Fight Aging! Newsletter, July 2nd 2012

July 2nd 2012




- The Other Harm Caused by Mitochondrial DNA Damage
- Perverse Incentives and Underestimations of Longevity
- An Interview With Aubrey de Grey
- Early Medical Nanorobots Will Look Like Cells and Bacteria
- Discussion
- Latest Headlines from Fight Aging!
    - Age-Related Visual Impairment in Decline
    - Alcor 40 Conference, October 19th 2012
    - A Step Towards Better Blood
    - Demonstrating Genetically Corrected Stem Cells as a Therapy
    - Comments on Chemopreservation Versus Cryopreservation
    - Calorie Restriction Reduces Loss of Synaptic Plasticity
    - Mitochondrial Haplogroup Associations With Longevity in China
    - Another Way of Searching for Longevity-Related Mechanisms
    - Popular Press on Organ Tissue Engineering
    - In Situ Tissue Engineering of an Artery


Mitochondria, the power plants of the cell, are very important in aging. Thus work towards biotechnologies to repair damage to mitochondria is also very important - and relatively close to realization, despite receiving far less funding than it deserves:

"As I'm sure you all know by now, mitochondria are swarming powerplants within the cell, descendants of symbiotic bacteria that bear their own DNA separate from the DNA in the cell nucleus. Mitochondrial DNA provides the blueprints for proteins making up the machinery of a mitochondrion, but it isn't as well protected or as well repaired as nuclear DNA. Given that a lot of reactive compounds are funneled through mitochondria in the processes that keep a cell powered, it is only to be expected that mitochondrial DNA becomes progressively more damaged over time. The range of mechanisms that have evolved to deal with that damage cannot keep up over the long term, and as a result a small but significant portion of our cells fall into ruin on the way to old age, becoming populated by dysfunctional, damaged mitochondria, and causing a great deal of harm to surround tissues and bodily systems by exporting a flood of reactive biochemicals. You can read a longer and more detailed description of this process back in the Fight Aging! archives.

"So that is one side of the issue of mitochondrial DNA damage and its contribution to degenerative aging - and that in and of itself would be more than enough to make mitochondrial repair biotechnologies a research priority. There are many different potential ways of fixing or rendering irrelevant mitochondrial DNA damage, and allowing mitochondria to continue to function as well as they did at birth for an indefinite period of time. The sooner one of them is developed into a working therapy the better.

"In considering mitochondrial damage there is another, more straightforward process at work, however. Many types of cell normally operate fairly close to the limit of the power provided by their mitochondria, including important cell populations in the brain and nervous system. As mitochondrial DNA damage accumulates with age, power production - meaning the pace at which adenosine triphosphate (ATP) is produced - falls off and cells either die or malfunction far more often than they did in youth."


Many of the institutions tasked with understanding trends in human longevity, a challenging task in this age of rapid development in biotechnology, operate under incentives that lead them to understate future estimates:

"A large industry is focused on getting these numbers right, or as close to right as is possible, as vast sums are promised to older folk, either as political entitlements or honestly obligated as a result of insurance contracts. Betting against increasing longevity seems like a fool's game, but nonetheless there is a lot of money to be made in that business - many large entities want to be protected from what is known as longevity risk, the risk that life spans will rise faster than expected and thus financial obligations will spiral out of control. Large entities are willing to pay for that insurance service, and taking on risk for a percentage is very much the core business of finance.

"In theory the people taking on that risk for a percentage know what they are doing, and they are the ones funding efforts to understand the risk - which in this case means models for future increases in human longevity due to advances in medicine and biotechnology. In practice? The risk gets sliced and diced and parceled out among the players in finance, that much is true. But I'm sure we all see the present results of that undertaking in other large industries, such as housing: when there is enough money involved the business becomes one of lies and politics, the fine art of pocketing profits, taking on unknown risks for short term gain, steering government policies, and raiding the public treasury to cover losses when it all goes south. When buying politicians and policy is a reasonable cost judged against the cost of contracts, buying politicians and policy becomes a part of doing business - and very lucrative, since it allows risk-bearers to try for the upside with the expectation that they will be bailed out if it fails.

