Fight Aging! Newsletter, June 17th 2013

June 17th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Publicity for Cryonics from Future of Humanity Institute Staff
  • Pluripotent Stem Cells Are There to Be Found in Adult Tissues
  • Warming Up to Cryonics
  • Arguing By Induction For an Absence of Boredom in an Ageless, Greatly Extended Healthy Life
  • A Little Methionine Restriction Research
  • Latest Headlines from Fight Aging!
    • A Profile of David Murdock
    • Implanting a Lab-Grown Blood Vessel
    • Rapamycin Improves Heart Function in Old Mice
    • Considering Reversal Cells in Osteoporosis
    • Arguing that Mitochondrial DNA Damage Isn't Simply Random
    • SENS Research Foundation Mentioned in Los Angeles Magazine
    • Improving the Delivery of Genes to Restore Sight
    • Investigating Fingertip Regeneration in Mammals
    • Reviewing the Literature on Calorie Restriction and Oxidative Stress
    • Calorie Restriction Versus Resveratrol Treatment


Some of the folk at the University of Oxford Future of Humanity Institute recently engineered a little publicity for cryonics. It's always pleasing to see good press for the cryonics industry, especially when those interviewed take the time to present membership with a cryonics provider like Alcor or the Cryonics Institute as a sensible and rational choice.

What is cryonics? It is the collection of technologies and service providers that offer long-term low-temperature preservation of the brain (vital) and body (probably not so vital). The goal is a chance at future resuscitation, once medicine, nanotechnology, and related fields have advanced to the point at which a stored person can be brought back to active life. It doesn't much matter whether this takes fifty or a hundred years or even longer: while preserved a patient has time to wait. If technology is advanced enough to restore a preserved individual, so the thinking goes, then it is also advanced enough to restore an aged brain to youthful function and repair the age-damaged body, or provide a tissue engineered replacement if you chose not to have your body preserved. Some people are even fine with a copy their brain running as software via future methods of whole brain emulation. That doesn't much help you yourself, the entity associated with your physical brain, but all too many people are fine with the other way of looking at things, which is that a copy of the self is also the self.

In short, cryonics is the only chance at a longer life in the future for those people who will not live long enough to benefit from rejuvenation biotechnology presently under development. Death by aging will one day be a thing of the past, but all too many people will still be claimed by aging between now and the advent of the first rejuvenation therapies. Cryonics is also a good backup plan: you never know how early you might be struck down by age-related disease, cancer in particular. Cryonics, like the life insurance usually used to pay for it, and like saving for retirement, is something that is best organized a fair way in advance.

It's worth noting that cryopreservation is not freezing, and in fact is distinguished by the many efforts taken to avoid freezing of any tissue, especially in the brain where the data of the mind is stored. Freezing damages cells through ice crystal formation, but infusion with cryoprotectant chemicals combined with low temperatures is used to produce a state of vitrification in cryopreserved tissues.

Oxford academics hope to be brought back to life

Three professors from England's Oxford University are paying to have their bodies frozen so they can be thawed out and brought back to life in the future. Philosophy professor Nick Bostrom and neuroscientist Anders Sandberg have signed up to pay nearly $79,000 to have their heads filled with "antifreeze" chemicals and stored in liquid nitrogen at -196C in the US after they die. Their colleague Stuart Armstrong has chosen to have his entire body frozen.

The men, who are the lead researchers at the Future of Humanity Institute, have reportedly set up monthly life insurance policies and pay about $40 a month to be frozen.

Three senior Oxford University academics will pay to be deep frozen when they die so they could one day be 'brought back to life'

Previous acolytes of cryonics have often been dismissed as head-in-the-clouds cranks, sci-fi buffs who have watched too much TV or victims of vanity. Britney Spears and Paris Hilton have both waxed lyrical about being frozen. Simon Cowell is believed to be among several dozen Britons who have joined a cryonics programme, although several hundred have reportedly shown interest.

But most of them are ordinary people - usually retirees who are thinking about defeating death. The science may be sketchy but the principle is simple: nothing ventured, nothing gained. But Prof Bostrom and his colleagues are young, highly educated specialists who have devoted their careers to humanity. If they are signing up for cryonics, one might think, perhaps we should all pay attention.

That latter reaction is exactly why it's a good thing to see well-publicized advocacy for cryonics from noted researchers. In many ways this is far better than any celebrity endorsement. To the fellow in the street scientists are the arbiters of truth, the people that tell you what is, the people who know best the nature of the world. Celebrities are just celebrities.


One of the emerging themes over the past few years of stem cell research is that various forms of pluripotent stem cell can be found in adult tissues. Pluripotency in a stem cell is the ability to differentiate to form lineages of any cell type in the body. The well known types of adult stem cell that researchers have cataloged over the past few decades are only multipotent, meaning that they are limited in the type of cell lineages they can create. A multipotent stem cell supports a particular tissue type made up of a few types of cell.

