reasonattlm

If you are willing to do that, one would hope that you are also willing to (a) actually assess the results with the more robust quantified self metrics, rather than just hoping and feeling, as so many people do, and (b) take full responsibility for any harms or legal issues you cause yourself in the course of experimenting, as so few people do.

The detailed guides section here contains a couple of posts that walk through this process for a couple of other items, but the same general outline applies in exactly the same way:

https://www.fightaging.org/self-experimentation/

To answer the question, human data showing meaningful benefits that could not be achieved via exercise or calorie restriction would be very interesting. Human data showing some reliable level of reproduction of the benefits of exercise or calorie restriction without side-effects would be good news for the present majority who don't put in the effort to stay in shape. Good news for supplement sellers as well - there is no shortage of people who would pay rather than exercise or eat less, even if the results were mixed or marginal.

In either case, the cost-benefit analysis runs along the lines of (a) as an individual, how much it is worth spending on a supplement that can capture a fraction of the benefits of exercise or calorie restriction, but also (b) is it worth making this a major focus of the research community, versus the rejuvenation biotechnology that can achieve far greater gains? I think (b) is always going to be answered in the negative, for me at least. No calorie restriction mimetic or exercise mimetic can possibly be as good as functional SENS repair biotechnologies. They cannot achieve the results produced by senolytics, or any of the other ways to remove the root causes of aging. If one looks at NAD+ research as the final stage of sirtuin-related calorie restriction research as a whole, it has taken as much funding to get here as it would to completely implement the SENS rejuvenation therapy package in mice. Yet we know that exercise and calorie restriction cannot add decades to healthy life, as is possible in principle for repair therapies.

The data here on human nicotinamide riboside supplementation seems promising in comparison to the results of past sirtuin research, but I'd like to see a larger study group. If that larger group shows similar results, then maybe this is worth it for individuals. Either way, it is appreciated that the authors avoided running a study in overweight individuals - in this part of the field, that just muddies the waters, given the very different effects of sirtuin manipulation on thin versus fat animals. Nonetheless, it still appears to be the case that this is essentially a way to gain some of the beneficial long-term effects of fitness without putting in the physical effort. I expect future NAD+ studies and exercise studies in older individuals to converge in some ways, showing overlapping effects on cellular biochemistry. It is arguable as to whether taking up exercise, eating less, or artificially increasing NAD+ levels should be termed rejuvenation. There is a certainly a sizable grey area at the intersection of repair, compensation, and overriding regulatory signals that respond to aging.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850851/

As it points out, the most obvious and promising of current prospects for reducing inflammation is the selective destruction of senescent cells. Though I think that the clearance and recreation of the entire immune system, to remove all of the senescent, exhausted, misconfigured, etc, immune cells is also a promising path, albeit further away from being safe enough to apply to old people.

About the most one can say about this is that manipulation of NAD+ levels is a better exercise mimetic than manipulation of sirtuins proved to be. What it helps to do is explain some of the underpinnings of studies that show a great deal of muscle loss is secondary aging - i.e. disuse. It also suggests that loss of capillaries is a more important mechanism in sarcopenia than other groups believe to be the case, though I think it very possible that this is secondary to stem cell activity loss. The evidence for stem cell decline to be the primary cause of sarcopenia is very good. [1] There is a faction that thinks capillary loss is important in all tissues. [2]

Go look at the studies showing resistance training to be pretty effective in seniors before getting excited about NAD+ boosters. The resistance training is probably cheaper and better. One still has studies such as the one showing that dietary nicotinamide doesn't do a great deal in mice [3] - like sirtuin manipulations, it helps fat mice a little, but is distinctly unimpressive otherwise.

Remember that calorie restriction extends life by 40% in mice, but probably five years or less in humans - the effects of all these stress response related mechanisms of metabolic manipulation work through a few overlapping core processes, and scale down with species longevity. That's why I see them as a dead end in comparison to other strategies.

