Fight Aging! Newsletter, February 16th 2015

February 16th 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • SENS Research Foundation Now Accepts Bitcoin Donations
  • Disappointing Comments on Longevity Science From Bill Gates
  • Comparing Aging and Chronic Kidney Disease
  • Killifish as a Platform for the Study of the Biochemistry of Aging
  • SENS Research Foundation Newsletter, February 2015
  • Latest Headlines from Fight Aging!
    • On the Potential Treatment of Cellular Senescence in Aging
    • More on Declining Fluid Drainage and Amyloid-β Accumulation
    • Suggesting Better Genome Maintenance in Naked Mole-Rats
    • On the Fear of Overpopulation
    • The Intricate Interplay of Aging and Cancer
    • Towards Eternal Youth For All
    • Mitochondrial and Cytoplasmic Oxidative Stress Have Opposing Effects on Lifespan in Nematode Worms
    • Proposing Dialysis-Like Blood Filtration and Augmentation in Order to Slow Aging
    • The Prospect of Using Antioxidants to Suppress Damage Following Stroke or Other Brain Injury
    • Targeting Interleukin-10 to Spur Immune Cells into Clearing Amyloid From the Brain


The SENS Research Foundation remains the only easy way for ordinary folk such as you and I to donate funds in certainty that we are helping to advance the state of rejuvenation biotechnology. It is also the only easy way for someone with a few million to spend to do the same, for that matter. The organization funds research programs and advocacy aimed at pushing past zones of slow progress and neglect in relevant fields of medical research, so as to speed the arrival of treatments for degenerative aging. There is a clear plan, but a lot to be done.

Thus while the well-funded stem cell and cancer research communities need little help beyond a few nudges to keep them on the right road, these are only two of seven areas of research in which significant advances are required in order to eliminate age-related disease and extend healthy lifespans by decades or more. There is far too little work taking place on clearance of senescent cells, or removing cross-links in old tissues, or mitochondrial repair, or breaking down the numerous forms of amyloid and other metabolic wastes that clog up important cellular processes. In all these areas the SENS Research Foundation is one of the few organizations persistently finding ways to move the needle, to speed things up, to bring more attention to the field. The scope of success here is at present only limited by funding: there are any number of scientists in the aging research community who would drop their present work in favor of SENS biotechnology to treat aging given the budget.

With that in mind, here is a little news for those who might have a few bitcoins left over after all the excitement of the past eighteen months or so:

Donate to SENS Research Initiatives via Bitcoin

SENS Research Foundation is now able to accept Bitcoin donations: go to and make the donation. Coinbase keeps your information confidential, so we don't see the donor. If you would like a tax receipt for your donation please send us your name and the amount of your donation via email.

Bitcoin remains an interesting endeavor, not for what most people think of as bitcoin itself, a payment system and currency, but rather for the underlying combination of cryptography and profit incentives that enables the maintenance of a reliable distributed ledger without the need for a centralized ledger-keeper. Any such ledger-keeper can be easily compromised by a determined attacker, whether criminal or representative of the state, and there is considerable value in a system that is inherently resistant to that sort of attack. The greater the participation in this system, the more secure it becomes: attackers would need immense resources to overwhelm the ledger, and they couldn't do so invisibly.

Rapid transfer of value between two parties anywhere in the world with no intermediary via bitcoins is really the least of what can be achieved with this sort of a system. The real value here isn't a currency, it is trust. You should think of the distributed ledger as a trust engine: the many computing mills churning away around the world on simple cryptographic algorithms are less engaged in mining bitcoins than they are in generating and ensuring trust. Thus programmable contracts are potentially much more valuable than bitcoin transfer, even considering only the simplest possibilities such as timed release of property or escrow without the need for a trusted third party to hold funds. Future iterations of the distributed ledger implementation will no doubt improve upon the options available, but the basic concept is here for the long term I think.


In a recent Reddit discussion, philanthropist Bill Gates had this to say about the present growth in research aimed at extending healthy life spans:

It seems pretty egocentric while we still have malaria and TB for rich people to fund things so they can live longer. It would be nice to live longer though I admit.

The comments were of course replicated far and wide in the echo chamber of the press: Gates has a soapbox of an enviable size, even among billionaires. The context here is the Silicon Valley network of wealth that, in quite different ways, funds both Google Venture's new California Life Company investment and the less flashy but so far much more important rejuvenation research and advocacy organized by the SENS Research Foundation. It is also worth recalling that Microsoft cofounder Paul Allen continues to pour a large amount of wealth into cutting edge biotechnology research. The philanthropy of the Bill and Melinda Gates Foundation by comparison is focused on improving the lot of the poor directly, as a matter of delivering and implementing existing technological capabilities rather than building completely new things. Though of course they do fund malaria and other infectious disease research in a big way, which is definitely cutting edge biotechnology.

Both advancing the cutting edge and delivering existing capabilities to the poor are viable approaches to making the world a better place. There must be progress at the cutting edge to produce new medicine and other important technologies. Much of the early stage novel, risky, ground-breaking research only happens because it is funded by philanthropy. Large funding sources in government and business are risk averse and much more interested in supporting incremental but certain progress - yet the only reason that progress even exists in the first place is that someone was willing to put money on the very early stage work that made it possible. Similarly once a new technology is shown to be possible it is a good thing to aid deployment and continued improvements in implementation that help ease the hurdles to bring the results to less fortunate regions of the world. That part of the development process has many of the same problems as early stage research: a lot of people willing to fund a sure thing, and far too few willing to sink money into solutions for what look like roadblocks and dead ends. The sure things never do much; it is the radical new approaches that enable real progress.

