reasonattlm

Read their publication list. The SRF collaborates with most of the important research groups in the field:

http://www.sens.org/research/publications

Also, see their research advisory board, which includes numerous respected researchers, leaders in their areas of work.

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

You might be familiar with senolytics, the clearance of senescent cells as a way to treat aging that is presently taking off in a big way in the research and development communities. Aubrey de Grey, cofounder of the SRF, called for that back in 2002, and the SENS programs have advocated for it since then:

http://www.sens.org/files/pdf/manu12.pdf

The SRF and original parent organization Methuselah Foundation seed funded Oisin Biotechnologies to work on gene therapy for senolytics a few years ago. Other lines of development have also spun off into companies in the SRF network.

Aging is the same cell and tissue damage that causes the age-relates diseases you mention. The only difference between aging and disease is how much damage you have, how far the cascade of cause and effect and secondary consequences has progressed. "Aging" is subclinical "age-related disease". There are few root cause forms of damage, but the cascade is as complex as our biochemistry, so there are any number of fatal endpoints and horrible declines along the way.

The only plausible near-future way to remove age-related disease is to periodically repair the damage that causes aging. Nothing else is going to work.

Consider this when thinking about living life to the fullest all the way up until death: if you are so healthy (meaning lacking in damage) that you don't suffer age-related disease, what are you going to die from? Your mortality risk is a function of the load of cell and tissue damage you currently bear. The only way to prevent age-related disease is to have a low load of damage, and consequently a low rate of mortality.

Given today's accident and murder rates, an ageless human undergoing comprehensive damage repair every decade or so would live for 1000 years or more before encountering a fatal happenstance. If you live much past a century from now, I'd have to imagine other technological options opening up that make that number seems small.

On overpopulation, it seems pretty clear from the research carried out on this topic that agelessness will not result in problematically large populations. Wealthy regions are already declining in population growth, and poor regions decline as they become wealthier. The poor are being lifted up rapidly.

See, for example, Demographic Consequences of Defeating Aging: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192186/

It also seems fairly clear that what people call overpopulation now would be better described as some mix of kleptocracy, war, other bad governance, and endemic poverty that in many cases is being addressed at a fast rate in comparison to past history. Given the long list of regions that have lifted themselves up from peasant farming to technology industries and wealth since the 1950s, one has to look at those that haven't succeeded in this, and ask why: it certainly doesn't correlate with number of people.

I think it important to note that the SENS research programs are just about 100% funded by philanthropy, with thousands of supporters over the years. This donation is a part of ~$6M from the year end fundraiser: about $500k from a lot of people in the community, Buterin's donation, $2M from the Pineapple Fund, and $1M from an anonymous donor.

Needless to say everyone in the SENS community is very pleased by this unexpected generosity. These funds will go a long way towards helping to push allotopic expression of mitochondrial genes (remove the contribution of damaged mitochondria to aging) and cross-link breakers (remove stiffening of arteries and loss of elasticity in other tissues) to completion over the next couple of years, not to mention a range of other important projects in rejuvenation research.

It makes us think that we're somewhere crucial in the tipping point for support and understanding of rejuvenation biotechnology as field.

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On this topic, I have a pet theory regarding wealth and its use to change the world. Historically, people who became extraordinarily wealthy have done so only after many years of work on projects that they were deeply invested in for the sake of the work, not for the sake of financial reward. Consequently they had no real idea regarding what to do with that wealth, other than to keep on moving forward in the shape that they had carved out for their lives prior to that enrichment. They became one with the process that brought them to where they were. Further, these were usually older people by that point, come to terms with the human condition, more comfortable with the world as it is, not as a younger and more fiery individual would have it be. Not everyone is worn down to acceptance - look at the large-scale, results-oriented philanthropy of Bill Gates, for example - but I think it is definitely the case that vision is often one of the early casualties of aging, and the advent of personal wealth doesn't change that situation for any given individual. For every Bill Gates there are another twenty billionaires who fail to change the world in any significant way beyond the ventures that earned them their fortunes.