Why does this matter? It's all about the efficiency and cost of research and development of regenerative therapies based on the use of stem cells. If researchers must locate and understand specific multipotent cell populations in order to regenerate a specific type of tissue, then a great deal of work remains on the way to a comprehensive regenerative medicine toolkit. Every type of multipotent stem cell has its own distinct behaviors and mechanisms, and requires a different environment to grow in useful numbers outside the body. Discovering how to make use of any specific type of multipotent stem cell has proven to be a slow process of trial, error, and educated guesswork. On top of that, researchers haven't yet reliably identified multipotent stem cells in all types of tissue, and most of the known populations are far from well understood. There are hundreds of cell types in the human body, and much left to accomplish.

If researchers can obtain a reliable, low-cost source of pluripotent stem cells, however, then that single resource can be used to generate any type of cell you want, starting from the same shared baseline. It greatly cuts down the complexity and work required to move forward with regenerative medicine. This is why the research community is so focused on embryonic stem cells and the reprogramming of ordinary cells into induced pluripotent stem cells. Pluripotent cells obtained directly from an patient's tissues, especially those that are easily accessed such as skin and fat, may be even better than induced pluripotent stem cells in terms of cost-effectiveness. Such a resource cuts out yet another step in the process of obtaining broadly useful patient-matched cells for research and regenerative therapies.

In recent years a few research groups have claimed the identification of pluripotent stem cells in adult tissue. They have given the cells various different names, such as very small embryonic-like stem cells (VSELs), but they might all be talking about the same thing - or they might not. Biology is always more complex than you think it is. Why shouldn't there be all sorts of variously potent cell types hiding away in our bodies in larger or smaller numbers?

Here is an open access publication from another research group to have isolated pluripotent stem cells in adult tissue. From a long term perspective, the more of this that happens the better, I think. It suggests that over the next decade or two regenerative research will move more rapidly than would otherwise have been the case:

Awakened by Cellular Stress: Isolation and Characterization of a Novel Population of Pluripotent Stem Cells Derived from Human Adipose Tissue

Recently, a new stem cell population has been isolated from mesenchymal tissues such as human skin fibroblasts and bone marrow stromal cells under cellular stress conditions. These cells, termed Multilineage Differentiating Stress-Enduring (Muse) Cells, are of mesenchymal stem cell origin and comprise 1-3% of the entire cell population. Muse cells exhibit characteristics of both mesenchymal and pluripotent stem cells. They are double positive for CD105, a mesenchymal stem cell marker, and stage specific embryonic antigen-3 (SSEA3), well known for the characterization of undifferentiated human embryonic stem cells (ES) from bone marrow aspirates or from cultured mesenchymal cells such as bone marrow stromal cells and dermal fibroblasts. They express pluripotency markers including [those used to create induced pluripotent stem cells], differentiate into cells of ectodermal, endodermal, and mesodermal lineages both in vitro and in vivo, and have the ability to self-renew.

Advantageously, Muse cells do not appear to undergo tumorigenic proliferation, and therefore would not be prone to produce teratomas in vivo, nor do they induce immuno-rejection in the host upon autologous transplantation. In addition, Muse cells are shown to home into the damage site in vivo and spontaneously differentiate into tissue specific cells according to the microenvironment to contribute to tissue regeneration when infused into the blood stream. Therefore, they exhibit the potential to make critical contributions to tissue regeneration in the absence of restrictions attributed to the difficult extraction of bone marrow stromal cells and human skin fibroblasts, and time-consuming purification methods such as cell sorting. In order to increase the viability of Muse cells as a source of tissue regeneration, a more accessible supply must be utilized.

Harvesting human adipose tissue by lipoaspiration is a safe and non-invasive procedure, and hundreds of millions of cells can be isolated from 1-2 liters of lipoaspirate material. Therefore, adipose tissue could prove the ideal source for Muse cell isolation as opposed to bone marrow or dermis. Using lipoaspirate material, we developed a novel methodology for the isolation of a population of human Muse cells under severe cellular stress conditions (long term incubation with proteolytic enzyme, 4°C, serum deprivation, and hypoxia). Purification of human Muse cells derived from adipose tissue (Muse-ATs) does not require the use of cell sorting, magnetic beads or special devices.


Cryonics is the industry and technologies that can provide long-term low-temperature storage of your body and mind following death. The balance of evidence presently favors the supposition that vitrification of cryoprotectant-infused tissue, avoiding ice-crystal formation, preserves the fine structure of neural cells in which the data of the mind is stored. That is the core of the matter: whether cryonics preserves the mind well enough to allow future technologies to repair and revive suspended people. If you are going to die prior to the advent of rejuvenation biotechnology, and this is a significant risk for most of us, then cryonics and its uncertainties are the only shot at a longer life in the future. It's a very reasonable wager, all told: a bet that the future of technological progress will continue, versus the certainty of oblivion found in the grave.