"Thus a web of perverse incentives grows, benefiting the connected few at the expense of the many. In the course of all of this, there is an increasing pressure (and ability) to obscure or water down unfavorable data, especially when the interests of profiteers and government appointees coincide. Again, we've all seen this come to pass numerous times in recent years and prior decades. It is the way of the world, and just as much so when it comes to the future of human longevity:

"In 1981, the United Kingdom (UK) Office for National Statistics estimated that male life expectancy at birth would rise to 74 by 2031. It hit that age in 1994. In 2002, the 2031 estimate was 81, but we are now expected to pass that in 2019. This systematic underestimation of official life expectancy increases occurs around the world. It is not an accident. It is deliberate. Politicians put pressure on official agencies to do this, so that the full cost of longevity increases does not fall on them or the current generation of voters. The reason is clear: If more accurate and hence higher projection of life expectancy were produced today, then social security contributions would have to rise now rather than later - and this would be politically very unpopular."


SENS Foundation cofounder Aubrey de Grey presented at the humanity+ conference in Melbourne, Australia, held earlier this year. Adam Ford, the conference coordinator, interviewed de Grey after the event, and later uploaded a slew of video segments from that interview to YouTube. You'll find a link to the playlist in the following Fight Aging! post:


Researchers are producing some impressive early technology demonstrations these days - assembled, artificial molecular machinery that starts to rival bacteria in complexity:

"If I mention medical nanorobotics, you might think of the designs put forward by Robert Freitas and others: molecular machines constructed largely from carbon that bear little relation to the cells and cellular system they are intended to interact with. Or you might think of the crude forerunners of those designs presently being tested in the laboratory, such as targeted nanoparticles and nanocontainers used to deliver drug compounds more precisely to where they are needed.

"But you and I are built out of nanorobots: each of our cells is effectively a structured collection of cooperating, programmable nanoscale robots. They are evolved rather than designed, but still represent a vast preexisting parts library for researchers interested in building the first generation of medical nanorobots. While it is true that there are good reasons for reinventing this wheel, such as gaining far greater performance than is possible from anything similar to our present biology, given that time is of critical importance in developing the next generation of medicine, why not use these existing designs?

"Researchers are already building the prototypes, far more advanced than simple targeted nanoparticles. Here, for example, is news of progress towards nanofactories. ... Scientists are reporting an advance toward treating disease with minute capsules containing not drugs - but the DNA and other biological machinery for making the drug. ... development of nanoscale production units for protein-based drugs in the human body may provide a new approach for treating disease. These production units could be turned on when needed, producing medicines that cannot be taken orally or are toxic and would harm other parts of the body. Until now, researchers have only done this with live bacteria that were designed to make proteins at disease sites. But unlike bacterial systems, artificial ones are modular, and it is easier to modify them. That's why [this research group] developed an artificial, remotely activated nanoparticle system containing DNA and the other 'parts' necessary to make proteins, which are the workhorses of the human cell and are often used as drugs. They describe the nanoscale production units, which are tiny spheres encapsulating protein-making machinery like that found in living cells. The resulting nanoparticles produced active proteins on demand when the researchers shined a laser light on them."





Friday, June 29, 2012
Steady progress in medicine has led to an ongoing reduction in many age-related conditions over the past few decades. Such as this, for example: "Today's senior citizens are reporting fewer visual impairment problems than their counterparts from a generation ago, according to a new [study]. Improved techniques for cataract surgery and a reduction in the prevalence of macular degeneration may be the driving forces behind this change, the researchers said. ... From 1984 until 2010, the decrease in visual impairment in those 65 and older was highly statistically significant. There was little change in visual impairments in adults under the age of 65. ... The [ study] shows that in 1984, 23 percent of elderly adults had difficulty reading or seeing newspaper print because of poor eyesight. By 2010, there was an age-adjusted 58 percent decrease in this kind of visual impairment, with only 9.7 percent of elderly reporting the problem. There was also a substantial decline in eyesight problems that limited elderly Americans from taking part in daily activities, such as bathing, dressing or getting around inside or outside of the home ... there are three likely reasons for the decline: (a) Improved techniques and outcomes for cataract surgery. (b) Less smoking, resulting in a drop in the prevalence of macular degeneration. (c) Treatments for diabetic eye diseases are more readily available and improved, despite the fact that the prevalence of diabetes has increased "

