for great upheaval for some years now, issuing ever more politely alarmed statements about their growing inability to predict the future longevity upside.

But none of that is relevant, as it is the result of medical advances in absence of any attempt to intervene deliberately in the aging process. What will distinguish the medicine of the past fifty years from the medicine of the next fifty years is exactly that. In the future researchers will be trying to slow or reverse the causes of aging, whereas in the past they achieved life extension through only inadvertent impact on those causes or expensive compensation strategies for the end results that do little to fix things.

Well, sure. Being older is so absolutely amazing in terms of experience, assurance, wealth, power, confidence, and so forth, that all those similar things can actually for a time outweigh the crumbling of your health and your increasing frailty and pain.

But only for a time.

It is a measure of how much people are predisposed to accept the status quo that we don't see far more engaged in serious, scientific efforts to apply modern biotechnology to build rejuvenation treatments. Certain death and present pain is more acceptable than effort, uncertainty, and change.

First, nice to think it'll happen in time for you personally. But it won't unless a lot more people support the right lines of research over the next ten years. That means those based on repair of causes of aging, the well-cataloged and uncontroversial forms of cellular and molecular damage that distinguish old tissue from young tissue. SENS programs are the exemplar, but a lot of stem cell work and cancer offshoot research (such as senescent cell ablation) falls into the same bucket. Most present research aimed at slowing aging by altering the way in which metabolism works (such as calorie restriction mimetic drug development) is not in any way likely to lead to large extensions of healthy life span, and especially not for those people already old when it is introduced. Most research aimed at the genetics of human longevity won't do much either, as it is just more of the same road to a hard, slow, expensive re-egineering of metabolism to obtain very tiny benefits. You can't add decades to healthy human life spans in the near term without damage repair as your primary approach. It isn't hard to see why: you can repair damage or slow it down, and the former of those approaches is very much better than the latter in terms of benefits delivered and guesstimated cost of producing treatments.

Secondly, there is presently no real reason to suppose that any of the demonstrated limits to human cognitive function are caused by anything other damage: loss of neurogenesis, build up of amyloid and other waste products, progressive demyelination due to a variety of processes, white matter damage from microstrokes resulting from vascular dysfunction, and onward for dozens of other types of harm. Every aspect of memory and executive function is slowed and degraded. The detailed maps of connections between damage and dysfunction are in most cases sketches or unproven or unknown or exceedingly complicated and open to debate. But there is so much damage that it would be going out on a limb to suggest that a periodically repaired brain wouldn't just keep on going, losing the old memories and generating new ones, not filling up.

There are bodily systems that do "fill up" and where we can make good arguments that they have structural issues with long-term operation and would fall over even if every component part worked fine perpetually. The immune system, for example, in its continual assignment of memory cells for herpesviruses such as CMV, may be working as evolved but nonetheless gradually destroying its own effectiveness. That can be argued reasonably, versus it all being the consequences of damage.

But there's no reason to think that any of the brain's processes are in the same boat at this stage. There is every reason to think that dysfunction is all damage until proven otherwise.

Lastly, having the opportunity to be in good health and wrestling with a century of memories while deciding what to do next? That beats the alternatives. High class problem.

If we define favorite as most often reached for in reference to present discussions, then probably this. People are persistently surprised by the expected results of cumulative gains in all areas of life, here also:

http://dx.doi.org/10.1371%2Fjournal.pbio.0020187

"Those who get first-generation therapies only just in time will in fact be unlikely to live more than 20–30 years more than their parents, because they will spend many frail years with a short remaining life expectancy (i.e., a high risk of imminent death), whereas those only a little younger will never get that frail and will spend rather few years even in biological middle age. Quantitatively, what this means is that if a 10% per year decline of mortality rates at all ages is achieved and sustained indefinitely, then the first 1000-year-old is probably only 5–10 years younger than the first 150-year-old."

The express router array is pretty easy to abuse, it's true. For example, as something you probably shouldn't ever do:

https://www.exratione.com/2013/03/nodejs-abusing-express-3-t...

I guess the Netflix situation is one of those that doesn't occur in most common usage; certainly dynamically updating the routes in live processes versus just redeploying the process containers hadn't occurred to me as a way to go.

Here's a toy pseudo-random generator I threw together the other day in the course of doing something else:

https://www.exratione.com/2014/10/four-word-phrase-pseudoran...

Not enough, I'd imagine.

It has always been a stronger thread in the tech community than elsewhere, but it is still only a thread. Take a survey of your office and you'll find few people who put any thought into radical life extension, mind uploading, and the rest of the visions of the future that were ideas in search of advocates in the 80s and are now in the very early stages of actual development.