Everyone gets to chose where they put their money and how they think about the world. It is nonetheless always disappointing to see influential people completely misunderstand the point of longevity science. Comments like those made by Gates could just as well have been applied to heart disease fifty years ago. Why are all those rich people funding heart treatments and better drugs for an age-related condition? Isn't that just selfish? Yet the distinct character of our era is that access to technology is comparatively flat: the progression of availability from expensive and inaccessible to accessible to the vast majority of people occurs very rapidly. Look at the spread of mobile phones and internet access over the past two decades as an example of what happens in a market where governments interfere far less than is done in medicine. Even in medicine, many of the medical technologies funded by rich people in past decades, and initially only available to the wealthy and connected in their earliest forms, are now available in places that include rural India and reaches of Africa. Such as those drugs for heart conditions.

Improving medicine is not about making things happen for the wealthy. It is about whether we all win together or we all lose together. Mocking or shunning improvements aimed at preventing the suffering and frailty of aging because some wealthy person might get the treatments first is lunacy: all technologies are available to the wealthy first and far in advance of the rest of us. That is what being wealthy gets you, pretty much by definition, and if it serves as an incentive to get them involved then all the better. They fund the first wave, and the rest of us obtain access in the later stages of development, when the new technology moves beyond prototypes and first generation implementations to become better, cheaper, and more robust.

Here is another way of looking at this: what causes the greatest harm to poor people? It isn't malaria. It is aging, and by a long, long way. Malaria killed in the vicinity of 650,000 people in 2012. In that same year somewhere north of 40 million people aged to death. More than three quarters of the world's population are exceptionally poor compared to the people we call poor in the US: so perhaps 30 million or more of those deaths fall into that demographic, fifty times as many as caused by malaria. I think it fair to say that degenerative aging places a far worse burden upon those individuals than on you and I. It is terrible for all of us, and kills all of us if we're lucky enough to evade the rest of the life's slings and arrows, but there's a big difference between being old and frail in agrarian poverty versus a first world city. If you are a rational, compassionate, utilitarian individual - and few are, sadly - then it should be clear that the best thing that can be done with limited resources is to work as rapidly as possible to produce effective treatments for aging that prevent and reverse age-related disease. Just getting a first generation of these treatments into the development pipeline at all, and not even taking any further steps beyond that to help speed things along, guarantees that the poor of the near future will have far better lives as a result. We would hope to do more than just that of course.

The greatest positive change we can create in the world is to eliminate the pain and suffering of aging through medical science. The outcome in terms of future lives saved and lives improved is so large in comparison to the treatment of any specific disease, even endemic diseases such as malaria, that it compels attention. That said, overall medical research funding is tiny in comparison to the wealth that flows through the entertainment industry, that goes towards killing people in ever more inventive ways, that is used to make candy, that changes the color of a US president's vest from red to blue, and so on. We like our wars and our circuses, and the scraps left over after that is done are all that goes towards making the world better by building new medical technologies. There is more than enough funding out there to cure every disease, to grow the life science research community by a factor of a hundred, and achieve countless other important goals besides. People just choose to spend it on other things, all ultimately pointless, forgotten, and irrelevant in the long term. The only thing that really matters is progress in technology, and especially in medicine, but persuading the world of that fact is still a hard sell.


Chronic kidney disease (CKD) is a particular unpleasant condition, not least because it accelerates many of the other manifestations of aging, but also because there is comparatively little that can be done to treat it at this time. There are lines of work based around suppressing fibrosis characteristic of aged, damaged kidneys, and also the potential use of stem cell therapies to regenerate healthy kidney tissue, but practical implementations are yet to emerge. Since a little less than 10-20% of the adult population in developed nations suffers from chronic kidney disease, depending on where you want to drawn the line, progress on the path to treatments has the potential to help a large number of patients.

One of the signs of failing kidney function is uremia, the increased presence of metabolic products such as urea in the bloodstream. It shows that the kidneys are not filtering as well as they should, and as levels of these unwanted products grow they are accompanied by a very broad range of damaging and increasingly serious consequences. Many of these consequences look a lot like the general progression of aging from the outside: increased frailty on many counts, and increased risk of suffering other age-related conditions.

In this open access review paper the authors seek to draw comparisons between the biochemistry of aged people without chronic kidney disease and younger people suffering the condition. There are numerous similarities, but is this a case in which those similarities are a learning opportunity? This is a question perhaps worth thinking about in the context of type 2 diabetes, a condition that can also be thought of as accelerating certain aspects of aging, and has for some time been used in animal studies as a model substitute for aging.

Aging and uremia: Is there cellular and molecular crossover?

Observation alone suggests that patients with end stage kidney disease (ESKD) are biologically older than their unaffected peers. As a group, ESKD patients have a morbidity and mortality profile similar to that of the geriatric population, and the pathophysiology of the uremic syndrome has interesting parallels with the aging process. Based on these thoughts it has been posited that kidney failure results in accelerated, pathological aging. Indeed there are striking analogies between the effects of aging and uremia on the structure and function of the heart and vasculature, with similar arterial stiffening-related changes seen in pulse contour, pulse wave velocity, and impedance, and similar structural abnormalities with wall thickening, decreased elastin, and increased collagen content.

Whilst much has already been written about the intriguing similarities that appear to exist between the aging process and CKD, comparatively little work has been undertaken looking at the cellular and molecular hallmarks of aging in the context of the known evidence concerning uremia-induced cellular and molecular pathways.

1) The principle cell death and survival molecular pathways consisting of apoptosis, necroptosis and autophagy are strongly interrelated and crossover at many points. Whilst our current knowledge on how these interacting pathways are controlled and regulated is far from complete there is a growing appreciation of how similar many of the molecular signalling induced by uremia and aging appear to be.

