Fight Aging! Newsletter, June 23rd 2014

June 23rd 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and 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 medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • The Relevance of Naked Mole Rats
  • AMA with Aubrey de Grey at /r/Futurology
  • Considering Atherosclerosis
  • Recent Progress in Understanding Salamander Regeneration
  • How to End Aging: Aubrey de Grey at TEDxOxbridge
  • Latest Headlines from Fight Aging!
    • Oxytocin and Muscle Regeneration in Aging
    • An Example of Alzheimer's Mechanisms Beyond Amyloid
    • Catabodies to Degrade Transthyretin Amyloid
    • Towards a Better Basis For Kidney Regeneration
    • More Quantification of Human Nuclear DNA Mutation Rates
    • Methionine Restriction and FGF21 in Mice
    • More Sitting, More Cancer
    • Memory Aging and Known Influences on Longevity
    • Transthyretin Amyloidosis as a Cause of Lumbar Spinal Stenosis
    • Vitamin D and Mortality


To what degree does it help to understand the mechanisms by which various species of long-lived mammals are in fact long-lived? That is an open question. There is a great deal of ongoing study of some of these species, such as naked mole rats, and efforts to at least sequence the DNA of others, such as some whales and longer-lived bats.

If we look to the more distant future, it seems fairly straightforward to argue that at the point at which it becomes possible to design new functional human genomes to support people with different metabolisms that nonetheless operate safely over the course of an extended lifetime, then yes, there might be a lot of beneficial alternative or additional modes of operation that can be pulled from the metabolic biochemistry of other species. Perhaps a significant fraction of the more beneficial aspects presently known to exist in other mammals can be made to work quite well in future variants of Homo sapiens machinatum. That isn't an unreasonable projection: it is all just a matter of knowledge and technology, and most of the fundamental technology needed to actually create alternative human genomes already exists or is near realization.

The research community is far behind on the knowledge front, however, and is thus a long, long way from being able to create any sort of stable alternative working metabolism in humans, let alone doing so safely. At the present time just trying to recreate the well-studied and easily achieved alternative metabolic mode of operation produced through the practice of calorie restriction is proving to be a challenge, with all too little to show other than an increase in knowledge after ten years and a few billion dollars - and this is really the first baby step on the road towards engineering entirely new human metabolisms that introduce other improvements.

So how much success should we expect from mining other species for their unusual and beneficial metabolic quirks in the near term? Researchers will certainly make good progress in understanding why naked mole rats are long-lived and immune to cancer in the next few years. There is momentum there. But that doesn't necessarily mean that scientists can then do anything with that knowledge immediately: knowing the signaling pathways or precise differences between rats and naked mole rats doesn't automatically result in ways to alter rats that will work. The operation of metabolism is fantastically complex, a linked web of protein machines all reacting to one another's presence. You can't alter anything in isolation, and it is always an expensive challenge to even prove safety for the comparative crude manipulations achieved today. So as I said above, it is an open question as to whether the outcome of the study of long-lived mammals is simply more knowledge or something more useful than that.

Here is a good popular science article that gives an overview of work on naked mole rat metabolism, details of some of the latest results, and the hopes of the researchers involved:

The end of aging: do naked mole rats have the secret to long, healthy lives?

When he first saw a naked mole rat in 1842, German naturalist and explorer Eduard Rüppell thought he might have found a diseased specimen because it lacked fur. But there's something special about naked mole rats that Rüppell couldn't have seen. Similarly-sized rodents, under ideal conditions, can live for five years or less. The life span of a naked mole rat is about six times as long. Even into their twenties, they barely seem to age, retaining strong heartbeats, dense bones, and remaining fertile. Scientists have dosed them with all sorts of carcinogenic chemicals and radiation, but unlike every other mammal, a naked mole rat has never once been observed to develop cancer.

Until recently, what let the naked mole rats conquer cancer and live so long was a total mystery. But over the past few years, a handful of researchers around the world have uncovered strange mechanisms inside their cells that seem to be the basis for the animals' uncommon longevity. The scientists' ambition is lofty, but not surprising: they want to harness these discoveries to one day vanquish cancer and battle aging in humans too.

Upon hearing about these discoveries, most people ask the same reasonable question: can they be applied to cure cancer and slow aging in humans? The answer, like many in science, is complicated. It's one thing to discover a rodent has marvelous adaptations that allow it to live a really long time. It's another entirely to put them in another species.