The present outer limits, the very dramatic falloff in survival past age 100, appears to be largely caused by senile systemic amyloidosis, based on autopsy evidence from the recent past. Misfolded proteins, amyloids, clog up your cardiovascular system until it fails. This will kill those who survive everything else. Unlike other better known forms of amyloid these are proteins involved in thyroid hormone transport.

The SENS Research Foundation funds some of the work on potential treatments for this condition, based on a new approach in biotechnology using what are called catalyic antibodies [1] to break down the amyloid, though it is fair to note that as in many of these things much of the research community interest where it exists at all lies in treating the rare genetic variant that young people can suffer. It's called transthyretin-related hereditary amyloidosis, but it is basically the same process - you can just only suffer it young if you have exactly the right rare mutation.

[1]: http://dx.doi.org/10.1074/jbc.M114.557231

It's amazing how much goes to line the pockets of politicians and their cronies, and with the flimsiest of expected outcomes on the part of those who give, in an age in which creating actually worthwhile things, new technologies and scientific progress, is cheaper than ever.

Watching this sort of thing, knowing that the researchers behind many very worthwhile lines of medical research that might bring great benefit to hundreds of millions struggle to raise a tenth of this amount over the course of years, is ever eye-opening.

We're not a very rational species.

It's amazing the stuff that gets funded in the research community in place of, you know, actually addressing the physical, biochemical causes of aging.

People overestimate the state of medicine with respect to autoimmunity, which is funny in a way because they are largely completely in the dark as to how fast medical research is moving in all fields, and think that many types of near future treatment are a lot further away than is in fact the case.

The workings of the immune system are rather like the workings of metabolism: the present vast knowledge, the stuff that takes years to learn and which encompasses many disciplines as no one person can know enough of all of it to make a career of that, is actually basically just a sketch of how things work. It is a map at the high level. When it comes to the all-important details there are decades of work left at even at the present pace and with the damn impressive biotechnology the research community has now in order to get to even a moderately complete picture.

So there's a reason why many forms of autoimmunity are really hard to diagnose, and why you'll find that a great many diagnoses of exclusion are mild autoimmune conditions: here's what's wrong with you, it's the bucket we put people in when you have some symptoms and all the tests we have come back negative or with ambiguous results. Those tend to be the ones where nothing can be done at present. The author of the article should at least be happy that she is one step up from that situation.

The immune system has so many ways of running awry due to malprogramming that there really should be more work done on more gentle ways to reboot it - strip out all immune cells and start over with the patient's stem cells to repopulate it. Aggressive reboot methods involving chemotherapy have been pretty effective when trialed, but that's not something you'd want to do unless there was no alternative.

The advent of biologics for immune suppression have turned the research community away from the possibilities of the wipe clean and start over approach, however, which I think might be a mistake in the long run.

There's always knowledge to be gained from comparative biology. But there's knowledge and then there's applicable knowledge. I think the odds of finding anything that can be ported to humans as a therapy or enhancement on a short enough timescale to be interesting (i.e. less than 20 years from now) are pretty remote. That's true for the process of mining the biochemistry of our fellow mammals, never mind the lower animals.

The unfortunately fact of the matter is that messing with metabolism is exceedingly hard. For example: researchers have spent billions and the past two decades earnestly trying to artificially produce some of the effects of calorie restriction, a beneficial altered metabolic state that is very easily studied in numerous species. What is there to show for all of this effort? One path (rapamycin) that might, maybe, produce a drug family that can recreate just a little of the calorie restriction response - but not soon. Perhaps ten years from now. There is still no full understanding of what is actually going on in calorie restriction, just a high level sketch. Most of the money spent went on what turned out to be a dead end (sirtuins). All in all a grinding, expensive process with little to show for it.

The situation is no different when we are talking about regeneration rather than aging. There are researchers studying salamanders, lizards, zebrafish, hydra (which might or might not be ageless), MRL regenerator mice, cancer-immune naked mole rats, and so forth. There is a growth in understanding of the species-specific biochemistry involved, but in the present environment, in which the research community can't even recreate or fully understand a simple response to environmental circumstance such as calorie restriction given decades and billions of dollars, then what are the odds that they can pull something out of non-mammalian species and make it work in people? Pretty small, I'd say.

The odds of learning lots of interesting things are on the other hand pretty high. If you want to go digging via Google you'll find that a great deal has been gained in recent years in the understanding of salamander regeneration, for example, and the MRL mouse story is also fascinating.

But as to the hydra (not the same thing as the Hydractinia of the article) I penned this a while back. It's as much applicable to regeneration issues as aging issues, and for the variety of lower animals that are highly proficient regenerators.