2) Aging and uremia share many important cellular characteristics such as increases in cell senescence, telomere shortening and exhaustion of stem cells. This provides further evidence that supports the contention that uremia can be considered as a form of accelerated aging.

3) The klotho gene was originally identified as being involved in the suppression of aging in transgenic mouse studies. Defective klotho expression resulted in mice having a premature aging phenotype, which had striking similarities to that of CKD patients. The deficiency in klotho seen in uremia and aging might underpin the enhanced cell senescence, apoptosis and stem cell depletion common to both states. Given that tissue klotho expression is greatest in the kidneys a common mechanism is perhaps to be expected.

4) Spontaneous post-translational protein modifications result from the non-enzymatic attachment of reactive molecules to protein functional groups. This process occurs in healthy individuals with aging, but is increased in certain disease states. Alterations to protein structure may result in functional changes, which can be pathogenetic. One of the most widely studied and publicised forms of post-translational protein modification is the formation of advanced glycation end products (AGEs) by the non-enzymatic modification of tissue proteins by physiologic sugars. AGEs accumulate in tissues as a function of increased production (e.g., in diabetes mellitus), decreased renal removal of AGE precursors (e.g., in advanced CKD) and time (as occurs in physiological aging). Increased oxidative stress and AGE generation are known to play a role in the pathophysiology of aging, and both of these events are present in patients with CKD and therefore represent two further potential crossovers between uremia and the aging process.

Based on this evidence it could be posited that the physical resemblance between advanced age and uremia is underpinned by shared cellular and molecular "abnormalities". These observations also reinforce the idea of the "uremic syndrome", in which dysfunctions in multiple body systems arise due to a pervasive defect at a cellular level. Information gathered by research into aging pathways and "anti-aging therapies" might inform interventions to avoid, slow the progression of or even reverse some of the pathological changes seen in uremia. Given that these pathways are seen throughout most tissues and cell types it is also possible that a single intervention might treat several pathologies. However, the aging process remains incompletely understood in healthy individuals, and those pathways that are known are complex and heavily interconnected. Disentangling these in the uremic syndrome, in which multiple co-existing and interdependent metabolic abnormalities arise, will be a challenge.

The point to take away here, I think, is that damage is damage. We suffer age-related degeneration and loss of function because our biology accumulates unrepaired damage of a variety of forms to cells and tissue structure. Clearly some of the detrimental outcomes resulting from damage accumulation reinforce one another to speed up the production of further damage. The whole of aging is an accelerating downward spiral: it isn't a linear process of advancing dysfunction. Frailty and mortality take hold much more rapidly in the later stages.


There are many trade-offs to be made in aging research, and most of them involve the balance between expended resources and time on the one hand and the expectation value of knowledge gained on the other. The challenge inherent in the present study of aging is that in terms of quality and usefulness of data there is still little that beats waiting and watching - sitting back and following the entire life span of your subjects, taking measurements as you go. This is wildly impractical for human aging, enormously expensive and unlikely to happen again any time soon for other longer-lived primates, given the debates over the structure and results of two presently running calorie restriction life span studies in rhesus macaques, and merely painfully expensive to arrange for mice. Things start to look up once you head on past mice to very short-lived species such as flies and nematode worms: the cost falls and studies of aging that produce quality data for that species become affordable, as well as being something that can be carried over the course of a few months.

What is the value of good quality data for nematode aging, under the influence of a variety of genetic alterations, environmental circumstances, and other treatments, however? Far less than if we magically had access to similar data for humans, that is certain, but to a surprising degree many aspects of the cellular biochemistry of aging are shared between very diverse species, even those as distant as humans and nematodes. The insights that can be obtained, while rarely if ever directly applicable across such a large gulf, are well worth the cost. They serve to steer much more expensive research in mammals, guiding the larger expenditures to the lines of work more likely to produce results. In turn work in mice serves to steer the again much more expensive process of producing applications of research for human use.

So short-lived animals whose biochemistry is well understood serve an important role in exploratory research. Starting there, even though far removed from human biology, ultimately reduces costs and rules out dead ends in the process of medical development and aging research considered as a whole. Further, a diversity of short-lived species to study is a good thing: comparisons between them can help to more efficiently identify initially promising findings that turn out to be peculiar to one species, which is a lot better than figuring that out only later, after five years of further mouse studies. Here is an example of scientists working to develop the infrastructure and understanding needed for a comparatively new addition to the species employed in the laboratory for aging research:

Tiny fish makes big splash in aging research at Stanford

"Live fast, die old" maybe isn't the catchiest motto. But, for the African turquoise killifish, it's apt. The killifish is one of the world's shortest-lived vertebrates, with some varieties living only four months. Old killifish display many characteristics of aging humans: declining fertility and cognitive function, a loss of muscle mass and an increasing likelihood to develop cancerous tumors. The fact that the fish shares many biological characteristics with humans makes it a promising candidate for the study of aging and longevity. But until now, scientists didn't have the necessary tools and information with which to conduct genetic studies.

Now, researchers have mapped the location of specific genes involved in aging and age-related diseases along the killifish's chromosomes. They've studied patterns of gene expression in its various tissues, and used genome-editing technology to mutate 13 genes thought to be associated with the aging process. This new biological tool kit, which the researchers have made publicly available, will make it possible to trace the effect of specific genetic changes on aging and the diseases that accompany it.

A short life span allows researchers to quickly assess the effect of genetic variations among different strains of fish. It also allows them to breed and raise hundreds of progeny for study within the span of months, rather than the many years required to conduct similar experiments in other vertebrates. "The life span of a mouse can be as long as three to four years. This is close to the average length of a postdoctoral or graduate student position. This means that it would be very difficult for a researcher to conduct a meaningful analysis of aging in the mouse within a reasonable time period."