[1]: https://www.urmc.rochester.edu/news/story/4788/stem-cells-ma...

[2]: https://doi.org/10.1159/000477402

[3]: https://doi.org/10.1016/j.cmet.2018.02.001

So it is interesting to speculate on the degree to which the benefits here are signaling versus cell integration. Clearly the big difference between past attempts is that a tissue-like set of organized cells are delivered rather than just free-floating unorganized cells.

In the paper here, researchers make an effort to map recent changes in secondary aging, picking combinations of metrics from past data that might offer insight into the biological age of patients. I would say that there is little reason to expect primary aging to have altered significantly in the past few decades, given the landscape of medical technology, but it is certainly up for debate as to whether medications that control blood pressure and cholesterol levels might have some effect. They have certainly become more prevalent and effective over the time covered by the study data.

Overall this is an interesting exercise, but of little relevance to the future of aging. Gains from here on out will increasingly arise from the development of rejuvenation therapies that can repair the damage of primary aging, rather than from lifestyle improvements such as reduction in smoking or obesity, or forms of therapy that selectively, partially override downstream consequences of aging (e.g. blood pressure) without actually changing the primary aging damage that causes those problems. Greater potential gains in health and life span might be achieved through addressing primary aging; the scope of increased longevity through better lifestyle choices is far more limited. Our remaining healthy life span will thus be determined ever more by progress in rejuvenation biotechnology as time passes.

One group is (I think overly) critical of present vitrification approaches and the planned future of those approaches. They believe that these approaches are broken, and nothing of value is preserved. I think this is just as ridiculous as saying there is no room for improvement - it is clearly the case that, e.g. nematodes vitrified using the present technologies can be restored and show preserved memory.

That group has a strong overlap with pattern identity theorists, who are quite comfortable with a copy of them living in the future, and throwing away the original brain.

So the intersection of these two groups is motivated to work on technologies such as aldehyde-stablized cryopreservation (vitrifixation) that are incompatible with the future goal of thawing, restoration, and repair, as they are not reversible short of far distant molecular nanotechnology. Their aim is to produce the best possible record of data of the mind with the intent of reading into a machine environment in the future, then discarding it.

To my eyes this is a terrible, terrible, mistaken view on identity, and one that will cause a great deal of existential harm when it is extended from theory to action.

The rest of the cryonics community is interested in a technology path that leads to reversible vitrification in the near future, and some kind of union with the tissue engineering / organ engineering community. They want the flesh restored and repaired, and the end goal of cryopreservation is some form of advanced cell/bio/nanotechnology that can achieve that end.

This is why Alcor, etc, is not adopting vitrifixation.

So on the one hand, great to see progress, and vitrifixation is an excellent advance in tissue preservation in the general sense. It will be of use in many areas of research. On the other hand, pattern identity theory seems to have many of the aspects of religion. A copy of you is clearly not you, and no amount of handwaving is going to make that the case.

The next few decades will be a slow process of proving that the SENS model works well, and that other models don't work well, when it comes to reversing age-related disease and producing rejuvenation in older individuals. There will be reluctant acceptance on the part of the mainstream, and development will largely shift to what works, slowly and late.

This can be seen in its infancy today in the rapid progression of work on senolytics. In just six years, clearance of senescent cells has already far outpaced the past few decades of work on calorie restriction mimetics, producing more impressive and reliable results in animal studies. Things that work are hard to ignore, so everyone now retrofits senescent cells into their models of aging and development - that didn't include them seven years ago - and continues to try to ignore the rest of the SENS to-do list. Senolytics development is becoming heavily funded, and is on its way to the clinic.

This process will reoccur every time the poorly funded bootstrapping side of the SENS research community manages to advance to the point of a technology demonstration, which happened in 2011 for cellular senescence. Expect this to happen for cross-link breaking sometime in the next few years, which will be just as impressive for cardiovascular aging as senescent cell clearance is for inflammatory/fibrotic conditions of aging.