-------------

Hydra are one of the few ageless species, or at least a good candidate for such: researchers have watched populations age for years with no signs of increased mortality rates or declining pace of reproduction. One might view these creatures as an incremental step up from bacteria or yeast: multicellular animals that can reproduce asexually via budding, and which are extremely proficient at regeneration.

One line of thought regarding the agelessness of hydra is that they simply consistently and relentlessly renew all the tissues in their body, which is accomplished by having very many stem cells that don't decline over time. Hydra might follow a strategy of eliminating the inevitable buildup of malformed proteins, aggregate waste products, and similar damage in individual cells by (a) sacrificing and then replacing damage-bearing cells, and (b) using the bacterial approach of moving as much damage as possible into one of the two daughter cells produced in any cell division. Since a hydra has no brain, any cell can be sacrificed at any time so long as it is replaced with an equivalent new cell - the whole organism can be replaced completely over any arbitrarily short period of time provided it can find the metabolic resources to do so.

There's nothing magical about making cell lineages last essentially forever. All bacteria do it, and even complex organisms like we humans are capable of it. There is, for example, the process that ensures that the first cells of a human child are biologically young and free from damage even though the parents bear decades worth of accumulated damage in their cells. It's also possible that hydra use an aggressive repair and renewal process of this nature, either when they bud or on an ongoing basis.

Aging doesn't happen because it has to, aging happens because it's almost always advantageous from an evolutionary perspective - that we age is an example of the success of the gene built upon the pain, suffering, and death of the individual who bears it. Though apparently this isn't the case for hydra, and many other types of life that are closer to what we might think of as self-replicating machines rather than populations of individual entities. One might argue that the big downside of individual entityhood is the need for brain cells that store data, and thus cannot simply be replaced at arbitrary times. Or perhaps one might argue that a necessary precondition for individual entityhood is a loss of the processes of aggressive regeneration and tissue replacement such that a thing like a brain might be able to evolve in the first place.

In any case, not everything that the aging research community works on is both interesting and potentially useful when it comes to intervening in human aging. Ongoing research into the biology of hydra is certainly interesting, but I'm dubious that we'll find anything that can inform us of a way out of our present predicament, the one in which we are aging to death. We and the hydra live in very different worlds, with very different requirements for success.

-----------

Some further hydra resources for the interested:

FoxO is a critical regulator of stem cell maintenance in immortal Hydra: http://www.uni-kiel.de/aktuell/pm/2012/2012-332-foxogen-e.sh...

Evolution of human longevity: lessons from Hydra: http://www.impactaging.com/papers/v4/n11/full/100510.html

In Swiss Lakes, Scientists Search For The Source Of Immortality: http://www.worldcrunch.com/tech-science/in-swiss-lakes-scien...

Hydra, a powerful model for aging studies: http://www.tandfonline.com/doi/full/10.1080/07924259.2014.92...

Aging is a global phenomenon of damage accumulation throughout the body: more damage means faster aging. People who show more damage in any one measure tend to show more damage in all the others too, as it all stems from a few root causes. This bears up in epidemiological studies, but there is a fair amount of individual variation.

Almost every decline in aging that can be measured can be correlated with near future mortality. Grip strength and walking speed are the common ones presently used, and finding others should be in no way surprising.

You don't need to crowdfund any more than it costs to convince a group with $1bn that they can make money on this by spending that to commercialize your demonstration. That is often just a few million, or even less, depending on how compelling your data and how good your connections.

Most of that $1bn and decade of time is make-work created by ever more risk-averse regulators. The actual process of creating something, making a product, and gathering reasonable data on safety is a fraction of that.

This displays a profound ignorance of the real situation, which is that the majority of useful early stage research is funded by philanthropy. Not by government, not by companies, but by people making donations. It doesn't come from the existing funding institutions because they almost never fund anything that hasn't already had its prototype and early stage research completed successfully. If you don't have your proof of concept you are not getting funded, and the institutions don't really care about where the starting point of the pipeline actually comes from. Every lab scrapes out funding from the corners of existing grants and petitions patrons to conduct what is arguably their most important work, which is to say the actual work of taking risks and creating new things.

What most people call research grants are nothing of the sort. They are development grants. The research already happened, and it was paid for by bootstrapped philanthropy.

In recent years a growing network of supporters of longevity science has emerged in the Bay Area entrepreneurial and venture community. It is a highly networked environment, and visible signs such as the Health Extension meetings are really just the tiniest tip of the iceberg. It is no accident that the SENS Research Foundation and its coordination of rejuvenation biotechnology research is based in the Bay Area: venture capitalist turned philanthropist Peter Thiel was one of the early high net worth donors to SENS research, and folk in the software engineering community have always made up a sizable fraction of the donors and supporters of first the Methuselah Foundation and then the SENS Research Foundation after it was spun off as an independent organization. Medicine is engineering, and aging is an engineering problem asking for a solution: this is something that is perhaps more clearly visible to people who have written code for a living at some point in their careers.