The killifish's rapid life cycle meant that researchers were able to generate fish carrying the mutations within 30-40 days, and stable lines - that is, fish with the mutation stably integrated into all their cells, which they will then pass on to all their progeny - within about two to three months. In contrast to laboratory mice, the length of killifish telomeres, which average around 6,000-8,000 nucleotides, is similar to that of humans. As a result, researchers were able to quickly see the effect of a telomerase-disabling mutation in the fish. Interestingly, fish in which telomerase activity was disabled displayed a variety of traits that are similar to those seen in humans with a disorder called dyskeratosis congenita, which is also due to a mutation in telomerase. The researchers conclude that the killifish is currently the fastest way to study diseases of telomere shortening in vertebrates. They are hopeful that the other mutant strains will be equally useful in their lab and in other labs worldwide.


The SENS Research Foundation coordinates fundamental research into the technologies needed for future rejuvenation treatments. There is in fact a very clear roadmap leading from where we are today to the means to repair the cellular and molecular damage that causes aging. Outside of stem cell research and cancer research, most of that roadmap is lagging far behind, however. There is little interest and little funding despite the fact that other causes of aging as just as important to the development of age-related disease as faltering stem cell activity and the conditions that give rise to ever higher risk of cancer with passing years. Thus the SENS Research Foundation staff aim to push past roadblocks and spur further progress where that progress is very much needed: in ways to repair mitochondrial damage or clear persistent cross-links from aged tissues, for example. These efforts are funded by philanthropic donations, so we get the progress we are willing to support. Certainly there is no other organization out there yet doing anywhere near as much to advance repair-based approaches to treating and reversing degenerative aging.

This month's newsletter from the SENS Research Foundation turned up in my inbox today. If that wasn't the case for you, you might consider subscribing or making a donation to help fund the important work carried out by the Foundation. The newsletter pointed out a short interview from late last year that I'd missed:

Q & A with SENS Research Foundation President, CEO and Co-Founder Michael Kope

SRF is a public charity, and we intend to transform the way the world researches and treats age-related disease, by promoting truly comprehensive regenerative medicine. The unique aspect of our work is our focus on a damage-repair paradigm, and we advance that with our own scientific research and with collaborative projects, conferences, events and education programs.

SRF supports three research projects at its Mountain View Research Center, and an additional fifteen projects at universities and institutes around the world. The list includes Oxford, Harvard, Yale, the Buck Institute and the Wake Forest Institute for Regenerative Medicine. The goals are as ambitious as removing the underlying causes of age-related diseases such as macular degeneration, atherosclerosis, Alzheimer's and cancer.

And we're not just research programs: educating the public, building a community of support, and training researchers to support a growing rejuvenation biotechnology field are also major endeavors of the organization. Our internship program is growing, our research advisory board is expanding, and rarely a week goes by without a speaking engagement or event on our calendars.

As is often the case the most interesting part of the newsletter is the Question of the Month section, which this time around looks what we know about cellular and molecular damage accumulation in very early life. While reading, it is worth bearing in mind that the application of reliability theory to aging best fits the observed data in models where individuals are born already possessing a modest but non-zero amount of damage.

Question of the Month #8: Aging Damage and Early Early Detection

Q: Because the cellular and molecular damage of aging is a by-product of metabolism, I have always assumed that it accumulates throughout our entire lives - from when we are a baby until we die. Is this true? Is there any research showing that very young children have low levels of tissue-stiffening crosslinks, extracellular aggregates like beta-amyloid, or intracellular aggregates (like lipofuscin or the ones driving atherosclerosis) in their tissues?

A: Scientists don't have any single, comprehensive answer to this broad question, in part because there hasn't been a systematic investigation into it, and in part because the answer likely depends on the specific kind of aging damage under consideration. To really answer it, one would need to begin an investigation for each aging-damage precursor by taking tissue samples from newborns, and then performing ongoing testing periodically throughout life. As a second-best, you'd do a cross-sectional study comparing neonates, five-year-olds, pubescent children, very young adults, and then adults, including ages spread fairly evenly across the remaining lifespan. It would be difficult to perform such studies both institutionally and technically, as they would be quite expensive and would involve sourcing tissue samples from individuals of all of these ages, acquiring consent to use them for studies, and securing funding to do all this.

From a technical standpoint, it is already difficult to quantify many kinds of aging damage even in older people. The extreme case here is the key tissue-stiffening crosslink glucosepane, which is very fragile when subjected to most laboratory tissue treatments and has heretofore needed to be painstakingly extracted from tissues using a laborious series of sequential enzymatic extractions. Happily, this is likely to change soon, thanks to excellent progress being made in research that SENS Research Foundation has been funding in the Spiegel Research Group at Yale for several years now, developing enabling technologies for the development of glucosepane crosslink breakers. And it is inherently even more difficult to probe tissue samples for aging damage in very young people, for the obvious reason that the damage is by definition present at much lower levels in very young people's tissues than it is in older people's.

What little data we do have on aging damage precursors in the very young comes, for instance, from autopsy studies of stillborn infants. All such infants have at least some lipid deposition in their arteries, with as many as 25% of them having the "fatty streaks" that are the first visible sign of accumulating foam cells. These early lesions are particularly common in infants born to mothers with high serum cholesterol. Children are also born with some mechanical fatigue and fraying of the complex, lamellar structures of the stretchy protein elastin that provide arterial tissue with its elasticity, and this damage progressively increases with age. And there is already crosslink damage in the trachea and the bronchi of the lungs of newborn rats.

