Exercise slows many of the degenerations of aging and – much like calorie restriction – this appears to be the result of changes in a multitude of biological processes and systems. In effect exercise adjusts the operation of your metabolism, moving it into a better configuration.

If you’d like a look under the hood, an overview of what is presently known of the biology that links exercise to improved long term health, you might read this recent open access review paper. It focuses on the heart, but the underlying mechanisms are of general interest:

It is generally accepted that regular exercise is an effective way for reducing cardiovascular morbidity and mortality. Physical inactivity and obesity are also increasingly recognized as modifiable behavioral risk factors for a wide range of chronic diseases, including cardiovascular diseases. Furthermore, epidemiologic investigations indicate that the survival rate of heart attack victims is greater in physically active persons compared to sedentary counterparts. Several large cohort studies have attempted to quantify the protective effect of physical activity on cardiovascular and all cause mortality. Nocon et al. in a meta-analysis of 33 studies with 883,372 participants reported significant risk reductions for physically active participants. All-cause mortality was reduced by 33%, and cardiovascular mortality was associated with a 35% risk reduction. Exercise capacity or cardiorespiratory fitness is inversely related to cardiovascular and all-cause mortality, even after adjustments for other confounding factors.

…

Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. … A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.

Being sedentary appears to be just as self-sabotaging as letting yourself become obese. It will lower your odds of living in good health for as long as you might like – and that is enormously important in this age of biotechnology. Every additional year is another year of progress in the laboratories, of progress in advocacy for longevity science, of progress towards rejuvenation therapies that could arrive in time for those of us reading this today. Failing to take care of your health will shift the odds against you, and it’s already the case that far too many people will die before the advent of repair technologies for the biological damage of aging. Why add to your risk becoming one of them?

Small steps: “The notion of transplanting adult stem cells to treat or even cure age-related macular degeneration has taken a significant step toward becoming a reality. … researchers have demonstrated, for the first time, the ability to create retinal cells derived from human-induced pluripotent stem cells that mimic the eye cells that die and cause loss of sight. Age-related macular degeneration (AMD) [gradually] destroys sharp, central vision needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD progresses with death of retinal pigment epithelium (RPE), a dark color layer of cells which nourishes the visual cells in the retina. While some treatments can help slow its progression, there is no cure. The discovery of human induced pluripotent stem (hiPS) cells has opened a new avenue for the treatment of degenerative diseases, like AMD, by using a patient’s own stem cells to generate tissues and cells for transplantation. For transplantation to be viable in age-related macular degeneration, researchers have to first figure out how to program the naïve hiPS cells to function and possess the characteristics of the native retinal pigment epithelium, RPE, the cells that die off and lead to AMD. … This is the first time that hiPS-RPE cells have been produced with the characteristics and functioning of the RPE cells in the eye. That makes these cells promising candidates for retinal regeneration therapies in age-related macular degeneration.”

Link: http://www.eurekalert.org/pub_releases/2011-03/gumc-sct031811.php

As noted in this paper, many researchers still fail to control for calorie intake in their studies – and thus their experimental results are largely worthless, given the impact of even mild calorie restriction on the life spans of laboratory animals: “Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed. Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic. Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds. Though still widely cited, studies showing life span extension using short-lived or ‘enfeebled’ rodents have not been shown to predict longevity effects in long-lived animals. We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. … These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents.”

Link: http://www.ncbi.nlm.nih.gov/pubmed/21424790

The SENS Foundation will be hosting the SENS5 conference in Cambridge, England at the end of August. Registration is open, and this note arrived in my in-box today:

I am writing to inform you that June 15th is the deadline for discounted registration and abstract submission for the fifth Strategies for Engineered Negligible Senescence (SENS) conference … The conference program features 33 confirmed speakers so far, all of them world leaders in their field. As with previous SENS conferences, the emphasis of this meeting is on “applied gerontology” – the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to the physical and mental robustness of young adults.

I notice that Caleb Finch will be giving the SENS Lecture, entitled “Regenerative medicine for aging: a new paradigm worth trying” – now there’s an example of progress in winning over the mainstream of aging research to the SENS approach of repair rather than slowing down aging. In this context, “regenerative medicine” means SENS; SENS Foundation founder Aubrey de Grey uses the term more expansively than the general public and media, who use it only in reference to stem cell therapies.