Cryptocurrencies, the first application of blockchain technologies, have resulted in a sizable number of people who have become enormously wealthy in a much shorter period of time, and at younger ages, than has typically been the case in the past. Even the dotcom bubble era and its immediate sequels didn't reach these levels of youthful enrichment, and that produced a fair number of people young enough and wealthy enough to set forth to remake sections of the world in the service of loftier agendas. They escaped being shaped by the processes of their enrichment to a great enough degree to retain fire and vision. Consider the willingness to put capital towards world-changing futurist ideals exhibited by Elon Musk, Peter Thiel, Mark Zuckerberg, and Sean Parker, to pick a few. But while that generation of high net worth individuals have certainly supported the life sciences, and in Peter Thiel's case SENS rejuvenation research, they largely haven't followed Thiel's support for the goal of treating aging as a medical condition, and Thiel himself has certainly not gone all-in. He hasn't followed the logic further towards its end, in that the only rational use for excess capital in this age is to develop viable treatments to reverse aging. When you can buy time with money, and not just for yourself, but for everyone, then that is the rational thing to do.

The wealthy of the blockchain community may well proceed differently. The times are different, for one, as rejuvenation research after the SENS model of damage repair is more broadly known and accepted nowadays. The technology industry of the Bay Area, still in many ways the spiritual center of modern software engineering and invention, includes a great many supporters of SENS, the Methuselah Foundation, and the SENS Research Foundation, and that number has grown considerably over the past fifteen years. Aging is an engineering problem, SENS is a set of repairs and a set of outlines for repair technologies, and engineers grasp that readily. It isn't a coincidence that there are so many engineers, software and otherwise, to be found participating in the past fifteen years of philanthropy to support progress in rejuvenation research, work based on periodic repair of the cell and tissue damage that causes aging. Now it is the case that many of those engineers in the cryptocurrency space are both young and suddenly wealthy, people who have not been worn down to an acceptance of the world as it is, have not become one with their process of enrichment. They are still willing to consider radical change to the status quo, full of the fire of success, and equipped with sufficient resources to push forward the research and development that they would like to see happen. Exciting times.

If you are interested in perusing some of the past decade of science on this topic, some links below. It is about equally devoted to looking at what happens in induced pluripotency versus what happens during embryonic development, induced pluripotent stem cells and embryonic stem cells being basically the same thing.

Elimination of damaged proteins during differentiation of embryonic stem cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472508/

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming https://doi.org/10.1016/j.cell.2016.11.052

Mitochondrial Rejuvenation After Induced Pluripotency https://doi.org/10.1371/journal.pone.0014095

Aging vs. rejuvenation: reprogramming to iPSCs does not turn back the clock for somatic mitochondrial DNA mutations http://dx.doi.org/10.21037/sci.2016.08.09

A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage https://doi.org/10.1038/nature24620

Any Rejuvenation Relevance for Roundworm Reproduction? http://www.sens.org/research/research-blog/question-month-16...

Only some of the damage repair methods require gene therapy, and in the case of allotopic expression to work around mitochondrial damage that is already demonstrated in human trials by Gensight.

You should look over the linked sub-pages here for an overview of the types of damage and approaches to repair.

http://www.sens.org/research/introduction-to-sens-research

I'd be more concerned about stem cell replacement therapies and lipofuscin removal as categories than anything requiring gene therapy, since in both cases there are a lot of targets and a lot of work to do.

For things like senescent cells and glucosepane cross-links, small molecule therapies will work (and already exist in the former case). In fact all targeted cell killing and specific molecule breakdown needs can probably be addressed sufficiently well via pharmaceuticals for a first generation effort.

There are a wide variety of life courses exhibited in the natural world, when plotting mortality risk over time. The human early start on an exponential increase is just one of them. Flies that reach a mortality risk plateau in late life is another - they just stop aging, they don't get any more damaged in ways that cause mortality than they already are. More complex organisms don't seem to exhibit this phenomenon, but the data for humans is pretty sparse at the ages of interest.

Naked mole rats and humans age for the same underlying reasons, the same types of accumulated damage. The difference in outcomes in terms of the shape of the mortality curve no doubt has to do with quality of repair mechanisms and resilience to particular forms of damage. Naked mole rats have less error-prone DNA replication, repair, and protein manufacture processes, a lack of lingering senescent cells pumping out inflammatory and destructive signals, a mitochondrial composition that is more resilient to oxidative stress (and they have plenty of oxidative damage, judging from the usual markers, they just seem to shrug it off; it doesn't cause further problems). The net result of this is that they do pretty well then fall off a cliff at the end.

