Present Areas of Focus in Regenerative Medicine

Whilst browsing PubMed today, I noticed an informative survey of publication trends in the field of regenerative medicine. The full PDF text is available from the journal for those of you who like to dig further:

The articles published in the journal Cell Transplantation - The Regenerative Medicine Journal over the last two years reveal the recent and future cutting-edge research in the fields of regenerative and transplantation medicine. 437 articles were published from 2007 to 2008, a 17% increase compared to the 373 articles in 2006-2007.

- Neuroscience was still the most common section in both the number of articles and the percentage of all manuscripts published.

- The increasing interest and rapid advance in bioengineering technology is highlighted by tissue engineering and bioartificial organs being ranked second again.

- For a similar reason, the methods and new technologies section increased significantly compared to the last period. Articles focusing on the transplantation of stem cell lineages encompassed almost 20% of all articles published.

- By contrast, the non-stem cell transplantation group which is made up primarily of islet cells, followed by biomaterials and fetal neural tissue, etc. comprised less than 15%.

- Transplantation of cells pre-treated with medicine or gene transfection to prolong graft survival or promote differentiation into the needed phenotype, was prevalent in the transplantation articles regardless of the kind of cells used.

- Meanwhile, the majority of non-transplantation-based articles were related to new devices for various purposes, characterization of unknown cells, medicines, cell preparation and/or optimization for transplantation (e.g. isolation and culture), and disease pathology.

I find it reassuring to see a heavy focus on neuroscience in regenerative medicine research. A few years spent watching progress in medical research has not changed my opinion on the need to develop repair technologies for the brain. It is the most vital end result. Our brains are the big deal - the big, complex, show-stopping deal - in regenerative medicine. It doesn't matter how well everything else goes if we can't figure out how to restore damage, age-related or otherwise, in a brain in situ.

All things considered, generating new, healthy human organs looks well on track to being a solved problem and available in the clinic within the next two decades. Researchers can presently grow bone in specific shapes in situ, and take complex organs from animals or human donors and replace all the tissue with the patient's own cells. This suggests that, even discounting the many other lines of tissue engineering research proceeding in parallel, all of the major organs will be replaceable for people who can tolerate the surgery required - except for the brain.

Restoring the brain will require a greater level of understanding as to how cells, regeneration, and growth are programmed and controlled. The end goal might be something like a steady flow of new, undamaged neurons to take the place of those that are lost. In conjunction with therapies to deal with the other aspects of age-related damage, such as the buildup of aggregates seen in Alzheimer's disease, that would go a long way towards setting up a brain for the long term. Or at least long enough for medical science to advance far beyond the bounds of present speculation.

ResearchBlogging.orgPark DH, & Eve DJ (2009). Regenerative medicine: Advances in new methods and technologies. Medical science monitor : international medical journal of experimental and clinical research, 15 (11) PMID: 19865067

Tuning the Immune System to Destroy Cancer

Our immune systems can destroy cancer - but the immune system grows less effective with age, and sometimes it fails in this task. That "sometimes" is enough to kill a quarter of humanity, the fraction of us who die from cancer. Researchers are closing in on the mechanisms that separate success from failure, however, and in the years ahead will be able to tune our immune systems to destroy cancer nearly 100% of the time: "A specific type of T helper cell awakens the immune system to the stealthy threat of cancer and triggers an attack of killer T cells custom-made to destroy the tumors ... The role of Th17, one of only four known types of T helper cell, opens a possible avenue for overcoming cancer's ability to suppress or hide from the body's immune system ... While there is much work to be done, these preclinical findings imply the possibility of taking a patient's Th17 cells, expanding them in the lab, and then re-infusing them as treatment ... Development of a vaccine to stimulate Th17 cells would be another possible application."

Link: http://www.sciencedaily.com/releases/2009/10/091029125534.htm

The Canadian Longitudinal Study on Aging

The Baltimore Longitudinal Study on Aging has been running since 1958, but this Canadian study is just getting started - a much larger project planned to run for decades: "Canadians are living longer, and older persons are making up a larger share of the population (14% in 2006, projected to rise to 20% by 2021). The Canadian Longitudinal Study on Aging (CLSA) is a national longitudinal study of adult development and aging that will recruit 50,000 Canadians aged 45 to 85 years of age and follow them for at least 20 years. All participants will provide a common set of information concerning many aspects of health and aging, and 30,000 will undergo an additional in-depth examination coupled with the donation of biological specimens (blood and urine). The CLSA will become a rich data source for the study of the complex interrelationship among the biological, physical, psychosocial, and societal factors that affect healthy aging." I suspect that the most important role for these studies in the future will be to more rapidly evaluate the effectiveness of specific longevity therapies as they arrive in the clinic.

Link: http://www.clsa-elcv.ca

Manipulation of Heat Shock Proteins as the Next Big Thing

The biotechnology that spirals out from the study of calorie restriction and metabolic determinants of longevity is growing in breadth. Sirtuins and companies like Sirtris are (unfairly or not) yesterday's news already - the big deals are done, and now it's down to the very unromantic grind of pushing an incrementally better drug for an age-related disease through the horror show that is FDA approval. Beyond sirtuins lie investigations of autophagy, of fat metabolism, and of course the heat shock proteins (HSPs), amongst other items. Looking ahead, I think there's a fair case to be made for the next Sirtris to be a company in the business of manipulating heat shock proteins, aiming to extend life and add healthy years - at least at the outset.