The SENS Foundation also recently issued a research report (in PDF format) for the first ten months of last year, with a year end report to follow. You should find it interesting to see funding amounts listed for the varying strands of SENS research, as well as insight into exactly what the researchers are up to at present:

I’m delighted to be able to share with you our research report, prepared for the first 10 months of 2010, by Tanya Jones (our Director of Research Operations), working with our researchers and my CSO Team. I thought it would be of interest to our supporters, and serve as a precursor to our 2010 Year End Report, which is currently under production as part of our finalizing our 2010 accounts.

…

SENS Foundation conducts intramural research in its Research Center in Mountain View, California. The primary focus of our intramural work is LysoSENS – investigating novel lysosomal hydrolases against intracellular aggregates that impair cell function – and we recently produced a detailed and comprehensive LysoSENS planning document in collaboration with our extramural project at Rice University.

We have also arranged for research in the MitoSENS strand – obviating mitochondrial DNA deletions – to be conducted at the Research Center, following the negotiation of a transfer agreement with Dr Corral-Debrinski covering materials produced, and used in, previous successful work by her group. Dr Matthew “Oki” O’Connor joined us in September to initiate this project.

The relative amounts devoted to each project clearly illustrate that the Foundation’s primary focus at this time is the LysoSENS project, and I can guess at some of the strategic reasoning there. Much money and many connections with industry might be gained through success in the LysoSENS platform. Not just aging, but many diseases could be effectively treated in their late stages through progress in bioremediation of this sort, and that means that big pharma and big biotech would be very interested in licensing agreements – which in turn would assist the Foundation in greatly expanding its purview and influence.

It is, however, frustrating to see far less funding devoted to MitoSENS, the project aimed at removing the contribution of mitochondrial DNA damage to aging. Everyone has an opinion, and mine (for what it’s worth, which isn’t all that much in this case, and nor should it be) is that mitochondrial repair would make a better primary focus. Irrespective of the methodology chosen, it seems clear that the research community as a whole is frustratingly close to something that will work to completely reverse mitochondrial damage, whether it is through allotopic expression as advocated by the SENS Foundation or periodic whole-body replacement of mitochondrial DNA as demonstrated in mice some years ago.

Yet the funds going towards mitochondrial repair – both here and generally – are in no way proportionate to the degree to which the research community believes mitochondrial DNA damage to be a cause of aging and longevity.

The advice I give myself on this issue is the same as I’ll give to anyone else in the same position: if you believe that too little funding is devoted to any given research goal, then get out there and do something about it. Earn money and donate it, and persuade others to do the same. After all, that’s exactly what Aubrey de Grey did in order to arrive at his present position: helping to direct a Foundation of his own creation where enthusiastic people are now writing annual reports on their progress towards engineering the end of aging.

From Science News: “the cells of organisms from yeast to humans regularly engage in self-cannibalism. Cells chew on bits of their cytoplasm – the jellylike substance that fills their bellies – and dine on their own internal organs … It may sound macabre, but gorging on one’s own innards, a process called autophagy, is a means of self-preservation, cleansing and stress management. … A munch here gets rid of garbage that might otherwise clog the system. A nibble there rids cells of malfunctioning parts. One chomp disposes of invading microbes. In lean times, all that stands between a cell and starvation may be the ability to bite off and recycle bits of itself. And in the last decade or so it has become clear that self-eating can also make the difference between health and disease. … Starvation inhibits an important biological signaling system, known as the mTOR pathway – named for a key protein involved in regulating cell growth and survival, cell movement and protein production. The inhibition of mTOR sets off a cascade of reactions inside the cell that end in autophagy and may be crucial to prolonging cell life and ultimately fending off cancer. A drug that inhibits mTOR, called rapamycin, has been shown to extend life span in mice. It and calorie restriction are [amongst a handful of] methods proven to prolong longevity, suggesting both may work through autophagy to make cells live longer.”