Where where I stand, work on understanding longevity in other species looks like just another path to slowing aging through altering metabolism. It is fascinating, but highly unlikely to produce therapies that will greatly extend life or restore health to the old. Slowing aging just slows down the accumulation of damage, which is of limited benefit to those already very damaged by aging. The only types of treatment that will be of great benefit to the elderly are those based on repair of the causes of aging, restoring the metabolism we already have rather than building a new one, as these are in theory capable of actual rejuvenation when realized. Since we might expect at least another two decades to pass before any useful and widespread medical technologies emerge from any lines of present research into treating aging, then we should firmly reject the goal of slowing aging in favor of the goal of repairing and reversing aging. Why work so hard on a course of action that will produce end results that are of no benefit to your older self?


The AMA, Ask Me Anything, events at Reddit have evolved over a few years into a sort of semi-formalized crowdsourced interview via bulletin board. Their success somewhat parallels the rise of crowdfunding projects and the steady demise of personal expectations of privacy, and I don't think that this is a coincidence in either case: it all factors in to the motivations, economic and otherwise, that encourage people to engage with an audience in this way. It is interesting to note that the online bulletin board as used in practice is only a little younger than the internet, four decades old or so now, and new yet new modes of use and cultural establishments built atop it still come and go with regularity.

The r/Futureology community at Reddit is an open forum for following and discussing technological advances relevant to the modern futurist viewpoint - which is essentially the transhumanist viewpoint, as the transhuman visions for technological development outlined in 1980s zines and the online forums of the 1990s are now either presently already in their infancy, or are otherwise quite widely accepted as being sensible mainstream ideas. Molecular nanotechnology, strong AI, and - most importantly - work on radical life extension and working rejuvenation therapies: these were all too recently derided and yet are now taken as common sense futurism. It is hopefully a short step from there to more people deciding to donate to speed up rejuvenation research rather than just waiting and hoping on the sidelines.

The moderators at /r/Futureology today hosted an AMA with Aubrey de Grey of the SENS Research Foundation, a prominent figure in the longevity science community who should need no introductions to the audience here. It is very pleasing to see de Grey in front of an appreciative, intelligent online audience who have some knowledge of the work of the Foundation and its great importance to our lives. I'll cut right to the most interesting point, but you should certainly scan the whole thing, as there are some other tidbits in there:

Aubrey de Grey AMA

Q: Mr. De Grey, has Google tried to hire you? Being a leader in your field of investigation I thought they'd bend over backwards to have you on board for Calico.

A: We're talking to them, but it's still very preliminary - they are taking their time to decide their direction.

The SENS Research Foundation's lab is of course just down the road from Google's HQ, and there probably half a hundred people in that town who are on first name terms with all three of de Grey, Sergey Brin, and Larry Page. Noteworthy support for the SENS vision of repair-based approaches to reverse age-related damage and disease has existed in the Bay Area technology and venture community for years, especially in those circles associated with Clarion Capital.

My prediction for the median expected outcome of the next few years of Google's California Life Company (Calico) initiative is that they will focus on what is currently mainstream, which is to say the genetics of longevity and efforts to slow aging via metabolic alteration. They will throw tens of millions of dollars at this, spawn several businesses, produce an enormous volume of new information, and fail to produce any way to meaningfully extend human life.

The hires made so far and most of the discussion to date has supported this view; I think that the network of SENS researchers and supporters, despite being very close at hand both in the network of relationships and physically, will have to grow larger yet before it can acquire large patron organizations such as Calico. I hope to be proven wrong and pleasantly surprised, but I expect to see the few entities in the sphere of aging research with a lot of funding and the will to use it to both try and fail with every path other than SENS before finally coming around to focus on rejuvenation biotechnologies based on repair of the known forms of damage that cause aging.

But who knows? The future is what we make of it. The SENS Research Foundation are not the only group putting forward largely repair based approaches to treating aging. There is a proposal from Spanish aging researchers put forth a year ago that differs in the details from SENS, but is otherwise very similar in intent, to pick one example. It is possible that the next wave of interest in treating aging and funding prospective therapies, once people have got the fixation on development and use of genetic technologies out of their system, will see varied groups arguing over what to repair and how. That would be a large step up from the present situation, in which the only research plans likely to produce functional treatments that reverse the harms of aging in the old are still on the margins of the scientific community, moving along slowly with little funding.

The most important thing to take away from this? The following, I think:

Q: Dr. De Grey, No questions, I just wanted to thank you for your passion and dedication to such an important cause.

A: Thanks back! So, what are you doing to help?


