Fight Aging! Newsletter, November 24th 2014

November 24th 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, 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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  • Recent Investigations into the Mechanisms of Atherosclerosis
  • Regenerative Medicine and the Future of Healthy Longevity
  • "We should not regard aging as a fact of life."
  • The Role of 3-D Printing in the Future of Medicine
  • Why Do We Advocate for Rejuvenation Research?
  • Latest Headlines from Fight Aging!
    • Anti-Aging Medicine: Notes on a Controversy
    • An Interesting Presentation on Aging Research
    • New Theorizing on Teleomere Length and Gene Regulation
    • Calorie Restriction and Age-Related Gene Expression Changes in the Brain
    • A Discussion of Modest Goals in Treating Aging
    • Increasing Interest in DNA Methylation in Aging
    • Suppressing PERK Improves Memory in Mice
    • Delivering Stem Cell Factor into Damaged Heart Tissue
    • More Investigations of Calorie Restriction in Long-Lived Mice
    • Lamin-B and Immunosenescence


Atherosclerosis is a particularly unpleasant age-related condition not because it causes great suffering along the way but because it is comparatively invisible right up until the point at which it kills you suddenly. In atherosclerosis the blood vessel walls are thickened by material that is largely composed of immune cells and the fatty remnants of dead cells. Eventually this material becomes unstable enough to cause major blood vessel failure or for a piece to break off and catastrophically block a blood vessel elsewhere in the body, leading to stroke or heart attack.

Once atherosclerotic plaques exist in earnest, they become a ongoing industry of inflammation, cell death, and restructuring on the inside of your blood vessels. The immune cells present in the area act to maintain inflammatory conditions that help to make things worse and attract more immune cells, creating an ever larger mess as time goes by. The starting point for this process involves cholesterols, however. Low-density lipoproteins (LDL) can become damaged by oxidative reactions and in large enough numbers their presence causes a response in blood vessel walls, wherein the tissues issue a call for immune cells to turn up and remove the unwanted damaged LDL molecules. Sometimes this all proceeds according to plan and the harmful LDL is removed, but sometimes the immune cells cannot cope with the ingestion of LDL and die. This can snowball into precursor fatty structures that will grow to become atherosclerotic plaques.

So progression of atherosclerosis is one of the many aspects of aging that can be sped by an environment of greater chronic inflammation in the body. But it is also driven by levels of damaged LDL. That second item is the link between causes of chronic oxidative stress in tissues, rising levels of oxidative molecules roaming to cause unwanted reactions and damaged proteins, and damage such as that of atherosclerosis. Damage caused to mitochondria over the course of aging in particular is thought to drive rising levels of oxidative molecules such as reactive oxygen species: some cells in every tissue become very dysfunctional as a result of this, overtaken by damaged mitochondria and turned into exporters of oxidative molecules. That flow of oxidative molecules can react with and damage important proteins such as LDL that travel far in the body via the circulatory system - and thus contribute to the roots of atherosclerosis over the years.

So I've sketched a picture here, but the reality is that these are complex mechanisms and in absence of repair technologies to remove one or another contribution to atherosclerosis it is hard to prove the degree to which various different sources contribute to the pathology of the condition. For example, there are other ways to modify LDL so as to cause pathology, but this is all the more reason to work harder on repair biotechnologies, as I see it. They are an investigative tool that compares favorably in projected cost and time at this point in comparison to the slow and painfully expensive approach of gathering a full understanding of any process in the aging of metabolism. That all said, here is an example of present research aimed at improving understanding of the causes of atherosclerosis, a paper that touches on some of those other means to alter LDL in harmful ways:

New immunological findings provide possible therapy for cardiovascular disease

Atherosclerosis is an inflammatory process where lipids in the form of LDL cholesterol (also called 'bad cholesterol') are stored in the artery walls. The activation of the immune system in the form of T-cells, among others, plays a vital role, particularly for rupturing the atherosclerotic plaques which, the primary cause of myocardial infarction and stroke. LDL is only taken up in the artery wall after modification, a process where oxidation is one probable underlying cause. Enzymes in the artery walls can also modify LDL making it inflammatory. Most basic scientific studies in the field are based on mouse models with genetic changes as mice cannot develop arteriosclerosis or cardiovascular disease.

[The researchers] studied inflammatory and immune defence reactions in atherosclerosis and cardiovascular disease using plaque cells and blood from patients with cardiovascular disease. The researchers have observed that the lipids (phospholipids) in modified LDL appear to be one of the primary causes. The research team has shown that LDL that is modified by enzymes in the artery walls can activate dendritic cells, which in turn play a key role in activating the T-cells. Non-modified, regular LDL on the other hand had no effect on these cells in the study. The research also indicates the possible existence of a mechanism, namely that stress proteins (also called heat shock proteins) are expressed, which is decisive when modified LDL activates the dendritic cells and T-cells. The study shows that a plasma protein Annexin A5 decreases inflammation and modulates immune reactions to modified LDL, which creates a protective effect.

Induction of Dendritic Cell-Mediated T-Cell Activation by Modified but Not Native Low-Density Lipoprotein in Humans and Inhibition by Annexin A5

Atherosclerosis is an inflammatory disease, where activated immunocompetent cells, including dendritic cells (DCs) and T cells are abundant in plaques. Low-density lipoprotein modified either by oxidation or by human group X-secreted phospholipase A2 (LDLx) and heat shock proteins (HSP), especially HSP60 and 90, have been implicated in atherosclerosis.

We previously reported that Annexin A5 inhibits inflammatory effects of phospholipids, decreases vascular inflammation and improves vascular function in apolipoprotein Eāˆ’/āˆ’ mice. Here, we focus on the LDLx effects on human DCs and T cells. Our data show that modified forms of LDL such as LDLx but not native LDL activate human T cells through DCs. HSP60 or 90 contribute to such T-cell activation. Annexin A5 promotes induction of regulatory T cells and is potentially interesting as a therapeutic agent.

You can clearly see the standard research approach here: look for ways to interfere in the details of the process of development (tinker with levels of Annexin A5 to try to reduce the inflammation levels caused by the presence of damaged molecules) rather than address the root cause (the presence of that damaged LDL in the first place). When you work from the end state backwards, points at which the process might be altered are the first things to be discovered. That doesn't mean it is a good approach, however. What it means is that it is the approach most likely to win further funding and a prospect of entering the drug development and regulatory pipeline as they are presently instantiated. Effectiveness of the research strategy as a whole is a much lower priority, sad to say.