Link: http://www.sciencenews.org/view/feature/id/70887/title/Dining_In

The modest goals of the mainstream longevity science community are outlined by one of its members in this article – to enable everyone to age as slowly as only some people presently do. No radical life extension or rejuvenation, as would be enabled by the damage repair approach to longevity science, but rather just a gentle slowing of aging, enabled by technologies that would probably not emerge in time to benefit those of us in middle age today. “It is the aging of our cells that causes us to develop most diseases, says Dr. Nir Barzilai, professor of medicine and genetics at the Albert Einstein College of Medicine in New York. ‘We know this, paradoxically, because of the amazing success we have had in treating heart disease. We have been able to save people from heart attacks with stents and bypass surgery – only to find that within a year or two they develop Alzheimer’s, diabetes or cancer at an alarming rate. Why? Because we have never treated the underlying aging of their cells. We have simply treated the disease manifestation.’ So, explains Barzilai, if we can find the processes in the body that control aging and find a way to treat them, we will be able to protect people from the diseases of aging. Barzilai heads a unique longevity study of more than 500 people who have reached the age of 100. The LonGenity study is looking at the genetic makeup of centenarians to identify the biological markers that explain why they live so long and so well. Because the remarkable thing about these people is not simply that they live to the age of 100, it is that they live to 100 in pretty good health. Just why they live that long without getting sick and dying is what Barzilai wanted to find out.”

Link: http://www2.macleans.ca/2011/03/17/living-like-a-centenarian/

A recent open access paper from a Spanish research group outlines yet another methodology to add to the growing list of ways to increase healthy life span in mice. Progress is signified by diversity these days; there are, I think, more than twenty different demonstrated methods of bringing about meaningful extension of life in mice as of today.

RasGrf1 deficiency delays aging in mice:

We observed that mice deficient for RasGrf1-/- display an increase in average and most importantly, in maximal lifespan (20% higher than controls). This was not due to the role of Ras in cancer because tumor-free survival was also enhanced in these animals.

Aged RasGrf1-/- displayed better motor coordination than control mice. Protection against oxidative stress was similarly preserved in old RasGrf1-/-. IGF-I levels were lower in RasGrf1-/- than in controls. Furthermore, SIRT1 expression was increased in RasGrf1-/- animals. Consistent with this, the blood metabolomic profiles of RasGrf1-deficient mice resembled those observed in calorie-restricted animals.

…

Our observations link Ras signaling to lifespan and suggest that RasGrf1 is an evolutionary conserved gene which could be targeted for the development of therapies to delay age-related processes.

The results are similar to those noted for PAPP-A knockout mice – both longer lives and less cancer. At this stage it’s anyone’s guess as to whether many of these methodologies in fact operate through the same thicket of connections and mechanisms in mammalian biochemistry. Time, and further research, will tell.

RasGrf1 was mentioned here last year in connection with the intriguing bi-maternal mice:

mice artificially produced with two sets of female genomes have an increased average lifespan of 28%. Moreover, these animals exhibit a smaller body size, a trait also observed in several other long-lived mouse models. One hypothesis is that alterations in the expression of paternally methylated imprinted genes are responsible for the life-extension of bi-maternal mice. Considering the similarities in postnatal growth retardation between mice with mutations in the Rasgrf1 imprinted gene and bi-maternal mice, Rasgrf1 is the most likely culprit for the low body weight and extended lifespan of bi-maternal mice.

This latest work adds weight to the supposition quoted above.

As a physician, there is probably no single question I get more frequently than “What causes cancer – and how can I avoid getting it?”

We human beings always tend to look for that “one elusive thing” that will solve our problems. Even doctors do it. But the reality is that many things in life are made up of many small factors which combine in mysterious ways to produce big results. Cancer is one of those big things. There are many relatively small contributors that “cause” cancer and affect how it grows and spreads, and this complexity is why questions about cancer’s cause and cure are so difficult to answer.

In this blog we’ll focus on a few tips for cancer prevention. In upcoming blogs we’ll consider some supplements you should consider that we believe will help reduce your risk of getting cancer, and also suggest some things you can do if you already have cancer.

• It is generally an accepted fact that too much fat can contribute to causing cancer. This established fact is all too often ignored. Being overweight raises your risk of breast cancer, colon cancer and prostate cancer, three types of cancerous tumors that are fat-related.  No doubt there are several other cancers that are also probably related to weight.

• Doctors also understand that inflammation can contribute to causing cancer. We’re not exactly sure why this is so, but there are healthy ways to diminish and even prevent inflammation in muscles and joints and so reduce cancer risk. Consider these simple ideas:

• Reduce your intake of animal fats and replace them with healthy fats. Most animal fats have what’s called a saturated omega 6 structure, and when your body metabolizes these fats, inflammation results. Healthy omega 3 fats, from sources including fish, krill, many nuts such as almond and walnuts, and some grains like flax, all reduce inflammation.
• Moderate exercise decreases inflammation. Be careful, though: over-exercising actually produces inflammation. So exercise in moderation. Exercise is what doctors call “dose dependent”: do it, but don’t over-do it.
• Along with moderate exercise, muscle-development also reduces inflammation. When a muscle exercises it produces anti-inflammatory peptides: the more muscle you have, and the more regularly it gets used, the more anti-inflammatory peptides you produce.