Friday, June 29, 2012
Cryonics provider Alcor is holding a 40th anniversary conference in October, and the presently announced program looks much like this: "Sebastian Seung on testing how well cryopreservation (and alternatives) preserves the connectome. Todd Huffman on brain scanning. Panel discussion on long-term financial planning, including investing strategies, inflation protection, and personal trusts. Aschwin and Chana de Wolf from Advanced Neural Biosciences on advances in cryonics-relevant research. Greg Fahy from 21st Century Medicine on advances in cryoprotection. Aubrey de Grey from the SENS Foundation. Joshua Mitteldorf on programmed aging. Anders Sandberg on 'Handling the unknowable and undecidable: rational decision making about future technology.' Catherine Baldwin on advances at Suspended Animation. Panel on medical monitoring devices for improving your chances of a quick response in case of a critical physiological failure. Max More on how to improve your prospects for an optimal cryopreservation."

Thursday, June 28, 2012
Why not aim to improve on blood? Its primary function is to carry oxygen, and it has evolved to do the bare minimum necessary on this front - separate any part of the body from a supply of oxygen for a minute or so and you're in trouble. It would be nice, for example, to have blood with a reserve capacity of a few hours, achieved using nanomachines that store the surplus oxygen that the body doesn't otherwise extract from air breathed in. Even if the heart stopped or blood stopped flowing in some vital tissue, you'd have those few hours to seek medical help. Here is a gentle first step towards the technologies of better blood: researchers "designed tiny, gas-filled microparticles that can be injected directly into the bloodstream to quickly oxygenate the blood. The microparticles consist of a single layer of lipids (fatty molecules) that surround a tiny pocket of oxygen gas, and are delivered in a liquid solution. ... report that an infusion of these microparticles into animals with low blood oxygen levels restored blood oxygen saturation to near-normal levels, within seconds. When the trachea was completely blocked - a more dangerous 'real world' scenario - the infusion kept the animals alive for 15 minutes without a single breath, and reduced the incidence of cardiac arrest and organ injury. The microparticle solutions are portable and could stabilize patients in emergency situations, buying time for paramedics, emergency clinicians or intensive care clinicians to more safely place a breathing tube or perform other life-saving therapies. ... The microparticles would likely only be administered for a short time, between 15 and 30 minutes, because they are carried in fluid that would overload the blood if used for longer periods ... the particles are different from blood substitutes, which carry oxygen but are not useful when the lungs are unable to oxygenate them. Instead, the microparticles are designed for situations in which the lungs are completely incapacitated. ... Intravenous administration of oxygen gas was tried in the early 1900s, but these attempts failed to oxygenate the blood and often caused dangerous gas embolisms. ... We have engineered around this problem by packaging the gas into small, deformable particles. They dramatically increase the surface area for gas exchange and are able to squeeze through capillaries where free gas would get stuck."

Thursday, June 28, 2012
This demonstrated technology platform has wide-ranging uses beyond muscular dystrophy. The ability to generate altered versions of a patient's own stem cell populations and then deliver them as needed could be a useful therapy for many conditions: "scientists have turned muscular dystrophy patients' fibroblast cells (common cells found in connective tissue) into stem cells and then differentiated them into muscle precursor cells. The muscle cells were then genetically modified and transplanted into mice. ... In this study, scientists focused on genetically modifying a type of cell called a mesoangioblast, which is derived from blood vessels and has been shown in previous studies to have potential in treating muscular dystrophy. However, the authors found that they could not get a sufficient number of mesoangioblasts from patients with limb-girdle muscular dystrophy because the muscles of the patients were depleted of these cells. Instead, scientists in this study 'reprogrammed' adult cells from patients with limb-girdle muscular dystrophy into stem cells and were able to induce them to differentiate into mesoangioblast-like cells. After these 'progenitor' cells were genetically corrected using a viral vector, they were injected into mice with muscular dystrophy, where they homed-in on damaged muscle fibres. The researchers also showed that when the same muscle progenitor cells were derived from mice the transplanted cells strengthened damaged muscle and enabled the dystrophic mice to run for longer on a treadmill than dystrophic mice that did not receive the cells."