One would hope that at some point, some people involving in this process make the realization that they could just implement the rest of SENS themselves, with the successful biotech company they are involved in. There are a number of existing companies/groups where this may well happen, if they grow sufficiently large.

We've only had a way to progress towards therapies for aging with this model of development for somewhere between 30-50 years, and no way to make progress towards therapies for aging with anything short of massive war-on-cancer style programs prior to the last 20 years. (Those programs didn't happen, but in a different world could have; arguably it wouldn't have made much difference as to where we are now, just as the war on cancer has only been a foundational effort for the last ten years of exponentially rapid development just prior to the advent of universal effective cancer therapies. It is possible that senolytics could have happened much earlier, decades ago, but finding and validating the candidate drugs would have been very hard back then). But now everything in biotech costs 100 times less than it did not so very long ago - that is really why things are heating up in applied longevity science.

The article also commits the usual journalistic sin of equating every effort. There is a vast difference between all of: eating a different diet; running a pharmaceutical discovery program aimed at a mechanism of aging; running that program to build a way to replicate calorie restriction; running that program to kill senescent cells or clear glucosepane cross-links. These activities have radically different expectation values in terms of best plausible outcome.

The biggest mistake most people make in their approach to the new world of rejuvenation science is to think of every possible methodology as having similar best plausible outcomes in terms of years gained. Nothing could be further from the truth.

We've only had a way to progress towards therapies for aging with this model of development for somewhere between 30-50 years, and no way to make progress towards therapies for aging with anything short of massive war-on-cancer style programs prior to the last 20 years. (Those programs didn't happen, but in a different world could have; arguably it wouldn't have made much difference as to where we are now, just as the war on cancer has only been a foundational effort for the last ten years of exponentially rapid development just prior to the advent of universal effective cancer therapies. It is possible that senolytics could have happened much earlier, decades ago, but finding and validating the candidate drugs would have been very hard back then). But now everything in biotech costs 100 times less than it did not so very long ago - that is really why things are heating up in applied longevity science.

The article also commits the usual journalistic sin of equating every effort. There is a vast difference between all of: eating a different diet; running a pharmaceutical discovery program aimed at a mechanism of aging; running that program to build a way to replicate calorie restriction; running that program to kill senescent cells or clear glucosepane cross-links. These activities have radically different expectation values in terms of best plausible outcome.

The biggest mistake most people make in their approach to the new world of rejuvenation science is to think of every possible methodology as having similar best plausible outcomes in terms of years gained. Nothing could be further from the truth.

https://doi.org/10.1073/pnas.1714478115

T cells develop from hematopoietic stem cells as part of the lymphoid lineage and have the ability to detect foreign antigens and neoantigens arising from cancer cells. In the thymus, lymphoid progenitors commit to a specific T cell receptor and undergo selection events that screen against self-reactivity. Cells that pass these selection gates then leave the thymus, clonally expanding to form the patrolling naive T cell pool.

The vast majority of vertebrates experience thymic involution (or atrophy) in which thymic epithelial tissue is replaced with adipose tissue, resulting in decreasing T cell export from the thymus. In humans, this is thought to begin as early as 1 year of age. The rate of thymic T cell production is estimated to decline exponentially over time with a half-life of ∼15.7 years. Declining production of new naive T cells is thought to be a significant component of immunosenescence, the age-related decline in immune system function. With the recent successes of T cell-based immunotherapies, it is timely to assess how thymic involution may affect cancer and infectious disease incidence.

It is clear from epidemiological data that incidence of infectious disease and cancer increases dramatically with age, and, specifically, that many cancer incidence curves follow an apparent power law. The simplest model to account for this assumes that cancer initiation is the result of a gradual accumulation of rare "driver" mutations in one single cell. Furthermore, the fitting of this power law model (PLM) can be used to estimate the number of such mutations. Exponential curves have also been used to fit cancer incidence data, resulting in worse fits than the PLM overall. Nevertheless, it is worth noting that exponential rates close to the declining curve for thymic T cell production can be seen to emerge from the incidence data, indicating the relevance of the thymic involution timescale. While the PLM fits well, it does not account for changes in the immune system with age. To better determine the processes underlying carcinogenesis, we asked whether an alternative model, based only on age-related changes in immune system function, might partly or entirely explain cancer incidence.

Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. Our hypothesis and results add to the understanding of infectious disease and cancer incidence, suggesting in the latter case that immunosenescence, rather than gradual accumulation of mutations, serves as the predominant reason for an increase in cancer incidence with age for many cancers. For future therapies, including preventative therapies, strengthening the functionality of the aging immune system appears to be more feasible than limiting genetic mutations, which raises hope for effective new treatments.

Paper: https://doi.org/10.1111/acel.12750

This age of biotechnology is also an age of comparative indolence and comfort. As the research community measures specific biochemical aspects of aging, such as the decline of the cardiovascular system, or metrics relating to immunosenescence in the immune system, we might question the degree to which the results are peculiar to our era. How much of aging is the result of our choices - to eat more and exercise less than our ancestors - rather than the result of inexorable processes of biochemical damage that we, as yet, have little influence over? (Conversely, how much of past aging was due to infectious disease, malnutrition, and other adverse external circumstances that are controlled to a much greater degree today?) This topic crops up fairly often in research into the effects of exercise on health, and the research noted here is a particularly striking example of the type.

The study authors find that the age-related decline of new T cells maturing in the thymus is negligible in some people, those who exercise much more than the rest of us. This diminished supply of new T cells is thought to be an important component of immune system aging, and the failure of the immune system is very influential over many other aspects of aging: senescent cell accumulation, frailty, loss of regenerative capacity, chronic inflammation, cancer risk, and so on. Yet when we look at the demographic evidence for spread of life span based on exercise, it appears to be, at most, 6 or 7 years (with a much larger divergence when it comes to state of health over time). What does this tell us about the likely gains resulting from rejuvenation therapies seeking to regenerate the thymus? Less than we would like, I suspect, and not just because it is hard to evaluate any one contribution to aging in isolation of all of the others.

The thymus atrophies over adult life, with active tissue necessary for the production of T cells being replaced by fat. The first major loss of active thymic tissue occurs at the end of childhood, however, in a process known as involution. Immune cells are generated at a tremendous rate in children in comparison to young adults; evolution selected for a system that would be highly effective at the outset, at the cost of later issues. When it is observed that old people in their 60s and 70s who maintained a high level of fitness throughout life exhibit much the same thymic output as young people in their 20s, that tells us little regarding the outcome were the thymus restored to the same level of active tissue as is present in children. Only a mild restoration, to move thymic activity from typical aged to typical young adult, would be comparable - and why would we stop there?

If these folk apply their technology to discovering senolytics and cross-link breakers, then great. If they apply it to finding mTOR inhibitors and geroprotectors, not so great.

There is a fork in the road for interventions in aging: one path leads to damage repair (e.g. senolytics to remove senescent cells, AGE-breakers to remove cross-links), the other to tinkering with metabolism in its damaged state (e.g. mTOR inhibitors and other tools that force greater stress response mechanism activation, the same thing that happens in calorie restriction and exercise). The former offers cost-effective rejuvenation of the old, the latter offers an expensive path to marginal slowing of aging and little benefit for people already old.

The germline and hydra must be brought forward every time someone says that aging is an inevitable, universal consequence of thermodynamics:

http://www.demogr.mpg.de/en/news_press/press_releases_1916/f...