Besides changing our fat consumption and reducing inflammation, here are two more things you can do to reduce your cancer risk:

• Most people know that too much sun can contribute to causing cancer. But you should know that moderate sun exposure, up to 20 minutes a day, may actually reduce cancer risk. (This may be related to Vitamin D which the body derives from sunlight.)

• On the positive side, you can reduce cancer risk by eating deeply pigments fruits, berries, and vegetables – the more, the better. Do your body a favor: add plenty of these cancer-fighting foods to your diet. They taste great, and they’ll help you stay healthier longer!

Researchers recently demonstrated that increased cellular housekeeping could slow neurodegeneration, and here a different group show the same outcome: “Cells, which employ a process called autophagy to clean up and reuse protein debris leftover from biological processes, were the original recyclers. A team of scientists [have] linked a molecule that stimulates autophagy with the reduction of one of Alzheimer’s disease’s major hallmarks, amyloid peptide. Their finding suggests a mechanism that could be used to eliminate built-up proteins in diseases such as Alzheimer’s, Down syndrome, Huntingdon’s and <a href="http://en.wikipedia.org/wiki/Beta_amylo&quot; the="The" molecule,="molecule," called="called" smer28,="SMER28," spurs="spurs" autophagy,="autophagy," which="which" in="in" turn="turn" eliminates="eliminates" unwanted="unwanted" materials="materials" such="such" as="as" amyloid-beta, the protein aggregates that cause Alzheimer’s plaques. Increasing autophagy, either through a drug or a natural process such as diet, could improve the outcome for people with neurodegenerative diseases … The researchers [tested] various compounds for their ability to reduce the buildup of amyloid-beta by exposing cultured cells to compounds known to activate autophagy. They then compared the effect of these compounds by removing growth factors from the culture medium, a well-established stimulant of autophagy known as ’starvation.’ The researchers found that SMER28 was the most effective compound, and focused their studies on it to characterize the cellular components involved in this phenomenon. They compared the effect of SMER28 on amyloid-beta formation using normal cells or cells where the expression of genes known to be involved in autophagy was reduced or abolished. They found that three important autophagic players were involved, and one of them was essential for SMER28’s effect.”

Link: http://www.eurekalert.org/pub_releases/2011-03/ru-mts031611.php

A recent early stage trial demonstrated that first generation autologous stem cell transplants should be beneficial even if provided long after a serious damage has occurred. Large numbers of transplanted stem cells, grown over a period of weeks from a patient’s own cells, can spur the body to heal injuries that would normally linger:

Heart Damage Improves, Reverses After Stem Cell Injections in a Preliminary Human Trial:

Researchers have shown for the first time that stem cells injected into enlarged hearts reduced heart size, reduced scar tissue and improved function to injured heart areas … while this research is in the early stages, the findings are promising for the more than five million Americans who have enlarged hearts due to damage sustained from heart attacks. These patients can suffer premature death, have major disability and experience frequent hospitalizations. Options for treatment are limited to lifelong medications and major medical interventions, such as heart transplantation

…

Using catheters, researchers injected stem cells derived from the patient’s own bone marrow into the hearts of eight men (average age 57) with chronically enlarged, low-functioning hearts.

“The injections first improved function in the damaged area of the heart and then led to a reduction in the size of the heart. This was associated with a reduction in scar size. The effects lasted for a year after the injections, which was the full duration of the study,”

…

“This therapy improved even old cardiac injuries. [Some] of the patients had damage to their hearts from heart attacks as long as 11 years before treatment.”

This is generally good news for people who presently bear injuries and damage – or expect to suffer damage in the years between now and when stem cell medicine is in its prime. The most plausible future outcome looks to be that even the early stage and comparatively crude transplant therapies will provide significant benefits above and beyond any present form of medicine.

