reasonattlm

As the article notes the procedure isn't effectively clearing out all of the old mitochondria, and dynamics can favor them in the future.

It is known that variations in mitochondrial DNA produce radical differences in competition between mitochondrial strains in the cell. That is how deletions affecting OXPHOS machinery cause one mutant to take over the whole population very quickly - some differences produce mitochondria that either replicate better or resist quality control more effectively. That one is one of the causes of aging, but the same principle exists for other differences between mitochondrial genomes. If you put two or more in a cell and let them fight it out, hard to say in advance what the outcome will be given present knowledge.

So, basically, the people working on mitochondrial replacement need to make their tools for cleaning out the old mitochondria more efficient. If 100% success is achieved, that genome isn't coming back.

Alternatively, actual gene therapy might be a better approach - though challenging if you want to edit mitochondrial genomes, as you have the same problem of coverage and competition. There is allotopic expression, moving mitochondrial genes to the cell nucleus, which is feasible via today's gene therapy. Given the amount of work needed to copy mitochondrial genes into the nucleus, however, the challenge being how to alter them so as to get the proteins produced back to the mitochondria, something that has been achieved for three genes so far, it might be more cost-effective to work on better clearance and replacement technologies for the near term of assisted reproduction needs.

And yet for aging? Lunacy.

Is this not an age of biotechnology? People have very, very odd attitudes towards the fatal medical condition known as aging that they do not bring out for any other medical condition.

The short answer to your question is that the impact of everything viable that is not SENS is probably going to be about the same as exercise or calorie restriction in your life span if you are in the middle of life now. Which is to say +10 years if you pick the right things, and the people building those things do a good job. That would be, say, the combination of a couple of successes in things building upon mTOR or stem cell or telomerase therapies or etc. Not resveratrol, not 99% of the other pharmaceuticals, not 99% of the possible gene therapies, and not 99% of what people are trying to sell you.

http://www.cell.com/cell/fulltext/S0092-8674(16)31664-6

Caveats:

1) Doing anything to the aging of cells in culture has next to nothing to do with what goes on inside aging tissues, or where it does that is heavily dependent on the details. The article doesn't tell you enough to decide, so you should look at the paper.

2) Doing anything that attenuates the effects of an accelerated aging phenotype, actually usually a DNA repair disorder, almost always has nothing to do with aging as it happens in normal individuals. You can hit mice with hammers, and then evaluate the effects of a hammer-blocking cage, but that doesn't tell you anything about aging - and for exactly the same reasons. This is generally true except when it is isn't, and that depends on the fine details. Again, go look at the paper.

3) The interesting experiment is the one in which pluripotency-inducing factors are upregulated in a normal mouse, but temporarily. This is the thing that people have looked at in the past and said, well, turning on widespread transformation of somatic cells into pluripotent stem cells sounds like a really bad idea. Cancer seems the likely outcome, and that has in fact been demonstrated in a couple of studies in mice, but there is also the point that your central nervous system rather relies upon maintaining the fine structure it has established in many cases, such as data stored in the brain. Running in and randomly reprogramming any CNS cells that take up the vector or the pluripotency signals seems like a bad idea on the face of it.

So on the whole it is fascinating that a good outcome was produced in the normal mice, analogous to the sort of thing that has been produced via stem cell transplants and telomerase gene therapies. But I'd still want to see what happens to the mice over the long term after that, and would expect cancer.

1) Doing anything to the aging of cells in culture has next to nothing to do with what goes on inside aging tissues, or where it does that is heavily dependent on the details. The article doesn't tell you enough to decide, so you should look at the paper.

2) Doing anything that attenuates the effects of an accelerated aging phenotype, actually usually a DNA repair disorder, almost always has nothing to do with aging as it happens in normal individuals. You can hit mice with hammers, and then evaluate the effects of a hammer-blocking cage, but that doesn't tell you anything about aging - and for exactly the same reasons. This is generally true except when it is isn't, and that depends on the fine details. Again, go look at the paper.

