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A great example of the way in which researchers leap to try to alter downstream consequences of aging. This impulse is why 99% of all efforts to treat aging as a medical condition are doomed to failure.

The research community has an institutional problem in that all the short-term incentives have them studying the biochemistry of the system in a broken (aged) state, and then working backwards towards causes. Each link in the chain takes years of work. The first place they stop is thus a long way removed from any root cause, but then the incentives work to say "prove your work is valuable" and someone tries to commercialize it.

All medicine for age-related disease (so far) is marginal precisely because it attempts to compensate for or tries to improve downstream consequences that are a long way removed from fundamental damage that causes aging.

You can change the oil as much as you like in a car that is failing for mechanical reasons, but the degree to which you gain benefit from that action is much what you'd expect. You can press the accelerator to try to drive a faltering engine faster. Same story. You fix problems by fixing the root causes, not by ignoring those root causes in favor of things that happen to be what is right in front of you.

There is a greater fool at the end of many paths of research and development, the wallet or collection of wallets that indirectly bankrolls the work. Early for-profit investment occurs because investors believe they can sell their stake at a higher price down the line. Other reasons exist, such as the desire to do good in the world, but are entirely secondary. Most investors, and certainly the wealthier ones, have a fiduciary duty to turn away from world-saving in favor of making money. The market for early for-profit investment in turn indirectly steers research interests and the ability to raise funds from other sources: whatever is presently hot is much more likely to receive grants and philanthropic sponsorship. The state of the market at the end of the development process thus reaches back to influence every part of the long chain of research and development. The predicted inclinations of the greater fool are the tail that wags the dog.

The greater fool of interest here is the one indirectly funding the ongoing construction of a grand catalog of human metabolism, an exhaustive accounting of the fine details of how our cellular biochemistry operates and ages. This is understood in outline, but beneath that outline lies an enormous unexplored space of protein interactions, causes and consequences, and the relationship of various states in the system to health at every level. The greater fool is told by various parties that the goal is to enhance healthy longevity, but that isn't really happening via these explorations of metabolism, and in truth doesn't have much of a hope of happening via this research strategy. Look at the past fifteen years of sirtuin research in connection with the calorie restriction response, wherein the greater fool was - collectively - the GlaxoSmithKline shareholder community following the Sirtris acquisition. Well-managed hype sputtered out quite quickly after that liquidity event into nothing more than a slightly greater understanding of a few very narrow areas of mammalian biochemistry. This process happens over and again for each new potential calorie restriction mimetic, or other methodology claimed to slow the progress of aging by altering the operation of metabolism. Yet there is always a greater fool willing to buy.

Even if a drug was developed to completely mimic the beneficial effects of calorie restriction, so what? That is a convenience device, no more. Those practicing calorie restriction have somewhat better health and somewhat less age-related disease, and might live as many as five years longer. It's a larger effect than any currently available medical technology can provide. Nonetheless, the large majority of those people do not and will not live to see 90 years of age in the environment of today's medical technology. They still live the last years of their lives in frailty and pain. Why spend billions on striving to create a convenience device to recreate some of this marginal effect, tiny in the grand scheme of things? Because some people can get rich doing it.

The recent history of medical development related to slowing aging is that some folk have found they can do very well thank you by promising the prospect of enhanced longevity, while delivering nothing of value beyond scientific knowledge. In different circumstances I might be inclined to praise this as a great hack on investment community culture: direct more funding into life science research rather than cat pictures on the internet, and take a deserved cut as the individual who manages to make that happen. There are certainly far worse things for the greater fool to be talked into doing with his or her money.

Today, however, this business of making hay while the sun shines, based on ways to slightly slow aging largely emerged from calorie restriction research, is a distraction from the prospect of real progress. Messing with metabolism in this way cannot even in principle produce meaningful rejuvenation: aging is damage, and slowing down the damage does nothing for people who are already old and damaged. Yet there are other research strategies that can achieve this goal: the better approach is to repair the damage that causes aging, following the existing detailed research plans that aim to produce new rejuvenation biotechnologies. These can in principle restore youthful function for the old, extend healthy life indefinitely, and should not be any more expensive to explore and develop than a continued future of whatever the next replacement for sirtuin research might be. If billions are spent, then let it be in the pursuit of technologies that do offer the possibility for everyone to live to 90, and in good health, lacking frailty, pain, and disease.

It's a fight to make this case. It shouldn't be, but it is. Attention continues to be soaked up by marginal, ultimately pointless efforts such as the one noted here. It won't let you live to be 90 in confidence, it won't create rejuvenation in the old, and no foreseeable evolution of this strategy can in fact provide those benefits. It is just more of the same search for the greater fool to retroactively bankroll the continuing mapping of metabolism.

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You might recall the hype surrounding sirtuins in cellular metabolism, followed by the breathless marketing of compounds supposed to affect their expression such as resveratrol, all of which went to the usual destination for such things, which is to say nowhere. Some knowledge was added to the grand map of mammalian biochemistry, some people were fleeced, some people made a bunch of money on the backs of promises that never materialized, and that was that. This happens over and again. Every time a new link is uncovered in the complex chain of protein machinery relating to cellular repair mechanisms, upregulated in many of the ways to extend life in lower animals, or calorie restriction, a practice that extends life in short-lived mammals such as mice, and along the way alters near every aspect of the operation of metabolism, then the marketing begins for any supplement that can be linked, tenuously or otherwise, to that research.