Cryopreservation is modestly expensive if you pay in a lump sum: usually more than $100,000, depending on which provider you go with and the details of your arrangements. Most people fund this service via life insurance, however. If you obtain a policy early enough in life the monthly payments are very cheap. It's not a terribly large amount of money even if you start in mid life.

Cryonics should be far more popular than it is. The cost is reasonable, any number of other businesses with multi-decade customer lifetimes prosper, and the potential upside is considerable. Four decades after its emergence from amateur practice into professional practice it remains a niche industry, while billions have gone to the grave over that same span of time. You might compare this with the same puzzling lack of interest in extending life through medical technology: at times one is forced to conclude that most people just don't care about living longer.

A generally favorable, well-researched, long article on the cryonics community recently emerged in the alternative online press. I think it's worth your time to read it all, and if you are presently trying to persuade anyone to see the merits of cryonics, then this would an excellent piece to pass along:

Are We Warming Up to Cryonics?

Some things should not be left to the last minute. For instance, having yourself frozen. The act of being preserved in a giant thermos cooled by liquid nitrogen in the hopes that the scientists of the future will figure out how to revive you and repair whatever it was that drove you to require freezing in the first place is no small matter. There are insurance policies to settle upon. Legal documents to notarize. Relatives to appease. And all of this must be done far enough in advance that arrangements can be made for a field response team to reach you on your deathbed and stand by until a doctor declares you medically deceased, at which time they will leap into action and begin your cryopreservation.

Legally speaking, cryonics is okay because it's considered an extravagant funeral practice. Its few practitioners would not argue with the notion that the procedure would be more effective if started before the heart has taken its final beats, but to do so would be illegal, even if the soon-to-be-deceased is a willing participant. Thus, the process waits for death, and the longer after death it begins, the worse off you are. This is why the Alcor Life Extension Foundation really doesn't like to accept last-minute cases.

One thing to note is this news of funding and initiatives presently in the works. You might not be keeping up with this sort of behind the scenes progress if you're merely interested in cryonics rather than being an insider:

If ever a group is going to coalescence behind the idea of obviating death as we know it, it's the one currently ruling Silicon Valley, which came of age at a time when it really felt like the right combination of smart people and money could solve any problem. And the most intriguing name to sniff around cryonics publicly is Peter Thiel, the billionaire investor who co-founded [PayPal] and was the first outside investor in Facebook. Thiel, who has made no secret of his belief in experimental science, and of his interest in technologies that could suspend or eliminate aging, has a separate fund set up to invest in more outré scientific endeavors. And Breakout Labs, as it's known, has provided seed capital to two cryonics-related start-ups founded by former Alcor employees.

Thiel (who declined an interview request) was also part of the conversation that laid the groundwork for a cryonics X-Prize that is currently in development. The prize, as constructed, would challenge applicants to freeze and then thaw a human organ so that it returns to a viable state. This would enable organ banks, potentially solving a huge global problem - the shortage of organs for transplant - and would be the first proof-of-concept that large, complex collections of tissue could be stored indefinitely at low temperatures without damage. It's not a huge leap from there to imagine the same thing being done with a whole organism.


It is usually the case that the first knee-jerk reaction in opposition to increased human longevity is based on the mistaken belief that life extension technologies would lead to people being ever more frail and decrepit for a very long time. This is far from the case, and it's probably not even possible to cost-effectively engineer a society of long-lived frail people - even if that was the goal to hand. If you are frail and decrepit then you have a high mortality rate due to the level of age-related cellular and molecular damage that is causing the failure and degeneration of your body and its organs. You won't be around for long. No, the only way to engineer longer healthy life is extend the period of youth and vitality, a time in which you have little age-related damage and your mortality rate is very low. Most present strategies are aimed to prolong that period of life, either by slowing the rate at which damage occurs (not so good) or finding ways to periodically repair the damage and thus rejuvenate the patient (much better).

Once people grasp that longevity science is the effort to make people younger for far longer, then the second knee-jerk objection arises. This is the belief that a very long-lived individual would become overwhelmed by boredom: they would run out of interest and novelty. This is by far the sillier objection, and there is absolutely no rational basis for it. Even a few moments of thought should convince you that there is far more to do and learn that you could achieve in a thousand life spans - and it's a little early in the game to be objecting to enhanced longevity on the basis that you can't think of what to do with life span number number 1001.

Considering boredom, futility, meaningless, and related matters, I noticed what appears to be an argument by induction in the article below. Mathemetical induction is a tool used in formal proofs wherein if you can prove that something is generally true for n and n+1 (where n is a natural number), and then show that it is true for 1, then you can conclude it must be true for all natural numbers. If it is true for 1, then it must be true for 1+1 = 2, and true for 2+1 = 3, and so on.