3) The interesting experiment is the one in which pluripotency-inducing factors are upregulated in a normal mouse. This is the thing that people have looked at in the past and said, well, turning on widespread transformation of somatic cells into pluripotent stem cells sounds like a really bad idea. Cancer seems the likely outcome, but there is also the point that your central nervous system rather relies upon maintaining the fine structure it has established in many cases, such as data stored in the brain. Running in and randomly reprogramming any CNS cells that take up the vector or the pluripotency signals seems like a bad idea on the face of it.

So on the whole it is fascinating that a good outcome was produced in the normal mice, analogous to the sort of thing that has been produced via stem cell transplants and telomerase gene therapies. But I'd still want to see what happens to the mice over the long term after that, and would expect cancer.

Telomerase gene therapies clearly slow aging and extend life in mice to some degree, but the actual mechanism involved is up for debate. We can argue that it has more to do with stem cell activity and influence on mitochondrial function for example than keeping cells out of senescence.

My comfort level for telomerase therapies would be increased by running them in dogs or another longer lived mammal with telomere dynamics that are closer to those of humans and observing the results there. Of course this might well be beaten out by actually running them in humans if the BioViva / Sierra Sciences collaboration gets their medical center running in Fiji to offer the gene therapy at a reasonable cost some time in the next year or two.

No-one in the scientific community, and certainly none of the people mentioned in the article, thinks that there is a limit to life span that cannot be overcome or changed through medical science. Olshansky is one of the principals of the Longevity Dividend initiative, for example, a group of researchers who want to slow aging and increase funding to the NIH for that goal. Vijg is on record a number of times over the years talking about slowing the aging process, and has collaborated with the SENS Research Foundation. Vaupel has long worked to popularize the concept of plasticity of aging in response to environment and medicine.

Aging is caused by a few distinct processes that are independent in the sense that removing one won't remove any of the others, and linked in the sense that each of them tends to speed up and make worse the consequences of the others. See the SENS outline or the Hallmarks of Aging paper for examples of categorization. It is perfectly possible for there to exist in these processes one that produces a very high rate of mortality at later age (100+) when it goes unaddressed. A very high rate of mortality looks a lot like a limit.

A good candidate for this process is the accumulation of transthyretin amyloid. This appears linked with mortality due to heart disease in younger old people (70-100), but only in 10% of cases based on analysis to date. Yet in supercentenarians, those 110 or older, transthyretin amyloidosis is the primary cause of death, based on the small number of autopsies carried out by those capable of such analysis. No presently available form of medicine does anything to reduce levels of this amyloid, and nor is there any presently available therapy that even aims at that goal.

However, there is a company, Pentraxin Therapeutics, that has a therapy capable of clearing this form of amyloid, somewhere in the glacial processes of Big Pharma development. Promising trial results were reported in 2015.

All aspects of aging are potentially modifiable and controllable, in the same way as any chronic disease state is given the technology to do it. That has absolutely nothing to do with present day demographics and whether or not we can talk about limits due to present mechanisms operating to produce aging. But I do think it is far more important than understanding the precise details of how aging arises and how mortality rates can be decomposed and assigned to specific components of aging.

Three articles in this issue address the role of vitamin and mineral supplements for preventing the occurrence or progression of chronic diseases. First, Fortmann and colleagues systematically reviewed trial evidence to update the U.S. Preventive Services Task Force recommendation on the efficacy of vitamin supplements for primary prevention in community-dwelling adults with no nutritional deficiencies. After reviewing 3 trials of multivitamin supplements and 24 trials of single or paired vitamins that randomly assigned more than 400 000 participants, the authors concluded that there was no clear evidence of a beneficial effect of supplements on all-cause mortality, cardiovascular disease, or cancer.