If you recognize the general pattern, then you should be well placed to see how things will play out for nicotinamide riboside. This is yet another molecule that can be used as a supplement, and which influences some of the mitochondrial biochemistry associated with cellular maintenance processes. In mice it has been shown to modestly reduce some forms of age-related decline, either by spurring greater maintenance or greater stem cell activity. It is an open question as how much of this will be recapitulated in humans; short-lived species are much more readily influenced by this sort of thing. Their life spans are plastic, and so are their metabolic operations. Regardless, it is of course the case that a bunch of people got together to form a company in order to sell nicotinamide riboside as a supplement. That company is called Elysium Health.

The differences between this and past efforts of this nature are that (a) more reputable scientists from the aging research field are involved, more is the pity for their reputations, and (b) the whole affair is just a little closer to a sensible take on how to make progress in the field, rather than being an absolute money grab. In fact I agree with a fair bit of what cofounder Leonard Guarente has said in public on his motivations for doing this: that progress must be made more rapidly, that there is a space between the worthless supplement market and the highly regulated world of medicine in which good work can be done, and that it is important to put new approaches out there in the world to gather data. I just don't think that this particular approach has any merit in and of itself. Regular readers will know my position on tinkering with metabolism via drugs and found compounds in order to gain tiny and dubious benefits. It is a a waste of time and effort, and definitely not the road to meaningful outcomes in the treatment of aging. Further, even putting that to one side, the founders of Elysium haven't gone about this in the right way at all. They should have sold their product as an open trial of nicotinamide riboside wherein people pay for participation, doubled the price of the supplement, and used that extra money to collect data from participants. Instead they, as everyone is, are corrupted by the fiduciary duty that comes with running a company where the primary focus is selling a branded supplement - so now they are in the supplement business, not the science business. It should be an object lesson for the next group who are thinking of doing something like this.

Personalized medicine is great if you want to charge people a lot of money for marginal results, or if you are in the sciences and your goal is full understanding of everything in human biochemistry.

But all the real, meaningful goals in medicine are basically the same for everyone, barring the very, very tiny number of people with serious genetic abnormalities. And even in their small genetically abnormal groups, the reason for their issues are the same for everyone with the same specific mutation.

99.99% of the population ages and suffers age-related disease for exactly same underlying reasons. The molecular damage is exactly the same. Ditto the pathogens that cause infectious disease. You tailor medicine to the pathogens, to the molecular damage, to the mutated gene in an inherited condition, not to the person. Rejecting personalized medicine is the most cost-effective way to proceed towards mass-manufactured, low-cost, effective medicine.

Fix the inherited diseases with gene therapy. Repair the molecular damage that causes aging. Build the technologies that effectively destroy pathogens. Don't focus on the tiny variations in individual responses to these things before you try to actually address the root of the problem. This is my complaint about personalized medicine in a nutshell: it is displacement activity, distracting from paths that will be far, far more effective in improving health and addressing medical conditions.

If Juvenescence puts serious effort into senolytics, then this will be useful. The more the merrier in that field to join Unity Biotechnology, Oisin Biotechnologies, SIWA Therapeutics, etc.

Everything else outside the SENS portfolio that can be accomplished via drug discovery to alter the operation of metabolism, focusing on known targets such as mTOR, is most likely a pointless waste of time and energy. It has been a pointless waste of time and energy for the past two decades, and I don't see that changing any time soon. The approach of trying to mimic calorie restriction or upregulate autophagy or mess with growth hormone/insulin metabolism or mimic exercise has very definite upper bounds on effectiveness.

The longevity dividend promise of "spend billions to add a couple of years of life expectancy by 2040" is underwhelming, and anyone out there talking about drug discovery to alter metabolism to slow aging is in that camp.

If billions are to be spent, then use them to follow the SENS approach of damage repair, not tinkering the system to slightly slow down the pace of damage accumulation. Only damage repair, such as via senolytics to clear senescent cell accumulation, can in principle produce rejuvenation of the old and greatly extended healthy life spans, more than just a few years.

It is not a coincidence that senescent cell clearance has in a few short years, just as soon as people started to try it in earnest, proven itself far more effective and reliable and useful than the past 20 years of people trying to mimic calorie restriction or boost autophagy.

A few years back, researchers found that manipulating levels of NF-κB in the hypothalamus influenced the pace of aging in mice [1]. That work was several steps removed from any idea as to what exactly was going on under the hood; changing the amount of a specific protein in circulation can have any number of effects, both direct and subtle. NF-κB is already an area of interest in the study of aging and metabolism, and so there are many mechanisms to speculate on in this context. There was indeed speculation at the time. Other indirect evidence suggests that the quality of cellular function in the hypothalamus is connected to the pace of aging, such as results arising from investigations of autophagy and its relevance in this part of the brain. Other researchers have made some inroads into mapping possible ways in which the hypothalamus might influence the operation of metabolism throughout the body in order to modestly speed or slow aging. It is well known that the hypothalamus regulates all sorts of aspects of metabolism, but the open question is which of these relationships are relevant to the matter at hand.