It is interesting to speculate on what the cliff might be, a high threshold of damage needed to break an important repair mechanism, or a slowly accumulating form of damage that only really hurts the mole-rat at high levels, for example, but this is probably not very relevant to human medicine.

We know why humans age. We know what the damage is. We don't need to poke around in other species for further illumination in order to make progress towards rejuvenation - we won't learn anywhere near as much as we will from selective repair of the damage in humans or in mammals that are similar to humans. We don't need to improve human damage repair systems (comparatively hard) when we can repair damage (comparatively easy). It clearly takes a few decades for pathological levels of damage to arise, which gives plenty of time to deal with it through periodic applications of therapy, given a working repair biotechnology.

The comparative biology of aging is pure science, unlikely to produce meaningful applications of medicine when compared with other courses of action.

Senescent cells generate inflammation. So every age-related condition with an inflammatory component - which is most of them - should be improved to some degree by that factor alone when senescent cells are removed, even putting aside other effects of senescent cell accumulation.

Senescent cells are not the only source of inflammation - the immune system has other sources of dysregulation. The degree to which their contribution is important will vary tissue by tissue and condition by condition.

Some studies show that a large fraction of astrocytes are senescent in the old human brain. Much larger than is the case for senescent cell fractions by number in other tissues. Too large to just go in and clear them all out in short order - tumor lysis and outright failure of the brain would be on the menu. You'd have to clear them out slowly over a period of time, allowing for their replacement. It is probably good that first generation senolytics won't get past the blood-brain barrier, as they would be pretty hard to use safely otherwise.

I think the problem in the cancer research community is much the same as the one in the aging research community, which is to say pursuing very inefficient strategies. My theory is that the root cause is similar, which is that researchers and funding institutions will follow a path of least resistance that runs as follows:

- investigate the biochemistry of the disease state in a fundamental research paradigm, fairly disconnected from incentive to build treatments, and very distant from root causes. They work backwards from the end state.

- find new discoveries, 99.9% of which can only lead to marginal strategies, because they are working backwards through proximate causes. If you mess with proximate causes, you are not building cures.

- nonetheless, a healthy dose of status arrives from the applicability of findings, so everyone involved is incentivized to oversell applicability. The researchers are usually less guilty, the institutional support network usually much more guilty (but look at David Sinclair as an example of the inverse).

- then the institutional funding for translational development, that really has no capacity to judge expectation value, and is staffed by exceedingly conservative people who are not going to get fired for deploying funding in exactly the same way as their predecessor, deploys money towards marginal strategies that really only arose as a form of status signaling.

So that something effective happens is entirely a happy accident.

As to where most of the blame lies, I'd say the translational research funding institutions. It is their job to pick good projects, and it should be their job to influence earlier parts of the chain towards higher expectation value research and prototyping. Doing that would be vastly cheaper than the present utter waste of value.

From other somatic cells, and ultimately from the tissue stem cell population. That population is impacted by aging, as you point out. However, the effects of replacing 1% of tissues over some period of time are going to be negligible in comparison to the effects of having 1% senescent cells, given that those senescent cells and the inflammatory, harmful signaling they generate are one of the reasons why the stem cell population is less active, and regeneration less effective.

Which is why the SENS portfolio includes a universal cure for cancer.

This is not as hard as people have been made to think it is. The present mainstream approach of the past few decades is just not a good one. It is picking strategies that are very expensive to implement, and that attack vulnerabilities that are peculiar to tiny subtypes of cancer. There are hundreds of subtypes of cancer, most of which are cheerfully capable of evolving their way around many of the existing attacks on their biochemical vulnerabilities. There are only so many scientists, only so much funding. If it takes twenty man-years to produce a therapy to tackle transient vulnerability A in subtype 1 of 1000, we'll never see the end of it. Yet this is largely what is happening.

What should be happening instead is the whole-hearted pursuit of vulnerabilities that are common to many, many types of cancer, or all cancers for preference.