Second, Grodstein and coworkers evaluated the efficacy of a daily multivitamin to prevent cognitive decline among 5947 men aged 65 years or older participating in the Physicians’ Health Study II. After 12 years of follow-up, there were no differences between the multivitamin and placebo groups in overall cognitive performance or verbal memory. Adherence to the intervention was high, and the large sample size resulted in precise estimates showing that use of a multivitamin supplement in a well-nourished elderly population did not prevent cognitive decline. Grodstein and coworkers’ findings are compatible with a recent review (3) of 12 fair- to good-quality trials that evaluated dietary supplements, including multivitamins, B vitamins, vitamins E and C, and omega-3 fatty acids, in persons with mild cognitive impairment or mild to moderate dementia. None of the supplements improved cognitive function.

Third, Lamas and associates assessed the potential benefits of a high-dose, 28-component multivitamin supplement in 1708 men and women with a previous myocardial infarction participating in TACT (Trial to Assess Chelation Therapy). After a median follow-up of 4.6 years, there was no significant difference in recurrent cardiovascular events with multivitamins compared with placebo (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]). The trial was limited by high rates of nonadherence and dropouts.

The large body of accumulated evidence has important public health and clinical implications. Evidence is sufficient to advise against routine supplementation, and we should translate null and negative findings into action. The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided. This message is especially true for the general population with no clear evidence of micronutrient deficiencies, who represent most supplement users in the United States and in other countries.

The first is that the FDA and similar organizations are demanding ever-increasing amounts of data and expense. The cost of drug approval has doubled, accounting for inflation, over the past ten to fifteen years alone.

The second item is that near all drugs have limited cost-benefit ratios - they simply don't make much of a difference. The reason for this is that most therapies do not address root causes, but rather proximate causes. Try making a damaged machine run better and longer without repairing the actual damage. It isn't easy, and the results are marginal. It is the same in biology. The reason why most therapies address proximate causes is because most research starts with the end stage disease and works backwards down the chain of cause and effect in cellular biochemistry in search of causes. At each new step in the chain, typically someone tries to build a therapy. And usually fails for the above reasons.

If a therapy provides an actual cure, no-one is standing on the sidelines talking about placebo effects. Look at, for example, the very effective cure for multiple sclerosis achieved through aggressive immune ablation. Is there anyone in that situation arguing that, oh, we must account for the placebo effect? Of course not. That would be dumb. Because the effect is very large, very beneficial, and very robust.

The problem is that too much medical development is aiming at the outset for results that are small, marginal, and only achieved in some patients.

One of the more intriguing of the recent ones is this from last year, strongly reinforcing the theory that most species lost proficient regeneration due to evolutionary battles between cancer and aging. The greater question is perhaps why there are any proficient regenerators among the vertebrates rather than why we can't do it.

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

"Whether the regenerative powers of zebrafish and salamanders represent ancient abilities that mammals have lost, perhaps in exchange for advanced tumor-suppression systems remains an open question for biologists. Most tumor suppressor genes, being extremely useful for preventing cancer and for forming tissues during development, are broadly distributed and conserved across many different species. Recent studies, however, suggest that one, the ARF gene, arose more recently in the avian and mammalian lineage, and has no equivalent in the genomes of highly regenerative animals. To explore whether this gene might play a role in preventing tissue regeneration in humans, the researchers added human ARF to the zebrafish genome and assessed how it affected the fishes' normal ability to regrow damaged fins after injury. They found that human ARF had no effect on the fishes' normal development or response to superficial injury, but when the researchers trimmed off the tip of a fish's tail fin, the gene became strongly activated and almost completely prevented fin regrowth by activating a conserved tumor-blocking pathway."

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

One of the more recent innovations in calorie restriction research has nothing to do with the science, and everything to do with figuring out how to pull more funding into the field. There is never enough funding for research in any field: going by how funds flow through our societies, it is easy to say that to a first approximation no-one really cares about progress in medicine. Bread and circuses, yes. Better technologies, better understanding of biology, and less disease, no. There is also a large difference between the funds available for non-commercial research versus money available and interested in investment in for-profit ventures. The latter is at least ten times the former, and much more easily arranged as well. Writing grants and raising philanthropic funding is a considerably harder job than pitching angels and venture firms; more effort for fewer dollars at the end of the day. But without the funding for non-profit research initiatives, there will be no new technologies ready to be carried forward in for-profit companies. It is one of the great frustrations of patient advocacy to know that the owners of countless millions of dollars are sitting on their hands, waiting for viable biotech companies, while the important research projects that will generate those companies struggle to raise hundreds of thousands to sustain shoestring budgets.