The team that investigated NF-κB in the hypothalamus has since been hard at work, seeking a better understanding as to why this part of the brain is important in the way in which metabolic processes determine individual variations in aging and longevity. In a recently published paper [2], the team now points to one particular small population of stem cells in the hypothalamus that diminishes with age; losing these cells more rapidly appears to speed processes of aging throughout the body. The researchers believe that signals generated by these cells are the mechanism of action, and a closer investigation of these signals is the next step in this line of research. It has to be said that this sounds quite similar to the situation for Parkinson's disease, at least at the high level, in which one small but critical population of cells in the brain is diminished at a different pace in different individuals, and where autophagy - and disruption of autophagy in aging - might be important in determining the rate of loss. It also clearly parallels what is known of the age-related decline of stem cell populations in all tissues. We become damaged, and stem cell loss and inactivity is a downstream consequence of that damage.

Either way, this might make an interesting target for cell therapy: certainly, replacement of stem cell populations is on the rejuvenation research checklist. Whether it is a priority in this case rather depends on the size of the effect, however, which in this study looks like a ~10% gain in life expectancy resulting from a single cell therapy treatment carried out in middle-aged mice. Unfortunately, significant changes in longevity in mice on the basis of altered metabolism so far do not translate to significant changes in longevity in humans, at least in the few areas where the data exists for comparison. The life spans of short-lived mammals are far more plastic in response to circumstances and interventions than those of long-lived mammals. In the case of stem cell replacement as a way to reverse declines, however, it is hard to say how the comparisons will turn out - the data just isn't there yet. It is the fond hope of many in our community that approaches based on repairing loss and damage, very different from approaches based on altering metabolism to modestly slow damage accumulation or resist the consequences of damage, will turn out to have similarly scaled effects on life span in mice and humans. Maybe so, maybe not. As I said, the data isn't there. In order to find out, rejuvenation therapies based on repair must be rigorously tested in humans, and that hasn't yet happened in any useful way, even in the stem cell field.

[1]: http://dx.doi.org/10.1038/nature12143

[2]: https://doi.org/10.1038/nature23282

Which might be controlled by immune ablation; safer targeted forms of destroying all immune cells would be a very good way to stop all forms of autoimmunity, and would act as a good backstop to immunotherapies in general.

Right now immune ablation is pretty rough chemotherapy, but has nonetheless been shown to put multiple sclerosis and type 1 diabetes into remission. There are new approaches to targeted cell killing under development now (such as Oisin Biotechnologies' system) that should be much better, with minimal side-effects. Couple that with a cell therapy to accelerate replacement of immune cells and it looks pretty promising.

Valter Longo's research is essentially aiming to answer some of these questions. He was looking for the 80/20 point at which reduction in calories produces much the same outcome as fasting. His current position is expressed by the fasting mimicking diet; you might go read the papers in which he outlines trial results and the data that forms the basis for the diet.

From a gene expression in mice point of view, none of it is exactly the same. Different but overlapping patterns of change for calorie restriction, isocaloric intermittent fasting, intermittent fasting with calorie restriction, methionine or other protein restriction, etc, etc. All different.

Also, all the data on exercise shows it does little to life span in comparison to calorie restriction, while both are vaguely comparable when considering healthspan. There are plenty of papers on this topic to read. Again, completely different set of changes and benefits.

From an HN audience perspective, perhaps the most interesting thing going on here in recent years is the way in which Longo's group managed to break out of the funding ghetto of aging research for this one part of the field by figuring out the plan and establishing the relationships to productize the research. This pulled in new money and support that allowed them to make good, new steps in quantifying the effects of reduced calorie intake. The cost is that we now have another set of marketing drones extracting rent from the regulatory capture /intellectual property morass for telling people to eat less, but you can decide for yourself whether this is clever hacking of a hopelessly corrupt system or adding to the problem.

The CALERIE study data seems pretty compelling to me. What more do you want?

Unity will be starting human trials this year, so far as we know.

Oisin will follow later this year or in 2018, if they keep to the standard way in which things work in biotech companies following an A round.

I have no idea what SIWA will be doing; they have been around on life support for a while, and now resurrected by the newfound money coming into the field. I'd imagine that their next step would be some form of trial, though it is unclear as to where exactly they are in their animal study schedule.

There are people self-experimenting with senolytic drug candidates now, though not in any way that will provide useful data. If you draw the line at candidates for which there is in vivo evidence in mammals, you're left with just the chemotherapeutics and foxo4-dri. (A pity that fisetin has no in vivo evidence yet...). The chemotherapeutics are worth skipping over, since they are ugly chemicals and really only a starting point for the development of analogs without the horrible side-effects, and foxo4-dri hasn't been tested in any formal way in humans yet.

At the pace at which new drug candidates are emerging and being tested, a couple of years from now would be a good time to be self-experimenting.

The trend of the past is the result of medicine and medical development that did not in any way attempt to address the causes of aging. Benefits have resulted from either (a) inadvertently slowing down the damage accumulation, or (b) compensating in some way without addressing the damage. In either case the benefits are small in the grand scheme of things. 0.1 years of life expectancy at 60 with every passing decade is not a large outcome, and we should not be surprised to find it small given that treating aging as a medical condition hasn't been the goal of research or implementation.

Trying to keep a damaged machine running without repairing the damage is expensive and futile. How far does changing the oil in a car or pressing the accelerator harder get you if you never fix anything that goes wrong in the engine? Similar situation.