Life Extension Leads to Meaningless Days? NO!

Person X lives a fulfilling and meaningful life for X number of years before that life is terminated by a sudden, massive heart attack.Now, imagine another person whom we shall label (not too creatively) 'Person 2′. Person 2′s life follows the same general path as person 1 with one exception: It is one day longer than person 1′s was. Now ask yourself: Is there any reason to suppose that this day, let us assume it is aTuesday, strikes person 2 as being meaningless despite the fact that all Tuesdays (and indeed every other day in person 2′s past) seemed worth living?

OK, so now imagine yet another person who goes by the label of... yes, you guessed it, Person 3. You can probably also guess that Person 3 lives one day longer than person 2. Once again, I can think of no reason why, where we have two people who live meaningful lives but one lives one day longer, that extra day would not seem worth experiencing. Put another way: If possible would persons 2 and 1 rather not be dead on Wednesday (the last day for person 3) when Monday and all preceding days were worth experiencing? So far as I can see, the answer to that question is, 'yes'. There seems to be no reason why this argument should not hold for any number of hypothetical people, each one of which lives one day longer than the last.

Unfortunately you can't prove conjectures about aspects of human nature with induction (or not yet, at least). What you can do is use it, as above, to mount a more convincing argument. This one is somewhat akin to one of the standard lines in any debate between a person who is in favor of greatly extending healthy life versus someone who isn't.

Advocate: So you are fine with aging and dying?

Deathist: Yes.

Advocate: So you are fine with dying right now, done and finished?

Deathist: Well, no.

Advocate: Why would you think any differently ten days, or a hundred days, or decades from now, if you still had your health and vigor?

Deathist: Um...

There seems to be a strange disconnect in many people's minds, in which they are vigorously in favor of being alive right this instant or next week, but they nonetheless believe that their future self of years ahead will be of a different opinion and want to die. Now if you're on the downhill slope of aging, in great pain, and your body is falling apart, desiring a stopping point is not unreasonable. (With the best of present options for those in that position being cryonics). But in a world of rejuvenation therapies, in which older life is just as healthy, low-risk, and full of possibility as younger life, what mysterious thing is going make people want to die?


Calorie restriction is definitely good for you, provided that you maintain an optimal intake of micronutrients in your smaller diet. There is a tremendous weight of evidence for the benefits of calorie restriction in animals and a large weight of evidence for benefits in humans: it improves near all short term measures of health, slows down the progression of near every measure of degenerative aging, and extends healthy life in most species. Research publications are usually more understated in their evaluation of calorie restriction, of course. See this, for example:

Caloric Restriction: Implications for Human Cadiometabolic Health

Evidence from animal studies and a limited number of human trials indicates that calorie restriction has the potential to both delay cardiac aging and help prevent atherosclerotic cardiovascular disease via beneficial effects on blood pressure, lipids, inflammatory processes, and potentially other mechanisms.

The candidate list of mechanisms by which calorie restriction likely delivers its benefits include reduced visceral fat, increased levels of autophagy, altered mitochondrial function, and metabolic changes caused by reduced levels of methionine in the body. All of these on their own have been shown to extend life and improve measures of health in animal studies. Many other measurable changes result from calorie restriction, but identifying which of them are definitively primary and which are definitively secondary is still a work in progress.

Methionine is one of the essential amino acids that your metabolism doesn't manufacture. You have to obtain it in the diet, and it's an essential component for the cellular manufacture of new protein machinery. There are all sorts of studies in mice and rats showing that if you keep the same dietary calorie level but strip out much of the methionine then the animals involved live longer, and exhibit many of the same changes in metabolism as occur from reduced calorie levels. Here is a recent example:

Methionine restriction affects oxidative stress and glutathione-related redox pathways in the rat

Lifelong dietary methionine restriction (MR) is associated with increased longevity and decreased incidence of age-related disorders and diseases in rats and mice. A reduction in the levels of oxidative stress may be a contributing mechanistic factor for the beneficial effects of MR. To examine this, we determined the effects of an 80% dietary restriction of Met on different biomarkers of oxidative stress and antioxidant pathways in blood, liver, kidney and brain in the rat.

Male F-344 rats were fed control (0.86% methionine) or MR (0.17% methionine) diets for up to six months. Blood and tissues were analyzed for [levels of the natural antioxidant] glutathione (GSH). related enzyme activities and biomarkers of oxidative stress. MR was associated with reductions in oxidative stress biomarkers [and] erythrocyte protein-bound glutathione after one month with levels remaining low for at least six months.