Of course, they would arrive far more rapidly and be far less costly in a world absent the FDA – but there is always medical tourism. A range of stem cell therapies that are presently forbidden from commercial development in the US have been available for several years elsewhere in the world:

The FDA forbids the development of new medical technologies long past the point at which any sane person would consider them a good risk, and in the process makes these technologies vastly more expensive. Medical tourism is a sane response to heavy-handed and unaccountable government employees: “Gregg Victor is one of the 1.5 million Americans who traveled abroad to get medical treatments last year. … More than a few were pursuing new stem-cell-based treatments unavailable in the States … ‘I am not waiting for the FDA to rule to get treatments,’ says Gregg Victor, who chose her clinic in Germany after spending a year and a half looking into stem cell treatments available all over the world. … Jordan happened upon TheraVitae, a Bangkok-headquartered biotechnology company that markets ‘VesCell stem cell treatments’ via licensing agreements with four clinics in Thailand … Thai doctors injected 25 million of his own stem cells into Jordan’s heart. Twenty thousand miles, 22 days, a cardiac arrest and $43,000 later, he came home to his wife with an ejection fraction between 30% and 35%. Even Jordan’s doctor had to admit he was happy with the results.” Results are mixed, much as you’d expect. Caveat emptor, and do your research – but a great many people are materially benefiting from technologies still forbidden by their own governments.

Via EurekAlert!: “A gene therapy called NLX-P101 dramatically reduces movement impairment in Parkinson’s patients, according to results of a Phase 2 study … The approach introduces a gene into the brain to normalize chemical signaling. … The study is the first successful randomized, double-blind clinical trial of a gene therapy for Parkinson’s or any neurologic disorder … Half of patients receiving gene therapy achieved dramatic symptom improvements, compared with just 14 percent in the control group. Overall, patients receiving gene therapy had a 23.1 percent improvement in motor score, compared to a 12.7 percent improvement in the control group. … Improved motor control was seen at one month and continued virtually unchanged throughout the six-month study period. … Gene therapy is the use of a gene to change the function of cells or organs to improve or prevent disease. To transfer genes into cells, an inert virus is used to deliver the gene into a target cell. In this case, the glutamic acid decarboxylase (GAD) gene was used because GAD makes a chemical called GABA, a major inhibitory neurotransmitter in the brain that helps ‘quiet’ excessive neuronal firing related to Parkinson’s disease. … In Parkinson’s disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement.”

Link: http://www.eurekalert.org/pub_releases/2011-03/nyph-gtr031411.php

It is good to see some of the larger and better funded life science research communities showing interest in targeting mitochondria – the more people working on this the better, as mitochondria are important in degenerative aging, but there is presently relatively little ongoing research into the practical approaches to mitochondrial repair: “Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases.”

Link: http://www.ncbi.nlm.nih.gov/pubmed/21470101

Some numbers to consider, since everyone and their dog seems to be talking about the disposition of inordinately large sums of money – and little else – at the moment:

• Between 1970 and 2000, increasing life expectancy added $3.2 trillion per year in effective wealth.
• The yearly cost of natural death: more than 50 million lives and $100 trillion in wealth.
• The estimated cost of developing robust rejuvenation in mice via SENS, the Strategies for Engineered Negligible Senescence: $100 million per year over ten years.
• The 2010 budget for the US National Institute on Aging: $1 billion.
• The 2010 budget for the US National Institutes of Health: in the vicinity of $35 billion.
• The NIH comprises perhaps a third of medical research funding in the US.
• The cost of acquiring sirtuin research company Sirtris: $720 million.

• The 2010 research budget at the SENS Foundation: a little over $650,000.

We all have our ideas as to how to spend money in ways better than the choices made by its current owner. It can be frustrating when the course ahead is so very clear indeed, yet not taken … but that is what advocacy is for. When you have a vision, share it, persuade others, and make it happen. When you don’t like the numbers you see in front of you, work to change them.