The common perception that the bodies of all living beings age, is wrong. This has now been proved by a long-term experiment with the freshwater polyp Hydra, a microscopic animal. In a unique long-term experiment researchers created artificial conditions for the tiny water animals with their flimsy tentacles, which were free of fatal natural threats like predators. For almost ten years they have cared for of about 1,800 of the Hydras. Overall, the team has counted 3.9 million observation days of individual Hydra. The number of natural deaths per year, however, can be counted on one hand. On average there have been only five. When a Hydra passed away it was mostly due to laboratory accidents, such as a polyp sticking to the lid of its bowl and then drying up or simply having been dropped on the floor. From of the few natural deaths that remained researchers calculated Hydra's mortality. It is so low that even several lifetimes of researchers would not suffice to observe the end of the lifecycle of the polyps. Even after 500 years five percent of a cohort will still be alive. For two out of twelve of the Hydra cohorts under investigation, the risk of death was actually so small, that it will take 3,000 years until only five percent of the polyps remained. "Hydra apparently manages to keep its body young because it does not senesce by accumulating damages and mutations, as most other living beings do. Hydra are probably able to follow a special self-preservation strategy, as its body and cellular processes are rather simple." For instance, Hydra are capable of completely replacing parts of the body that are damaged or are somehow lost. It can even fully regenerate if its body is destroyed almost completely thanks to a high number of stem cells. Stem cells are capable of developing into any part of the body at any time. Additionally, as Hydra replaces all of their cells within only four weeks, it regularly and quickly expels all cells that have been changed genetically by mutations. Thus, damages have little chance to accumulate.

Current thinking on why near all species fail to behave like hydra looks somewhat like this:

http://arxiv.org/abs/1103.4649

Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual and evolutionary forces should prevent it, but many species show signs of senescence as individuals age. Here, I will propose a model for aging based on assumptions that are compatible with evolutionary theory: i) competition is between individuals; ii) there is some degree of locality, so quite often competition will between parents and their progeny; iii) optimal conditions are not stationary, mutation helps each species to keep competitive. When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool. Even though individual selection forces always win over group selection ones, it is not exactly the individual that is selected, but its lineage. While senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions. We age because the world changes.

Sufficiently good preventative medicine will save money, because it will address the root causes of aging and thereby reduce risk and severity of age-related disease, while lengthening healthy and overall life span. It doesn't even have to be cheap. It just has to be less cheap than the cost of attempting and failing cope with aging.

But in practice it will largely be cheap.

Senolytic therapies to clear senescent cells are a pharmaceutical approach to age-related conditions that improves the situation for near all individuals and pathologies of aging, cost-effectively. Those tested to date reduce inflammation, partially resolve loss of regenerative capacity, turn back atherosclerosis, restore loss of tissue elasticity to some degree, effectively treat osteoarthritis, effectively treat fibrosis, clear out many forms of bad immune cell, remove a contributing cause of Parkinson's disease, and so for for a much longer list. The reason it will be so much better is that it targets a root cause of aging, a form of damage, and directly repairs at least some of it (25-50% of senescent cells destroyed in some of the measured tissues for some of the approaches).

One of the candidate therapies, dasatinib/quercetin, costs ~ $30-100 / dose. Take it once every few years.

Just ahead, in the next few years, there is the start of a massive shift in medicine for the old, medicine associated with the greatest costs. It is beginning now.

The medicine of the past few decades has really aimed at doing just this, however, extending life without fixing the underlying problems. It is the heroic model of medicine, throw everything at the symptoms rather than the cause: compensating or patching over the problems, tinkering with metabolism, intervening in consequences or secondary contributing factors, but never going near the root causes.

It has been expensive. It has eked out only marginal, incremental gains. It is a history of failure dotted with the occasional hard-won success. It has conditioned people to think that this model is the only way forward. It is wrong, bad, and the research and development community need to adopt a better way forward.

I think that when senolytic therapies to clear senescent cells become more widely used, that will be a pleasant surprise - to find a pharmaceutical approach to age-related conditions that improves the situation for near all individuals and pathologies of aging, cost-effectively. It reduces inflammation, partially resolves loss of regenerative capacity, turns back atherosclerosis, restores loss of tissue elasticity to some degree, effectively treats osteoarthritis, clears out many forms of bad immune cell, removes a contributing cause of Parkinson's disease, and so for for a much longer list. The reason it will be so much better is that it targets a root cause of aging, a form of damage, and directly repairs at least some of it (25-50% in some tissues for some of the approaches).