There is one very good one, which is that cancers must lengthen their telomeres, and there are only two ways for that to happen, neither of which should really be operating in somatic cells. So block telomerase, block ALT, and get that hooked up to some kind of cancer-cell-targeting-mechanism of the sort that has been under development for the past decade, and that will work to kill any cancer. A number of high profile groups are working on telomerase sabotage ( https://www.eurekalert.org/pub_releases/2015-01/usmc-rtt1231... ), and the SENS Research Foundation has been funding the necessary research to address ALT ( http://www.sens.org/research/introduction-to-sens-research/c... ), still at comparatively early stages.

There are other, prospective targets. The comparative biology crowd is reverse engineering naked mole rats to figure out what it is that makes them next to immune to cancer. There are a few leads there; p21, ARF, hyaluronan, alpha2-macroglobulin, etc. Another recent discovery relates to re-engaging the limitation on processing nutrients; apparently all cells have a food limiter, and all cancers abuse that limiter in order to enable rampant replication. Re-enable the limiter and cancers wither: https://www.salk.edu/news-release/salk-scientists-curb-growt...

So there is no shortage of possibilities for people who want to kill all cancer. There is no excuse for continuing the wasteful business as usual of the past decades. This is an age of revolutionary progress in biotechnology - we should act like it and aim high.

They amount to a few percent of tissues in most cases. In mitotic tissues they will be replaced in the same way as any cell is replaced when it dies, by replication. In post-mitotic tissue cell therapy might be needed, but that hasn't so far been an issue in mice. It might be an issue for the human brain. Remains to be seen.

Senolytics, to clear senescent cells, is a fundamentally different and more theoretically sound approach in comparison to trying to override signaling that is partially downstream of the presence of senescent cells. It also works far more reliably and for many more aspects of aging in mice.

Senescent cells are one of the root cause of aging. Signaling changes in old blood are downstream of the root causes of aging - secondary and later consequences.

Senescent cells are created by the operation of normal processes of healthy, youthful metabolism, and if their numbers can be periodically culled, then their contribution to aging will be removed.

If your car is flagging, you repair the engine by replacing a damaged part, not by pressing the accelerator harder. Removing senescent cells is replacing a damaged part. Overriding signaling changes is pressing harder on the accelerator, while ignoring the damage.

Safe, yes, but I think "promising" is more aimed at the investors than a reflection of reality. Both Alkahest and Ambrosia's results are essentially ambiguous, which reflects the equally ambiguous animal data for plasma transfusion.

This isn't going to stop other people from trying analogous things.

The Conboys are trying apheresis to strip out harmful factors from old blood ( https://www.leafscience.org/conboy-interview/ ), which seems to me unlikely to move the needle either, and other groups are trying to identify and deliver signals from young blood.

What all of these things have in common is that they are failing to address root causes. Why does signaling change in old blood and tissues? Because the cells that generate that signaling are either damaged or reacting to damage. Trying to force the signaling to be more youthful has very definite limits - it might compensate a little for one consequence of the damage, but that damage is still there, still producing all of the other problems that it causes. The "change the signaling" approach requires the research community to map every single one of potentially hundreds or thousands of individual changes, then understand which are relevant, and then run individual projects for each one. It just won't happen - look at the cancer research community for a guide as to how slowly that sort of scenario progresses.

The plausible outer limits of signaling adjustment are probably indicated by the effects of first generation stem cell therapies, which largely work through the signals introduced by the transplanted cells. Assume that something somewhat better than that can be achieved: meaning temporarily improved regeneration, less increased cancer risk than was originally suspected, but not much of an impact on aging and age-related disease, when considered in the context of the bigger picture of what is possible.

(What is possible if people would just stop tinkering with downstream consequences and start repairing the root cause damage. At least the flurry of interest in senolytics is a start in that direction, and should hopefully prove the point by being so very much better and more cost-effective than just about everything else on the market when it comes to treating age-related conditions).

There are a lot of people thinking about beneficial factors in young blood and harmful factors in old blood. Some are looking at period apheresis of blood to remove harmful factors, some are investigating transfusions, some looking at delivery of factors directly.

I don't see this area of work as a useful way forward to major impact on human aging and life span, though it will no doubt increase understanding of the way in which metabolism reacts to the causes of aging as they increase. Like much of what goes on in the research community, it is an effort to tinker with secondary and later aspects of aging. Changes in factors in the blood are not the cause of aging, they are the consequence of cellular reactions to the causes of aging. So this sort of work is changing the oil and cleaning the spark plugs in the hopes of small gains rather than repairing and replacing the failing engine parts in the hopes of large gains.