Calorie restriction is a particular challenge in this context. It is a lifestyle choice, not a drug or an antibody or something else that the medical industry understands how to package, market, and sell. It is nothing more than eating sensibly and eating less. Anyone can choose to do it. It is free and straightforward and well-documented. Yet the effects on long-term health and aging in ordinary individuals are much larger than anything that can be generated by the presently available panoply of drugs and other interventions. That, I should say, is more a statement on the poor quality of present medicine when it comes to treating aging as a medical condition than it is on the benefits of calorie restriction. It is a case of something being better than nothing: no presently available medicine deliberately addresses the root causes of aging, for all that the first therapies that will do that are in development at various stages. The nature of calorie restriction means that there has been little to no for-profit investment aiming to better characterize its benefits. Rather, all that funding was directed towards mapping the biochemistry and haphazardly testing the established drug libraries to find something that triggered any of the same effects. The search for such calorie restriction mimetics is well documented elsewhere, so I won't dwell on that, beyond noting that the outcome of ten to fifteen years of work and a great deal of money is, so far, nothing of any practical use.

So to calorie restriction itself, and how to obtain for-profit funding for research into eating less, and eating less in an effective way. The innovators here are Valter Longo and colleagues, who have achieved the goal of pulling in for-profit funding on the backs of turning specific implementations of fasting and low-calorie diets into FDA-approved therapies, such as an adjuvant in cancer treatment. The magic of regulation means that companies can manufacture a medical diet on the basis of research, and then use the barriers set up via intellectual property and regulatory pronouncements to charge an inordinate amount for what is, basically, a little bit of food that anyone could throw together after reading the papers to obtain the target calories, protein, micronutrient levels, and so on. That in turn means that the principals of these companies are willing to pay for the supporting research. On the one hand it's a depressing example of the distorted priorities that emerge from regulation of medicine, on the other one feels a certain admiration for Longo et al for having successfully hacked the system to fund the useful results they have produced these past few years. Quantifying the degree to which fasting alters the immune system, and quantifying the degree to which low-calorie diets and fasting are effectively equivalent in altering metabolism, are both helpful new information for those who practice forms of calorie restriction and intermittent fasting. In any case, here is a pointer to the less useful outcome from all of this, which is to say the medical diet. It comes across as a bad parody of itself, but that seems fairly true of most medical diet products - you can go look at ProLon yourself.

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."

Which still leaves open the question of how and why the early parts of this avalanche got started in England but not in Taiwan or Japan or Sardinia as analogous islands, and why the actual timing as opposed to any other plausible century.

1) 25% median life extension in mice: http://dx.doi.org/10.1038/nature16932

2) Reverses aspects of lung tissue aging in mice, including loss of elasticity: http://insight.jci.org/articles/view/87732?key=a306472a4316d...

3) The missing link in diabetic retinopathy: http://dx.doi.org/10.1126/scitranslmed.aaf9440

4) A factor in atherosclerosis development: http://dx.doi.org/10.1126/science.aaf6659

Which really just scratches the surface of the enormously amount of research accumulated since the 1960s on the role of senescent cells in aging and age-related diseases. The lung tissue paper above is a particularly good read if you want to get a sense for the nuts and bolts of the issue. Senescent cells secrete signals that disrupt tissue structure and cellular behavior, and even at 1% of the population, that is enough to produce pathology. But on the other hand, 1% is small enough to clear without major disruption, so targeted destruction is a very plausible technology, and removing some fraction of these cells as a one-time treatment should be all upside. Repeat as needed.