Which is not to skip over the fact that there is a thriving medical biotech venture community in that part of the world as well. It just doesn't get as much press, and the people involved have historically tended to be just as conservative and quiet about the prospects for treating aging as the rest of the life science research community. Sometimes change must come from the outside, which is exactly what happened in this case.

Before funding SENS research the Methuselah Foundation initially focused on the Mprize: a research prize aiming to spur the research community into doing more work and speaking more publicly about efforts to extend healthy life span and produce rejuvenation in the old. At the time the prize launched, the silence of the research community and their unwillingness to push the boundaries, educate the public, and get on with treating aging was a real issue and a cultural roadblock to progress. That this state of affairs has changed dramatically is due in no small part to the efforts of the Methuselah Foundation and the networking that took place as a direct consequence of the existence of a research prize.

In a different world the Mprize might still be generating press and progress even today, but it was hampered by an unfortunate happenstance of research, in that one of the first methods discovered to extend life span in mice was so effective that it has yet to be surpassed or even matched, more than ten years later. It is hard to have a contest when there are no new winners emerging on a short enough time frame to interest the public. For my money, I'd wager that producing mice that live longer than growth hormone receptor knockout mutants won't happen without the implementation of SENS rejuvenation treatments, ways to extend life by repairing damage (and thus reversing aging) rather than slowing the progression of damage (and thus slowing aging).

Nonetheless, the Mprize was a successful vehicle to produce change in the aging research community: this is the interesting thing about research prizes, that they don't have to achieve their stated competitive goals or even look like they worked as a contest in order to produce the desired outcome, a revival of effort in a specific field of research and development. Success is all about networking and attention, which in turn leads to fundraising and greater activity where before there was little. The Methuselah Foundation still runs the Mprize, but is presently focused on speeding up organ tissue engineering through the New Organ Prize: working to ensure that patient-specific organs built from stem cells exist soon rather than twenty years to thirty years from now.

So perhaps this leaves a space for a next generation of research prizes in longevity science, and it turns out that folk in the Bay Area venture community think that is the case - and if there is one thing that these people are good at, it is networking, the lifeblood of a research prize initiative. So take a little time to peruse the Palo Alto Longevity Prize and note the panoply of advisors and research teams signed up to compete. The actual details of the prize are of technical interest, especially since they lean in the direction of supporting repair over slowing aging, but they are far less important than what is taking place behind the scenes as a result of this initiative.

This is another point of reinforcement for my view that this effort is going to look much like a mix of the Ellison Medical Foundation plus Sirtris: vastly expensive and with little other than knowledge to show for it once investors give up, because the researchers are from the outset trying to do something that is very hard, and which even if achieved will produce only small benefits. (Which is to say carry on trying to make drug candidates like Rapamycin do something useful enough to become a clinical treatment, bashing the square pegs at hand into the circular holes of regulation and clinical benefit).

"The AbbVie partnership seemingly makes it clear that Calico will be a drug discovery and development company, which is what many observers expected based on Mr. Levinson’s background in drug development."

In the best scenario, five years of this will raise the water level enough for more meaningful approaches than calorie restriction mimetics, autophagy inducers, and other attempts at slow-aging drugs that have consumed billions to date with nothing to show for it, to raise significant funds themselves. In the worst scenario, it burns investors for a decade on the whole topic.

It is a real time of choice and opportunity at the present. The lumbering monolith of mainstream research can continue to pursue things like Human Longevity Inc and rapamycin derivatives that are probably going to be profitable yet achieve next to no useful gain of human life span (because again they are doing hard things that can only achieve small benefits at best) or, hopefully, some form of disruption for a better path will overtake enough of the community to make a difference.

It is clear that far from everyone in the research community thinks that old school drug discovery, farming the natural world to take potshots at restructuring metabolism so as to work slightly better when damaged by age (without in any way fixing the underlying damage!) is the smart way forward. There is SENS, there are the European researchers behind the Hallmarks of Aging manifesto, there are some of the Russian contingent with novel ideas. The near future doesn't have to be an enormous waste of time and money that will go nowhere but to generate voluminous databases, entirely bypassing any realistic opportunity for achieving actual rejuvenation and repair of the causes of aging. But I fear that it will, based on what we're seeing the big money do.