The future will be radically different because researchers are now resolved to treat aging as a medical condition, to investigate the causes, and to intervene. The debate now is over the best way to go about it, and alas most of the research community remains fixated on the path that will cost a great deal and achieve next to nothing, which is to say efforts to alter the operation of metabolism so as to modestly slow down the aging process. Calorie restriction mimetics, autophagy enhancement, and etc.

If you want better results, you have to look to the rejuvenation research of the sort carried out by the SENS Research Foundation, the Big Pharma groups clearing amyloid, the new senescent cell clearance startups, etc. Slowing aging by altering metabolism is the expensive road to nowhere. Repairing the causes of aging is the more efficient, faster road to rejuvenation of the old and the prevention of aging.

The interaction between medical technology and specific biological mechanisms determines limits to human life span. Given the sparse nature of demographic data for extreme old age, there is plenty of room to debate whether or not there exists one or more mechanisms of aging that have not been impacted in any meaningful way by improvements in medical technology over the past century, and which, on their own, can produce a very high rate of mortality in late life. That circumstance would look a lot like a limit to human life span, one that doesn't appear to be affected by medicine - but that is only because the right medicine hasn't been created yet.

One mechanism that springs to mind here is the accumulation of transthyretin amyloid, found in one small study to be the majority cause of death in supercentenarians, but which appears to have only a smaller impact on mortality in younger old age - it is implicated in something like 10% of heart failure cases, for example. Can we argue that advances in medicine and public health over the past century have had little to no impact on the accumulation of misfolded transthyretin deposits in tissues, and thus this mechanism acts as a limit on life span? Or do some of these improvements in fact produce an small, incidental reduction in amyloid burden in later life? The evidence to support any of the possible positions on these questions is presently lacking.

Whatever the state of effective limits on life span today, however, the limits on life span tomorrow are determined by progress towards rejuvenation therapies. There are treatments under development that can clear transthyretin amyloid from tissues, for example, such as the work of Pentraxin Therapeutics, or the catalytic antibody development funded by the SENS Research Foundation.

There are certainly startups / small companies working on rejuvenation therapies, however, ways to repair the forms of damage that cause aging rather than merely slowing down that damage a little as is the case for calorie restriction mimetic drug development.

See for example these entities working on means to selectively remove senescent cells, with Unity Biotechnolgy being the one connected to Buck Institute researchers:

https://oisinbio.com/

http://unitybiotechnology.com/

http://www.siwatherapeutics.com/

The presence of senescent cells have been shown to directly cause failure of regeneration, fibrosis, fibrotic lung diseases, loss of tissue elasticity, blood vessel calcification, faster progression of atherosclerosic lesions, arthritis, chronic inflammation, immune system dysfunction, and retinal degeneration, just to name a few items from papers published in the past two years. More links are being established in research papers with each passing year. The removal of these cells has been shown in mouse studies to quickly reverse the age-related progression of many of these items.

Some references for those who want to dig in.

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

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

In general, the consensus in the research community is that we shouldn't expect more than an additional ~5 years from the life-long practice of calorie restriction. The evolutionary argument is that the calorie restriction response evolved very early on in as a way to enhance fitness given seasonal famines. A season is a long time for a mouse, not so long for a human, so only the mouse evolves a very plastic lifespan. The practical argument is that 5-10 years is about the largest effect that could exist and still be hard to pull out from existing demographic data of restricted calorie intake in a bulletproof, rigorous way. Obviously any much larger effect would have been discovered in antiquity and be very well known and characterized by now.

So that said about longevity, it is very clear that calorie restriction does better and more reliable things for health in ordinary humans in the short term of months and mid-term of few years than any presently available enhancement technology can replicate.

A good deal of research into aging is focused on trying to recreate the calorie restriction response. So far this has consumed billions with little of practical use to show for it beyond increased knowledge of some thin slices of cellular biochemistry relating to nutrient sensing and energy metabolism. It has proven to be very hard and very expensive to get anywhere here.

So calorie restriction itself is free and reliable in its effects. Everyone should give it a try. There are, however, far more important areas of aging research to direct funding to instead of trying to recreate this effect with pharmaceuticals. In an age in which meaningful rejuvenation is possible to create in the years ahead (see, for example, clearance of senescent cells, something that calorie restriction can only slightly achieve in a very tiny way, while drug candidates are managing 25-50% clearance) it seems just plain dumb to instead be chasing expensive, hard ways to only slightly slow down aging.

The AnAge database may be of interest to those who like to think about this sort of thing.

http://genomics.senescence.info/species/query.php?search=Ani...

http://genomics.senescence.info/species/nonaging.php

Note the sponges, particularly this one:

http://genomics.senescence.info/species/entry.php?species=Sc...

"Animals of this and similar species of Antarctic sponges grow extremely slowly in the low temperatures. Estimates based on growth rates suggest a very long lifespan in this and similar animals. One two meter high specimen in the Ross Sea was estimated to be 23,000 years old, though because of sea level fluctuations in the Ross Sea it is unlikely that such an animal could have lived for more than 15,000 years. Even if 15,000 years is an overestimate, which may well be the case, this specimen appears to be the longest-lived animal on earth."

Physical activity is the likely mediating mechanism between acting younger and gaining modest benefits by some measures. Since the development of lightweight accelerometers, studies of physical activity have demonstrated strong correlations between even modest activity of the housework/gardening variety and health in old age. There is a mountain of further research demonstrating the benefits of increased moderate exercise and lesser forms of activity in older people.