But that is somewhat beside the point. The important thing here is that organizations like the Society for the Rescue of Our Elders have come into being and are surveying the field for things they can do to impact aging, ways to accelerate the otherwise very slow progress of clinical translation in a field of research that is, on the whole, still pretty reluctant to actually make waves and public noise. Given who is involved in the Society, it will mean a lot of garbage in addition to the actually useful stuff like senolytics, but overall it is much better to have people actively trying to organize trials to gain evidence rather than not. That speeds up the process of winnowing out the useless, marginal projects and promoting the useful ones, on the basis of the results rather than debate over mechanisms.

No-one in the field is particularly impressed with Calico at this point in time. Calico is the second coming of the Ellison Medical Foundation, which is to say they're just analyzing the details of aging and expanding on the NIH budget. Nothing they are known to be doing is likely to have the slightest impact on the progression of rejuvenation therapies.

E.g. some resources in which people are less than complimentary:

http://www.sens.org/research/research-blog/question-month-16...

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

https://www.vox.com/science-and-health/2017/4/27/15409672/go...

There are plenty of others if you want to go look for them.

Think about how complex machines fail. Reliability theory is a good tool for this, and has been used to effectively model how aging works, as failure of units in a system of redundant units.

https://doi.org/10.1006/jtbi.2001.2430

You will see that there is no good way to compress the tail end of mortality and consequences resulting from accumulated unrepaired damage. The only cost-effective path is to postpone it indefinitely through periodic repair of that damage.

Aging is damage, and mortality/disability rises with damage. Effective treatments for aging are forms of repair of damage, of which only senolytics presently exist in any form that is available. Once you accept this model, you can start to reason about the effects of various approaches, and everything makes a lot more sense.

And a different, policy-of-medicine-and-rejuvenation interview with de Grey from a politically focused site here:

http://merionwest.com/2018/01/08/an-interview-with-anti-agin...

That would only be the case in the models where senescence is blocked completely.

If instead for a short time killing some fraction of all currently existing senescent cells, the effect on cancer risk should be a reduction, due to decreased inflammatory signaling from those cells. The senescent cells that are hanging around at any given moment in time aren't helping you in any way; they're not reducing the risk of cancer. If there are enough of them, they are in fact increasing the risk of cancer due to messing with the surrounding environment. If those senescent cells ever actually helped, then that help was applied at the time the cell became senescent - and shortly thereafter it became a liability that should be destroyed.

There are emerging exceptions to that view, such as adaptive senescence in the immune system and possibly in support cells in the brain, but fortunately both of those should be largely moot points for the early senolytic therapies, and don't seem to be obstacles in old mice.

I'll get to publishing a detailed essay on that topic at some point in the near future. The less detailed precursor overview can be found here:

https://www.fightaging.org/archives/2017/05/planning-a-singl...

You don't need a doctor to figure out a treatment plan, you just need to put in some time to get familiar with reading research papers, the terminology, how researchers describe things, and the methodology used to move from animal to human exploratory studies. And an understanding of the risk - as doctors are usually pretty bad at explaining that in any case. It really isn't rocket science, and it is all copiously documented in scientific and other literature.

Also D+Q isn't administered monthly, it is a one-off treatment that, assuming it works in humans in the same way it does in mice, certainly wouldn't need to be done more than once every few years. It removes the cells it can remove, and then isn't going to do any more until new senescent cells arise at their slow pace. The people out there taking it frequently as though it were a supplement are just not acting sensibly, and don't understand the research.

Rejuvenation therapies and treatments that slow the progression of aging won't be tested in humans by waiting to see. They will be tested using quick before/after measures of biomarkers of aging. Those biomarkers are under development, and numerous types exist somewhere in the slow scientific process of standardization and debate. Here applied to calorie restriction, for example:

https://academic.oup.com/biomedgerontology/article/73/1/4/38...

"We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank (https://calerie.duke.edu/). The CALERIE trial randomized N = 220 nonobese adults to 25% caloric restriction (n = 145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n = 75) for 2 years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera–Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans."