I'm in much the same boat. I have great admiration for those who have pulled off the mid-life career switch into biotechnology. There's one of those folk at the Buck Institute working on senescent cells with Judith Campisi of UNITY, in fact, transitioned over from a former entrepreneurial business career. He quit that, went back to school, and there he is, being a scientist and advancing the state of the art: http://www.buckinstitute.org/content/kevin-perrott

But for me, the math works out such that the road of greatest efficiency is to channel money into research funding via organizations like the SENS Research Foundation that I know are going to make good use of it, and have a great track record of making good use of past donations.

http://www.prnewswire.com/news-releases/unity-biotechnology-...

Which includes reference to the latest research they've published, on senescent cells in atherosclerosis pathology. This crowd likes timing their press and their research releases.

My comments:

------- The whispers of late have had it that UNITY Biotechnology was out raising a large round of venture funding, and their latest press release shows that this was indeed the case. The company, as you might recall, is arguably the more mainstream of the current batch of startups targeting the clearance of senescent cells as a rejuvenation therapy. The others include Oisin Biotechnologies, SIWA Therapeutics, and Everon Biosciences, all with different technical approaches to the challenge. UNITY Biotechnology is characterized by a set of high profile relationships with noted laboratories, venture groups, and big names in the field, and, based on the deals they are doing, appear to be focused on building a fairly standard drug development pipeline: repurposing of apoptosis-inducing drug candidates from the cancer research community to clear senescent cells, something that is being demonstrated with various drug classes by a range of research groups of late. Senescent cells are primed to apoptosis, so a nudge in that direction provided to all cells in the body will have little to no effect on normal cells, but tip a fair proportion of senescent cells into self-destruction. Thus the UNITY Biotechnology principals might be said to be following the standard playbook to build the profile of a hot new drug company chasing a hot new opportunity, and clearly they are doing it fairly well so far.

So this, I think, bodes very well for the next few years of rejuvenation research. It indicates that at least some of the biotechnology venture community understands the likely true size of the market for rejuvenation therapies, meaning every human being much over the age of 30. It also demonstrates that there is a lot of for-profit money out there for people with credible paths to therapies to treat the causes of aging. It remains frustrating, of course, that it is very challenging to raise sufficient non-profit funds to push existing research in progress to the point at which companies can launch. This is a problem throughout the medical research and development community, but it is especially pronounced when it comes to aging. The SENS view of damage repair, which has long incorporated senescent cell clearance, is an even tinier and harder sell within the aging research portfolio - but one has to hope that funding events like this will go some way to turn that around.

From the perspective of being an investor in Oisin Biotechnologies, I have to say that this large and very visible flag planted out there by the UNITY team is very welcome. The Oisin team should be able to write their own ticket for their next round of fundraising, given that the gene therapy technology they are working on has every appearance of being a superior option in comparison to the use of apoptosis-inducing drugs: more powerful, more configurable, and more adaptable. When you are competing in a new marketplace, there is no such thing as too much validation. The existence of well-regarded, well-funded competitors is just about the best sort of validation possible. Well funded competitors who put out peer-reviewed studies on a regular basis to show that the high-level approach you and they are both taking works really well is just icing on the cake. Everyone should have it so easy. So let the games commence! Competition always drives faster progress. Whether or not I had skin in this game, it would still be exciting news. The development of rejuvenation therapies is a game in which we all win together, when new treatments come to the clinic, or we all lose together, because that doesn't happen fast enough. We can and should all of us be cheering on all of the competitors in this race. The quality and availability of the outcome is all that really matters in the long term. Money comes and goes, but life and health is something to be taken much more seriously.