But ultimately the end is the same. You can't reliably exercise your way to 90, even. The majority of people who are exceptionally fit die before reaching that milepost in the environment of the last 90 years of medical technology. The future of health and longevity in later life will be increasingly determined by medical technology, and nothing else. Aging is damage, and that damage can be repaired given suitable biotechnologies to do so.

DNA methylation patterns correlating strongly with age are a very promising tool when it comes to assessing treatments for the processes of aging. Companies offer various implementations now - see Osiris Green for a cheaper example, to pick one. In the SENS view of aging as accumulated molecular damage, epigenetic changes are a reaction to that damage; a secondary or later process in aging. We'll find out over the next few years how the rejuvenation therapy of senescent cell clearance does against this measure, now that things are moving along there.

But you shouldn't think it impossible to construct useful metrics of biological age more simply. There are a number of excellent papers from the past few years in which researchers assemble weighted algorithms using bloodwork, grip strength, and other simple tests as a basis into something that nears the level of discrimination of the epigenetic clock.

When it comes to a biomarker of aging, there are lots of promising candidates. Researchers will spend a lot of time arguing before they come to any sort of pseudo-standard for that task. Industry (today meaning the companies developing senolytic therapies for the clinic) will overtake them and, I'd wager, adopt one of the epigenetic clocks because it basically works well enough to get along with, and can be cheap in some forms.

What is wealth? Let me try a slightly non-standard answer to that question. Wealth is a measure of your ability to do what you would like to do, when you would like to do it - a measure of your breadth of immediately available choice. Therefore your wealth is determined by the resources you presently own, as everything requires resources.

For the sake of argument, let us say that your resources presently amount to a leather bag containing a hundred unmarked silver coins. Interestingly enough, by the "what would you like to do" measure, you are fantastically more wealthy than any given ancestor put in the same position of ownership. You have immensely greater choice. Clearly there is more to wealth-as-choice than present property. We must also consider the historical investment made into increasing choice, and into lowering the cost of specific - usually popular - choices. The engines of technology and open, free markets are turned by people to create new, better, cheaper choices. The choice to fly, the choice to remain alive with heart disease, the choice to avoid that heart disease.

Where do silver coins - or indeed, any other resources you might own - come from? Where does investment come from? After all, we don't come into this world with the proverbial silver implement between the teeth. No, we worked for those coins. We spent time and negotiated payment for that time. Why? Because time is valuable.

But time spent alive, measured in the ticking of heartbeats, is more than valuable - it is wealth itself, the source of all other measures of wealth. All property was created by someone, somewhere, taking their time. The creation and exchange of property is a way to make time fungible, transferrable, a more valuable resource. Time spent alive is the root of all property, all human action, and thus all wealth - both the silver in your pocket that provides for present choice, and the wealth of possible choices created by past investment.

Time is everything. How much have time you spent reading this far? Could you have been doing something more useful, more optimal from your perspective? We make these small evaluations constantly, because time is the most valuable thing we have.

We all go through engineering our cycles of property and time; how can we best optimize time to generate property that can be used to make our time more effective? We do this in small ways and large, but everyone does it. Some people do it so effectively they launch themselves into property escape velocity, exponentially increasing the effectiveness of their time and exploring the outer limits of what it means to maintain ownership of a great deal of property.

Interestingly, despite the grand importance of time as the absolute foundation of wealth, very little progress has been made in the most obvious optimization of all: creating property that can create more time. More heartbeats, more health, more time spent alive and active. Rejuvenation medicine, capable of repairing the damage of aging. Tissue engineering to generate replacements for worn organs. The cure for cancer. If you could do all that, then the much more productive form of escape velocity becomes possible - longevity escape velocity. Why strive to maintain an empire of property that will crumble to dust when the degenerations of age catch up with you when you could be that fit-looking guy having a blast swimming in the breakers every other Sunday for as long as you like?

Wealth is exactly time, and here we are, bordering the era of biotechnology for the repair of aging. Planning ahead for the best possible personal future starts with investment now. Think about it.

For broader context, this might be used to help explain the well known link between the age-related decline in mitochondrial function (and consequence lowered production rate of ATP) and the age-related development of aggregates such as amyloids and tau. Aggregates are age-related, but one needs explanations as to why that is the case. Other proximate causes include declining cellular garbage collection mechanisms, aggregation of other proteins (protein A spurs aggregation of protein B), failure of mechanical clearance via peristaltic channels, and so forth. It's never just one thing.

Like many lines of research manage to achieve, this finding adds a little more emphasis to the need to restore mitochondrial function in the old. Clearing damaged mitochondria, delivering replacement mitochondria to cells, allotopic expression of mitochondrial genes, and so forth.

This is a good demonstration of the point that artificial organs don't have to be the same as the real thing, they just have to be similar enough for the subset of tasks desired.

This is especially true for chemical (liver) or cell (thymus) factory organs. Just because the research community can't yet manufacture blood vessel networks needed for large organs doesn't mean they can't use fully or mostly functional organoids to produce benefits. It is possible in principle to patch a diseased liver with many organoids, or put thymus organoids into lymph nodes, and so forth.