Wednesday, June 27, 2012
There is some ongoing interest in plastination (or chemopreservation) as a possible alternative to cryonics (or cryopreservation) - though not yet enough for an initiative to arise that offers that service. Here is commentary on this topic: "Even if chemopreservation can be demonstrated to preserve the intricate wiring of the brain, it can be safely assumed that there will not be a massive change in demand for brain preservation technologies ... As a consequence, providers of chemopreservation will most likely operate in the same environment as providers of cryonics. That means that, as a general rule, there will be a delay between pronouncement of legal death and the start of procedures. ... There is an understandable tendency to compare brain preservation protocols under ideal conditions and favor the method that produces the best preservation. But support for either technology cannot be solely based on results produces under controlled lab conditions. Personal survival technologies should be evaluated under conditions that are most likely to be encountered by organizations that will offer them. ... One interesting aspect of the cryonics vs chemopreservation debate, though, is that it appears that some people simply feel more comfortable with one of the approaches. People who have shown the slightest interest in human cryopreservation can get really excited about the idea of chemical brain preservation. This indicates that if both approaches would be pursued actively, the growth of chemopreservation would not necessarily be at the expense of cryonics but there would be a growth in the total number of people making bio-preservation arrangements aimed at personal survival. [But] chemopreservation is not at the stage where it can be responsibly offered. The growth of this field requires a committed group of individuals who will research, develop, and implement this program. Chemopreservation does not need to be perfected before being offered (neither was cryonics) but so far most advocacy has been mostly at the conceptual level."

Wednesday, June 27, 2012
Another of the many benefits of calorie restriction is outlined in this paper: "The author focused on the functional decline of synapses in the brain with aging to understand the underlying mechanisms and to ameliorate the deficits. The first attempt was to unravel the neuronal functions of gangliosides so that gangliosides could be used for enhancing synaptic activity. The second attempt was to elicit the neuronal plasticity in aged animals through enriched environmental stimulation and nutritional intervention. Environmental stimuli were revealed neurochemically and morphologically to develop synapses leading to enhanced cognitive function. Dietary restriction as a nutritional intervention restored the altered metabolism of neuronal membranes with aging, providing a possible explanation for the longevity effect of dietary restriction. These results obtained with aging and dementia models of animals would benefit aged people."

Tuesday, June 26, 2012
Mitochondria are the power plants of the cell and are important in aging: damage to their DNA contributes to degenerative aging through a complex process, and differences in mitochondrial resistance to damage is thought to go a long way towards determining variation in species life span. So it should not be surprising to see associations between different mitochondrial DNA haplogroups and human longevity, as is the case here: "Human longevity is an interesting and complicated subject, with many associated variations, geographic and genetic, including some known mitochondrial variations. The population of the Bama County of Guangxi Province of China is well known for its longevity and serves as a good model for studying a potential molecular mechanism. In this study, a full sequence analysis of mitochondrial DNA (mtDNA) has been done in ten Bama centenarians using direct sequencing. [Mitochondrial DNA was also] analyzed for a total of 313 Bama individuals with ages between 10 and 110 years. The results showed that there were seven mitochondrial variations [and] four haplogroups [in] 10 Bama centenarians. In the D-loop region of mtDNA, the mt146T occurred at a significantly lower frequency in those is the older age group (90-110 years) than in the middle (80-89 years) and in the younger (10-79 years) groups. The mt146T also had lower systolic blood pressure and serum markers such as total cholesterol, triglyceride and low density lipoprotein than did mt146C in the older age group. ... These results suggest that the mt146T/C polymorphisms in Guangxi Bama individuals may partly account for the Bama longevity."