Atherosclerosis is a fearsome age-related condition, as it is quite possible to suffer the progressive build up of arterial plaque with few or no apparent symptoms all the way up until some of it suddenly ruptures to cause the catastrophic blockage of blood flow known as an infarction, and that either cripples you or kills you over the course of an exceedingly painful few minutes. If this affects your heart or your brain you will be lucky to survive, and luckier to recover.

The various contributing causes of atherosclerosis are numerous, each layer of cause and effect feeding into the one above. An incomplete list might include: the evolved reaction to disturbed blood flow in blood vessel walls; the details of fat metabolism; accumulation of lipofuscin constituents such as 7-KC in macrophages attracted to blood vessel damage; damaged cholesterol molecules created by the toxic output of cells overtaken by damaged mitochondria; and last but far from least the standard issue risk factors for all of the common age-relate diseases: becoming fat, being sedentary, and taking up smoking.

I'll point out the recent article on atherosclerosis quoted below as it caught my eye by virtue being interesting and balanced within its own lack of vision regarding the treatment of the condition. The author discusses diet, which is of little consequence in comparison to the outcome of medical research. Atherosclerosis is not a modern condition, and indeed the progress in health over the past few centuries has rendered us far better off at any given age than our distant ancestors. If we see more of atherosclerosis and its threat of sudden death today, it is because we have engineered longer lives, control of the lion's share of serious infectious disease, and the medical technologies need to pay closer attention to the progression of atherosclerosis as we age. Now more people survive or never even see the mortal threats that thinned the ranks of those who came before us:

Death by Affluence?

Many different societies in human history have mummified their dead, using naturally occurring cold, hot, or dry conditions with or without embalming, and HORUS researchers took these ancient corpses, from different societies and times and continents, and put them through CT scanners. The deposits of atherosclerosis proved common. They were present in a third of the mummies, despite their average age at death being 36 (an age which does not fit neatly with the idea of a "natural" life being blissfully healthy). Atherosclerosis was as easily spotted in the dead gatherer-hunters as in the late pastoralists; as common in those who had lived on fish and seafood as in those who feasted on steak.

The HORUS study cannot tell us anything about the superiority of one diet over another, but it does reveal that when it comes to tackling atherosclerosis by altering diet and lifestyle, there may not be a magic preventive or cure. Far from being the peculiar side effect of modernity, problems with blood vessels narrowing and hardening occur routinely with age in all human societies. The foggy idea that modern life fosters atherogenesis - a notion that for too long was accepted without having been properly examined - evaporates under the sunlight.

Outside of the SENS vision of reversing and preventing age-related disease by fixing root causes, which include the lipofuscin and damaged mitochondria mentioned above, much of medical science operates at a higher level in the chain of consequences. Researchers aim to interfere much further along, in attempts to reduce the severity of the results without reducing the the severity of the underlying causes. This doesn't sound very sensible when put this way, and from a high level perspective it really isn't the best way forward. Medical science works this way because, constrained by regulation, research tends to run backwards from the end state of a defined, named disease, so the first new things discovered are the proximate causes. Thus when it comes time to try to create profitable therapies from these discoveries, the development community has to work on patches that make things somewhat better for late stage disease rather than working on methods of prevention and repair that can stop the disease from ever happening in the first place, and cure it for those who do suffer its effects already. This state of affairs will change, and it has to change if we are to see great improvements in the health of the elderly and the prospects for defeating age-related disease.

Here is an example of the sort of research that results from the working backwards approach, the identification of risk factors in metabolism that might be modified to reduce the accumulation of root causes. This is of course of limited utility to those already damaged, as it does nothing to remove existing damage:

New research can improve heart health

Danish researchers [have] shown that people with variation in a gene that inhibits a specific protein in the blood - the so-called apolipoprotein C3 - have a significantly lower level of normal blood lipids than people without this gene variation [as] as well as a significantly reduced risk of cardiovascular disease. Furthermore, the same individuals also have a 41 per cent lower risk of arteriosclerosis. The research is highly relevant as at least one pharmaceutical company has a drug in the pipeline which inhibits precisely apolipoprotein C3.

The scientific results are based on two of the world's largest population studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, with a total 75,725 participants who were followed for 34 years.


How is it that salamanders can regenerate major organs and limbs, while mammals cannot? There is some interest in this question in the medical community, for all the obvious reasons, although it remains unknown as to how challenging it will be to pick out specific elements in the biochemistry of another species and port them over to we humans. Any given case might be made to work with near-future biotechnology or might prove to be unfeasible for the foreseeable future, but we won't know until researchers make it 80% of the way to the final goal. Thus there is funding and enthusiasm in a range of laboratories for work on better understanding the essential differences in regeneration between salamanders and mammals, spurred on by incidental, unrelated discoveries such as a breed of mice capable of healing some wounds without scarring, or a better grasp of the rare cases in which human fingertips grow back.