This sort of thing will get underway in earnest if there isn't any real movement on the blood vessel network problem within the next few years.

There is a good argument for it not to be about the innovators, but rather about the long buildup of compound growth in land use, longevity, and wealth in the preceding century in England, distinctly from other areas of Europe. The thought leaders and innovators of that era and the preceding centuries tended to be cosmopolitan, mobile, and well connected between parts of Europe, so one can't really invoke them as though they were geographically fixed, a regional phenomenon.

http://ideas.repec.org/p/cte/whrepe/wh016301.html

During the 17th and 18th century the English economy underwent a dramatic transformation: its capacity to feed and increasing population increased impressively. ... Perhaps for the first time in the history of any country other than a land of recent settlement, rapid population growth took place concurrently with rising living standands.

...

The notion of life expectancy provides the most important tool to examine the phenomenon of mortality, taking into account the age structure of the population. Life expectancy at age x is the average number of years that a person of age x will still survive at a given date. The most commonly used indicator is e(0), life expectancy at birth (or at age 0), but sometimes other statistics like e(1), e(5), e(20), e(50), are also tabulated. Their main advantage is that they capture age-specific mortality profiles: for instance, an increase in mortality concentrated in the age-group between 20-25 (due, for instance, to a long war) would affect e(0) but not e(30) because the probability of survival, given that a person is already 30, does not change.

Decisions about future capital and consumption are not taken by the agent when he is born but, rather, when he is twenty or twenty five years old. Therefore, the relevant survivial profile for considering the influence of mortality over investment choices is given by adult life expectancy. In fact, making the distinction between e(0) and adult life expectancy is expecially important for our problem because adult mortality behaves in a completely different way from infant and child mortality in the first half of the 18th century: adult mortality rates decreased very sharply from the end of the 17th century, while infant and childhood mortality rates were unusually high between 1680 and 1750.

..

If life cycle inspiration was present in rural England in the 18th century, farmers who were becoming aware that old people were gradually living for longer periods must have been more concerned about their own means of subsistence in the future. This may have been an important stimulus to reduce consumption, increase savings and take into account longer horizons.

It isn't news to the audience I usually talk to that the California Life Company, or Calico for short, Google's venture into aging research, is secretive. Outside of the staff, few people can do more than read the tea leaves regarding what exactly they are up to. The high level summary is that Google is channeling a large amount of funding into some sort of long-term development plan for therapeutics to treat aging as a medical condition. Over the past few years Calico has made sizable development deals with pharmaceutical and biotechnology companies, and hired some of the most noteworthy names in the aging research community. It is usual for biotechnology and drug development companies to be fairly secretive in their early stages, for reasons that largely relate to investment regulations. At some point they have to talk about what they are doing, however, given that the goal is clinical trials, customers, and revenue.

It may be the case that Calico is simply following the standard biotechnology startup game plan over a longer time frame and with more funding than is usually the case, including the secrecy portion of that plan, but by now most of those interested in faster progress and beneficial upheaval in the research community have written off Calico as a venture unlikely to make any meaningful difference [1] [2]. Given who has been hired to lead it, and given the deals made, the most likely scenario is that Calico is the second coming of the Ellison Medical Foundation. By that I mean an organization that is essentially running more of the same research funded at the National Institute on Aging, with a poor or absent focus on clinical translation, and constrained in goals to the paradigm of drug development to slightly slow the progression of aging. In this area you will find things like calorie restriction mimetics, pharmaceutical enhancement of autophagy, and so forth. The past twenty years of research have made it clear that it is very hard and very expensive to produce even marginally effective and reliable drugs capable of slowing aging through the adjustment of metabolic processes. Yet this is exactly what most research groups continue to try.

There is an alternative approach. Instead of altering the poorly understood intersection between metabolism and aging in an attempt to slow the damage of aging, instead periodically repair the quite well cataloged list of fundamental cell and tissue damage that causes aging. This approach is exemplified by senescent cell clearance - a way to extend healthy life and turn back symptoms of aging and age-related disease that is already showing itself more robust and useful than any of the present drug candidates aimed at altering the operation of metabolism to slow aging. Senescent cell clearance as a way to reverse aging has been pushed by the SENS rejuvenation research advocates for more than 15 years [3], with good evidence as support. Yet over that span of time the majority of the research community rejected damage repair in favor of focusing on efforts to slow aging, efforts that have not succeeded in producing useful therapeutics with sizable results on human health.

That rejection was clearly not sound. Once efforts started in earnest on development of methods of senescent cell clearance, it required only the past few years to robustly demonstrate its effectiveness as a rejuvenation therapy [4]. It is gathering ever more attention now - but not from Calico, so far as we know, and not from the majority of the research community that continues to work on slowing aging through adjustment of metabolism, an approach to aging as a medical condition that is demonstrably marginal and expensive. The funding used to bring senescent cell clearance up to its present point of proven success is a tiny fraction of what has been spent on so far futile efforts to produce calorie restriction mimetic drugs [5] that would, even if realized, be far less effective and far less useful to patients.

On the whole I think Calico is most likely a larger than usual example of the primary problem in aging research: the dominance of initiatives that put their funds towards complex, lengthy, and uncertain projects that even in the best of circumstances are only capable of producing poor outcomes for patients. In short, the problem is an unwillingness to pursue the repair and rejuvenation approach that is demonstrably more effective than the adjusting metabolism to slow aging approach. Excessive secrecy is a minor quibble in comparison.