Now with all of that said, one interesting item to ponder in connection to this round of funding for UNITY is the degree to which it reflects the prospects for cancer therapies rather than the prospects for rejuvenation in the eyes of the funding organizations. In other words, am I being overly optimistic in reading this as a greater understanding of the potential for rejuvenation research in the eyes of the venture community? It might be the case that the portions of the venture community involved here understand the market for working cancer drugs pretty well, and consider that worth investing in, with the possibility of human rejuvenation as an added bonus, but not one that is valued appropriately in their minds. Consider that UNITY Biotechnology has partnered with a noted cancer therapeutics company, and that the use of drugs to inducing apoptosis is a fairly well established approach to building cancer treatments. That is in fact why there even exists a range of apoptosis-inducing drugs and drug candidates for those interested in building senescent cell clearance therapies to pick through. Further, the presence of large numbers of senescent cells does in fact drive cancer, and modulating their effects (or removing them) to temper cancer progress is a topic under exploration in the cancer research community. So a wager on a new vision, or a wager on the present market? It is something to think about. -------

Not enough of the research community is doing the other thing, the repair and reversion of differences between old and young tissues carried out in advance of full understanding, so as to aim at cures rather than delay.

Alzheimer's, funnily, is in a much better position than most other age-related diseases because a large chunk of the mainstream of the research effort is actually directed towards a repair-of-the-differences approach - removal of amyloid via immunotherapy in this case. That choice of strategy isn't true for heart disease, diabetes, dementia, etc, etc. If we want to see cures for age-related disease, there must be a sweeping change in the research community's high level strategy, towards repair of fundamental damage that distinguishes old tissues from young tissues, and away from tinkering with the disease state to slow it down or to compensate for some of its effects.

What they are doing is reasonable as an immediate extension of trying to map the disease process front to back, which is what pure research should be doing. The outcome of that, however, tends to be that people end up manipulating biochemistry to slow the disease process rather than fix it. You can get useful results out of this - see statins, for example. But you can't get cures. People who take statins will still end up in the same bad place in the end, just a little later. Also, it is very expensive to find safe new states for cellular operation that provide a decent benefit:harm ratio.

One right thing to do in Alzheimer's is map the whole thing end to end, them make a decision on what to do. An enormous task that is basically the same thing as understanding the human brain end to end - which is a good thing in and of itself, and if Alzheimer's provokes that work (in the same way that AIDS provoked analogous major efforts to understand viral biochemistry) then good. But in the short term that doesn't produce useful therapies.

The other right thing to do is to identify the fundamental differences between young, non-diseased tissue and aged, diseased tissue and work to revert them - even if you don't know how they are causing harm. Successful removal will tell you a great deal about the significance, and steer other research, and in the best case produce a useful therapy. Thus a focus on amyloid and tau, and immunotherapies to clear them, and dysfunctions in cerebrospinal fluid clearance mechanisms, with approaches ranging from simple mechanical adjustment of fluid drainage channels behind the nose to proposed stem cell therapies for the choroid plexus to addressing immunosenescence in the brain's immune system.

However, Alzheimer's is such a multifaceted condition that researchers tend to focus on reverting one of these items, then don't produce wondrous benefits because the other mechanisms are still in play, and then the people who prefer to slow disease progression instead arrive to argue that this means they shouldn't look at this direct approach of reverting differences. To fix Alzheimer's will likely require clearance of both amyloid and tau, and even then it is likely that since 60% of sufferers also have vascular dementia, it will be challenging to produce good trial outcomes under the present regulatory system.

If damage repair doesn't work, that means you're not repairing enough of the damage.

[1]: https://arxiv.org/abs/1103.4649

Alzheimer's is as inflammation-driven as, say, heart disease. Which is to say that inflammation is a meaningful contributing factor along with all the other meaningful contributing factors. This is primarily these conditions are linked with obesity, because visceral fat is a major source of inflammation.

E.g.:

http://www.southampton.ac.uk/news/2016/01/blocking-brain-inf...

http://www.manchester.ac.uk/discover/news/treatment-option-f...