One of the many possible future banners for applied longevity science is to call these treatments capable of extending healthy life span simply "regenerative medicine." In past years, regenerative medicine has referred to the output of the stem cell research community: ways to manipulate and transplant cells in order to create regrowth and healing to a degree that would not normally occur. But why not broaden the usage to include repair of damage within cells, and removal of metabolic waste in tissue structures between cells? It isn't such a leap. The stem cell research community is presently largely focused on building treatments for the old, and thus these researchers will have to solve many of the issues affecting old cells one way or another in order to render their therapies effective.

Looked at this way, "regeneration" and "rejuvenation" are really not so different in meaning. Aging is a matter of accumulated damage that is beyond the capacity of the body to heal, and regenerating old tissue by removing some that damage might as well be called rejuvenation. Such a treatment would remove some of the differences between old tissue and young tissue, and would aim to restore function to a point closer to that of a youthful, healthy individual. In isn't hard to think of aging as an illness, a progressive medical condition, when looking at things in these terms, and that seems to me to be a good viewpoint on the situation if it inspires more people to help do something about it.

Here is an enthusiastic two part piece that mentions regenerative medicine, advanced research such as the SENS programs, as well as other work on immunotherapies and clearance of senescent cells. All of this is in the context of looking ahead to the near future of new therapies and improvements in maintenance and restoration of human health:

Can Regenerative Biotechnology Extend Our Productive Lives?

"It's obvious to me that university laboratories can't do it alone," says University of Southern California professor of gerontology and biological sciences Caleb Finch. "Big Pharma can't do it alone. A marketplace of ideas has to be developed. Those of us who come to these meetings have an increasingly broader set of professional alliances. You get a high table of very smart people around you who represent different disciplines and technologies."

"Disease-modifying cell therapy is very quickly becoming a reality," declares Stephen Minger, chief cellular scientist at GE Healthcare in the United Kingdom. "We're all piling on this now. Until recently, pharma and biotech had no interest in the field - now everybody and his brother is setting up a cellular therapy program. There are a lot of Phase I and Phase II trials under way, with patients getting benefits. We're progressing very rapidly. A lot of money is being pumped in."

"Chronic diseases of aging account for the vast majority of health care expenditures," points out biochemist Judith Campisi, of Lawrence Berkeley National Laboratory and the Buck Institute for Research on Aging in Novato, Calif. "Traditionally, medicine has dealt with them by specializing. But people who study cancer, or neurodegenerative diseases like Alzheimer's, or painful osteoarthritis, or chronic obstructive pulmonary disease or congestive heart failure ... they don't talk to each other. The evidence in medicine is growing, however, that old age is malleable. It may not be inevitable. There are underlying basic processes, and if we could intervene [at that level], no longer treat [separate diseases] but treat aging processes like cellular senescence, it would totally transform medicine." Campisi has been experimenting with a recombinant drug that successfully flushes senescent cells from elderly transgenic mice - a far cry from proving efficacy in humans. And even the lifetime of these mutant lab mice is extended by only another 20 to 25 percent, she notes.

The Big Breakthrough in Rejuvenative Medicine

Immunotherapy is a revolutionary "personalized" medical technique by which blood is harvested from a patient; and the genetic machinery of its T cells - the body's potent main defense against most pathogens but normally unreactive to cancer cells - is altered by introducing an inactivated, genetically modified HIV virus. The souped-up blood is reinfused. The patient's own T cells now can detect signature proteins on the cancer cells and swarm to destroy them.

Several immunotherapeutic approaches such as chimeric antigen receptor therapies are under active investigation for a variety of cancers. Results in initial trials have been highly encouraging - in some instances, astonishing. Moreover, notes Stephen Minger, major pharmaceutical companies and niche startups are "piling on this now." "Individualized cell therapy is at the inflection point," he maintains. "It's going to change fundamentally the way we treat cancer ... [but it also holds promise for] orthopedic indications, repair of bone and cartilage ... organogenesis ... autoimmune diseases like multiple sclerosis, lupus, inflammatory bowel disease and Crohn's disease, where there's been very little therapy available and patients are sick all the time and in a lot of pain ... .

"We're starting to see clinical benefits from targeted immune therapies that spare normal tissue and are completely curative," he summarizes. "It's not just a niche. We're looking at treating very large patient populations to whom we've had very little to offer before. Now we have to address how to deal with millions of them a year. There's a huge amount of excitement around this. We're all ecstatic. But the hard stuff is ahead of us. It's going to be totally, totally disruptive."


It is not correct to view aging as set in stone, an immutable part of the human condition. Degenerative aging is just another medical condition, an unpleasant one at that, caused by biochemical processes in the body that are just as open to discovery, cataloging, and intervention as those of any disorder. The only thing that separates us from real, working rejuvenation treatments capable of restoring youthful vigor and health to the old is the same thing that once separated humanity from a cure for smallpox or effective management of infant mortality. In other words medical technology. Bringing aging under medical control and extending healthy lives indefinitely is just a matter of progress in applied biotechnology, and the research community is actually much closer to meaningful advances on this front than most people imagine to be the case.

However, precisely because the public are largely in the dark when it comes to the promising state of longevity science, that research community could very well simply remain ever close to promising advances for decades with little meaningful progress towards breakthroughs and commercialization. At the large scale, and over the score or more of years needed to forge entire new fields of medicine and bring them to maturity, funding and progress very much depend on public awareness and support for the cause. Currently the majority of the most promising scientific programs based on repair of the damage of aging, such as those coordinated by the SENS Research Foundation, are funded at exploratory levels only. In the broader research community it is still considered somewhat novel and adventurous to publicly back the strategy of treating the mechanisms of aging as a cause of disease rather than the traditional approach of engaging in ultimately futile attempts to patch over the diseases that are the end results of aging, one by one, and in isolation.