[1]: https://www.technologyreview.com/s/603087/googles-long-stran...

[2]: http://mendelspod.com/podcasts/brian-kennedy-and-aubrey-de-g...

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

[4]: http://dx.doi.org/10.1038/nature16932

[5]: http://blogs.sciencemag.org/pipeline/archives/2008/04/24/720...

It is worth noting that the real challenge in gene therapy at this time is not editing the genes, but in getting sufficient coverage of edited cells (and especially progenitors and stem cells) in an adult individual to achieve the therapeutic goal and make it last.

(Most studies of genetic alterations in the broader sense have bypassed this challenge by working with animal lineages, or animals in which the editing happens in the earliest stages of development, when there are very few cells needing to be changed. The alteration then propagates during embryonic and later development).

There have been a number of very promising studies in the past year or two with regard to gene therapies to apply to adults, such as animal studies that demonstrated a cure for an inherited muscular dystrophy, but in the bigger picture, comprehensive coverage of tissues and cells is still something that the research community is in the midst of getting to grips with.

The complexity of cellular biochemistry is why the most effective near-term approaches to medical biotechnology involve sidestepping the need to learn very much more about how it all works in detail. They are engineering rather than scientific efforts.

This is most apparent in aging research, though the principle applies to most medicine. The idea is to identify the root cause differences between normal and diseased metabolism, a task that is a lot easier than figuring our how exactly those root causes propagate and expand into the disease state over time. Root causes are those that have no other cause beyond the normal operation of cells. You then intervene to revert the root cause differences and see what that does to metrics of disease state and progression. The goal is to return metabolism to its normal state, a state that we don't fully understand, but that we know works.

A practical example is the presence of senescent cells. They cause problems, they are not present in large numbers in young, healthy people, so remove them. Removing them sidesteps the whole involved process of trying to understand exactly how they cause problems, in detail, at the level of cellular mechanisms. Researchers are working on that goal of full knowledge, but it will be years until that slowly starts to produce useful therapeutic options, and there are probably decades yet in any research program or combination of research programs that seeks to alter the behavior of senescent cells to make them less harmful. Meanwhile, removing senescent cells works reliably to improve health and turn back disease, and you don't need to know why that happens in order to obtain the benefits, beyond the high-level sketch of "less harmful signaling".

Unfortunately most medical research takes an entirely different approach, which is to start with analysis of the disease state (complex, expensive, slow) and then work back through proximate causes of disarray. At each point at which a therapy might be attempted, try to adjust the proximate cause. Since this doesn't touch on root causes, it is usually marginal, and even the successes just postpone the inevitable.

Trying to understand why someone lived this long is something of a pointless endeavor. It is random chance, plus a little genetics. If genes double your odds of making it past 100, then that is still 2% odds for people reaching that age now. By 117, with ~50%+ yearly mortality past 110, well, the odds are not good whatever your diet and past lifestyle might have been.

Running around analyzing the genetics of supercentenarians isn't really all that useful from the point of view of making people live longer. Doubling a tiny chance is still a tiny chance, and their longevity has a lot more to do with randomness than with anything else.

Perhaps more interesting is asking why these people die, what are the causes. Different ages are characterized by a different prevalence of disease; cancer hits a maximum mortality rate and then fades as a major cause in the oldest old, for example. From the few autopsies performed, supercentenarians appear to predominantly die of senile systemic amyloidosis, a clogging of the cardiovascular system with misfolded transthyretin that appears to play a lesser role in heart failure in younger old age.

If we want to ask why human life span seems to have a rough upper limit (though 50%+ yearly mortality for any combination of causes is going to look a lot like a hard limit when stretched over 20 years), then this form of amyloidosis seems to be one of the places to look.

Interestingly, this form of amyloidosis has an inherited version that shows up in young people, so despite the institutional reluctance to work on medicine to treat the causes of aging, there are actually a number of therapies in development and trials, some of which can selectively remove this form of amyloid. At some point the research community will wake up to this form of amyloid being a contributing cause of heart failure (a process underway judging by recent papers on the topic), at which point we might well see a leap in the observed upper limit to human life in the decades following more widespread use.

The described strategies in this article are still a matter of working where the light is shining, not where it would be most effective. This is an age of genomics, genomics is popular and widely appreciated, and it is thus easy to raise funding for genomic work. Therefore people are trying to build personalized and per-cancer methods based on specific genes. The ability to raise funding for work is far more of a determinant of direction taken than expectation of quality of results, sadly.

So this is just an incremental update of the old strategy of trying to find a better chemotherapeutic for each cancer. It isn't going to work fast enough and well enough. There are not enough researchers and isn't enough funding to tackle every one of the hundreds of cancers and their subtypes in any reasonable about of time via the one project per cancer approach.

The only viable approach to a sweeping cure for cancer is to identify commonalities shared by very large fractions of all cancers. The chimeric antigen receptor strategies are a step in this direction, producing a technology base that has a much lower cost of adaptation to each new cancer in the class that they can target, rather than needing a whole new project from scratch. But is only a modest step.