It's important to remember, however, that from the perspective of developing the therapies we need to delay and prevent degenerative aging, it doesn't matter whether or how much of these various aging lesions are present in very young people. Whatever their level may be, and whatever their rate and mechanisms of accumulation, the aging damage that is already present in the bodies of young adults is clearly harmless at the low levels at which it's present, as evidenced by the (by definition) youthful good health that college students and thirtysomethings enjoy. It's only decades later, as the level of cellular and molecular damage in different tissues accumulates to a characteristic "threshold of pathology," that enough of a given tissue's functional units are disabled to overcome its evolutionarily-inbuilt redundance and meaningfully impair tissue function.

In order to restore and maintain youthful health and functionality, then, we don't need to eradicate aging damage from the tissues of aging people; nor do we need to begin treating healthy young adults to push their burden of aging damage down to levels typical of children. Rather, we only need to develop rejuvenation biotechnologies capable of periodically removing, repairing, replacing, or rendering harmless enough of a tissue's molecular and cellular damage as to restore its structural integrity to what it is in young adults - complete with its original, lower but nonzero level of damage. At that point, the rejuvenated body will be structurally and functionally young, and its metabolic derangements will be restored to health as a downstream consequence of the intrinsic order of the youthful body. With this return to normal functionality at every level will come restored health, vigor, and vitality that ongoing periodic treatment can maintain - for many years longer at first, and ultimately indefinitely.


Monday, February 9, 2015

With advancing age ever more cells in any given tissue in the body are found to be in a senescent state. These cells have permanently exited the cell cycle in response to damage or stress, most likely in order to suppress cancer risk, but their accumulation causes progressive harm to tissue structure. One promising approach to removing this contribution to degenerative aging is the use of targeted cell destruction therapies, such as those under development in the cancer research community. Periodic clearance of senescent cells would prevent the dysfunction they cause, and while this research is poorly funded in comparison to its potential, a few groups are working on it.

Cellular senescence is a process in which cells at risk of becoming cancerous adopt a state of permanent growth arrest. While this process prevents tumor formation (a cell that does not divide cannot become a tumor), senescent cells may also cause or contribute to aging and age-related conditions. The senescent phenotype is complex, and consists of many changes to the nature of the cell: permanent arrest of cell division; morphological changes; beta galactosidase expression and other epigenetic changes including the senescence-associated secretory phenotype in which senescent cells secrete a myriad of factors with potent biological activities. This senescence-associated secretory phenotype, or SASP, is the most potentially damaging effect of senescent cells. While senescent cells account for less than 10% of total cells in aged tissues, the SASP allows these cells to play a much larger role than their relatively small numbers would otherwise suggest. It is hypothesized that this aspect of senescent cells is what drives aging or age-related conditions.

Senescence as a therapeutic target for aging. If senescent cells are so bad, why not get rid of the genes that cause the formation of senescent cells in the first place? Evidence from humans and animals indicates this is not an effective strategy. For example, mutations in the retinoblastoma or P53 genes, the two most essential pathways for senescence, result in strong predisposition to cancer. Therefore, the loss of the cells' ability to undergo senescence would cause a person to die of cancer long before they would grow old enough to worry about the effects of senescent cells.

What about killing the senescent cells that have already formed in the body? This could allow cells to senesce and prevent cancer, but could then eliminate them from the body before they produce harmful effects. In 2011, a group of researchers decided to test this idea using a mouse engineered to kill senescent cells when the mice were given a drug. The results were astonishing: the mice were prevented from developing a host of issues including cataracts and loss of fat, hair, and muscle. They proved to be healthier in most ways than untreated mice. This new therapeutic option, termed "senolysis" (lysis or breaking down of senescent cells), is currently being tested by several aging researchers for its effectiveness in treating the conditions of old age.

Now that senescent cells have been demonstrated to cause many of the conditions of old age, the field of senescence research is primed for a renaissance that could result in a host of new strategies for the therapeutic treatment of aging.

Monday, February 9, 2015β-accumulation.php

Amyloid-β is a species of misfolded protein that forms solid clumps in the brain. Its accumulation and related processes are associated with the progression of Alzheimer's disease. This isn't a slow progress of gathering waste, however, as levels of amyloid-β are quite dynamic. It is more the slow deterioration in mechanisms associated with ongoing clearance. So in addition to the great level of interest in developing treatments to clear amyloid-β from brain tissues, there is also much ongoing research relating to understanding why amyloid presence increases with age. One contribution is possibly a decline in the function of various drainage paths that occurs for much the same reasons as the general decline in blood vessel function throughout the body:

In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain.

CSF-ISF exchange and interstitial solute clearance was evaluated in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was also evaluated. Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.

Tuesday, February 10, 2015

Naked mole-rats (NMRs) live nine times longer than other similarly sized rodent species and show comparatively few signs of degeneration in functional health along the way. There is considerable interest in understanding exactly why this is the case: what are the important differences in the biochemistry of this species? Progress on this front is probably not going to directly result in ways to extend healthy life in humans, but it will help to prioritize efforts to treat the causes of aging by understanding which of the possible contributions are most important.

Genome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Our study is the first step in a comparative genomics approach to study GM in relation to aging and cancer. Focusing on human, mouse, and NMR because of their contrasting aging phenotypes and the availability of high-quality genome sequences, we investigated copy number differences of GM genes and discovered that very few GM genes have been lost among these three species during evolution.

Interestingly, we found NMR to have a higher copy number of CEBPG, a regulator of DNA repair, and TINF2, a protector of telomere integrity. NMR, as well as human, was also found to have a lower rate of germline nucleotide substitution than the mouse. While we can only speculate whether the two genes with additional copies in the NMR, CEBPG and TINF2, confer a significant advantage, for example, through an increase in gene dosage, it is possible for a subtle difference at the genomic level to have a large phenotypic effect, such as increased lifespan.