I agree that mitoTALENs look promising, as does some early work on delivering RNA to mitochondria so that the necessary proteins get made even in the absence of genes. That said, I'd have said the same about exploiting mechanisms in leishmania [1] to deliver useful molecules to mitochondria if you'd asked me five years ago. That line of work seems to be in the doldrums too at this point, not much progress to be seen.

The most promising sign is the metasign - that we can compare and contrast so many different approaches, and complain because some are not getting more attention. Yet overall things are happening.

[1] http://www.sciencemag.org/content/314/5798/471

Fortunately you probably won't have to go more than another ten years or so with that condition before it can be treated via either allotopic expression [1] of mitochondrial genes (e.g. as demonstrated for the single gene mutation in LHON [2]), delivery of whole replacement mitochondria [3], or possibly protofection of an entire replacement mitochondrial genome, although that latter item seems to have stumbled to one of those funding-related halts so common in research [4]. The others are presently pursued, though by no means as aggressively as the potential benefits merit. Everyone need mitochondria repair, not just people with inherited or other global genetic defects of the mitochondria.

[1]: https://en.wikipedia.org/wiki/Allotopic_expression

[2]: http://archopht.jamanetwork.com/article.aspx?articleid=18145...

[3]: http://dx.doi.org/10.1016/j.transproceed.2013.11.133

[4]: https://www.fightaging.org/archives/2012/10/what-happened-to...

Everyone should have the option of upgrading to better, damage resistant mitochondria, or the option to purchase effective maintenance of mitochondrial function. Some haplotypes are objectively better than others, allowing greater athletic ability or resistance to age-related disease, but we can go beyond even just picking haplotype.

Progressive damage to mitochondrial DNA is an important contribution to degenerative aging. Wholesale replacement of either mitochondria or mitochondrial DNA (via any one of four or five different approaches) is a very viable near term goal. All of the necessary component of such a treatment have been demonstrated in animals and human cells in the laboratory over the past decade, leaving just the painfully slow regulatory and development process.

Some data for you:

http://www.chronicdiseaseimpact.com/

Some items for context:

1) Almost all high risk, new, next generation early stage research is funded by philanthropy. Major funding institutions won't give anyone money unless they can essentially demonstrate a proof of concept, and that what they have works. Similarly the for profit world doesn't tend to fund high risk new fields, but steps in at about the same point as public institutional funding.

2) Almost all funded research for the major killers involve diseases of aging, and almost all of that research is aimed highly inefficient ways of producing marginal gains. Which is to say that researchers work backwards from the very complex end state of a disease, attempting to produce a treatment from each new proximate cause they uncover. These treatments largely involve attempts to manipulate a very complex and poorly understood state of metabolism / biology. Only a very, very tiny slice of all this research funding goes towards prevention or repair or other ways to address the root causes of these diseases of aging, which is to say the processes aging itself. Until this changes, progress is only very loosely coupled to levels of funding. You can spend a bunch of money paying people to drain a lake with spoons, or you could spend a lot less doing something better and more effective, and that's really a fair analogy for where medical research is with respect to the diseases of aging. A disruption is underway, but it is going very slowly, as things tend to in the research world, and hasn't yet had much of an impact on the bulk of the mainstream.

Absent progress in medical science, your odds of achieving that end are very remote. 75% of everyone, including most of those with the best diet and lifestyle choices behind them, are dead by 90 at the present time. The winnowing is precipitous over the next ten years following that: 1% make it to 100. Few of those lack serious health issues that greatly impact their ability to enjoy life.

Unless something changes these odds are improving only very slowly, with less than a year added to life expectancy at 60 every decade. This is an incidental trend, brought about despite the fact that no-one has really tried to seriously address the root causes of aging and age-related disease in the past.

If you really want to live to be old, and do so in good health, then the way to increase the odds is to get out there and make a difference: contribute to research funds, advocate for more longevity science, ways to treat the root causes of aging rather than patching over the late stage consequences. The whole field of medicine as it pertains to aging and age-related frailty and disease must be disrupted and change greatly from where it stands today.

There are people trying to pick up the pace for complex organs. Fifty years is way too long. See the New Organ initiative, for example. Lots going on there behind the scenes:

http://neworgan.org

Recent progress with the thymus is an unexpected gift. It is expected that achieving the same with other organs is going to be pretty challenging, lacking such a short cut. Hence the need to speed things up: advocacy and alliances and research prizes.