That said, it is quite clear that research into provoking stress response isn't going to do much for longevity in humans, even while it may do useful things for long-term health in the same way as exercise and calorie restriction do. In addition to calorie restriction, growth hormone receptor knockout can be compared in mice and humans with Laron syndrome - the large gains in mouse life span don't occur in humans.

However, research into repairing the damage that causes aging is a whole different ball game. A completely different strategy, set of mechanisms, overall approach, and effect on the individual. A reversal of aging rather than a slight slowing of aging. We have no idea how results in mice will map to results in humans. So it is worth keeping an eye on the ongoing pilot trials and forthcoming larger trials of clearing senescent cells in human patients.

Actionable things for humans at the moment appear to look like trying senolytic drug candidates in rational self-experimentation, with before/after tests of metrics linked to tissue stiffness, inflammation, kidney and heart function.

Clearing senescent cells very clearly produces a degree of rejuvenation in mice, and can turn back progression of aging and specific age-related diseases via a sizable number of metrics.

Of those senolytic drug candidates, dasatinib plus quercetin if you're fine with short burst of chemotherapeutics, or FOXO4-DRI if you are fine with using peptides lacking human data. Both of which should be filed under the "risk that needs to be well understood" category. Or you could wait a few years for the first human trials to run through and more data and better drug candidates to arrive.

But these things are on the menu of possibilities, and are not expensive at all to carry out as exploratory tests.

The author of this overview, Laura Deming, runs the Longevity Fund, and has a research background in the study of aging. She merits congratulations for being, I think, the first by a few years to put together a longevity-focused fund, now joined by e.g. Jim Mellon's Juvenescence venture, Methuselah Fund, Apollo Ventures, etc.

Rejuvenation research after the SENS Research Foundation model of repairing the known root causes of aging is a massive arbitrage opportunity. It remains the case that most people just don't get it, and are thus enormously undervaluing research and companies in this space. That is changing in senescent cell clearance, but six or seven other nascent areas of research and development are in exactly the same position senescent cell clearance was in back in 2010 - no attention, little funding, low valuation, huge potential for breakout gains in said valuation on producing a technology demonstration for rejuvenation in animal models.

It seems likely that the Longevity Fund will do well on the basis of having invested in Unity Biotechnology alone, even putting aside any other successes. The article linked here is a useful overview, with copious references, of the type of work presently taking place in the aging research community. It well illustrates that, aside from senescent cell clearance, nearly everything that counts as a major interest by funding and number of scientists involved is a form of tinkering with stress response biochemistry to modestly slow aging - not addressing root cause molecular damage by repairing it, but rather messing with metabolism to slow damage accumulation. Nowhere near as helpful.

Given what we know, where the data exists to compare outcomes between short-lived and long-lived species, the approach of altering metabolic processes to enhance beneficial stress response mechanisms is not going to move the needle all that far in humans. The results should be exercise-like and calorie-restriction-like in that they have worthwhile effects on long-term health, assuming that the cost of development and treatment is low, but they won't add much more to life expectancy than those two items are capable of achieving - which means perhaps the low end of five to ten years at best in our species, assuming life-long commitment to the intervention. Given that senescent cell clearance is a going concern, and other damage repair approaches such as cross-link breaking should follow in the years ahead, we can hope that the focus of the research community will shift as other approaches prove themselves much more cost-effective and successful.

People who think that rejuvenation therapies are only for the rich are not paying attention.

Look at first generation senolytic drug candidates that clear ~25% of senescent cells in mice, varying by tissue type. These vary from $100 per dose, for things like dasatinib plus quercetin, to a few thousand dollars per dose where you need a biotech company to one-off synthesize it for you, such as foxo4-dri. One dose is needed every few years - more than that won't help further.

The story will be the same for glucosepane cross-link breakers.

The trend in this type of technology is towards engineered small molecule / enzyme / peptide / etc that will cost next to nothing a decade after it is introduced, and can in any case be manufactured to order in China and shipped in if the patent holder decides to try charging monopoly rates. Alternatively, gene and cell therapies that can be mass produced, all the complexity baked into that manufacture, and then administered by a bored clinician. The cost will be similar to present day biologics, which are largely in the $1-10k/dose range. Again all of these treatments will be once-every-few-years, not any more frequently. That is the point of damage repair as a strategy - you only need to do it as often as the damage builds up. There is no point in doing it any more often.