Thus while the stem cell and cancer research edifices include factions that are doing the right things and heading in the right directions for their slices of treating aging, there is definitely a way to go yet towards a research community and a public that are enthusiastically in favor of the most effective means to treat the causes of aging. That level of support will be needed if we are to ultimately remove from the human condition all of the pain, suffering, and death that aging causes. Getting to that point of widespread support is a slow grind: thousands of years of myth and tradition, and the modern education everyone receives both formally and informally, produce people who believe wholeheartedly that aging is a fact of life, something set in stone, a thing that is what it is. Yet that simply isn't true anymore. In an age of revolutionary progress in biotechnology, aging is as much a part of the human condition as we choose to let it be, and that starts now by choosing to support the right research programs.

"We should not regard aging as a fact of life"

The European: Dr. de Grey, for many years, people thought of human aging as inevitable, as part of our biology. Is that still true?

de Grey: I would not say that it is wrong. Aging is certainly a side effect of being alive. It is the accumulation of damage that the body does to itself as a by-product of its normal operations. In that sense it is exactly the same as the aging process of a car or an airplane. So really it is not even biology, it is just physics. The big mistake that people make is not in their understanding of what aging is, but in the misunderstanding of what the diseases of old age are: things like Alzheimer's, cancer, or cardiovascular disease.

The European: How are they mistaken?

de Grey: Most people think of those diseases as like infections - things that could be eliminated from the body using sophisticated medicine. An enormous amount of money and effort is being spent on that, although it is impossible to cure them because these things are part of aging and of being alive in the first place. The only way we can ever tackle those diseases is by tackling the whole package. By preventative maintenance against the damage of being alive.

The European: With stem cell therapies, for example?

de Grey: That is one part of it. But aging is not one single process but an accumulation of a lot of different types of damage in different organs and body parts as a result of different processes. In order to comprehensively tackle all of these types of damage, we have to do a lot of different things at the same time.


The European: Who would be able to afford these therapies?

de Grey: That's a good question. These therapies will not be expensive. They will be made available to everybody who needs them. Because unlike today's high-tech medicine which is very expensive, these therapies will pay for themselves. They will save us all of the money we are currently spending trying to keep people alive with medicine that doesn't work. This will also have an enormous number of very effective indirect economic benefits. One is that the children of the elderly will be more productive because they won't have to spend any time looking after their sick parents. The older but healthy people themselves will be continuing to contribute wealth to society instead of just consuming wealth. Any way you look at it, it would be economically suicidal at the national level for any country not to make these therapies available for everyone who is old enough to need them.

The European: How soon could these therapies be made available?

de Grey: In 2004, I first started making predictions about how quickly we would develop them. Back then, I said it would probably take around 25 years. But it was simply a 50/50 probability. I always acknowledged that there is at least a 10% chance that we won't get them ready for another hundred years in case we found new problems. But a 50/50 chance is enough to be worth fighting for. But what it really depends on is funding. At the earlier stages of the research, the funding is of course the most difficult to obtain, because people are not yet convinced that the research will eventually succeed. So over the past ten years, during which I would have hoped that we would have gotten to obtain a really decisive dramatic result, we only made about three years of progress. But that's about the amount of progress that I would have expected to make with the amount of money that we have actually received.

A point on the cost of treatments for aging: it is odd that many people believe that such treatments would be very expensive. Perhaps it is instinctive to associate great benefit with great cost, or perhaps people immediately think of the most expensive treatments available today, such as complex surgeries that need teams of highly trained professionals and lengthy aftercare. Those highly trained professionals are exactly why complex surgeries are expensive, however. You are paying for their time in a market that, for various reasons good and bad, has far too few highly trained medical professionals. Compare that situation with some of the most technically advanced treatments presently in widespread use, such as the so-called biologics used to control some autoimmune conditions. The cost of developing that technology was vast, yet infusions of mass-produced biologics cost a tiny fraction of a complex surgery, and that is because they are delivered in a half-hour appointment by a clinical assistant whose fee is a tiny fraction of that commanded by a surgeon. All of the complexity is baked into the research and initial development of a manufacturing industry, and so the eventual cost in the clinic is low and falling.

All of the potential treatments for aging, means to repair the cellular and molecular damage that causes degeneration, frailty, pain, and suffering, will be much more like the mass produced biologic infusion than the surgery. They will be drugs and custom proteins that clear out metabolic waste, replacement cells, gene therapies, and similar items. Everyone suffers the same forms of damage, and little customization of treatments will be needed. Where there is customization it will likely involve the use of your own tissue samples to generate a supply of your own cells that can be formed into the types needed to replenish aging stem cells and other diminished cell populations. That is a service that is even today in the process of becoming an industrial-scale industry, creating cells to order, and prices will fall just as for all other widely used biotechnologies.

So in short, effective treatments for aging will be expensive on the front end, in research and development, briefly expensive during clinical trials when the details are still being worked out and those costly and all too rare trained medical professionals are required in large numbers, and then cheap when mass-produced for the clinic.


3-D printing is a tool that has blossomed given the cheap computing resources to control it. It has long been possible to print three-dimensional structures in a variety of mediums, but efficient automation makes it cheaper to do this reliably and repeatedly, and also allows for the accurate manufacture of objects with very small scale features. Since cheap computing resources also drive progress in biotechnology, it is only natural that advances in tissue engineering go hand in hand with 3-D printing. These possibilities had to occur at the same time, as they depend on the same underlying technological capabilities. Tissue engineers want the ability to produce structures that mimic the collagen scaffold of the extracellular matrix, webbed with blood vessels and all sorts of other structural features on scales varying from millimeters to micrometers. As a goal that is yet to be achieved completely, but so far good enough attempts have been produced to create several less complex forms of tissue: a scaffold is printed and in the process of its construction is seeded with cells and proteins that encourage growth.

Researchers have been working with 3-D printers for some years now. Some of the formative research programs and first companies in the space are on their way to being a decade old, such as Organovo, whose founders count the Methuselah Foundation among their investors. The focus today is still largely on the production of products for research groups, producing small tissue structures such as printed blood vessels that can speed up the research process. Later, we will see more in the way of larger organs and tissue sections printed for transplant, not research. That is not too many years ahead.