This is actually a point worth making twice: when limits to lifespan are discussed, we're not talking about actual limits per se, but effective limits. A very large mortality rate, possibly coupled with rapid growth in mortality rate over time, looks a lot like a hard barrier to further progress in practice, but there is still the chance that someone could beat the odds. Where the data for supercentenarians is good enough to fill in tentative mortality rates with large error bars, up to age 115, that rate is around 50% annually [1]. The mortality rate may increase greatly after that point, and that would be entirely expected given the absence of more than the one certified example making it past 120, but it is very unclear from the limited data. Mortality rates reflect actual physical processes, the accumulation of forms of cell and tissue damage that cause the suffering, death, and disease of old age. The damage is the same, but the proximate causes of death for supercentenarians are quite differently distributed from those of younger old people, prior to a century of age. The majority appear to be killed by transthyretin amyloidosis [2] that clogs up the cardiovascular system, and that is becoming known to play a much lesser - but still significant role - in heart disease in earlier old age. Could this form of amyloidosis be the candidate for a process that is not all that affected by the past century of changes in medicine and lifestyle, and that becomes much more important in extreme old age than early old age? Possibly. The only way to know for sure is to build ways to clear this form of amyloid [3] and see what happens.

The natural state of aging is a function of damage and how medicine addresses that damage - which is poorly and next to not at all at the present time. Almost all medicine for age-related conditions fails to address their root causes, the cell and tissue damage of aging [4], and takes the form of patching over that damage in some way or coaxing biological machinery to cope slightly better with running in a damaged environment. Predictably it is expensive and only marginally effective in comparison to true repair. As above in the comments on amyloidosis, find a way to repair that problem and life span will increase, as the machinery of biology will be less damaged and less worn down into high rates of failure. That is the point to take away from this discussion. It has to be said that the lead of the study, Jan Vijg, comes across as very pessimistic on aging in his comments here when considered in comparison to past remarks and collaborations with SENS folk [5] that I've seen from him. That is the case even granting that he is in the camp of researchers who believe there is no alternative to a very slow and expensive reengineering of human metabolism in order make incremental gains in life span and slowing of the aging process.

[1]: http://dx.doi.org/10.1007/978-3-642-11520-2

[2]: http://dailybruin.com/2010/03/04/autopsy-115-year-old-aids-r...

[3]: http://www.uclb.com/news-and-events/news-post/potential-new-...

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

[5]: http://dx.doi.org/10.1159/000357670

http://dx.doi.org/10.1007/s00705-015-2392-4

DRACO, double-stranded RNA activated caspase oligomerizer, is a broadly applicable antiviral technology that has been under development at a slow pace for quite some time now. You might recall some publicity back in 2011, for example, but that marked the results of years of earlier work. DRACO attacks infected cells, not the viruses themselves, following the principle of finding a common vulnerability to target rather than trying to tailor therapies to every different variety of attacker. Despite technology demonstrations to show effectiveness against a broad range of very different types of virus, and the fact that this technology can in principle be applied to near any type of virus, there is next to no ongoing funding for DRACO. It stands as an example of the fact that you can build a better mousetrap and still have the world ignore you. In this case DRACO is languishing despite grave concerns regarding spreading viral resistance to existing drugs, and billions devoted to constructing new drugs that are just more of the same.

Advocacy and philanthropy are often the only ways forward for a new medical technology that is a radical departure from the present status quo. This is a lesson to keep in mind when we talk about the various branches of medical research. It is hard to obtain funding in the life sciences in any meaningful fashion, and the organization of funding for any ongoing serious effort has become a baroque effort involving many players, all of whom are operating with perverse incentives that only serve to slow down progress and make funding less effective on a dollar for dollar basis. For example the large funding bodies are extremely risk-averse, and thus almost never fund the most important early-stage and high-risk projects, the science that is actually science, at the forefront and involving new discoveries. These funding bodies only ever put money into ongoing development wherein which the researchers can already demonstrate proof of concept and an understanding of the mechanisms involved. Getting to that point for any new line of research requires creative accounting and the help of philanthropic donations, and even so there is far too little actual science taking place in major laboratories.

Obviously it has been a long time since humans have experienced a natural lifespan in the one rigorous no-technology definition of the term. Is maximum lifespan moving much? Hard to say. The data gets really sparse out beyond 110, where estimated mortality rates are 50%+/yr, and really sparse the further back in time you look.

So it isn't unreasonable to hold the position that maximum life span is increasing, but slowly. Adult life expectancy at 60 is going up a year every decade, but there are so few people living to > 115 that you can't really say much about their statistics. Maybe that is going up too.