The Methuselah Foundation invests in a variety of companies, and one of them is Silverstone Solutions. Here the Foundation notes a demonstration of the company’s product: “In what is the largest single-hospital kidney swap in the history of California, five patients received five kidneys from healthy donors in a marathon series of operations on Friday, April 1st 2011 … ‘Paired donation’ is the procedure that makes it possible, a relatively new phenomenon in transplantation surgery that allows for a live kidney going to someone who has a friend or relative willing to donate an organ not compatible for them but a match for someone else. The donor matches one who needs a kidney and that patient’s incompatible donor matches someone else and so on, like a chain. … Imagine that – multiple lives being extended in one fell swoop! This is one of many reasons why Methuselah Foundation has proudly invested in Silverstone Matchmaker, a break-through computer software that makes the pairings possible. It quickly computes the myriad of possible matches in a pool of prospective donors and recipients, minimizing time and effort that the transplant center needs to reach this goal. … That is why we proudly extend an angel financing arm, funding the development of the bleeding-edge improvements to the Silverstone technology called MatchGrid. This event is in keeping with Methuselah Foundation’s strategy of making investments in life-extending technologies that work RIGHT NOW (dangit!) and that also have long term positive implications for general life extension in the tissue engineering realm. Our long term vision for this technology? We hope that its massive and super performance data management system will eventually play a role in the an envisioned ‘Postscript’ language that can send printing instructions for creating new tissues and eventually organs to be used by tissue printers such as Organovo’s sci-fi worthy 3D tissue printer, another founding angel investment by you, the donors of Methuselah Foundation.”

http://blog.methuselahfoundation.org/2011/04/hot_dog_a_record-breaking_5-transplant_kidney_swap.html

The process of understanding how to manipulate stem cells goes hand in hand with being able to coax them into forming more complex structures, recapitulating the path taken during the original development of the body when young. The state of the art at the present time is crude in comparison to what takes place in our bodies: the only way that researchers can presently obtain complex tissues is by using the extracellular matrix extracted from donor tissue as a guide for new growth. That guidance is as much chemical as structural, which is illustrated in the following recently announced research.

‘Retina in a Dish’ is the Most Complex Tissue Ever Engineered in the Lab:

Researchers in Japan have grown a retina from mouse embryonic stem cells in a lab, but this isn’t just another incremental advance in tissue engineering. Scientists claim their “retina in a dish” is by no small degree the most complex biological tissue yet engineered.

If the breakthrough can be adapted to work with human cells, it could provide a retina that is safe for transplantation into human eyes, providing a potential cure for many kinds of blindness. That’s still years away, but in the meantime the lab-grown mouse tissue could provide researchers with a wealth of information on eye diseases and potential treatments for them.

Cultured mouse embryonic stem cells self-organize into a complex retinal structure:

Starting with the culture conditions they had established for retinal differentiation, the researchers added matrix proteins that they hoped would encourage the formation of the more rigid retinal epithelial structures. They then seeded the culture with mouse [embryonic stem] cells. Within a week, the cells began to form small vesicles and differentiate into two different tissue types: Cells on one side of the vesicles formed the mechanically rigid pigment epithelium, while cells on the other side differentiated into a more flexible tissue that folded inward in the shape of an embryonic optic cup – the retina’s precursor.

As you can see, researchers remain a long way away from growing a transplant-ready human retina from cells alone – but this is still an important step forward in the path towards producing such a thing. What is learned here will also inform efforts to build the thousand other tissue types we’d like to be able to produce from scratch.

The evidence points toward mitochondrial structure and function being very important in the progression of aging within a species and differences in life span between species. Here researchers review some of the mechanisms involved: “Mitochondria are considered major regulators of longevity, although their exact role in aging is not fully understood. Data from different laboratories show a negative correlation between reactive oxygen species (ROS) generated by complex I and lifespan. This suggests that complex I has a central role in the regulation of longevity. Here, we review data that both support and refute the role of complex I as a pacemaker of aging. We include data from our laboratory, where we have manipulated ROS production by the electron transport chain (ETC) in Drosophila melanogaster. The by-pass of complex I increases the lifespan of the fruit fly, but it is not clear if this is caused by a reduction in ROS or by a change in the NAD+ to NADH ratio. We propose that complex I regulates aging through at least two mechanisms: (1) an ROS-dependent mechanism that leads to mitochondrial DNA damage and (2) an ROS-independent mechanism through the control of the NAD+ to NADH ratio. Control of the relative levels of NAD+ and NADH would allow the regulation of (1) glyco- and (2) lipoxidative-damage and (3) the activation of sirtuins.” Amongst other things, the NAD+ / NADH ratio determines how much in the way of damaging free radicals a cell exports into the surrounding environment.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21471732

You might recall that the Immortality Institute raised funds for a test of laser ablation of lipofuscin, to run on nematode worms using commercially available laser equipment:

The good news for today is that the longevity science grassroots centered at the Immortality Institute have successfully raised $8,000 to fund research into laser ablation of lipofuscin. Those funds will be matched up to $16,000 at the SENS Foundation and put towards work on a method of eliminating one form of damaging metabolic byproducts that build up with age.