Levels of free GSH in blood were increased after 1-6 months of MR feeding whereas liver GSH levels were reduced over this time. In MR rats, GSH peroxidase activity was decreased in liver and increased in kidney compared with controls. No changes in the activities of GSH reductase in liver and kidney and superoxide dismutase in liver were observed as a result of MR feeding. Altogether, these findings indicate that oxidative stress is reduced by MR feeding in rats, but this effect cannot be explained by changes in the activity of antioxidant enzymes.

You might compare the comments above with the two calorie restriction research papers I pointed out earlier today - you'll quickly see the similarities, such as the fact that the behavior of antioxidants and oxidants in metabolism is complex and hard to tie to the observed benefits in health and longevity. All in all it is convincing to argue that methionine sensing is at the heart of the metabolic changes that produce the benefits of calorie restriction.

From the practical standpoint of day to day effort and willpower, I'd say that that there isn't much difference between eating a calorie restricted diet and a methionine restricted diet. The latter is harder by far to organize, I think. You certainly couldn't do it without a lot of research, extra food preparation, and meal planning, and there are few resources out there to help you short-cut the process. Calorie restriction, on the other hand, just requires you to keep count and be sensible, plus of course to have a willingness to be hungry for some time every day. It's that latter item that most people find a challenge, in this age of ubiquitous, cheap, tasty food. Calorie restriction also has a far greater weight of supporting evidence for benefits to health in humans, which is probably the most important factor of those mentioned here, but every choice you make has trade-offs.


Monday, June 10, 2013

David Murdock is one of the few billionaires interested enough in human longevity to talk about it in public and work towards doing something about it. Unfortunately he is focused only on diet and thus will fail to achieve his own stated goal of living far longer than any man has ever done, and will fail to help anyone else to do the same. You can't eat your way to an extremely long life, no matter how good your diet might be. Most of the healthiest people die before reaching Murdock's advanced age of 90, and he is fortunate to have lived as long as he has. In a world of billions, random chance will deliver a small population of people who are very wealthy, interested in ineffective means of living longer, and who also, coincidentally, live for a long time.

Diet only affects your health - which is a good enough reason to try for a sensible diet and lifestyle. It isn't the key to extreme longevity, however. It remains the case that only way to enable people to reliably live far longer than they would otherwise have done is the development of new medical science focused on repairing the cellular and molecular causes of aging.

David Murdock, at age 90, has the look and energy of a man many years younger. The chairman of Dole Foods, the world's largest marketer of fruits and vegetables, has stated that he expects to live to 125, thanks to his lifestyle, diet and exercise regimen. In the early 1980s, about the same time Murdock bought a controlling interest in the conglomerate of which Dole was a part, his wife, Gabriele, was ill with advanced-stage ovarian cancer. The couple spent nearly two years traveling the world seeking information about potential cures. After Gabriele died in 1985, at age 43, Murdock stuck with many of the healthy lifestyle habits the couple discovered during their quest.

Murdock, whose net worth is estimated by Forbes to be $2.4 billion, has also committed more than $500 million toward the creation of the North Carolina Research Campus and David H. Murdock Research Institute in Kannapolis, N.C. There, researchers from government, industry, non-profit groups and eight universities can take advantage of advanced technology and agricultural resources to collaborate on studies that explore the potential health benefits of plants in boosting longevity and warding off what the institute calls "lifestyle-related disorders," like diabetes, obesity, Alzheimer's disease and cancer. The campus also supports public campaigns to promote healthy choices.

Murdock's commitment to biotechnology research is admirable and a far better legacy than most high net worth individuals manage. The focus of this work will have next to no impact on human longevity, however.

Monday, June 10, 2013

The tissue engineering of large blood vessels is a very different matter from growing the intricate networks of small blood vessels needed to support tissue. The former goal is far less challenging, for one thing, and researchers are thus further along in bringing the creation of new veins and arteries to the clinic. Here is news of progress on that front:

In a first-of-its-kind operation in the United States, a team of doctors at Duke University Hospital helped create a bioengineered blood vessel and implanted it into the arm of a patient with end-stage kidney disease. The procedure, the first U.S. clinical trial to test the safety and effectiveness of the bioengineered blood vessel, is a milestone in the field of tissue engineering. The new vein is an off-the-shelf, human cell-based product with no biological properties that would cause organ rejection.

Using technology developed at Duke and at a spin-off company it started called Humacyte, the vein is engineered by cultivating donated human cells on a tubular scaffold to form a vessel. The vessel is then cleansed of the qualities that might trigger an immune response. In pre-clinical tests, the veins have performed better than other synthetic and animal-based implants.

Clinical trials to test the new veins began in Poland in December with the first human implantations. The U.S. Food and Drug Administration recently approved a phase 1 trial involving 20 kidney dialysis patients in the United States, followed by a safety review. Duke researchers enrolled the first U.S. patient and serve as study leaders. The initial trial focuses on implanting the vessels in an easily accessible site in the arms of kidney hemodialysis patients. More than 320,000 people in the United States require hemodialysis, which often necessitates a graft to connect an artery to a vein to speed blood flow during treatments.