Over the past decade a steady series of research results have increased knowledge of the mechanisms of salamander regeneration, both in terms of how different cell populations are behaving, and at the lower level of changes in protein levels, signaling pathways, and gene expression. Here is another piece of the puzzle, though it is clearly still a long way from here to a level of understanding that enables safe manipulation of mammalian cells via this mechanism to create greater feats of regeneration:

Salamanders give clues to how we might regrow human limbs

Although we do not yet understand the exact mechanisms by which salamanders are able to regrow their limbs, we do know that this animal regeneration takes place by the reprogramming of adult cells. This means that for regeneration to take place, adult cells - such as muscle cells - that form the limb have to lose their muscle identity and proliferate to give rise to new cells that will contribute to form the new structure. This process is rarely found in mammalian cells and this has been suggested as the basis for their poor regenerative abilities.

We recently found a critical component of the reprogramming mechanism. In our [study], we demonstrated that the sustained activation of a molecular pathway (a group of molecules in a cell that work together to control a particular function or functions) - called the ERK pathway - plays a key role during the natural reprogramming of salamander muscle cells. Only when the ERK pathway is constantly switched "on" are the cells able to re-enter the cell cycle, which is key to their regenerative potential.

We also compared salamander and mammalian muscle cells. In contrast to salamander cells, we found that mammalian cells can only activate the ERK pathway transiently, and fail to keep the pathway switched "on". Critically, we found that if we forced these mammalian cells to keep the ERK pathway activated (by giving them a piece of DNA that allows them to produce a protein that activates the pathway), the cells could produce the proteins involved in cell cycle re-entry. This suggests that the manipulation of the pathway could contribute to therapies to enhance the regenerative potential in humans.

Sustained ERK Activation Underlies Reprogramming in Regeneration-Competent Salamander Cells and Distinguishes Them from Their Mammalian Counterparts

In regeneration-competent vertebrates, such as salamanders, regeneration depends on the ability of various differentiated adult cell types to undergo natural reprogramming. This ability is rarely observed in regeneration-incompetent species such as mammals, providing an explanation for their poor regenerative potential. To date, little is known about the molecular mechanisms mediating natural reprogramming during regeneration. Here, we have identified the extent of extracellular signal-regulated kinase (ERK) activation as a key component of such mechanisms. We show that sustained ERK activation following serum induction is required for re-entry into the cell cycle of postmitotic salamander muscle cells, partially by promoting the downregulation of p53 activity.

Remarkably, while long-term ERK activation is found in salamander myotubes, only transient activation is seen in their mammalian counterparts, suggesting that the extent of ERK activation could underlie differences in regenerative competence between species.


When it comes to extending the healthy human life span and eliminating the suffering caused by age-related disease - and indeed by aging in general - the overwhelming majority of the world's population lie somewhere in the midst of disinterest, disbelief, and ignorance. To a first approximation no-one really cares about medical science, for all that they owe their health to this field of research and development. Similarly despite living in the midst of an age of radical change, with completely new technologies and medical therapies turning up every few years, people generally assume that the rest of their lives will take roughly the same course as did those of their parents and grandparents. If you bring up the topic of great longevity through medical science, often as not the notion is rejected out of hand: people express no interest in their own longevity, or claim not to want to live any longer than their grandparents managed.

All of this is why there must be advocacy for longevity science. In a world in which more than 100,000 people die horribly every day due to degenerative aging and its consequences, while everyone else ambles heedlessly to the same fate, it is vital that some of us speak out, so as to change minds and raise funds for the research programs that can bring an end to all of this suffering and death. Aging is just a medical condition, and will one day be bought under control in the same way as any medical condition: through hard work, research funding, and new clinical treatments.

Medical biogerontologist Aubrey de Grey is one of the more vocal and energetic advocates involved in the present generation of scientific initiatives to treat aging. He and a sizable network of allies associated with numerous foundations and associations have accomplished a great deal in the past decade, changing the culture of the aging research community, and making inroads into changing broader perceptions of aging and medicine held among the public at large. In addition to this work, de Grey helps to manage ongoing research at the SENS Research Foundation, an organization he co-founded in order to accelerate the development of a planned list of biotechnologies needed to create real, working rejuvenation treatments.