The finding that the NMR has a slower nucleotide substitution rate is interesting, particularly in the context of their longevity, and suggests that GM in NMR is superior to GM in the mouse. As more genomes become sequenced and annotated to higher quality, these findings can be validated further, elucidating the role of genome maintenance in modulating lifespan. Our findings in this comparative analysis of GM in human, mouse, and NMR suggest that NMR has more robust GM than mouse, which could play a role in the former's extreme longevity.

Tuesday, February 10, 2015

As regular readers well know I think that fears of overpopulation following healthy life extension are essentially ridiculous, on a par with raising the prospect of boredom as a reason to reject longevity science and thus force billions to suffer and age to death unnecessarily. Led by the hairshirt teachings of environmentalism perhaps a majority of people believe the world to be overpopulated today, but the regions usually pointed out as examples are characterized by terrible governance, poverty created by war and kleptocracy in the midst of a wealth of resources, human and otherwise, that go unused.

The common Malthusian vision of overpopulation - that we will run out of oil, or food, or land, or any other resource because there are more people - is driven at root by the failure to appreciate economics, how the world works and what drives human action. The world changes and people react to potential shortages and rising prices by developing new technologies and new resources. Those who cannot look beyond what exists today will always cry that the sky is falling, as they think in terms of dividing a fixed set of resources that never changes. Those arguments were made in every past era: the Roman age had its authors who thought that doom lay ahead if there were too many more people. In reality these views are always wrong, time and again. Even land is effectively unlimited given access to the rest of the solar system and sufficiently advanced construction technologies.

Many worry that radical life extension or the elimination of death will lead to overpopulation and ecological destruction. In other words, while it may be best for individuals to live forever, it might be collectively disastrous. However, I don't believe that overpopulation and its attendant problems should give researchers in this area pause. So I argue that we should try to eliminate death, dealing with overpopulation - assuming we even have to - when the time comes. My suggestions may be considered reckless, but remember there is no risk-free way to proceed into the future. Whatever we do, or don't do, has risks. If we cease developing technology we will not be able to prevent the inevitable asteroid strike that will decimate our planet; if we continue to die young we may not develop the intelligence necessary to design better technology. Given these considerations, we shouldn't let hypotheticals about the future deter our research into defeating death. The tragedy of 150,000 people dying every single day - 100,000 of them from age-related causes - is a huge price to pay for speculative hypotheses about the future.

Note too that this objection to life-extending research could have been leveled at work on the germ theory of disease, or other life-extending research and technology in the past. Don't cure diseases because that will lead to overpopulation! Don't treat sick children because they might survive and have more children! I think most of us are glad we have a germ theory of disease, and treat sick children. Our responsibility is to help people live long, healthy lives, not worry that by doing so other negative consequence might ensue. We are glad that some of our ancestors decided that a twenty-five year life span was insufficient, instead of worrying that curing diseases and extending life might have negative consequences. Most importantly, I believe it is immoral for us to reject anti-aging research and the technologies it will produce, thereby forcing future generations to die involuntarily. After anti-aging technologies are developed, the living should be free to choose to live longer, live forever, or even die young if they want to. But it would be immoral for us not to try to make death optional for them.

Wednesday, February 11, 2015

Aging and cancer have evolved hand in hand, and numerous aspects of our biology play an important role in both. At the simplest, highest level we have things like the decline in stem cell activity and tissue maintenance with age as a part of the evolution of human life span as a balance between death by cancer and death by functional failure of organs. There is also the role of senescent cells in both suppressing and promoting cancer, and their accumulation as a cause of degenerative aging. There are many other more complex and less well understood relationships between aging and cancer, but this review focuses largely on cellular senescence as a comparatively new area for building interventions:

A growing body of evidence supports the view that the complex relationship between mechanisms underlying aging and cancer evolves with organismal chronological age. Significant progress has been made in defining cell-autonomous and cell-nonautonomous mechanisms that in young and adult organisms simultaneously delays aging and suppress tumor formation. Furthermore, it is now well established that the intricate interplay between mechanisms underlying aging and cancer reflects the proliferative history of cells and is impacted by the progression of a cellular senescence program. Recent findings imply that the advancement of the multistep cellular senescence program imposes antagonistically pleiotropic effects on aging and cancer.

Despite an important conceptual advance in our understanding of the complex interplay between mechanisms underlying aging and cancer, we are still lacking answers to the following fundamentally important questions. Which of the numerous morphological and functional changes observed in various types of senescent cells in culture and in vivo are universal hallmarks of a state of cellular senescence - and, thus, which of these changes can be used as diagnostic biomarkers of cells entered such a state in any tissue? Given that the progression of the cellular senescence program imposes antagonistically pleiotropic effects on aging and cancer what therapeutic interventions have a potential to be used not only for enhancing those effects that are anti-aging and/or anti-cancer but also for attenuating those effects that are pro-aging and/or pro-cancer?

Recent findings in mice engineered for a reversal of the cellular senescence state by a drug-inducible telomerase reactivation or for a late-life immune clearance of senescent cells by their drug-inducible elimination suggest that small chemicals can be used for: (1) a protein target-specific pharmacological enhancement of the beneficial for organismal healthspan effects imposed by the cellular senescence program; and/or (2) a protein target-specific pharmacological attenuation of the deleterious for organismal healthspan effects inflicted by this program.