Print Thyself: How 3-D printing is revolutionizing medicine

Central to the lab's work are three customized 3-D printers, each worth a quarter of a million dollars. Lewis led me through a warren of corridors and offices to a room where one of the printers sat on supports. It was immense. The base of the printer was a granite block five feet long, four feet deep, and a foot high, weighing a ton and a half. The printer does such fine-scale work that a stable base is essential, Lewis said. Resting on the block was a flat stage or platform, above which, in a vertical row, stood four rectangular steel containers, each a foot or so tall - the ink dispensers. A tangle of colored wires connected the dispensers to some machinery behind them, and each dispenser was controlled at the top by a robotic arm. To the side sat a large monitor and a computer, which controlled the printer.

Each dispenser contained a different biological material, Lewis explained. One held an aqueous suspension of chemically treated collagen, which serves as the matrix on which many of the body's tissues take shape. Two others held suspensions of fibroblasts, the gristly cells that form the body's connective tissue. The last dispenser contained the fugitive ink that Lewis had developed to create channels within materials. On the computer, Kolesky called up a software program and found an image representing the block of tissue that he would be printing. It looked like a rectangle of semi-clear gelatin, within which was a vascular network: a channel entered at one end and branched into smaller vessels, which looped around and ultimately joined back into a single vessel that exited at the other end. It was a simple network, approximating the way that an artery divides into smaller capillaries that eventually recombine into a vein.

The dispenser with the fugitive ink moved quickly and almost imperceptibly, releasing an exceptionally thin stream of what looked like agar onto the glass slide. The printer clacked and clattered like a busy riveting machine. In a minute or so, the job was done; the printer had left a trail of gelatinous ink that exactly matched the pattern on the computer. The stream of ink was about a tenth of a millimetre in diameter, and the entire pattern covered an area a little larger than a matchbook. The printer wasn't rigged to finish the job, but Kolesky explained what would typically happen next. The other ink dispensers would take their turn, laying down a lattice of collagen and fibroblasts that would solidify around the network of fugitive ink, encasing it in tan-colored living tissue. To drain the fugitive ink, Kolesky would place the tissue on a chilled stone cube; this would cause the ink to change from a gel to a liquid, after which he could then extract it with a small suction device. The end result would be a block of living tissue suffused with intricate vessels capable of carrying nutrients to the cells within.

The last step was to me the most remarkable. Once the vessels were empty, Kolesky would take a suspension of endothelial cells - the cells that line the insides of blood vessels - and inject it into the vessel network. The cells would settle in and multiply to line the insides of the channels, effectively turning the channels into blood vessels. And then the cells would spread - they would begin to branch off the existing vessels and form new ones. In effect, Lewis and her team have created an environment that the cells consider home - it is far more natural to them than a petri dish or the inorganic scaffolds that had previously played host to cultured tissues.

"I like to say that we design the highway and then get out of the way and let the endothelial cells create their own driveways," Lewis said. "It's better to rely on the intelligence of the cells themselves in terms of how they like to sprout."


Yesterday, I had occasion to spend six hours or so in the emergency room of a medical center largely focused on treating serious conditions that are most prevalent in old people. A part of that experience by necessity involved listening to the comings, goings, and conversations of those present. These are not private places: they are typically divided visually by screens but with no way to avoid overhearing the staff and patients. The people there are generally not too concerned about privacy in the immediate sense in any case, having far more pressing matters to focus upon.

So, by proxy, one gets to experience small and somewhat wrenching slices of other people's lives. It is very easy for even those who follow aging research and speak up for rejuvenation treatments to forget just how hard it is to be very old. It's one thing to know about the catalog of pain, suffering, and loss of capabilities, the conditions we'd like to find ways to turn back, and another to watch it in action. It is, really, a terrible thing to be frail.

A fellow was brought in a little while after I arrived, a 90-something man who looked a lot better on the exterior than perhaps your mental picture of a 90-something individual might be. Tall, and surprisingly lacking in wrinkles stretched out on the rolling gurney under blankets, a mess of cables, and an oxygen mask. That he had had fallen was what I heard from the conversation of the medics, and was in pain. He cried out several times as he was moved from the gurney. It took some time and care to do it without hurting him more, given his weakness.

He seemed confused at first, but that was just my misperception: you try being 90 and in pain some time and see how well you do while you're being moved around and told to hold this and let go of that. The fellow answered the bevy of questions the receiving staff had for him, but the thing that caught at me was the time he took with the answers, and the questions he just missed. He was coherent, even quite sharp at times, not on any more painkillers than a handful of Tylenol, as I later heard, but he clearly struggled with something that we younger folk all take for granted: parse the question, find the information, form up a reply and speak it. Cognitive ability in all these areas becomes ever less efficient with old age, and there's something hollowing about hearing what is clearly a capable guy set back for a dozen seconds by a short question about one of the details of his fall. The medic repeated the question a few times and in different ways, which was clearly just making the information overload worse.

It sticks with you to be the observer in this situation and clearly and suddenly realize that one day that faltering older person will be you, trying and often failing to force your mind into the necessary connections rapidly enough for the younger people around you. I know this, but knowing it and having it reinforced by being there are two very different things. An aged person is no less intelligent, far more experienced, wiser and all the rest, but the damage to the structure of the brain that occurs even in those without dementia means that making use of all of that in the way it deserves is near insurmountable.

The fellow's 60-something daughter arrived a little later to provide support and fill in more of the details. A story was conveyed in bits and pieces: that he was near blind now, and just about too frail to walk safely, even with a frame. The blindness explained a great deal of what had sounded to my ignorant ears as confusion in the earlier part of the fellow's arrival: we assume all too many things about those around us, such as the use of sight in an unfamiliar environment, or the ability to walk, or think quickly - and all of this is taken from us by aging. The fellow lived with his wife still, and she was of a similar age to him. His wife was not there because she herself was too frail to be undertaking even a short trip at such short notice. That seemed to me a harsh blow on top of the rest of what old age does to you. At some point you simply cannot do everything you'd want to as a partner. You are on the sidelines and at the point at which your other half is most likely to die, you are most likely unable to be there.

In this case the fellow was in no immediate danger by the sound of it. By good luck this was in no way likely to be a fatal accident, but rather another painful indignity to be endured as a part of the downward spiral of health and ability at the end of life. Once you get to the point at which simply moving from room to room bears a high risk of accident, and this is by no means unusual for a mentally capable person in their 90s, then it really is just a matter of time before you cannot live for yourself with only minimal assistance.