Here is a recent presentation given by de Grey at TEDxOxbridge entitled "Rejuvenation biotechnology: the sweet spot between prevention and treatment of age-related ill-health":

Most infectious diseases have been easily prevented: sanitation; vaccines; antibiotics; carrier control. Age-related diseases have not. If historical rates continue, US healthcare spending will be 34% of GDP by 2040. In 2010, the US spent $1.186 trillion on healthcare for 65+ people.

Aging is: The life-long accumulation of damage to the tissues, cells, and molecules of the body that occurs as an intrinsic side-effect of the body's normal operation. The body can tolerate some damage, but too much of it causes disease and disability.

Age-related diseases are caused by aging! Thus, they are: widespread now that infections are "rare"; staggeringly costly; universal if you live long enough; not medically curable, in the strict sense. But they, and aging itself, are nonetheless medical problems and medically preventable in principle.


Monday, June 16, 2014

Researchers have discovered an unexpected effect of oxytocin on muscle regeneration. One has to wonder just how much the fact that use of oxytocin is already approved by regulators factors into this work: there is a strong incentive for researchers to look for new marginal effects in the existing set of approved drugs and compounds rather than work on radically new and better medical technologies. This is because regulators impose vast costs on novel technologies, but only very large costs on reuse of existing treatments in new ways, and this structure percolates all the way back up the research chain due to its effects on funding. This is just one of many detrimental distorting effects of regulation on the course, speed, and effectiveness of medical research.

A few other biochemical factors in blood have been connected to aging and disease in recent years, but oxytocin is the first anti-aging molecule identified that is approved by the Food and Drug Administration for clinical use in humans. "Unfortunately, most of the molecules discovered so far to boost tissue regeneration are also associated with cancer, limiting their potential as treatments for humans. Our quest is to find a molecule that not only rejuvenates old muscle and other tissue, but that can do so sustainably long-term without increasing the risk of cancer."

The new study determined that in mice, blood levels of oxytocin declined with age. They also showed that there are fewer receptors for oxytocin in muscle stem cells in old versus young mice. To tease out oxytocin's role in muscle repair, the researchers injected the hormone under the skin of old mice for four days, and then for five days more after the muscles were injured. After the nine-day treatment, they found that the muscles of the mice that had received oxytocin injections healed far better than those of a control group of mice without oxytocin. "The action of oxytocin was fast. The repair of muscle in the old mice was at about 80 percent of what we saw in the young mice."

Interestingly, giving young mice an extra boost of oxytocin did not seem to cause a significant change in muscle regeneration. "This is good because it demonstrates that extra oxytocin boosts aged tissue stem cells without making muscle stem cells divide uncontrollably." The researchers also found that blocking the effects of oxytocin in young mice rapidly compromised their ability to repair muscle, which resembled old tissue after an injury.

Monday, June 16, 2014

The prevailing focus in Alzheimer's disease (AD) research is on removal of amyloid, solid aggregates of misfolded proteins, considered the main agent of harm. More sophisticated researchers consider why there is more amyloid in the brains of Alzheimer's patients, and the elderly in general, and how that comes about and how it might be prevented. For example the SENS research program includes periodic removal of all amyloids as a goal because the presence of amyloid is a fundamental difference between old and young tissue, and therefore should be eliminated as a part of any repair-based rejuvenation treatment.

No consensus goes unchallenged in medical science, however, and there are a range of alternative views and proposed mechanisms for the harm caused by Alzheimer's disease, some of which add to the amyloid viewpoint as this one does. That there is further damage caused by amyloid that is not restored by simply removing the amyloid deposits is an incentive to develop periodic amyloid clearance treatments. These should be applied to healthy people throughout life, so as to prevent amyloid ever rising to the level at which it causes these further harms. All too much of the research community remains entirely committed to the model of waiting until the late stages of disease and then trying to repair everything that goes wrong at that time, however.

[This] research was motivated by the recent failure in clinical trials of once-promising Alzheimer's drugs being developed by large pharmaceutical companies. "Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer's drugs, but they failed the test after they unexpectedly worsened the patients' symptoms." The research behind those drugs had targeted the long-recognized feature of Alzheimer's patients' brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die. "The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer's disease."

[The] research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called "reactive astrocytes" in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to the hippocampus, an area of the brain that is critical for learning and memory. "Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals' poor performance on tests of learning and memory."

The high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

"After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone."