Wednesday, February 11, 2015

The progression of degenerative aging is presently the greatest cause of pain and suffering in the world, so why are we not all greatly in favor of working towards medical technologies capable of preventing the detrimental results of aging? Beyond removing frailty and disease, a side-effect of therapies capable of halting all age-related dysfunction through the repair of accumulated damage to cells and tissues is we'll all live very much longer in good health and youthful vigor.

The yearning for eternal life and youth has been a preoccupation of humans for millennia. Yet quite a few people remain unconvinced that cheating death is a good idea. For every promising advance in cancer treatment or hip replacement, a chorus chimes in with a warning about being careful what we wish for: Sure, we're curing diseases and easing pain, but perhaps the cost - in health and in dollars - is too high. This approach isn't just wrong; it's almost criminally obtuse. These objections conflate the physical process of aging with the mere passage of years. Our quest must be - as it has been for all of recorded history - not merely to live a long time, but to slow and stop the process of aging. Eternal youth, not just long life.

The current medical paradigm is to go after each individual disease as it emerges in a perpetual game of therapeutic whac-a-mole. The result is that individuals begin to accumulate infirmities. About 50 percent of Medicare beneficiaries are being treated for five different chronic conditions. This is ultimately a losing proposition, because aging bodies accrue more and more lethal and disabling conditions that compete to kill them. Patients routinely survive health crises that would have done them in even a generation earlier, but to what end? If an older patient doesn't die of a heart attack, prostate cancer could do him in. If a stroke doesn't get her, the Alzheimer's will. Ultimately, more than 25 percent of Medicare spending goes toward the 5 percent of beneficiaries who die each year.

There is a better way. We must look beyond individual pathologies to their root, aging itself. If anti-aging treatments can maintain people in the state of health of the average 30-year-old, the onset of chronic illnesses will be forestalled and health care and pension expenditures will be much lower. And it increasingly looks like we may actually be able to slow or even stop the aging process, to the tremendous benefit of humanity.

If bodies can be kept young, they will be less vulnerable to diseases at any chronological age. If 55 really were physiologically the new 45, the incidence of cardiovascular disease would go down by about 50 percent and the prevalence of cancer would be cut by nearly 80 percent. Bodies age in much the same way that automobiles do. In the course of roaming around the world, they accumulate damage, which, if not repaired, leads to a breakdown. Unlike automobiles, human bodies do have some capacity for fending off hurts and for self-repair, but those mechanisms eventually wear out. Fortunately, researchers are making considerable progress in figuring out credible ways to repair the damage and thus slow down the aging process.

Thursday, February 12, 2015

Oxidative stress refers to higher levels of oxidizing molecules present in and around cells, causing more damage by reacting with protein machinery that must then be repaired. Work over the past two decades has show that raising or lowering levels of reactive oxygen species (ROS) produced by the mitochondria within a cell can extend or shorten life in lower animals such as nematode worms: the outcome obtained depends on the details of the process. Cells react to the presence of ROS with increased housekeeping activities, so a modest increase can lead to a net reduction in damage while a large increase overwhelms repair systems and causes greater harm.

Since ROS do have a variety of roles in cellular metabolism, and are not just agents of harm, it matters greatly where in the cell ROS levels are altered. In this paper researchers explore localized increases in ROS levels in nematode cells by selectively deleting genes that encode varieties of superoxide dismutase antioxidant proteins. These antioxidants reside in various different compartments of the cell, and so reduced levels lead to increased ROS, but only in the areas of the cell where the antioxidant is normally present:

Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work indicates that low levels of ROS can be beneficial and promote longevity. In this paper, we use a long-lived mitochondrial mutant C. elegans strain clk-1 to further examine the relationship between ROS and lifespan. While it was originally believed that clk-1 mutants had increased lifespan as a result of decreased ROS production, ROS levels have been shown to be increased in clk-1 worms.

Increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan. Interestingly, treatment with paraquat robustly increases the already long lifespan of the clk-1 mitochondrial mutant, but not other long-lived mitochondrial mutants such as isp-1 or nuo-6. To genetically dissect the subcellular compartment in which elevated ROS act to increase lifespan, we deleted individual superoxide dismutase (sod) genes in clk-1 mutants, which are sensitized to ROS. We find that only deletion of the primary mitochondrial sod gene, sod-2 results in increased lifespan in clk-1 worms. In contrast, deletion of either of the two cytoplasmic sod genes, sod-1 or sod-5, significantly decreases the lifespan of clk-1 worms.

Further, we show that increasing mitochondrial superoxide levels through deletion of sod-2 or treatment with paraquat can still increase lifespan in clk-1;sod-1 double mutants, which live shorter than clk-1 worms. The fact that mitochondrial superoxide can increase lifespan in worms with a detrimental level of cytoplasmic superoxide demonstrates that ROS have a compartment specific effect on lifespan - elevated ROS in the mitochondria acts to increase lifespan, while elevated ROS in the cytoplasm decreases lifespan. This work also suggests that both ROS-dependent and ROS-independent mechanisms contribute to the longevity of clk-1 worms.

Thursday, February 12, 2015

Parabiosis research in which the circulatory systems of a young and old mouse are connected has led to a cataloging of differences in circulating factors in old versus young blood. Researchers have demonstrated that resetting the levels of GDF-11 in old mice produces beneficial effects, probably through reactivation of stem cell populations and thus increased repair and maintenance of tissues. Other important signaling molecules will no doubt be discovered and manipulated in the years ahead.

Outside of the ability to energize native stem cell populations, there may not be too much more here, however. Even that has to be cautiously approached because of the risk of spurring cancer - the consensus is that the fading of stem cell activity reduces cancer risk, but at the cost of a slow decline in tissue and organ function. Much of the rest of the aging process is driven by things like accumulation of metabolic waste products that the body breaks down only slowly, if at all, however, things that are not much affected by stem cell activity. So it may well be that parabiosis research and the resulting manipulation of factors in the blood is one of the first stepping stones to a future of stem cell therapies that discards transplantation in favor of controlling a patient's own stem cells, but nothing more.