If the bioengineered veins prove beneficial for hemodialysis patients, the researchers ultimately aim to develop a readily available and durable graft for heart bypass surgeries, which are performed on nearly 400,000 people in the United States a year, and to treat blocked blood vessels in the limbs.

Tuesday, June 11, 2013

Long term administration of rapamycin has been demonstrated to slow aging in mice, and here one aspect of that outcome is examined in more detail:

Elderly mice suffering from age-related heart disease saw a significant improvement in cardiac function after being treated with the FDA-approved drug rapamycin for just three months. The research, led by a team of scientists at the Buck Institute for Research on Aging, shows how rapamycin impacts mammalian tissues, providing functional insights and possible benefits for a drug that has been shown to extend the lifespan of mice as much as 14 percent.

Researchers at the Mayo Clinic are currently recruiting seniors with cardiac artery disease for a clinical trial involving low dose treatment with rapamycin.

In this study, rapamycin was added to the diets of mice that were 24 months old - the human equivalent of 70 to 75 years of age. Similar to humans, the aged mice exhibited enlarged hearts, a general thickening of the heart wall and a reduced efficiency in the hearts ability to pump blood. The mice were examined with ultrasound echocardiography before and after the three-month treatment period - using metrics closely paralleling those used in humans. Buck Institute [researchers] said age-related cardiac dysfunction was either slowed or reversed in the treated mice.

"Rapamycin affected the expression of genes involved in calcium regulation, mitochondrial metabolism, hypertrophy and inflammation. We also carried out behavioral assessments which showed the treated mice spent more time on running wheels than the mice who aged without intervention."

It sounds a lot like increased exercise has as much to do with the outcome as direct effects of the drug. Exercise, like calorie restriction, has a powerful influence on all aspects of health.

Tuesday, June 11, 2013

Researchers are digging deeper into the mechanisms underlying the loss of bone that accompanies aging. A complete understanding of how imbalances occur between ongoing bone creation and destruction that takes place at the cellular level should eventually lead to ways to manipulate that process:

By analyzing biopsy specimens from patients with postmenopausal osteoporosis and primary hyperparathyroidism, investigators have begun to pay increasing attention to "reversal cells," which prepare for bone formation during bone remodeling. The hope is that these reversal cells will become critical therapeutic targets that may someday prevent osteoporosis and other bone disorders.

In adults, bones are maintained healthy by a constant remodeling of the bone matrix. This bone remodeling consists of bone resorption by osteoclasts and bone formation by osteoblasts. A failure in the delicate balance between these two processes leads to pathologies such as osteoporosis. How these two processes are coupled together is poorly understood. "Reversal cells may represent the missing link necessary to understand coupling between bone resorption and formation and to prevent osteoporosis."

Reversal cells actually cover more than 80% of the resorbed bone surfaces. Using histomorphometry and immunohistochemistry on human bone biopsies, researchers found that the reversal cells colonizing the resorbed bone surfaces are immature osteoblastic cells which gradually mature into bone forming osteoblasts during the reversal phase, and prepare the bone surface for bone formation. Researchers also found that some reversal cells display characteristics that suggest an "arrested" physiological status. These arrested reversal cells showed no physical connection with bone forming surfaces, a reduced cellular density, and a reduced expression of osteoblastic markers.

Biopsies from postmenopausal patients with osteoporosis showed a high proportion of arrested cells, but no such cells were found in biopsies from patients with primary hyperparathyroidism, in which the transition between bone resorption and formation is known to occur optimally. [Larger] arrested cell surfaces were associated with bone loss. "Our observations suggest that arrested reversal cells reflect aborted remodeling cycles which did not progress to the bone formation step. We therefore propose that bone loss in postmenopausal osteoporosis does not only result from a failure of bone formation as commonly believed, leading to incomplete filling of resorption cavities, but also from a failure at the reversal phase, uncoupling bone formation from resorption."

Wednesday, June 12, 2013

Mitochondria are the swarming powerplants of the cell, a bacteria-like herd of self-replicating machines that produce the chemical energy stores that power cellular processes. They bear their own DNA, and damage to this mitochondrial DNA (mtDNA) damage is important in aging. Per the mitochondrial free radical theory of aging, some types of mitochondrial DNA damage spread throughout the population of mitochondria in a cell, subverting the quality control mechanisms that normally destroy damaged mitochondria. This leads to harmfully altered mitochondrial function and malfunctioning cells that export damaging reactive compounds into the surrounding tissues.

At this point the fastest way to confirm theories on aging and mitochondrial DNA damage is to implement one of the ways to replace or repair mitochondria DNA. There are a range of potential methods that might result in therapies. In the future, people will probably have their mitochondrial DNA globally refreshed every few decades, removing this contribution to degenerative aging.