One of the candidate therapies, dasatinib/quercetin, costs ~ $30-100 / dose. Take it once every few years.

I think it very hard to argue that this is going to cost the world money. The reason why present strategies have poor results is because they are terrible at achieving their goals. They have tiny effects. Do better, and the picture changes.

There is definitely a conversation taking place in the research community regarding the degree to which the genetics of intelligence and the genetics of physical robustness overlap to provide some contribution to the intelligence-longevity relationship. The size of the longevity-wealth and intelligence-education-wealth relationships make it challenging of course, which is why much of the more interesting data is in lower species.

Bees, for example: https://www.scientificamerican.com/article/old-and-wise/

"The ability to handle stress could be a component of system integrity; better overall stress resilience may contribute to both higher IQ scores and longer life."

There are still twin studies in our species, of course: http://www.lse.ac.uk/website-archive/newsAndMedia/news/archi...

“Our research shows that the link between intelligence and longer life is mostly genetic. So, to the extent that being smarter plays a role in doing a top job, the association between top jobs and longer lifespans is more a result of genes than having a big desk. However, it’s important to emphasise that the association between intelligence and lifespan is small. So you can’t, for example, deduce your child’s likely lifespan from how he or she does in their exams this summer.”

And GWAS studies over large populations: http://dx.doi.org/10.1038/MP.2015.225

"These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples."

https://doi.org/10.1371/journal.pgen.1007108

"Recent single-cell studies point to the possibility that essentially all cells have unshared mutations in their genomes. In view of this extensive genetic diversity, it is perhaps not surprising that mutations that confer a proliferative advantage are readily detected as clonal populations of increasing abundance and size in the elderly. These clonal populations might lead to loss of organismal health through the functional decline of tissue and/or the promotion of disease processes, such as cancer. In this review, we summarize recent research that supports the notion that aberrant clonal expansion (ACE) resulting from cancer-associated mutations are common in noncancerous tissue and accumulate with age. We propose ACE to be a previously underappreciated aging phenotype that is universal in most organisms, affects multiple tissues, and likely helps explain why aging is the biggest risk factor for cancer."

http://dx.doi.org/10.1016/j.chom.2017.03.002

Not all pathogens are equal; cytomegalovirus may be far more important than the rest:

https://doi.org/10.3389/fimmu.2017.01953

And historically, reducing the burden of infectious disease already has increased life expectancy and reduced/postponed incidence of age-related disease:

http://www.slate.com/articles/health_and_science/science_of_...

Which is a suggestive model, by the way, not direct evidence. The best direct evidence would be to restore the pace of immune cell creation - such as via regeneration of the thymus (via FOXN1, or BMP4, or tissue engineering), cell therapy to replace or increase the pool of hematopoietic stem cells, etc. - and then see what happens. This sort of thing is five years out; there are people working on it, though more of those and more funding would certainly be a good thing. It would certainly be possible to push forward a startup today based on thymic regeneration or hematopoietic stem cell transplantation; the science is more or less ready for it.

--------

T cells develop from hematopoietic stem cells as part of the lymphoid lineage and have the ability to detect foreign antigens and neoantigens arising from cancer cells. In the thymus, lymphoid progenitors commit to a specific T cell receptor and undergo selection events that screen against self-reactivity. Cells that pass these selection gates then leave the thymus, clonally expanding to form the patrolling naive T cell pool.

The vast majority of vertebrates experience thymic involution (or atrophy) in which thymic epithelial tissue is replaced with adipose tissue, resulting in decreasing T cell export from the thymus. In humans, this is thought to begin as early as 1 year of age. The rate of thymic T cell production is estimated to decline exponentially over time with a half-life of ∼15.7 years. Declining production of new naive T cells is thought to be a significant component of immunosenescence, the age-related decline in immune system function. With the recent successes of T cell-based immunotherapies, it is timely to assess how thymic involution may affect cancer and infectious disease incidence.