Tuesday, June 26, 2012
Researchers are developing all sorts of methods for sifting through the mass of data on protein machinery used in our bodies, and some groups are finding novel ways to identify possible longevity-related proteins: "Despite a 10-100-fold difference in maximum lifespan (MLS), most known mammal species show similar phenotypes of aging. This observation suggests that the genetic determinants of mammalian aging and lifespan may be relatively plastic. The classical evolutionary theory of antagonistic pleiotropy posits that aging is an effect of the decrease in selection pressure that occurs after successful reproduction. Conversely, lifespan extension has been shown to occur when selection pressure increases in later age. Still relatively unexplored are the specific molecular mechanisms that determine differences in mammalian lifespan. Many mechanisms are possible and likely occur simultaneously, including changes in the sequence, structure, function, and expression of RNA and proteins. Here, we focus on changes in proteins caused by fixed substitutions. In this context, two recent studies predicted a simple consequence of the evolutionary theory: we might expect that proteins necessary for long mammalian lifespan would have fewer substitutions, i.e. show more conservation, in long-lived versus short-lived species. Thus, it may be possible to identify aging-related proteins [by] inferring and comparing some measure of such preferential substitutions, here called 'longevity-selected positions', among the several dozen mammal species whose proteomes are available. ... We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-Müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and [its] longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein's activity in a lifespan-specific manner."

Monday, June 25, 2012
Building new organs from a patient's own cells is a goal that is gaining more attention from the wider public and the mainstream press: "What if dying patients waiting for an organ transplant could receive a custom, lab-grown replacement rather than waiting for a donor organ? To some, this may sound like science fiction - and in many ways, it still is. But the advances in the field of regenerative medicine that made headlines last week suggest such lab-grown organs may become reality in the future. ... The idea of using a patient's own cells rather than relying on those of a donor is important because it eliminates the need to find a 'match.' For any transplant procedure there is a concern that tissues from a donor will be rejected by a recipient's body. Even though doctors carefully analyze specimens under a microscope to find the most compatible individuals, and even despite the powerful drugs used to prevent the recipient's immune system from attacking the new body part, the risk of rejection still causes doctors to hold their breath in the days following a transplant. Custom-made organs from a patient's own tissues would solve this problem, obviating the need for strong immune-suppressing medications that come with significant side effects. The other potential benefit lies in availability. Growing a replacement tissue or organ in the lab eliminates the dependence on waiting for a donor to die. These parts cannot be grown overnight, but with people currently waiting months to years for donor organs, there might be a point at which the amount of time taken to grow a replacement is shorter than the wait for a donated one. It's a bright future. But many hurdles remain before widespread use becomes a reality."

Monday, June 25, 2012
The logical progression for tissue engineering is to move to building inside the body rather than building outside and then transplanting the resulting new tissue. Here is an example of that trend: "The host site, the artery in this case, is an excellent source of cells and provides a very efficient growth environment. This is what inspired us to skip the cell culture altogether and create these cell-free synthetic grafts. ... [Researchers] designed the graft with three properties in mind. First, they chose a graft material - an elastic polymer called PGS - that is resorbed quickly by the body. Then, they examined graft porosity and selected parameters that allow immediate cell infiltration. [They wrapped] the vascular graft with a fibrous sheath to trap the cells. Finally, [researchers] wanted a coating for the grafts that would reduces blood clotting and bind many growth factors, so they used heparin, a molecule that does just that. ... [Researchers] made grafts as small as 1 mm in diameter and monitored the graft's transformation in vivo for three months. Because the graft was highly porous, cells were easily able to penetrate the graft wall, and mononuclear cells occupied many of the pores within three days. Within 14 days, smooth muscle cells - an important blood vessel builder - appeared. At 28 days, cells were distributed more evenly throughout the graft. At 90 days, most inflammatory cells were gone, which correlated with the disappearance of the graft materials. The artery was regenerated in situ and pulsed in sync with the host. Furthermore, the composition and properties of the new arteries are nearly the same as native arteries."