Tuesday, June 17, 2014

A comparatively small number of misfolded proteins form solid aggregates in tissue due to the change in chemical properties caused by this misfolding, and the result is called an amyloid, and a consequent medical condition is called an amyloidosis. The best known type of amyloid is that associated with Alzheimer's disease, but for many of the others it isn't as clear as how these aggregates cause damage. Nonetheless amyloids all accumulate with age, and thus should be removed by any comprehensive suite of rejuvenation treatments.

One of the other amyloids clearly linked to harm is misfolded transthyretin (TTR), which is implicated as the cause of death in most people who make it to very advanced ages. In the very elderly this form of amyloid clogs the cardiovascular system. There is also an inherited variant of TTR amyloidosis that occurs rarely in younger people due to an unfortunate genetic mutation, and as is often the case in these matters most past research has focused there.

Here is a pointer to a recent paper that results from SENS Research Foundation funded work on one possible way to safely break down transthyretin amyloid, removing its contribution to age-related mortality through the use of catalytic antibodies, thought to be a type of functional component in the innate immune system. If selective antibodies effective at breaking down this form of amyloid are established by searching through the many different types present in humans, then these few proteins can be manufactured in bulk and used as the basis for a treatment:

Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the [correctly folded] TTR (phyTTR).

IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins.

The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function. Catalytic IgMs may clear misfolded TTR and delay amyloidosis [and] the innate antibody repertoire is a source of selective catabodies to toxic proteins.

Tuesday, June 17, 2014

Researchers are step by step establishing a better understanding of kidney regeneration that should improve efforts to spur regrowth and repair through stem cell treatments and other forms of regenerative medicine:

Doctors and scientists have for years been astonished to observe patients with kidney disease experiencing renal regeneration. The kidney, unlike its neighbor the liver, was universally understood to be a static organ once it had fully developed. "We wanted to change the way people thought about kidneys - about internal organs altogether. Very little is known even now about the way our internal organs function at the single cell level. This study flips the paradigm that kidney cells are static - in fact, kidney cells are continuously growing, all the time."

[Researchers] conducted a study using a "rainbow mouse" model, a mouse genetically altered to express one of four alternative fluorescent markers called "reporters" in each cell. "We were amazed to find that renal growth does not depend on a single stem cell, but is rather compartmentalized. Each part of the nephron is responsible for its own growth, each segment responsible for its own development, like a tree trunk and branches - each branch grows at a different pace and in a different direction."

Using the rainbow mouse, the researchers were able to pinpoint a specific molecule responsible for renal cellular growth called the "WNT signal." Once activated in specific precursor cells in each kidney segment, the WNT signal results in robust renal cellular growth and generation of long branches of cells. "Our aim was to use a new technique to analyze an old problem. No one had ever used a rainbow mouse model to monitor development of kidney cells. It was exciting to use these genetic tricks to discover that cellular growth was occurring all the time in the kidney - that, in fact, the kidney was constantly remodelling itself in a very specific mode."

"This study teaches us that in order to regenerate the entire kidney segments different precursor cells grown outside of our bodies will have to be employed. In addition, If we were able to further activate the WNT pathway, then in cases of disease or trauma we could activate the phenomena for growth and really boost kidney regeneration to help patients. This is a platform for the development of new therapeutics, allowing us to follow the growth and expansion of cells following treatment."

Wednesday, June 18, 2014

Nuclear DNA is essentially a big complicated molecule, and stuck in the middle of the dynamic environment of the cell it accumulates damage due to reactions with other molecules. Near all of this damage is repaired quickly, but only near all. So we accumulate somewhat random mutations scattered across our cells as we age. There is some debate over whether this is actually a cause of general age-related degeneration over the present human life span versus only a cause of cancer.

This paper looks at human mutation rates in the exome, a classification that includes only small fraction of our DNA, but which is thought to encompass most of the important known mutations associated with various diseases. There is thus an energetic community that studies this small part of the genome:

The inability of genomic variants to fully explain known or suspected inherited and spontaneous components of a wide variety of diseases may indicate that there may be additional undiscovered factors that complicate analysis. These factors include the number and rapidity with which one accumulates genomic variants, which if known could be compensated for, like ethnicity and sex. Genetic characterization of aging, therefore, may hold a key to questions regarding the importance of acquired somatic variants, variation in aging within a population, and their role in human diseases. Adding time and the accompanying mosaic changes as variables may enhance the accuracy and utility of population-scale analysis of human traits and disease.