It is clear from epidemiological data that incidence of infectious disease and cancer increases dramatically with age, and, specifically, that many cancer incidence curves follow an apparent power law. The simplest model to account for this assumes that cancer initiation is the result of a gradual accumulation of rare "driver" mutations in one single cell. Furthermore, the fitting of this power law model (PLM) can be used to estimate the number of such mutations. Exponential curves have also been used to fit cancer incidence data, resulting in worse fits than the PLM overall. Nevertheless, it is worth noting that exponential rates close to the declining curve for thymic T cell production can be seen to emerge from the incidence data, indicating the relevance of the thymic involution timescale. While the PLM fits well, it does not account for changes in the immune system with age. To better determine the processes underlying carcinogenesis, we asked whether an alternative model, based only on age-related changes in immune system function, might partly or entirely explain cancer incidence.

Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. Our hypothesis and results add to the understanding of infectious disease and cancer incidence, suggesting in the latter case that immunosenescence, rather than gradual accumulation of mutations, serves as the predominant reason for an increase in cancer incidence with age for many cancers. For future therapies, including preventative therapies, strengthening the functionality of the aging immune system appears to be more feasible than limiting genetic mutations, which raises hope for effective new treatments.

-------

"Cancer immunosurveillance is a process by which an organism's immune system recognizes transformed cells in order to inhibit the growth of neoplastic tissue. It comprises the first phase of immunoediting and is also known as the elimination phase."

Paper: https://doi.org/10.1126/scitranslmed.aan4488

https://doi.org/10.18632/aging.100640

"Why do humans live longer than other higher primates? Why do women live longer than men? What is the significance of the menopause? Answers to these questions may be sought by reference to the mechanisms by which human aging might have evolved. Here, an evolutionary hypothesis is presented that could answer all three questions, based on the following suppositions. First, that the evolution of increased human longevity was driven by increased late-life reproduction by men in polygynous primordial societies. Second, that the lack of a corresponding increase in female reproductive lifespan reflects evolutionary constraint on late-life oocyte production. Third, that antagonistic pleiotropy acting on androgen-generated secondary sexual characteristics in men increased reproductive success earlier in life, but shortened lifespan."

https://arxiv.org/abs/1103.4649

"Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual and evolutionary forces should prevent it, but many species show signs of senescence as individuals age. Here, I will propose a model for aging based on assumptions that are compatible with evolutionary theory: i) competition is between individuals; ii) there is some degree of locality, so quite often competition will between parents and their progeny; iii) optimal conditions are not stationary, mutation helps each species to keep competitive. When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool. Even though individual selection forces always win over group selection ones, it is not exactly the individual that is selected, but its lineage. While senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions. We age because the world changes."

https://www.demogr.mpg.de/en/news_press/news/press/forever_y...

“A long-term experiment with the freshwater polyp Hydra, a microscopic animal: observing many hundreds of them for almost ten years, researchers calculated that Hydra’s mortality permanently stays constant and extremely low. For most species, including humans, the probability of dying within a specific year rises with age. Scientists regard this as an indicator of the decay of the aging body. For Hydra, evolution seems to have found a way to escape the mechanisms of the physical deterioration of getting older. Hydra apparently manages to keep its body young because it does not senesce by accumulating damages and mutations, as most other living beings do. Hydra are probably able to follow a special self-preservation strategy, as its body and cellular processes are rather simple. For instance, Hydra are capable of completely replacing parts of the body that are damaged or are somehow lost. It can even fully regenerate if its body is destroyed almost completely thanks to a high number of stem cells. Stem cells are capable of developing into any part of the body at any time. Additionally, as Hydra replaces all of their cells within only four weeks, it regularly and quickly expels all cells that have been changed genetically by mutations. Thus, damages have little chance to accumulate."