Here researchers argue that the spread of mitochondrial DNA damage to all the mitochondria in a cell can't be just random, and thus has be driven by some advantage in selection - such as the ability to fool quality control mechanisms, as is proposed in mitochondrial theories of aging. If damaged mitochondria are culled by the cell less often, they will eventually out-compete undamaged mitochondria.

Mitochondrial DNA deletions accumulate over the life course in post-mitotic cells of many species and may contribute to aging. Often a single mutant expands clonally and finally replaces the wild-type population of a whole cell. One proposal to explain the driving force behind this accumulation states that random drift alone, without any selection advantage, is sufficient to explain the clonal accumulation of a single mutant.

Existing mathematical models show that such a process might indeed work for humans. However, to be a general explanation for the clonal accumulation of mtDNA mutants, it is important to know whether random drift could also explain the accumulation process in short-lived species like rodents. To clarify this issue, we modelled this process mathematically and performed extensive computer simulations to study how different mutation rates affect accumulation time and the resulting degree of heteroplasmy. We show that random drift works for lifespans of around 100 years, but for short-lived animals, the resulting degree of heteroplasmy is incompatible with experimental observations.

Wednesday, June 12, 2013

Here is a recent article from the local Los Angeles press, in which the author manages to touch on a broader range of the pro-human-longevity community than is usually the case:

What researchers do know is that there are limits to how far we can naturally extend the human life span. L. Stephen Coles, a UCLA lecturer and executive director of the Gerontology Research Group, documents and studies "supercentenarians" - people who live to 110 or longer. When he started tracking the longest-lived humans around 2000, "the oldest [known] person in history was a Frenchwoman named Jeanne Calment, who died in 1997 at the age of 122," Coles says. "I thought that because average life expectancy had increased significantly over the last hundred years, it meant someone would break her record." But that hasn't happened. "It's been more than 15 years, and no one has come close."

Even if scientists do find a way to create more supercentenarians, should they? Blogging for The Huffington Post last year, unofficial Hollywood Conscience Jamie Lee Curtis declared that any attempt to conquer aging was an affront to nature. "I am appalled that the term we use to talk about aging is 'anti,' " she wrote. "Aging is as natural as a baby's softness and scent. Aging is human evolution in its pure form. Death, taxes, and aging."

But she's missing the point, says Maria Entraigues, the L.A.-based outreach coordinator for the SENS Research Foundation, a Northern California nonprofit that focuses on longevity research. "I always tell people, Why is it not 'natural' to get sick?" Entraigues says. "Why do we go to the doctor? Aging is the same thing. If there's something we can do about it, we should."

Aubrey de Grey, a Cambridge University computer scientist turned antiaging theorist, launched SENS, short for Strategies for Engineered Negligible Senescence, in 2009. Fifty years old with a Rasputinesque beard, de Grey has gained fame through his appearances at TED talks and on The Colbert Report, among other venues, making the case that aging can be vanquished. He's proposed that seven specific types of damage cause human beings to deteriorate over time, including cellular mutations, an accumulation of "junk" inside and between cells, and a gradual loss of important cells in the brain and other organs. If it were possible to fix all or even some of these problems, he argues, the diseases and frailty that come with old age could be postponed or even reversed. And he believes it's possible that aging itself will be brought under medical control - via maintenance treatments of gene therapies, stem cell therapies, and immune stimulants - within our lifetimes.

Thursday, June 13, 2013

Researchers have produced an improvement in methods of gene therapy used to treat some rare forms of blindness, and which may allow the use of gene therapy in the treatment of more common forms of degenerative blindness that occur in old age:

Three groups of researchers have successfully restored some sight to more than a dozen people with a rare disease called Leber's congenital amaurosis. [They] achieved this by inserting a corrective gene into adeno-associated viruses (AAV), a common but benign respiratory virus, and injecting the viruses directly into the retina. The photoreceptor cells take up the virus and incorporate the functional gene into their chromosomes to make a critical protein that the defective gene could not, rescuing the photoreceptors and restoring sight.

Unfortunately, the technique cannot be applied to most blinding diseases because the needle often causes retinal detachment, making the situation worse. Yet the standard AAV used in eye and other types of gene therapy cannot penetrate into tissue to reach the photoreceptors and other cells, such as retinal pigment epithelium, that need to be fixed.

[Researchers] set out to find a way to "evolve" AAV to penetrate tissues, including eye and liver, as a way to deliver genes to specific cells. [They have] generated 100 million variants of AAV - each carrying slightly different proteins on its coat - [and] selected five that were effective in penetrating the retina. "Building upon 14 years of research, we have now created a virus that you just inject into the liquid vitreous humor inside the eye and it delivers genes to a very difficult-to-reach population of delicate cells in a way that is surgically non-invasive and safe. It's a 15-minute procedure, and you can likely go home that day."