In an attempt to begin to address this gap, we hypothesized that the inherited genome is not static but rather dynamic with time with individual experiences punctuating genomes differently. To test this hypothesis we used exome sequencing of normal epithelial samples from three healthy individuals serially collected at different ages in their life. We found the human genome to be dynamic, acquiring a varying number of mutations with age (5,000 to 50,000 in 9 to 16 years). These mutations span across 3,000 to 13,000 genes, which commonly showed association with Wnt signaling and Gonadotropin releasing hormone receptor pathways, and indicated for individuals a specific and significant enrichment for increased risk for diabetes, kidney failure, cancer, Rheumatoid arthritis, and Alzheimer's disease - conditions usually associated with aging.

[This demonstrates] that the exome of an individual is dynamic and constantly experiences environmental and evolutionary pressures and over time enriches for deleterious variants. This finding indicates that the accumulation of somatic variants and possibly the rate of accumulation will contribute to how an individual ages, and prompting age-related diseases. It challenges our existing approach in population-scale sequencing studies and establishes "age" as an important variable that must be accounted for in the analysis and interpretation of any given human genome. These observations are supportive of new paradigm, "Multiple genomes per individual".

Wednesday, June 18, 2014

All near alternatives to calorie restriction with optimal nutrition are attracting more scientific attention these days, among them intermittent fasting and methionine restriction. All three of these have been demonstrated to extend life in mice and rats to varying degrees, and the collection of mechanisms involved appears to be somewhat different in each case: overlapping sets of metabolic reactions to low levels of food or reduced amounts of one of a few dietary constitutents such as methionine.

It is interesting to see FGF21 levels mentioned in the methionine restriction study below, as using genetic engineering to increase the levels of FGF21 in mice has been shown to extend life by influencing one of the better known longevity mechanisms in mammals. Everything touches on everything else in metabolism, and the diversity of methods by which aging can be slowed in laboratory species really reflects a smaller number of core mechanisms that can be altered in many different ways:

Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals.

Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice.

Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight.

Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.

Thursday, June 19, 2014

One of the more interesting results from the study of health and lifestyle choices in recent years is the finding that time spent sitting correlates with increased mortality and a shorter life expectancy regardless of whether or not individuals also exercised. As for all such statistical investigations, there is a lot of room to speculate as to the web of related associations and which of them are actually contributing meaningfully to differences in health. This metastudy expands on the picture by looking specifically at cancer risk:

Sedentary behavior is emerging as an independent risk factor for chronic disease and mortality. However, the evidence relating television (TV) viewing and other sedentary behaviors to cancer risk has not been quantitatively summarized. We performed a comprehensive electronic literature search for published articles investigating sedentary behavior in relation to cancer incidence. Because randomized controlled trials are difficult to perform on this topic, we focused on observational studies that met uniform inclusion criteria.

Data from 43 observational studies including a total of 68936 cancer cases were analyzed. Comparing the highest vs lowest levels of sedentary time, the relative risks (RRs) for colon cancer were 1.54 for TV viewing time, 1.24 for occupational sitting time, and 1.24 for total sitting time. For endometrial cancer, the relative risks were 1.66 for TV viewing time and 1.32 for total sitting time. A positive association with overall sedentary behavior was also noted for lung cancer. Sedentary behavior was unrelated to cancers of the breast, rectum, ovaries, prostate, stomach, esophagus, testes, renal cell, and non-Hodgkin lymphoma.

[We conclude that] prolonged TV viewing and time spent in other sedentary pursuits is associated with increased risks of certain types of cancer.

Thursday, June 19, 2014

This open access review paper looks over some of the better known ways to modestly slow aging and extend healthy life in laboratory animals and their relationship with the progressive degeneration of memory with advancing age:

The aging process has been associated with numerous pathologies at the cellular, tissue, and organ level. Decline or loss of brain functions, including learning and memory, is one of the most devastating and feared aspects of aging. During the past century, age-related memory impairments have emerged as one of the top public health threats. Both psychiatric and neurodegenerative disorders comprising schizophrenia, depression, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are associated with age-related memory impairment. In humans, cognitive decline starts in mid-life and deepens with advancing age suggesting that the greatest risk factor is age itself. Thus, ultimately, prevention of these pathologies necessitates thorough understanding of the molecular mechanisms underlying their links with the aging process.

Learning and memory are fundamental processes by which animals adjust to environmental changes, evaluate various sensory signals based on context and experience, and make decisions to generate adaptive behaviors. Age-related memory impairment is an important phenotype of brain aging. Understanding the molecular mechanisms underlying age-related memory impairment is crucial for the development of therapeutic strategies that may eventually lead to the development of drugs to combat memory loss.