When talking with his daughter while he waited on a doctor and medical assistants to come and go with tests and updates, the fellow was much faster in his responses, though this was interrupted by a series of well-meaning but futile attempts to ease his pain by changing his position, each as much an ordeal as the move from the gurney had been. The conversation between father and daughter had the sense of signposts on well-worn paths, short exchanges that recapitulated the high points of many discussions that had come before. She wanted her father to move into an assisted living facility, and this fall was the latest in a line of examples as to why it was past the time for this - she simply could not provide all of the support needed on her own. She wasn't even strong enough herself to be able to safely get him back up on his feet after a fall. He was concerned about cost and the difficulties of moving, uncertainties and change. They went back and forth on this for a while. "We have to accept that it's just going to be more expensive as we get older," she said at one point, and he replied "I think you're getting the picture now," and laughed. There wasn't much to laugh about, but we can all do it here and there under these circumstances. I believe it helps.

I walked out of there after my six hours of hurry up and wait was done. They were still there, and whenever it is he leaves to go home it is unlikely it will be on his own two feet. But this is a scene I'll no doubt be revisiting at some point in the future, some decades from now, playing the other role in this small slice of life. What comes around goes around, but I'd like it to be different for me, and more importantly to be different for millions of others a lot sooner than my old age arrives.

Which leads to this: why does Fight Aging! exist? Why do we do this? Why advocate, why raise funds for research programs into ways to treat aging that may take decades to pay off? We do this because we can help to create a future in which there will be no more emergency rooms like the one I visited, no conversations about increasing disability, no pain, and no struggles to answer questions as quickly as one used to. No profound frailty. All these things will be removed by the advent of therapies that can effectively repair the causes of aging, curing and preventing frailty and age-related disease, and the sooner this happens the more people will be spared.


Monday, November 17, 2014

The "anti-aging" marketplace demonstrates that it is quite possible to build a successful business, even a successful industry, on the basis of delivering something that doesn't actually exist. In this case, that phantom product is the means to reliably slow or turn back the aging process. Many of those in the industry are - or at least were at the outset - quite sincere about seeking to help people and produce meaningful benefits for their customers, but unfortunately once money starts rolling in due to substitutes and shams those original noble goals are always subverted.

Historically, the existence of the "anti-aging" marketplace has a lot to do with why the legitimate research community long suppressed public discussion of and work on interventions in the aging process. They did not want to be associated with snake oil salesmen in any way, shape, or form. This is becoming a matter of recent history now, increasingly irrelevant in the face of a zoo of long-lived laboratory animals and public support from notable scientists for the goals of slowing aging through metabolic alteration or reversing aging by repairing the cellular and molecular damage that causes degeneration.

Those who do not learn from history are doomed to repeat it, however, so while the conflict between the scientific establishment and the "anti-aging" market is no longer dragging down and isolating legitimate longevity science in the same way it was, it is good to understand what happened over the past few decades: why progress was much slower than it might have been, and why it required a considerable struggle within the research community to open up public discussion of extending healthy human life spans. There is, after all, still a very strong "anti-aging" movement based on the same old lies and fraudulent products - it just isn't as much of an impediment to real scientific progress as was once the case, but that won't necessarily continue the way we'd like it to. This open access paper is in Portuguese, and the automated translation is of mixed quality, but still worth reading:

In academic and medical circles, it is certain that the strengthening of geriatrics and gerontology contributed to a much greater attention to aging. However, the path to a greater community for geriatrics and gerontology and aging sciences did not happen without setbacks. Despite the US community of biogerontologists (as well as geriatricians and other gerontologists) having developed since the late 1930s, some forty years later it was still stigmatized by the historical legacy of mythology and quackery that characterized the aspirations and practices of prolongevity. An aura of disbelief lasted until the mid-1970s in initiatives aimed at prolongevity, affecting any scientists that worked on aging, including gerontologists and geriatricians.

Now, in 1970, the demographic transition was already under way in the US, as in other core countries, and even then, the idea prevailed that a medicine and science of aging were illegitimate. However, since then, such an assumption is not longer the case, that change occurring alongside the growing number of seniors who demand specific attention, and who are attended by professionals of aging. In other words, one can say that the geriatric-gerontological field was a franchisee with access to the fields of science, and its legitimacy has been recognized as more was learned about aging.

But here we come to the year 2010, and a new course of events unexpectedly rushes over what seemed stabilized. The geriatric-gerontological field rid itself of the question of legitimacy, but this now returns, and from a direction in which it is least expected: since the mid-1990s, doctors - peers - are questioning whether the practice in geriatrics and gerontology are indeed the most effective in preventing the complications of aging. Announcing themselves to be in possession of something more innovative in terms of scientific action on aging, and identifying themselves as questioning the mainstream, practitioners of antiaging medicine are causing a stir among geriatricians and gerontologists. The latter accused the former of charlatanism and bad faith; the first and the second accused of denying patients the chances of aging well (an ideal of aging that has been carefully constituted and supported on the shoulders of geriatrics / gerontology to have legitimacy and recognition!).

In this article we will explore the roots of this controversy, with the intent to understand what is their place in the field of knowledge about aging and what it shows us about the production of our sociotechnical collective term that emphasizes the importance of science for the constitution of modern society. We start by explaining how geriatrics and gerontology were structured and legitimized as the science of aging, emphasizing the points that are targets of questioning by anti-aging medicine. We then look at the emergence of that other way of thinking about aging, which will allow us to get into the history of the controversy itself.

Monday, November 17, 2014

There are a number of people, researchers and advocates, in the longevity science community who have a good understanding of present research and knowledge, but who then build on that understanding to assemble what look to me to be completely the wrong conclusions about how best to proceed towards extending healthy life spans. The fellow who writes Anti-Aging Firewalls is one such individual. He is very much in favor of dietary supplements and other presently available means of metabolic alteration to impact aging, which seems to me to be a huge waste of time and effort. It is massively complex, the data is always ambiguous, and nothing in this area can be demonstrated to approach calorie restriction and exercise in terms of benefits delivered.

Note that neither calorie restriction nor exercise, despite the proven benefits for human health, will reliably let you live to age 90. Three quarters of each new aging cohort will be dead by that point and that includes a majority of those who led exemplary lifestyles. So no, tinkering with supplements is not the path to the future of longevity. Instead all that wasted effort should be focused on supporting and expanding work like that carried out by the SENS Research Foundation: building the rejuvenation technologies that don't presently exist, and which could offer the ability to reliably live in good health to age 90 and beyond. Too many people spend their time in the futile search for something that works now, when they only thing that will do any good is to work on making the treatments that will work tomorrow.