This piece is a great example of entirely the wrong way to think about this issue.

The procession of mechanisms is as follows, starting with layer 1:

- calcification

- cross-linking

- vascular smooth muscle dysfunction

Which gives you layer 2:

- vascular stiffness

Which then, entirely and all by itself ( http://dx.doi.org/10.1371/journal.pcbi.1003634 ), causes layer 3 by messing with the feedback mechanisms for blood pressure control:

- hypertension, raised blood pressure

Which then causes layer 4:

- microvascular damage, such as stroke, kidney issues

- major vascular damage and sudden death when combined with atherosclerosis

- cardiac hypertrophy, which is a maladjustment to hypertension

Calcification may be secondary to cellular senescence and other inflammatory mechanisms. Persistent cross-linking may be made worse by dietary sugars, or may not - the better studied forms of sugary by-product are not all that relevant to persistent cross-linking that stiffens tissue. You can read up on glucosepane to learn more about that. The vascular smooth muscle dysfunction is probably caused by a combination of inflammatory mechanisms and everything else that changes with age and poor health, such as metabolic syndrome.

So if thinking about fixing hypertension, you want to be watching people building cross-link breakers, such as the Spiegel team at Yale, funded by the SENS Research Foundation, or people clearing out senescent cells, such as the current brace of senolytic therapy companies, one of which was seed funded by the SENS Research Foundation. Watching the groups looking into smooth muscle may or may not go anywhere; it is very hard to say at this stage whether there is any one target that might help enough for the usual pharmaceutical development approach to work well enough to care about in the near term.

The biggest thing? Since arguably sometime in the 1930s the technological capacity has existed to store at least the brains of dead individuals at liquid nitrogen temperatures indefinitely, waiting on a future that can restore them. In a different, better world, the funerary industry was swept aside by mass cryopreservation, and the vaults of those who would one day live again would be now be vast. The biggest thing we get wrong is that we continue to equate clinical death to oblivion, rather than it being only the second worst thing that can happen to you, and acting accordingly.

It is getting more attention these days, and the older discoveries have had enough following attention to be fairly widely known in the field. It isn't a line of research I've followed specifically, but if you look at PubMed you can follow the trail over the past decade.

https://www.ncbi.nlm.nih.gov/pubmed/?term=nlrp3

They have a histogram by year, and papers looking it over in the context of inflammation are getting quite common. I'd expect some sort of trial to emerge in the next few years, it seems to be getting to that point.

There is a range of research to suggest that Alzheimer's is a metabolic disorder with high level similarities to type 2 diabetes. You might look up "type 3 diabetes" - which is not an official designation, but sufficiently discussed in the research community and associated with Alzheimer's disease that when a different form of (definitely) age-related diabetes was discovered recently, it had to be called type 4.

Equally, don't look for single causes. There are multiple contributing factors, all of which interact with one another, and many of which have multiple causes. E.g. amyloid buildup can be in part failure of clearance by immune cells, in part failure of drainage of cerebrospinal fluid through the cribiform plate, in part generation by lingering spirochete infection, etc.

Paper: https://doi.org/10.1038/nature25158

The research noted here improves the understanding of how inflammation acts to drive the progression of Alzheimer's disease, despite being secondary to the well-known deposition of amyloid-β observed in the condition. Alzheimer's disease is considered to be in part an inflammatory condition. Rising levels of chronic inflammation occur with aging, in the brain and elsewhere in the body, and there is plenty of evidence for inflammation to contribute to a good many age-related conditions. The ordering of cause and effect in Alzheimer's is still somewhat up for debate, but there is evidence for the cascade to begin with amyloid-β, that then produces inflammation as the immune cells of the brain react to it, which in turn leads to tau aggregation. The paper here adds nuance to that possible ordering, suggesting that amyloid-β and inflammation form their own feedback loop, spurring one another forward.

The immune system of the central nervous system is its own creature, quite different in its details from the immune system of the rest of the body, and arguably much more integrated and necessary for the correct function of the brain than is the case in other organs. Nonetheless, similar classes of age-related dysfunction arise, and inflammation is one of the results regardless of protein aggregation such as the formation of amyloid deposits. Immune cells become overly active, but at the same time less effective at carrying out their assigned tasks. Inflammation is a necessary part of the immune response to many of the issues it might have to deal with, typically those that involve destruction, as as removal of senescent or potentially cancerous cells, and mounting attacks upon the pathogens that constantly try to invade the body and brain. If permanently switched on, however, inflammation begins to disrupt all of the other necessary tasks of the immune system, such as those relating to regeneration or shepherding the correct function of brain cells.