Studies in invertebrate animal models have taught us much about the physiology of aging and its effects on learning and memory. In this review, we survey the molecular mechanisms and genes associated with longevity that have also been implicated in cognitive aging. We further focus on recent work in invertebrate model organisms linking learning and memory impairment with age./td>

Friday, June 20, 2014

Transthyretin (TTR) amyloidosis, also known as senile systemic amyloidosis, occurs as a misfolded form of transthyretin forms solid deposits in tissues. In young people this is only threatening when accompanied by rare genetic mutations that greatly accelerate the process, but ongoing accumulation of this amyloid throughout life happens to everyone. If you live to a very great age and survive all of the other forms of age-related disease, then this amyloid will grow to clog your cardiovascular system and kill you. Safe removal of this transthyretin amyloid must thus be a part of any future rejuvenation treatment, and so the SENS Research Foundation funds some lines of research, such as work on catabodies that can break down amyloid deposits. Unfortunately this is in general a small, poorly funded area of research - few groups are looking into TTR amyloidosis, which is why non-profits like the Foundation are trying to hurry matters along.

In this open access paper researchers suggest that in earlier old age TTR amyloid causes other issues, in particular a painful form of degeneration known as lumber spinal stenosis - though more work than was accomplished here would be needed for proof. Producing treatments for this manifestation of amyloidosis would probably be more of a motivation for developers to work on ways to remove amyloid, as there are more patients and thus greater potential revenue from a therapy. So it goes:

Senile systemic amyloidosis (SSA) derived from wild-type transthyretin is a fairly common condition of old individuals, particularly men. The main presentation is by cardiac involvement, which can lead to severe restrictive cardiomyopathy. SSA is, however, a systemic disease, and amyloid deposits may appear in many other tissues but are thought to be without clinical symptoms outside the heart. Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits.

Lumbar spinal stenosis is a clinical syndrome of usually elderly individuals that depends on narrowing of the lumbar spinal canal. It is characterized by compression of sensory and motoric nerves to the lower limbs, leading to an often disabling condition. The pathogenesis is probably heterogeneous but includes disc degeneration with disc height decrease and secondary facet-joint subluxation leading to osteoarthritis. Also a degenerative spondylolisthesis of the affected spinal segment may be involved in most cases. Other central factors are general degenerative processes in cartilage and ligaments, including ligamentum flavum.

We questioned whether lumbar spinal stenosis sometimes could be a manifestation of undiagnosed SSA. In this first report we have studied the presence of amyloid in material obtained at surgery for spinal stenosis in 26 patients. Amyloid was found in 25 subjects. Transthyretin was demonstrated immunohistochemically in 5 out of 15 studied resected tissues. Four of the positive materials were analyzed with Western blot revealing both full-length transthyretin (TTR) and C-terminal TTR fragments, typically seen in SSA. We conclude that lumbar spinal stenosis quite frequently may be a consequence of SSA and that further studies are warranted.

Friday, June 20, 2014

I rarely discuss supplements in the context of longevity, as there is little to say: the weight of scientific evidence is overwhelmingly against most of what is sold under claims of providing some benefit to long-term health. Much of what is written out there in the world on this topic is written by people who sell supplements, and who therefore have every incentive to lie to you and lie to themselves in order to keep up a revenue stream. There are just a few exceptions to this state of affairs, where the state of evidence swings in the direction of benefits and few harms for ordinary people who are not vitamin deficient, and one of them is vitamin D.

Even here it isn't that there is an iron-clad case for taking it, just a decent case: there is good evidence for vitamin D levels in blood to correlate statistically with decreased mortality, there is very little sign of any harms from supplementing with vitamin D in animal and human studies, and vitamin D is very cheap. However it is magical thinking to assume that taking vitamin D to raise levels in blood will have the same effect as a natural variation observed in a population - one could imagine scenarios in which an artificially induced increase in vitamin D levels shuts off some useful process, for example, or in which natural variations in vitamin D levels are a side-effect of a beneficial process that is unaffected by supplementation. So there must still exist evidence to show that supplementing over the long term does actually produce benefits.

The rational person should spend all of five minutes thinking this through, make a decision, and then move on to much more important matters. The potential benefit here is not large in comparison to the potential outcomes of improved medical science over the next few decades, such as work on the SENS vision for rejuvenation biotechnology, so if we're going to spend time on thinking about longevity, far better for that time to go to SENS.

To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences [we undertook a] meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US [consisting of] 26,018 men and women aged 50-79 years

25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses.

[We conclude that] despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.


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