There is also a paper from some months back that is open access, and thus provides much more information for those who like to get at the source. This covers earlier work in which they manipulate cell signaling to regrow an existing thymus in situ and restore it to youthful activity:

http://dev.biologists.org/content/141/8/1627.full

This is good news for work on immune system rejuvenation, some of which is very focused on restoring the thymus to youthful activity. Immunosenescence is an important contribution to the frailty of aging. One of the issues with an aged immune system is that for various reasons it runs out of competent immune cells to tackle new threats. Means of restoring that population of cells include (a) a more active thymus, (b) clearing out dead wood memory T cells that are hanging around being useless, as that will spur the creation of naive T cell replacements, and (c) plain old cell therapies along the lines of culturing vast numbers of immune cells and infusing them on a regular basis.

A lot of this is very close to practical in the technology demonstration sense today, but of course regulation is the big roadblock in most of the world. It'll take a decade to get this through the very hostile-to-anything-new regulatory system, and of course treatments will only be ever be approved for very sick and damaged people. The existing regulatory system will never approve a thymus rejuvenation procedure for someone who is "only" old and immunosenescent, because that is not defined as a disease - that is a healthy person who is merely old, and shouldn't be treated at all in the eyes of the regulator. That must change, but the pressure for that will largely come from medical tourism if the course of recent history vis a vis first generation stem cell treatments is anything to go by.

Some years ago, transplantation of a thymus was shown to have benefits in mice along these lines, restoring a supply of immune cells, and that was good enough to attract more interest. Regrowing the existing atrophied thymus or putting a new one in place has thus been on the agenda for a while, e.g. in an ongoing SENS Research Foundation / Wake Forest Institute for Regenerative Medicine collaboration. That is a more traditional tissue engineering approach, with nanoscale scaffolds, a lot of work on cell differentiation strategies, and so forth. The ability to rejuvenate or regrow the thymus entirely from just a small population of cells, or a few altered protein levels, has come out of left field as something of a pleasant surprise.

It is only very recently that scientists figured out how to determine how old a lobster is [1], as they show so very few signs of aging. Crustaceans are a pain to work with in this respect as they shed and regenerate almost everything that might be used to easily mark age, and the behavior and capabilities of a fifty year old lobster are not noticeably different from a ten year old lobster. They do age, however, just in nowhere near the same way as mammals.

A number of lower animals seem to have indefinite life spans, but that may be because few people are willing to put in the time to figure out whether they only have very, very long life spans. Hydra, for example, are one of those cases. [2] These species are not terribly relevant to any human medicine. Hydra are (probably) long-lived because they are ferociously competent regenerators, little packages of stem cells essentially. Once you have a complex nervous system you can't run the "regenerate everything all the time" model, however, as the fine structure of your brain needs to stay the way it is.

The AnAge Database lists a few more species considered to have negligible senescence that are of more interest because they are more complex organisms. [3] Longevity figures are often a question mark here, as there is too little study to determine what life spans actually are if these animals are left alone in a place where they have food and won't get eaten or diseased.

[1]: http://www.huffingtonpost.com/2012/11/30/lobster-age_n_22159...

[2]: https://www.fightaging.org/archives/2012/11/investigating-th...

[3]: http://genomics.senescence.info/species/nonaging.php

Actuarial escape velocity is a term popularized by Aubrey de Grey, first put forward a while back and then in a 2004 PLoS Biology paper [1] following some of the bioethics debates of the past decade. Most of you will probably recall those debates in the context of somatic cell nuclear transfer, embryonic stem cells, and therapeutic cloning, but the various appointed bodies pontificated on aging and longevity science as well. Generally to say how terrible it was to even think about extending healthy human life, but hey, what can you expect? That is more or less the default position that most people still hold today [2].

To a certain degree one has to come to terms with the fact that most people in the world hold incoherent views on the topic of aging to death. If asked most of them say they want to: they want to do exactly the same thing they see other people doing. Conformity is a hell of a drug. But if asked if they want to suffer heart disease or Alzheimer's, they don't want that.

Then there is the hairshirt environmentalist death cult that tells us we're destroying the world, there are too many people, and we should all die. That is not actually much of an exaggeration of the actual viewpoints espoused. This has so pervaded society that you can find the average person on the street is concerned about living too long because they are someone burning up a limit faster. It's ridiculous. People look at the horrible consequences of war and kleptocracy in various regions [3], and buy into the propaganda that this would somehow go away if fewer people were involved: that it isn't the mass murder, or the oppression, or the theft of resources, or the enforced poverty, but just a matter of how many people there are. They fuse this into the desire to confirm to the lives of their parents, and justify the continued lemming-like walk towards the suffering and pain and disease of aging.

But if you ask them if we should cure any of those diseases, they're all for that. They just don't want to live longer. But this is the greatest incoherence: age-related diseases are age-related diseases because they are caused by the underlying processes of aging. The only true cure is to repair the damage of aging [4] that causes these diseases. As for all machines, if you fix the damage it lasts longer in good condition [5]. Extension of healthy life and true cures for age-related disease are flip sides of the same coin.