For a number of years now, some researchers have departed a little way from the mainstream focus on removal of amyloid-β to consider an anti-inflammatory approach to building therapies for Alzheimer's, but this line of research hasn't made a sizable impact yet. Reducing inflammation in a usefully targeted way is still quite challenging, as the immune system is very complex, though promising noises are emerging from research groups investigating NLRP3 as a target. That also happens to show up in the research here as a part of the connection between immune cells, amyloid, and inflammation.

The research community still lacks a reliable, ready to be productized method of producing vascular networks capable of supporting an organ.

However, mass-manufacture of organoids is definitely a thing that can be worked on today. Functional organoids for kidneys and livers might be able to replace many transplants, as you can in principal deploy them in volume, stick them onto and into the existing kidney or liver and they will help. The studies of transplantation have been done in animals, and they work. The same goes for the thymus, possibly lungs, heart muscle, and a variety of other tissues in which functional small sections or thin sheets can be grown from a patient's cells.

The idea would be to build an organoid manufacturing business, and by the time it gets large someone will have solved the blood vessel network problem, and you move on to organs at that point.

Find research you like, find a syndicate of investors, and do the legwork to bring those two things together. This is going on today in the matter of rejuvenation research - people talking about and funding the early stage startups they like that happen to be following the SENS model for cell and tissue damage repair. You don't even have to be wealthy to do this, just someone who can talk to be people and knows something about the science. Scores of people in the network built around the SENS Research Foundation are doing their part to make relationships and get the right people talking to one another in order to launch startups working on the desired types of therapy.

That is how it is done.

From the point of view of people with funds to spend, there is more that can be done to influence research than just sitting around waiting for startups to present themselves.

Investing is something that investors do moderately well - there is a method and a discipline and a body of tradition and knowledge. But it isn't the only thing that investors can do to speed the development of longevity science. What the investment community should do, attempts to some degree, but remains very poor at accomplishing, is the process of nudging along pre-commercial scientific efforts, of strategically funding specific research projects in order to produce a new crop of longevity science companies. This seeding of the field can be highly effective, as the SENS Research Foundation has demonstrated over the past decade or so, yet for the most part even personally interested investors leave philanthropy in their field to other people. Thus funding for truly radical, high-risk, high-reward new research is next to non-existent. The other side of the coin, targeted funding for medical research projects with excellent prospects, or that are only a few years and a million dollars away from the leap to a candidate therapy and a startup, nudging them into the target zone, is also very thin on the ground.

This is a point that Peter Thiel has been making for a few years under the heading of "radical philanthropy." The investor community does conduct philanthropy, but in an ad-hoc fashion, without much organization, rigor, or discipline. There is no body of tradition and knowledge in the same way as exists in the business of for-profit investment. Thus great many philathropic ventures conducted by investors are ultimately largely a waste, failing to achieve the practical ends that are possible in principle because they fail to meaningfully advance research towards the clinic. Money is poorly used, and there is little in the way of deliberate, carefully efforts to nudge promising research across the line. This is strange given that it is a very good way to be positioned as the primary investor in ventures in a field that an individual might want to see move faster.

All of this is to note that the launch of a company happens a long way after the start of the development process, and investors should become involved well before that point if they want to better achieve their goals. Many of the donors to SENS rejuvenation research projects initiatives are investors themselves, and some are presently coming together as a loose community of peers to invest in the startups that are now beginning to emerge from research efforts. Yet this is still at the present time, even hard-won as it is, only one increment better than a collection of happenstance events and connections, tumbling in more or less the right direction and working out because everyone involved has much the same goal in mind - which is to say therapies to treat aging, and sooner rather than later. Building on what has been learned so far, better and more organized ways to meld philanthropy and investment might be assembled. A community with deep pockets that can build the intricate networking tools and the energetic, highly networked approach to for-profit investment that presently exists should be able to make the leap over the barrier to organize and assist the non-profit research pipeline as well.