The best way forward appears to me to be blockade of telomere extension: sabotaging telomerase [1] and alternative lengthening of telomeres [2], a small collection of mechanisms. If developed, it can be applied to all cancers, as all cancers depend absolutely on telomere lengthening. They can't evolve their way around it, as is the case for many existing methods of targeting particular mechanisms in a type of cancer. It is too fundamental a part of cellular biology. Blockade of telomere lengthening would be absolutely and determinedly the full stop at the end of all cancers - and would cost no more to develop than any one or two existing therapies that can treat only one subtype of cancer.

[1]: https://www.eurekalert.org/pub_releases/2015-01/usmc-rtt1231...

[2]: https://www.lifespan.io/campaigns/sens-control-alt-delete-ca...

An interesting topic to look into is the effect of deuterium on longevity in various species. It appears to induce a form of hormesis at low levels (perhaps) or improve resistance of certain important cell structures to oxidative damage (perhaps). [1]

The company Retrotope [2] is trying to do something with what is known of this biochemistry.

Deuterated drugs after the fashion of the one in this article are probably not going to be delivering enough deuterium to trigger this sort of effect, however.

[1]: http://onlinelibrary.wiley.com/doi/10.1002/bies.201600040/fu...

[2]: https://www.retrotope.com/

There are a small number of known advantageous mutations already present in a small number of humans that could be introduced to larger numbers via CRISPR, brought to the clinic as a somatic gene therapy for adults. This is an enormous market in comparison to "merely" curing all genetic disease, as near every adult human would be able to benefit.

Not much movement in getting that into the clinic yet, however, for reasons that are entirely cultural. The first company to get one of these working via medical tourism will make a lot of money. CRISPR makes that goal pretty easy in comparison to the past.

These changes include things like extra follistatin or knocking out myostatin to gain greater muscle growth and less fat tissue, or removing or disabling ANGPTL4 to reduce heart attack risk by 50%. There are others along the same lines and more are being discovered as sequencing becomes ever cheaper.

The comparative lack of effort to make enhancement gene therapies a reality is nothing short of crazy, given the observed benefits in the few humans lucky enough to already have these variants or loss of function mutations.

Bear in mind that researchers have colonies of thousands of these animals, and in all the time people have been looking, only a tiny number of cases of cancer have been cataloged in this species. [1] Compare that with the cancer incidence and mortality rates in other mammals.

The present thinking on various mole rat breeds and their cancer resistance is that they have more active and more useful cancer suppression gene activities for p16, p21, p27, ARF, etc, and that their tissues have a lot more high molecular weight hyaluronan than peer species [2]. Disabling the gene producing the hyaluronan makes them vulnerable to cancer, and that appears connected to p16 activity.

The important outcome of the particular setup for naked mole rat biochemistry may be that their cells are a lot more sensitive to crowding, and will more readily self-destruct when that happens. Without that, cancer is more easily induced.

[1]: http://dx.doi.org/10.1177/0300985816630796

[2]: http://www.rochester.edu/news/show.php?id=6572

Cancer, like aging, is an example where much of the research community is undertaking very challenging and expensive work with marginal expectation value because that dovetails well with the types of fundamental research that can be funded, not because of any expectation that it is the best approach with the highest expectation value. This is an age of genetics, genetics is popular, and so people are getting funded for personalized medicine and ever more intricate mapping of cellular biology.

But there are hundreds of types of cancer, and taking the genetics/drug discovery approach for each of them is its own distinct and massively expensive undertaking. It'll never get done: the research community and its funding sources are not large enough to make significant progress on the whole of the problem in the next few decades. This isn't hacking cancer, this is hacking the cancer funding institutions in order to obtain funding to get on with the fundamental life science research goal of mapping all of cellular metabolism. Cancer is the excuse, but not the goal.

This is a cultural problem.

Hacking cancer would be to sit down and say, ok, the economics of this are not working, we need to find common points to target, a way to produce a universal cancer therapy at no greater expense than one of these single cancer therapies.

Some immunotherapies, like CAR-T approaches, are a small step in this direction, something that can be applied to multiple cancers with a lower cost of customization per cancer type.

The best target, however, is to block telomere lengthening; disabling both telomerase and alternative lengthening of telomere (ALT) mechanisms. This is a small area of biochemistry in comparison to the scope of most single cancer explorations. All cancers depend on telomerase or ALT or both. All of them. No exceptions. No cancer can evolve its way around a suppression of these mechanisms. It will simply die, losing its ability to replicate uncontrollably. Some noted research groups are making early inroads into disabling telomerase in a targeted way. ALT remains to be dealt with, but is easier to work with than telomerase interdiction by virtue of the fact that ALT doesn't happen in normal cells.

A telomere lengthening interdiction treatment would be applicable to all cancers, and it doesn't appear to be more expensive to develop than any other approach to a specific cancer. That is what hacking cancer research looks like; identifying a way to completely change the economics of the situation, and redirect the primary effort back to producing an effective cures as soon as possible.

Lastly, I have to fundamentally disagree with the final lines of this article; cancer can absolutely be dealt with robustly by killing cancer cells. You just need to be selective enough, early enough, and comprehensive enough, and raising the bar on these items is the whole point of the field.

It happens over a shorter timeframe than funerals are needed to explain. The past decade or decade and a half has been long enough to see outsiders having significant influence in the aging research community, steering it from determined non-intervention to greater willingness to work towards therapies capable of addressing the causes of aging. All of the players are the same at the start and the end, aside from the new faces coming in from outside.