Lipofuscin is the name given to a collection of various waste products of metabolism that are hard for the body to break down. They build up inside cells, collecting in the recycling mechanisms of lysosomes and causing cellular housekeeping to progressively fail over time. Ways to safely break down lipofuscin are very much required as a part of the envisaged package of future rejuvenation biotechnology that can prevent and reverse aging.

One proposed methodology for tackling lipofuscin is the use of pulsed laser light targeted at very specific molecules and molecular bonds: in theory, it should be possible to significantly impact lipofuscin levels without harming the cells that contain this gunk. Whether this is the case in practice remains to be seen, but it is an approach well worth testing: after all, lasers are already routinely used in dermatology to achieve conceptually similar goals, and the cost of this test is minimal in the grand scheme of things. Hence the laser ablation project funded by forward-looking donor and organized by the Immortality Institute.

You’ll find recent updates on the state of the laser ablation test in the Longecity thread for the project:

Here is the basic agenda for the remainder of the project:

1) Test the effect of 8ns pulses on worm lifespan, at many different intensities. … The beam coming straight out of the laser has terrific coherence and a nice tophat profile, which although it is 8ns, which is a little harsh, it is wonderfully consistent, great at destroying pigments, and we can rest assured that all worms on the slide are getting the exact same exposure every time.

2) Examine effect on worm activity/livelihood. Since the worms grow distinctively and progressively less active in the 2nd half of their life, this can be used to roughly assess quality of life changes; i.e. if worms are all dying at the same time, but at 75% lifespan, laser-treated groups are still quite active, this could be seen as a definite extension of useful lifespan.

3) Examine changes in pigmentation, if any. I may even be able to rig up a crude blacklight setup and get some fluorescence going. Or we could lop two months of the end of the 8-month project and buy a basic fluorescence scope with the extra $2500

…

4) Assess the effect of laser treatment on a more long-lived strain of worms (such as DAF-16 mutants), as well as the wild-type. This could provide useful clues as to what is going on, whichever way the results go.

…

It’s still taking awhile to breed more DA1116 worms. I can see how this is going to go – things are going to stretch out a bit, partly due to my schedule and partly due to using long-lived worms, and the nature of lifespan experiments in general. Therefore I propose using experiments as milestones instead of sticking to a fixed weekly or monthly schedule. Thus the project will span at least 8 complete lifespan experiments, regardless of how long it takes to complete them. The remaining ‘monthly’ salary and expense checks could be sent at the start of experiments 3, 5 and 7 – which will doubtless end up being more than one month apart. This definitely seems more appropriate to me – that way all of our gracious donors get the same amount of science for their money, regardless of how long it takes.

The fluorescence scope may or may not be purchased for this project, depending on how our financial situation pans out on this end. It may end up being budgeted as part of a future project proposal instead; but we can cross that bridge when we get there.

I’ll let everyone know as soon as the worm zapping begins.

One of the Immortality Institute volunteers visited the lab recently, and so you’ll find photographs of the equipment, work area, and researcher in the thread to go along with the updates.

By way of a reminder, the Institute continues to raise funding for their next project, an investigation of microglia transplantation as a therapy for age-related neurodegeneration. $5,500 of the needed $8,000 has been raised, and futher donations are very welcome. Every dollar donated will be matched by an additional dollar from the Institute and its sponsors, so that the completed fundraiser will send $16,000 to the laboratory that will carry out the research:

Cognitive functions of the brain decline with age. One of the protective cell types in the brain are called microglia cells. However, these microglia cells also loose function with age. Our aim is to replace non-functional microglia [in mice] with new and young microglia cells derived from adult stem cells.

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The full PDF format research proposal is available: the work will be carried out by a graduate research assistant and will cost $16,000. This is the essence of our present era of biotechnology: a task that would have occupied a whole laboratory and its equipment in the 1980s, and cost a great deal of money if it was even possible at all, is now something that a skilled graduate-level life scientist can organize and run himself within an established lab.