And if treatments for aging were widespread and available, all those people who say they want to die on the same schedule as their parents would use them, and live longer, and get over it. But without their support the necessary research will not run fast enough to save most of them. They'll die for their wrong ideas, right on the eve of the transition to a world of indefinite life spans achieved through medical science that can control the causes of aging.

[1]: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC423155/

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

[3]: https://www.fightaging.org/archives/2009/08/there-is-no-over...

[4]: http://sens.org/research/introduction-to-sens-research

[5]: http://en.wikipedia.org/wiki/Reliability_theory_of_aging_and...

This very recently launched crowdfunding site is a spin-off venture [1] of the Bay Area based Buck Institute for Research on Aging [2].

A bunch of people (such as the folk at experiment.com ) are in search of the magic bullet that makes KickStarter-like crowdfunding work well for research. I don't think a straight port can work, as the incentives and motivations are all very different. But I'm optimistic that someone will find the magic recipe that will open the floodgates.

This is an age of distintermediation, and crowdfunding seems like something that will inevitably take over a chunk of the sort of research fundraising that presently flows through big per-disease charities. But do people who go beyond a nebulous support for curing a specific disease really want to pick and choose projects, or are they happier rooting for teams? If the latter, science crowdfunding may inevitably shift in the direction of a LabCures-like approach.

[1]: http://www.marinij.com/novato/ci_26246445/new-buck-institute...

[2]: http://www.buckinstitute.org/

Disappointingly, but expectedly, the stub website for Calico further reinforces the point that they are not likely to soon take any path that will produce meaningful results for human longevity. They are following the Longevity Dividend [0] approach in essence, which at the high level aims to increase understanding of the intersection of genetics, metabolism, and aging to produce ways to slow aging gently. Ambition here is to aim for an increase of 7 years of life expectancy over the next two decades, a figure given a couple of times by Jay Olshansky. Examples of research include work on sirtuins, that has consumed a billion dollars and produced nothing of use, and other attempts to produce caloric restriction mimetic drugs. The near future in the Longevity Dividend vision is basically more of the same: vastly expensive attempts to alter the operation of metabolism in order to slow down aging.

Genetics is hot, and it is easy to raise funds for nowadays. See the launch of Venter's Human Longevity Inc, for example. But I see this in connection with work on longevity as looking for the keys under the lamp, because that is where the light is, not because it is where you are likely to obtain results. The comparative genetics of human longevity should be irrelevant to work on aging: we all age because of the occurrence of the same forms of cellular and molecular damage. Outside of rare mutations, genetics has nothing to do with that - the same damage happens to everyone. The target should be repair of that damage, not trying to expensively slightly slow the pace at which it arrives.

That the metabolic manipulation approach to treating aging has such popularity despite the lack of results is a mystery. The other way, the repair approach, has the same lack of results - but that is because next to no money is heading in that direction. We have the early demonstration that targeted removal of senescent cells extends life in accelerated aging mice [1], for example, and ample reason to believe it is beneficial for ordinary individuals, but it took philanthropic funding to move that research forward at all. Institutions want to see standard issue drug development and manipulation of metabolism because it is the mainstream of medicine and the expected thing: the round peg for the round hole of regulation. This has nothing at all to do with whether it is the best path forward.

This all further points to the fact that if we want to see meaningful results in longevity science, measured in years of health gained for people who are already old, then we need to produce results that demonstrate the futility of the mainstream path taken by Google, the sirtuin researchers, and Human Longevity Inc, etc, and deonstrate that repair approaches can do far more for far less money. The senescent cell targeting is probably the closest work to that point.

Based on what I've seen of Calico to date, I'm expecting it to be a more publicized version of the Ellison Medical Foundation as an initiative: an extension of work already taking place at the NIA and in companies like Human Longevity Inc, and something that fails to step outside that box. It will produce general benefits in terms of data and knowledge, and absolutely fail to meaningfully extend human life. This will continue until someone changes the approach to this work to focus on repair of the causes of aging [2] rather than metabolic tinkering to slow aging. The latter is a slow road to marginal end results that can do next to nothing to help the people who grew old waiting for them to arrive.

[0]: https://www.fightaging.org/archives/2013/10/advocating-the-l...