The proposal quoted below is one logical next step following on from present research indicating factors in old blood can be manipulated for benefit. The author suggests a sophisticated form of periodic blood filtration and augmentation, in which the level of some factors is reduced and others raised. Whether this particular technology comes to pass or not depends strongly on the details of the ongoing cataloging and manipulation of important signaling molecules in animal studies, of course.

This hypothesis proposes a new prospective approach to slow the aging process in older humans. The hypothesis could lead to developing new treatments for age-related illnesses and help humans to live longer. Scientists have presented evidence that systemic aging is influenced by peculiar molecules in the blood. Researchers discovered elevated titer of aging-related molecules (ARMs) in blood, which trigger cascade of aging process in mice; they also indicated that the process can be reduced or even reversed. By inhibiting the production of ARMs, they could reduce age-related cognitive and physical declines and lead to slower rates of aging.

A prospective "antiaging blood filtration column" (AABFC) is a nanotechnological device that would fulfill the central role in this approach. An AABFC would set a near-youth homeostatic titer of ARMs in the blood. In this regard, the AABFC immobilizes ARMs from the blood while blood passes through the column. The AABFC harbors antibodies against ARMs. ARM antibodies would be conjugated irreversibly to ARMs on contact surfaces of the reaction platforms inside the AABFC till near-youth homeostasis is attained. The treatment is performed with the aid of a blood-circulating pump. Similar to a renal dialysis machine, blood would circulate from the body to the AABFC and from there back to the body in a closed circuit until ARMs were sufficiently depleted from the blood.

The optimal application criteria, such as human age for implementation, frequency of treatments, dosage, ideal homeostasis, and similar concerns, should be revealed by appropriate investigations. If AABFC technology undergoes practical evaluations and gains approval, it would hold future promises such as: 1) prolonged lifespans; 2) slowed age-related illnesses in the elderly; 3) reduced health expenses; 4) reduced cosmetic surgeries performed on the elderly; 5) healthier astronauts in extended outer space journeys; 6) reduced financial burden of advanced care for the elderly imposed upon both government and society; and 7) rejuvenating effects in healthy, non-aged individuals.

Friday, February 13, 2015

Much of the damage done following an ischemic stroke occurs when blood flow returns: there is a sudden and overwhelming production of reactive molecules and cells die as a result. Given sufficiently potent and safe antioxidants, this harmful process could be suppressed provided a treatment is delivered rapidly:

Injectable nanoparticles that could protect an injured person from further damage due to oxidative stress have proven to be astoundingly effective in tests to study their mechanism. Combined polyethylene glycol-hydrophilic carbon clusters - known as PEG-HCCs - could quickly stem the process of overoxidation that can cause damage in the minutes and hours after an injury. The tests revealed a single nanoparticle can quickly catalyze the neutralization of thousands of damaging reactive oxygen species molecules that are overexpressed by the body's cells in response to an injury and turn the molecules into oxygen. These reactive species can damage cells and cause mutations, but PEG-HCCs appear to have an enormous capacity to turn them into less-reactive substances.

The research targeted traumatic brain injuries, after which cells release an excessive amount of the reactive oxygen species known as a superoxide into the blood. These toxic free radicals are molecules with one unpaired electron that the immune system uses to kill invading microorganisms. In small concentrations, they contribute to a cell's normal energy regulation. Generally, they are kept in check by superoxide dismutase, an enzyme that neutralizes superoxides. But even mild traumas can release enough superoxides to overwhelm the brain's natural defenses. In turn, superoxides can form such other reactive oxygen species as peroxynitrite that cause further damage.

The researchers hope an injection of PEG-HCCs as soon as possible after an injury, such as traumatic brain injury or stroke, can mitigate further brain damage by restoring normal oxygen levels to the brain's sensitive circulatory system. "This could be a useful tool for emergency responders who need to quickly stabilize an accident or heart attack victim." The study also determined PEG-HCCs remain stable, as batches up to 3 months old performed as good as new.

Friday, February 13, 2015

The immune system incorporates a large number of very sophisticated mechanisms for clearing debris, killing errant cells and pathogens, and removing unwanted metabolic waste. Therefore many research groups aim to harness and steer immune cells to achieve specific goals, such as the clearance of amyloid beta deposits associated with Alzheimer's disease. There are many different approaches to developing immune therapies of this nature, some more sophisticated than others. Here is one of the less complex possible approaches:

New research shows that the body's immune system may be able to clear the brain of toxic plaque build-up that is the hallmark of Alzheimer's disease, reversing memory loss and brain cell damage. Alzheimer's disease is an irreversible, progressive brain disease that causes problems with memory, thinking and behavior. Brains with Alzheimer's disease show build-up of a sticky plaque -- made of a protein called beta-amyloid -- that induces memory loss. When afflicted with Alzheimer's, the immune system, which typically rids the body of toxic substances, becomes imbalanced and inefficient at clearing those plaques.

Researchers used genetically modified mice to show that blocking a substance called interleukin-10 activates an immune response to clear the brain of the beta-amyloid plaques to restore memory loss and brain cell damage. Alzheimer's-afflicted mice in which the immune cells were activated behaved more like mice without the disease in various learning and memory tests. Future studies will test the effectiveness of drugs that target interleukin-10 in rats that the scientists have genetically modified to develop Alzheimer's disease. "Our study shows that 'rebalancing' the immune response to wipe away toxic plaques from the brain may bring new hope for a safe and effective treatment for this devastating illness of the mind."


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