So all that said, here are a pair of presentations where the first is really quite good, being an opinionated view of aging research and its prospects, and the second is not, being a dive into largely pointless approaches that can do little for long-term health even in the best of outcomes.

Aging is multilayered. The aging of a living organism is both a manifestation and a result of complex changes in composition, structure and function across all levels of biological organization from molecular pathways, cell components and cells, to organs and tissues, to whole-body systems. Yet it is rarely studied that way: almost all research investigations have been carried out at a specific single level of organization and often in isolation with a relatively narrow focus. Research is reductionist and highly focused. This is the methodology and culture that dominates biological and biomedical research across the entire spectrum of research activities internationally. This traditional strategy has unquestionably led to significant progress and remarkable insights. But a more integrated approach is needed if we are ever to have a fully developed, fundamental understanding of aging and longevity and their relationship to health.

So, how does science speak with regard to aging? With many tongues. Important findings about aging can come from cancer research, Alzheimer's disease research, genetics and epigenetics research, studies of animals and plants, population health studies, and aging research studies. They can come from just about everywhere in the life sciences. They can be inconsistent, pushing different viewpoints. The contributing scientists mostly do excellent work. But they don't always talk with each other. It is a Tower of Babel! Understanding aging takes us into just about every area of human biology and medicine. The field is incredibly broad and deep and consists of many disparate areas of studies. Most scientists are only partially aware of what other scientists producing related results are doing, and can be unaware that others have solved part of the problem that they are addressing. So, what is presented here is my own story of what is known about aging.

Tuesday, November 18, 2014

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. They shorten with each cell division, one part of a limiting mechanism for the number of times that somatic cells can replicate. Average telomere length in tissues is a function of pace of cell division, activity of the telomere-lengthening enzyme telomerase, and the pace at which stem cells deliver fresh new long-telomere replacement cells. All of this varies widely by tissue type and other factors, and average telomere length in easily measured tissues tends to decrease with ill health and age, most likely as a result of declining stem cell activity.

All of this tends to suggest that telomere length is a measure of secondary and later consequences of aging, and is not in and of itself a primary cause of aging. The counterargument to that is provided by studies in which enhanced telomerase activity lengthened life span in mice, but it isn't clear at this point whether lengthening telomeres is the reason for that outcome, versus other functions of telomerase or cellular reactions to altered levels of that enzyme. Continuing this theme, these researchers suggest a mechanism by which changing telomere length could alter the regulation of gene expression, and thus cellular behavior, for a wider range of genes than previously suspected:

[Researchers] found that the length of the endcaps of DNA, called telomeres, form loops that determine whether certain genes are turned off when young and become activated later in life, thereby contributing to aging and disease. "Our results suggest a potential novel mechanism for how the length of telomeres may silence genes early in life and then contribute to their activation later in life when telomeres are progressively shortened. This is a new way of gene regulation that is controlled by telomere length."

Even before the telomeres shorten to the critical length that damages the DNA, the slow erosion in length has an effect on the cell's regulation of genes that potentially contributes to aging and the onset of disease. The [findings] required the researchers to develop new methods for mapping interactions that occur near the endcaps and to use an extensive array of methodologies to verify the impact. Specifically, the team showed that when a telomere is long, the endcap can form a loop with the chromosome that brings the telomere close to genes previously considered too far away to be regulated by telomere length. Once the telomere and the distant genes on the same chromosome are close to each other, the telomere can generally switch those genes off.

Conversely, when telomeres are short, the chromosome does not form a loop and the telomere can no longer influence whether target genes are switched on or off. The researchers were able to identify three genes whose expression patterns are altered by telomere length but believe this number is the just the tip of the iceberg. "We have developed the concept that telomere shortening could be used as a timing mechanism to respond to physiological changes in very long-lived organisms, such as humans, to optimize fitness in an age-appropriate fashion."

Tuesday, November 18, 2014

The practice of calorie restriction with optimal nutrition, a lowered calorie intake while maintaining necessary dietary micronutrient levels, slows near all measures of aging in laboratory animals such as mice. The human studies of calorie restriction show pretty impressive results on shorter term measures of health, greater benefits than any presently available medical technology can provide to an essentially healthy individual at any age. If calorie restriction was a drug, it would be a household name, which probably explains why so much effort is devoted to the development of calorie restriction mimetic drugs. Sadly that is actually a very poor approach to producing treatments for aging, as the calorie restriction response is exceedingly complex: near everything in the operation of metabolism changes in response to lowered food intake, researchers are nowhere near the level of understanding required to proceed effectively, and even if successful the end results will be of only slight benefit.

Thus we shouldn't take our cues for the future of longevity science from its past investigations of natural variations in longevity: the future must look more like engineering, an undertaking in which researchers attempt to repair the cellular and molecular damage that causes aging rather than work on ways that merely gently slow down the damage accumulation. You can't use calorie restriction to reliably live to age 90 and beyond, it just modestly improves your odds. The only way to reliably live much longer in good health is to develop actual, working rejuvenation treatments based on damage repair as a strategy.

In any case, here is an example of the sort of research that helps to maintain the presently high level of interest in calorie restriction mimetic development among researchers:

Neuroscientists [have] shown that calorie-reduced diets stop the normal rise and fall in activity levels of close to 900 different genes linked to aging and memory formation in the brain. Researchers say their experimental results, conducted in female mice, suggest how diets with fewer calories derived from carbohydrates likely deter some aspects of aging and chronic diseases in mammals, including humans. "Our study shows how calorie restriction practically arrests gene expression levels involved in the aging phenotype - how some genes determine the behavior of mice, people, and other mammals as they get old. [It adds] evidence for the role of diet in delaying the effects of aging and age-related disease."

While restrictive dietary regimens have been well-known for decades to prolong the lives of rodents and other mammals, their effects in humans have not been well understood. Benefits of these diets have been touted to include reduced risk of human heart disease, hypertension, and stroke, [but] the widespread genetic impact on the memory and learning regions of aging brains has not before been shown. Previous studies [have] only assessed the dietary impact on one or two genes at a time, but [this] analysis encompassed more than 10,000 genes. For the study, female mice, which like people are more prone to dementia than males, were fed food pellets that had 30 percent fewer calories than those fed to other mice. Tissue analyses of the hippocampal region, an area of the brain affected earliest in Alzheimer's disease, were performed on mice in middle and late adulthood to assess any difference in gene expression over time.