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

"Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems."

https://doi.org/10.1073/pnas.1714478115

"For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor."

And of course the SENS synthesis of the compelling evidence for aging to be the consequence of accumulated damage of various sorts:

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

"Many things go wrong with aging bodies, but at the root of them all is the burden of decades of unrepaired damage to the cellular and molecular structures that make up the functional units of our tissues. As each essential microscopic structure fails, tissue function becomes progressively compromised – imperceptibly at first, but ending in the slide into the diseases and disabilities of aging. Decades of research in aging people and experimental animals has established that there are no more than seven major classes of such cellular and molecular damage, shown in the table below. We can be confident that this list is complete, first and foremost because of the fact that scientists have not discovered any new kinds of aging damage in nearly a generation of research, despite the increasing number of centers and scientists dedicated to studying the matter, and the use of increasingly powerful tools to examine the aging body. In its own way, each of these kinds of damage make our bodies frail, and contribute to the rising frailty and ill-health that appears in our sixth decade of life and accelerates thereafter."

"Can memory be retained after cryopreservation? Our research has attempted to answer this long-standing question by using the nematode worm Caenorhabditis elegans, a well-known model organism for biological research that has generated revolutionary findings but has not been tested for memory retention after cryopreservation. Our study's goal was to test C. elegans' memory recall after vitrification and reviving. Using a method of sensory imprinting in the young C. elegans, we establish that learning acquired through olfactory cues shapes the animal's behavior and the learning is retained at the adult stage after vitrification. Our research method included olfactory imprinting with the chemical benzaldehyde (C6H5CHO) for phase-sense olfactory imprinting at the L1 stage, the fast-cooling SafeSpeed method for vitrification at the L2 stage, reviving, and a chemotaxis assay for testing memory retention of learning at the adult stage. Our results in testing memory retention after cryopreservation show that the mechanisms that regulate the odorant imprinting (a form of long-term memory) in C. elegans have not been modified by the process of vitrification or by slow freezing."

Yet you undertake continual efforts to remain alive, embracing the use of food and medicine - technologies developed purely and entirely to stave off naturally occurring death.

I feel that you haven't fully examined your own position on this matter.

https://www.economist.com/news/science-and-technology/216900...

There is also some interesting work spurred by the Brain Preservation Prize:

http://www.brainpreservation.org/small-mammal-announcement/

https://doi.org/10.1016/j.cryobiol.2015.09.003

"We describe here a new cryobiological and neurobiological technique, aldehyde-stabilized cryopreservation (ASC), which demonstrates the relevance and utility of advanced cryopreservation science for the neurobiological research community. ASC is a new brain-banking technique designed to facilitate neuroanatomic research such as connectomics research, and has the unique ability to combine stable long term ice-free sample storage with excellent anatomical resolution."

Then bear in mind that most aging research is still purely investigational, not aimed at producing any sort of intervention. Calico falls into this category, more is the pity.

Then bear in mind that of the interventional research, most of that is focused on calorie restriction mimetic or similar stress response tinkering that can't possibly significantly extend human life span.

Then at the far bottom of this funnel, with a tiny amount of funding, is rejuvenation biotechnology of the sort advocated by the SRF, repair the damage that causes aging in order to reverse aging.

So, yes. Very underfunded.

Then if we look at cancer research, there is a different problem and effort to change the split of research strategy and allocation of dollars. Cancer research has progressed very slowly because there are hundreds of subtypes of cancer and researchers have been pursuing strategies that only tackle one, or only tackle a mechanism that cancers can evolve away from. What is needed for progress in cancer research is greater funding and attention for strategies that are general to many or all cancers, and which cancers cannot evolve away from. Such as CAR-T therapies, or a few other types of immunotherapy that are comparatively general, or have low costs of adaptation to different cancers, or interdiction of telomerase and ALT to prevent cancers lengthening their telomeres, or the like. The latter of those is a SENS Research Foundation initiative.