[1]: http://dx.doi.org/10.1038/nature10600

[2]: http://www.sens.org/research/introduction-to-sens-research

Too right. We live in a world of suicidal barbarians [0] walking in lockstep to suffer and die on the same schedule as their parents, yet so afraid of being old that they will not think of it, even to do something about it. Ask the man in the street if he wants people not to suffer, not to grow old, and he will likely reject the concept. [1]

Scientists are telling the world quite openly, and have been for more than a decade, that we can treat aging. We can work to slow it [2], to reverse it [3], to control it through medicine in just the same way as we have controlled infectious disease in the past. All it takes is support and money. But unlike cancer research, people just don't seem willing to listen. In their minds, aging is set in stone, and altering it is an uncomfortable prospect. Yet the mourn the 90% of their relatives who die of old age, and they watch them suffer - but they don't want to do anything about it when faced with the choice to do something about it.

It gets even worse when you realize that most of the very, very few people who are doing something to tackle aging are going about it in a way that is guaranteed to produce terrible, mediocre results. This is steered by the state of regulation and the the fact that it is way easier to raise money in biotech for things that won't do much for aging in a practical sense, but will do a great deal to illuminate how exactly it progresses.

It is a funny world. Most of the research community agrees that aging is damage accumulation. Yet they near all raise funds for and work on ways to tinker with epigenetic changes, protein levels, and metabolic processes that are way down the chain of events, late stage reactions to reactions to reactions to damage that are right next door to end pathology. The state of regulation means you can only treat end state pathology, the things they call diseases of aging, and so research starts there and traces back. So, oh look, despite the fact that everyone agrees it is all about root cause damage, they're all trying to put band-aids over the very late consequences of damage without actually addressing the underlying damage at all! No wonder it doesn't really work all that well.

Exhibit A is the billions spent on trying to just recapture some of the small effects of calorie restriction on slowing aging: this is the easiest, most obvious, best studied altered state of metabolism, and fifteen years of work by hundreds of researchers yields knowledge about genes and epigenetics and metabolism (perhaps adding 1% of what there is to be known but is not yet known) yet nothing of practical use to extend life. Exercise and eating less are still the most effective strategies, and this in the midst of a revolution in biotechnology.

The researchers who argue that aging is programmed, that all these epigenetic changes are the things you should be treating because they are the primary cause of aging rather than damage, must be laughing. There they are, losing the debate, a minority position, in a terrible position from a point of view of hard evidence, and the other side - who call programmed aging nonsense - are nonetheless doing their research for them. Crazy.

All that money and time flushed, effectively. No such thing as useless knowledge, but there is certainly such a thing as knowledge with little to no practical value insofar as reversing aging goes. The horrible irony of it all is that we just don't need to know much more about the fine details of how exactly aging progresses than we already do. We have programs like SENS [3] that are supported by luminaries in the research community [4]. SENS says repair the known forms of root cause damage that lead to aging. End of story. Here are the forms of damage that the community consensus tells us cause aging [5]. Here are proposed fixes from the community. Let us do it. It bypasses present ignorance and the difficulty of altering metabolism to slow aging, and just moves directly to rejuvenation by damage repair. We are machines, and machines can be repaired, and when you repair them it extends their health life expectancy. Reliability theory works. [6]

Yet SENS is a tiny thing, a seed at present: one small community and distribution of minor labs amidst a field of dozens of much larger ones. It is the future because it has to be: it is the only practical way to make the medical control of aging work. The question is how long it will take to properly disrupt the field, and there is still a way to go there, especially given the enormous enthusiasm for the genetics of aging as typified by the direction taken by the California Life Company and Human Longevity, Inc. They are looking where the light is: greater understanding of metabolism and genetics is not the way to go, but that's where the tens of millions of dollars are going at the moment. It will all come to merely an improvement in present day medicine focused on patching the late stages of aging, and produce little to nothing in the way of extended life - certainly not in comparison to what could be done with actual rejuvenation by repair rather than just slowing things down by tinkering with metabolism.

Aging is simple at root. Baring a few exceptional, rare and horrible mutations, everyone ages in exactly the same way and for exactly the same causes: the damage is the same. The same mass produced repair strategies in the SENS vision will work for near everyone. Genetic variations are meaningless and irrelevant to the damage repair model, and the damage repair model is the only possible way to extend healthy life by decades within our lifetimes. Yet the mainstream forges ahead with trying to understand the minutiae of natural differences between aging in different people, in the hope of grabbing a year here, a year there, by patching and tinkering metabolism into altered states that will hopefully do more good than harm. It is a poverty of vision, a waste, a loss of time. The potential gains can never be as great as simple trying to repair the damage, the types of which we know and are well described.

[0] https://www.fightaging.org/archives/2011/05/when-did-we-beco...

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

[2] http://www.healthspancampaign.org/film/

[3] http://sens.org

[4] http://www.sens.org/about/leadership/research-advisory-board

[5] http://www.sens.org/research/introduction-to-sens-research

[6] http://en.wikipedia.org/wiki/Reliability_theory