Wednesday, November 19, 2014

Many researchers involved in longevity science initiatives have very modest goals. They are looking into how to alter metabolism to modestly slow the progression of aging, which is an enormously complex task and the research community is presently barely at the outset of obtaining a sufficient understanding to proceed effectively. Even with success, the possible benefits that can be achieved via slowing aging as much as, say, calorie restriction does are small in humans - and no-one has come close to achieving that target yet despite fifteen years of work and at least a billion dollars in funding. So the researchers involved here accurately predict expensive, slow, and gradual progress.

When I say "small" in connection with what calorie restriction can provide I mean a greater benefit to long term health than any presently available medical technology can produce in basically healthy people, and a few years added to overall life spans. This is nothing in the grand scheme of what is possible through other approaches, however. Instead of trying to alter an enormously complex system such that it wears and damages at a slower pace, researchers should be trying to fix that damage. Let us keep the metabolism we have, but regularly repair it. Aging is nothing more than damage, and repair would mean rejuvenation, an approach that is limited only by its effectiveness in how many years of healthy life it can add. Further, the damage that causes aging is already known and cataloged: the only research needed is to develop the means to remove it, and in most cases research groups already have strategies in mind.

So the future can be one of expensive, slow progress to a mediocre end goal that will provide very little help to old people, or a faster path to rejuvenation treatments that can actually reverse the frailty and suffering of aging. Sadly the research community remains largely fixated on the former path rather than the latter at this time, which is why it is very important to support the work of disruptive research groups like the SENS Research Foundation who are working on the better approach to treating aging and gathering allies in the scientific community.

Most scientists say we are no closer to eternal life today than we were all those years ago. The word "immortality" elicits a mixture of laughter and earnest explanations about the difference between science and science fiction. Conversations about longevity, however, are an entirely different story. Researchers are optimistic about recent efforts to delay the effects of aging and, perhaps, extend life spans. But at the same time, the scientific community is wary of how quickly these findings are packaged and resold by companies promising a fountain of youth. "It's probably worse today than it's ever been. As soon as the scientists publish any glimmer of hope, the hucksters jump in and start selling."

Understanding the process of aging and developing treatments that might slow the rate at which people grow old could help doctors keep patients healthy longer. We won't be able to stop or reverse aging, but researchers are interested in slowing its progress, such that one year of clock time might not equal a year of biological time for the body. That could delay the onset of diseases like cancer, strokes, cardiovascular disease and dementia, which become more prevalent as people age. "By targeting fundamental aging processes, we might be able to delay the major age-related chronic diseases instead of picking them off one at time. For example, we don't want to have situation where we, say, cure cancer and then people die six months later of Alzheimer's disease or a stroke. It would be better to delay all of these things together."

This is where the field known as the biology of aging is moving - to develop drugs that will increase life span and what researchers refer to as health span, the period of life when people are able to live independently and free from disease.

Wednesday, November 19, 2014

Epigenetic mechanisms such as DNA methylation alter the pace at which specific proteins are manufactured. Epigenetic patterns are constantly in flux in our cells, changing in response to circumstances, the most interesting of which is the accumulation of cellular and molecular damage that causes aging. Now that researchers have demonstrated that some patterns of DNA methylation change in a fairly reliable way with age, reliable enough to be used to determine age from tissue samples in fact, there is perhaps a greater interest in exploring the details:

Although every person's DNA remains the same throughout their lives, scientists know that it functions differently at different ages. As people age, drastic changes occur in their DNA methylation patterns, which are thought to act as a "second code" on top of the DNA that can lock genes in the on or off position. However, what the consequences of these changes are remains a mystery. To begin deciphering this process, [scientists] studied methylation patterns in the blood cells of 1,264 persons ages 55 to 94 who participated in the Multi-Ethnic Study of Atherosclerosis (MESA).

The researchers found age-related differences in DNA methylation in 8 percent of the 450,000 sites tested across the genome. Most of these changes did not seem to affect which cellular genes were turned on or off. However, [the team] did find a small subset of age-linked DNA methylation changes - 1,794 of the 450,000 sites tested - that were associated with altered gene expression. Out of this subset, 42 sites were associated with pulse pressure, a measure of vascular health that is known to change with age. "Our work suggests that most of the age-associated changes in DNA methylation do not have an obvious effect on cellular function, in this case altering gene expression, and some of them may just amount to noise. The methylation sites that are linked to altered gene expression are good candidates as potential drivers of the negative effects of aging, especially the small subset linked to pulse pressure. Our findings provide new insights into the aging process."

Future studies will try to test the relationship between these methylation sites and specific health outcomes. Eventually, the scientists hope to be able to target and reverse specific sites that are involved with age-related diseases.

Thursday, November 20, 2014

There is a fair amount of work taking place these days on ways to manipulate the efficiency of memory processes:

The brain's process of formulating memory is linked to the synthesis of proteins; high rates of protein production will lead to a strong memory that is retained over the long term, while a slow rate of protein production leads to weak memories that are less likely to be impressed on a person's long-term memory and thus forgotten. [Researchers] sought to examine the activity of a protein called elF2 alpha, a protein that's known as the "spigot" or regulator that determines the pace of protein synthesis in the brain during memory formation.

From earlier studies the researchers knew that there are three main molecules that act on the protein and either make it work, or stop it from working. During the first stage they sought to determine the relative importance and the task of each one of the molecules that control the activity of efF2 alpha and as a result, the ability to create memories. After doing tests at the tissue and cell levels, the researchers discovered that the main molecule controlling the efF2 alpha's activity was the PERK molecule. "The fact that we identified the PERK as the primary controller had particular significance. Firstly, of course, we had identified the dominant component. Secondly, from previous studies we already knew that in generative diseases like Alzheimer's, PERK performs deficiently. Third, PERK acts on various cells, including neurons, as a monitor and controller of metabolic stress."