The engineered virus works far better than current therapies in rodent models of two human degenerative eye diseases, and can penetrate photoreceptor cells in the eyes of monkeys, which are like those of humans. [This] could greatly expand gene therapy to help restore sight to patients with blinding diseases ranging from inherited defects like retinitis pigmentosa to degenerative illnesses of old age, such as macular degeneration.

Thursday, June 13, 2013

Young mammals, and occasionally adults, can regenerate lost fingertips. This seems like a good place to learn more about the mechanisms of regeneration, gaining insight into why it is that mammals cannot replicate the feats of limb and organ regeneration exhibited by species such as salamanders and zebrafish. More importantly, researchers hope to find that it is practical to adjust human biology to allow this sort of exceptional regeneration:

If a salamander loses its leg, it can grow a new one. Humans and other mammals are not so fortunate, but we can regenerate the tips of our digits, as long as enough of the nail remains. This was first shown some 40 years ago; today researchers finally reveal why it is that nails are necessary. Working with mice, [researchers] have identified a population of stem cells lying beneath the base of the nail that can orchestrate the restoration of a partially amputated digit. However, the cells can do so only if sufficient nail epithelium - the tissue that lies immediately below the nail - remains.

The process is limited compared with the regenerative powers of amphibians, but the two share many features, from the molecules that are involved to the fact that nerves are necessary. "I was amazed by the similarities. It suggests that we partly retain the regeneration mechanisms that operate in amphibians."

The nail base contains a small population of self-renewing stem cells, which sustain the nail's continuous growth. This ongoing growth depends on signals carried by the Wnt family of proteins - if this signalling pathway is disrupted, mouse nails cannot form. The team found that the same pathway is involved in the regeneration of lost mouse toe tips. After amputation, the Wnt pathway is activated in the epithelium underlying the remaining nail and attracts nerves to the area. Through a protein called FGF2, the nerves drive the growth of mesenchymal cells, which restore tissues such as bone, tendons and muscle. Within five weeks, the digit is good as new.

However, none of this can happen if the digit is amputated too far back, and too much nail epithelium is lost. In such cases, the Wnt pathway is never activated, the nerves do not extend and the other tissues cannot regenerate.

Friday, June 14, 2013

Oxidative theories of aging place the blame for the damage of aging on reactive oxidizing molecules, generated most notably in the mitochondria of your cells, and which tend to break the protein machinery they react with. Oxidative stress is the term given to ongoing damage (and efforts to repair it) caused by the presence of oxidative molecules in and around cells. Levels of oxidative stress can alter as a result of heat, exposure to ionizing radiation, the details of diet, and all sorts of other environmental influences.

The relationship between oxidative stress and the pace of aging is far from straightforward, however. There is more oxidative stress with age, but this is an expected result of carrying a high level of cellular and molecular damage. Some very long-lived species, such as naked mole rats, show very high levels of oxidative stress but don't appear to be particularly harmed by it. Mild oxidative stress can be beneficial, triggering increased cellular maintenance for a time to produce a net benefit. Oxidative compounds are also widely used in our biochemistry for necessary signaling purposes.

You can see the nature of this complex relationship between oxidative stress and aging by looking at what happens in interventions that reliably slow aging and extend life, such as calorie restriction in rodents:

Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends lifespan in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules.

The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. [In] a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.

While thinking about antioxidants and their effect on aging, it's important to remember that location matters immensely. Ingested antioxidants of the sort you can buy in the store are convincingly demonstrated to do nothing for your health, and there is evidence to suggest that they are actually mildly harmful - for example by blocking some of the oxidant-based signaling mechanisms the body uses to dial up cellular housekeeping and muscle growth responses after exercise. Meanwhile researchers are demonstrating benefits in mice by targeting designed antioxidant compounds to the mitochondria in cells, the place that most oxidants are generated. Those antioxidants are not yet available for the rest of us, however. The antioxidant pills from the store don't deliver their contents to your mitochondria, and are thus not terribly helpful.

Friday, June 14, 2013

Researchers here compare the effects of calorie restriction and dietary resveratrol on the pace of sarcopenia, the age-related loss of muscle mass and strength. What I take away from this is that calorie restriction produces meaningful results on this front, albeit modest in comparison to what we'd like to see, and resveratrol doesn't.

Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR+RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 x Brown Norway rats.

CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR+RSV) paradigms showed a protective effect in the soleus and plantaris muscle. Sirt1 protein content was increased by 2.6-fold in WG but not RG muscle with RSV treatment, while CR or CR+RSV had no effect. PGC-1α levels were higher (2-fold) in the WG from CR-treated animals when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment.

These data suggest that short-term moderate CR, RSV, or CR+RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study.


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