Researchers continue to investigate how to replicate the limb regeneration found in lower animals: “Move over, newts and salamanders. The mouse may join you as the only animal that can re-grow their own severed limbs. Researchers are reporting that a simple chemical cocktail can coax mouse muscle fibers to become the kinds of cells found in the first stages of a regenerating limb. Their study, the first demonstration that mammal muscle can be turned into the biological raw material for a new limb … their ‘relatively simple, gentle, and reversible’ methods for creating the early stages of limb regeneration in mouse cells ‘have implications for both regenerative medicine and stem cell biology.’ In the future, they suggest, the chemicals they use could speed wound healing by providing new cells at the injured site before the wound closes or becomes infected. Their methods might also shed light on new ways to switch adult cells into the all-purpose, so-called ‘pluripotent’ stem cells with the potential for growing into any type of tissue in the body. The scientists describe the chemical cocktail that they developed and used to turn mouse muscle fibers into muscle cells. [They] then converted the muscle cells turned into fat and bone cells. Those transformations were remarkably similar to the initial processes that occur in the tissue of newts and salamanders that is starting to regrow severed limbs.”

Link: http://www.eurekalert.org/pub_releases/2011-04/acs-scc040611.php

The evolutionary view of cancer and aging is that these end points stand in opposition: complex organisms such as mammals evolve to some point of balance between risk of cancer and certainty of accelerated aging. This happens because the mechanisms that suppress cancer also inhibit the necessary regenerative capacity to maintain tissue function: it’s largely a matter of how free cells are to divide and multiply, taking into account the increasing levels of damage and mutation with age – which increase the chance of a cancer developing.

In research focused on this balance between aging and cancer, two genes – and the proteins they produce – are especially important: p53 and p16. Both can suppress cancer, but at the cost of accelerated aging:

• On p53 and Aging
• Understanding a Tumor Suppression Gene

p16 has been particularly interesting of late because it appears to be a plausible candidate for the cancer immunity observed in naked mole rats:

the mole rat’s cells express a gene called p16 that makes the cells ‘claustrophobic,’ stopping the cells’ proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells’ growth barely changed

Unfortunately, as recent research illustrates, making use of this knowledge isn’t as easy as just ramping up p16 gene expression in other mammal species:

“I didn’t anticipate that increased production of the p16 tumor suppressor protein would so readily promote aging,” says Enders, who led the study. “The p16 protein has been previously associated with aging, and we know its expression increases during late stages of aging. But the idea that its expression would be sufficient to generate features of aging was surprising.”

Although scientists know that loss of p16 is associated with numerous human tumors, they know much less about the function of p16 in normal cells and tissues. To explore this, Enders’ team engineered a strain of mice that enables them to control p16 expression in various tissues and at various times in an animal’s lifespan. They quickly found that turning on p16 blocked cell proliferation in normal tissues.

The implications of blocked cell proliferation emerged when they expressed p16 in animals that were not yet fully mature. “They developed features of premature aging,” Enders says. “To my knowledge, this is the first model that induces striking characteristics of premature aging where there is no macromolecular damage. The premature aging appears to be the result of blocking cell proliferation.”

In this respect, p16 is very similar in behavior to p53. But that in fact means that there is great promise inherent in p16 research: a few years ago, Spanish researchers engineered their way around the aging-cancer balance in mice for p53, producing mice that suffered less cancer and lived 50% longer than normal. Trying a similar approach with p16 sounds very plausible. It is also possible that their work is analogous to the biology of naked mole-rats, animals that manage to live vastly longer than the members of other similarly sized rodent species, and this despite their evolved usage of p16 and apparently complete immunity to cancer. Equally, mole-rats might exhibit yet another completely different configuration of mammalian biology – one that it may soon be possible to reverse engineer and test in mice.

Answers to this sort of speculation still lie in the near future, but research into the biochemistry of p16 and p53 is worth keeping an eye on. Few other methodologies can claim to have extended healthy life in mice by as much as that mentioned above, and, furthermore, somewhere in the biology of these species lies a way to simply turn off cancer.

The Methuselah Generation is a documentary film in progress, far enough along that the filmmaker is putting out early versions: “Is aging a disease that can be cured? Is it possible to live forever? Even if we could, should we? The Methuselah Generation (working title) is a 3D verite documentary about the science and philosophy of Life Extension – the scientific hypothesis that individuals may be capable of extending human life beyond anything humans have yet imagined. The story will follow a select few individuals at the forefront of this movement as well as those skeptical and antagonistic toward the goals of life extension. The film will follow five protagonists as they progress with their movement to change humanity. Through intimate interviews, observational shooting and provocative imagery, this character-based 3D documentary will explore the big philosophical ideas of Life Extension, while also examining the scientific feasibility – the film will explore the what, how and (most significantly) the WHY of long-lived humans.”

Link: http://davidalvarado.info/le.html