After paralyzing PERK's activity or reducing its expression through gene therapy the researchers measured a 30% increase in the memory of either positive or negative experiences. The rats also demonstrated improved long-term memory and enhanced behavioral plasticity, becoming better able to "forget" a bad experience. "With this study we proved that we are capable of strengthening the process of protein synthesis in the brain and of creating stronger memories that last a long time. We have paved the way for the possible development of drugs that can slow the progress of incurable diseases like degenerative brain conditions, Alzheimer's chief among them."

Thursday, November 20, 2014

In the years ahead stem cell medicine will most likely transform into a field largely based on manipulating existing cell populations in situ in the body rather than generating cells outside the body for transplantation. In many types of transplantation it appears that benefits are produced because the transplanted cells alter the local signaling environment in ways that cause native cells to better maintain and repair tissues, not because the transplanted cells are actually doing any of the work themselves. So ultimately researchers will want to directly issue those signals or otherwise alter native cells so as to change their behavior for the better. Some of the necessary work on that front is already taking place:

Researchers administered stem cell factor (SCF) by gene transfer shortly after inducing heart attacks in pre-clinical models directly into damaged heart tissue to test its regenerative repair response. A novel SCF gene transfer delivery system induced the recruitment and expansion of adult c-Kit positive (cKit+) cardiac stem cells to injury sites that reversed heart attack damage. In addition, the gene therapy improved cardiac function, decreased heart muscle cell death, increased regeneration of heart tissue blood vessels, and reduced the formation of heart tissue scarring. cKit+ cells are a critical cardiac cytokine, or protein receptor, that bond to stem cell factors. They naturally increase after myocardial infarction and through cell proliferation are involved in cardiac repair.

"It is clear that the expression of the stem cell factor gene results in the generation of specific signals to neighboring cells in the damaged heart resulting in improved outcomes at the molecular, cellular, and organ level. Thus, while still in the early stages of investigation, there is evidence that recruiting this small group of stem cells to the heart could be the basis of novel therapies for halting the clinical deterioration in patients with advanced heart failure."

Friday, November 21, 2014

Calorie restriction extends healthy life in mice, and so does removing or blocking the activity of growth hormone through genetic engineering. The reasons for enhanced longevity in both of these cases are well studied but still far from fully understood, as both produce very broad alterations in the enormously complex processes of cellular metabolism. Trying both methods together is a way to perhaps shed some light on the more important mechanisms involved, however.

Ames dwarf (df/df) mice are homozygous for a spontaneous recessive mutation of the prophet of pituitary factor-1 (Prop1) gene, which inhibits development of three specific anterior pituitary cell types - somatotrophs, lactotrophs and thyrothrophs. The absence of these cell types in the df/df mice leads to deficiency of growth hormone (GH), prolactin (PRL) and thyrotropin (TSH). Interestingly, however, these mutants live significantly longer (40-60%) and healthier lives compared to their normal siblings. Ames dwarf mice phenotypically appear normal at birth but they grow at a slower rate and reach only half of the normal adult body weight, compared to their normal littermates. These mutant mice also exhibit very low levels of insulin-like growth factor-1 (IGF-1) and thyroid hormones. Furthermore, they have a reduced body temperature, but their food and oxygen consumption per gram of body weight are increased. Ames dwarf mice are less prone to cancer. These mutants show increased insulin sensitivity and glucose tolerance, thus displaying no diabetic phenotype. Furthermore, Ames dwarf mutants have reduced response of skeletal muscle to high levels of insulin, which might be important for their control of glucose homeostasis and as well their positive effects in extended longevity

Calorie restriction (CR), is the only efficient intervention which delays aging and extends lifespan. Laboratory animals subjected to reduced caloric intake, exhibit a number of beneficial effects including extension of lifespan, reduced body weight, plasma glucose and insulin levels; and improved insulin sensitivity and health span. Studies in various animal species revealed that CR delays aging, decreases cholesterol levels and blood pressure. Studies involving mice and rats support the concept that CR delays the aging process and reduces the incidence of several age-related diseases including type 2 diabetes and cancer. In addition, it has been shown that the prolongation of life can be greater than 40% in mice under CR regimen; with even greater extension of longevity in non-mammalian models.

Based on extensive studies of CR and Prop1 mutation on insulin signaling, metabolism and aging there is some evidence that indicates that Ames dwarfism and CR may act through similar mechanisms but they are certainly not identical. We studied the effects of calorie restriction (CR) on the expression of insulin signaling genes in skeletal muscle and adipose tissue of normal and df/df mice. The analysis of genes expression showed that CR differentially affects the insulin signaling pathway in these insulin target organs. Moreover, results obtained in both normal and Ames dwarf mice indicate more direct effects of CR on insulin signaling genes in adipose tissue than in skeletal muscle. Interestingly, CR reduced the protein levels of adiponectin in the epididymal adipose tissue of normal and Ames dwarf mice, while elevating adiponectin levels in skeletal muscle and plasma of normal mice only.

Friday, November 21, 2014

The aging of the immune system isn't just a matter of damage, it is also inherent in the structure of a limited number of immune cells over time becoming ever more devoted to remembering threats rather than fighting them. As this research suggests there is the damage to think about as well, however:

As animals age, their immune systems gradually deteriorate, a process called immunosenescence. It is associated with systemic inflammation and chronic inflammatory disorders, as well as with many cancers. The causes underlying this age-associated inflammation, and how it leads to diseases, are poorly understood. Insects have an immune organ called the fat body, which is roughly equivalent to the mammalian fat and liver. It is responsible for many immune functions.

[Researchers] found that the fruit fly fat body experiences a great deal of inflammation in aged flies. [The] gradual reduction of a protein called lamin-B in the fat bodies of aging flies is the culprit behind fat body inflammation. Lamin-B is part of the lamin family of proteins, which form the major structural component of the material that lines the inside of a cell's nucleus. Lamins have diverse functions, including suppressing gene expression, and they are found in an array of tissues and organs. In humans, diseases caused by mutations in lamins are called laminopathies and include premature aging.

B-type lamins have long been suspected to play a role in gene suppression by binding to segments of DNA. The team's work revealed that when the fruit fly fat body was depleted of lamin-B, the normal suppression of genes involved in the immune response is reversed, just as it would be in response to bacterial infection or injury, but in this case there is no apparent infection or injury. The un-suppressed immune response initiates the inflammation.


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