Equally it isn't unreasonable to hold the position that transthyretin amyloid aggregation is a fairly equitable process that will absolutely kill everyone prior to 130. That it acts as a hard full stop on how far you can get with, even if you avoid everything else. (That this form of amyloid is what kills the majority of supercentenarians is the conclusion drawn from the limited autopsy data for people that old).

This of course is because no currently available medical technology greatly impacts transthyretin amyloid (though Pentraxin Therapeutics completed initial human trials of a clearance therapy in 2015 - stuck in regulatory/Big Pharma hell, but it works). You can be as heavily treated with the best of medicine as you like, but that amyloid is still accumulating, and eventually it clogs your cardiovascular system and you die.

If there was no transthyretin amyloid in the picture, I'd wager we'd have 120yr-olds in the same way that we have 110yr-olds today - a larger number of them, but still small. We'd also have 10-20% less heart disease at all ages, and a range of other conditions that are caused in old people by this form of amyloid. Amyloid clearance is a good thing, there should be more support for it.

I wager that this sort of thing is already taking place quietly on a small scale, given the large and growing number of people with access to the necessary tools and ability to do this.

[1]: http://news.iupui.edu/releases/2015/12/myostatin-warden-musc...

Everything that isn't repairing the root cause damage of aging is going to be a much less effective way of going about things if the goal is to avoid cardiovascular events of that nature. Keeping a machine from a specific failure mode without actually repairing the damage that raises the odds of that failure mode is a much harder thing to do than to enact repair.

This is largely why medicine for age-related conditions has been an incremental process over recent decades: advanced enough to do sensible things with downstream consequences of damage, and so produce marginal effects at sizable investment of time and resources but for various reasons unwilling or unable to address the damage itself. The reduction in heart disease over the past 30 years has been an enormous achievement when considered within these bounds: really going above and beyond, finding ways to keep the accumulation of damage from having the same level of consequences and juggling biochemistry to keep running at a lower failure rate for longer.

But still incremental, and to really solve the problem you have to repair the damage. Nothing else is going to do the job.

The historical problem with mining the bacterial world has been that only about 1% of all bacterial species can be cultured in the laboratory. That was solved a couple of years ago with an ingenious low-tech approach called the Ichip. The people who solved it went on an ad-hoc, short fishing expedition and found a new viable antibiotic candidate the first time they tried. [1]

The future of antibiotics, like the future of a large chunk of drug development, is thus going to involve mining bacteria for the weapons they use on one another and the tools they use to eat things. We'll never run out of those, and we'll have more candidates than we know what to do with once people make a serious go of using the new methods of culturing bacteria. [2]

[1]: http://www.the-scientist.com/?articles.view/articleNo/41850/...

[2]: https://www.edge.org/response-detail/26701

The truth of the matter is that most of the mapping of molecular biochemistry being done in this age of enormous datasets and genetics is of very little immediate application. Meanwhile paths that can use what we already know to generate enormous impact on disease get little attention. This is an age of personalized medicine as the mainstream, but really the overwhelming majority of serious disease mechanisms, those that are age-related or infectious, are exactly the same for everyone. Personalized medicine is a wondrous machine for making money by the look of it, but won't deliver on its promises.

For example in cancer the best path forward is to turn off telomerase and ALT, preventing telomere lengthening. That will work for all cancers, one type of treatment for every cancer type, and will cost no more to bring to fruition than any one of the recent examples of cancer therapies brought to market. But that gets a fraction of the attention that goes towards mapping every last part of the genetics and cellular biochemistry of cancer. The efforts to create therapies that spin off from that type of mapping work are largely very limited, in that they involve targeting a mechanism or marker very specific to only one or a few of the hundreds of types of cancer, and even those types are capable of evolving away from that marker or mechanism when it is successfully targeted.

Cancer is hard because the research and development community largely follows a terrible high level strategy for implementation of therapies, even though in the long term the mapping strategy is exactly what scientists should be doing.