Heat shock proteins are molecular chaperones, and their activities in the body are boosted by exercise and calorie restriction, two line items known to extend healthy life in laboratory animals and produce impressive health benefits in humans. Put simply:

Molecular chaperones detect proteins that are misfolded, and have the ability to refold those proteins into the appropriate, non-toxic shape. Additionally, if the protein is so badly misfolded that it cannot be repaired, the molecular chaperones can also recruit other proteins that have the ability to "tag" the toxic protein for destruction by the cell. This tag, called ubiquitin, directs the misfolded protein to a cellular apparatus known as the proteasome, whose function is to degrade the toxic protein into its constituent amino acids for recycling.

Damaged proteins and damaged cellular components are themselves a source of further damage, as they cause the cell's machinery to run awry - and aging itself is nothing more than the accumulation of damage and its side-effects. The goal of a number of groups working on heat shock proteins is, ultimately, to slow down the progression of aging by boosting the beneficial activities of these and other chaperones. The FDA, however, does not consider aging a medical condition, and thus will not approve any therapy aimed at slowing the pace of aging - so the profit-making research and development of potential first generation longevity therapies is all sidelined into providing some small benefit in the late stages of age-related diseases.

The present hope for advocates such as myself is that the fundamental research performed prior to this inevitable sidelining is still useful, still available to the broader scientific community, and still advances the state of the art - and that it will be picked up for later development in regions where appointed and largely unaccountable officials don't threaten to throw people into jail for developing and marketing longevity medicine. But I digress.

One of the companies presently working on manipulation of molecular chaperones is CytRx. Via one of their recent releases, I was directed to this presently open access paper:

The transcription factor HSF1 initiates the prolific induction of HSP when cells are exposed to protein damage. HSPs are molecular chaperones that protect the proteome by folding denatured polypeptides and promoting the degradation of severely damaged proteins. Activation of HSF1 is coupled functionally to fundamental pathways of longevity and orchestrates the evasion of aging through HSP induction and antagonism of protein aggregation. In addition to mediating protein quality control, some HSPs such as Hsp27 and Hsp70 directly protect cells against damage-induced entry into death pathways.

However, the heat shock response declines in potency over the lifetime, and enfeeblement of the response contributes to aging by permitting the emergence of protein aggregation diseases, reduction in cellular vigor and decreased longevity. ... Molecular chaperones play an important role in the deterrence of protein damage during aging and their expression is required for longevity. Chemical stimulation of HSP synthesis might therefore be a significant strategy in future design of antiaging pharmaceuticals.

On this subject, you might recall the work of Cuervo on restoring function to aging tissue by restoring the process of chaperone-mediated autophagy to youthful levels.

Dr. Cuervo found that the chaperone surveillance system, in particular, becomes less efficient as cells become older, resulting in a buildup of undigested proteins within the cells. She also detected the primary cause for this age-related decline: a fall-off in the number of lysosomal receptors capable of binding chaperones and their damaged proteins. Could replenishing lost receptors in older animals maintain the efficiency of this protein-removal system throughout an animal's lifespan and, perhaps, maintain the function of the animal's cells and organs as well?

Which it did, to deserved acclaim. That researcher makes the point again in a recent review paper:

This review discusses chaperone-mediated autophagy (CMA), a type of autophagy set apart from other autophagic pathways owing to its selectivity and distinctive mechanism by which substrates reach the lysosomal lumen. CMA participates in quality control and provides energy to cells under persistently poor nutritional conditions. Alterations in CMA have recently been shown to underlie some severe human disorders for which the decline with age in the activity of this pathway might become a major aggravating factor. Prevention of the age-dependent decline in CMA has major beneficial effects on cellular and organ homeostasis and function, revealing that CMA is an essential component of the anti-aging fight.

This sort of thing seems to be where the field of metabolic manipulation is headed next.

ResearchBlogging.orgCalderwood, S., Murshid, A., & Prince, T. (2009). The Shock of Aging: Molecular Chaperones and the Heat Shock Response in Longevity and Aging – A Mini-Review Gerontology, 55 (5), 550-558 DOI: 10.1159/000225957

TEDMED Day 2 Coverage

From MedGadget: "Also before lunch was the science of aging pair up with Aubrey de Grey, CSO of the SENS Foundation, and David Sinclair, professor at Harvard Medical School. If you've not heard of these gentlemen before, both view aging as a disease but both are approaching aging in very different ways. Aubrey spoke first and has a more futuristic view of aging. His mantra is that aging is metabolism caused cellular damage that leads to organism pathology, and the human body, just like cars, can be made to run longer with adequate maintenance and repair. He views age related problems as belonging to seven types and in order to tackle aging, all seven cellular and molecular problems need to be cured. Aubrey also coined the idea of a Longevity Escape Velocity (LEV), which is the point of life span where progress in aging science is occurring faster than the degradation of the body itself. He believes that if someone is able to live to 150 years old, then by that point the progress in the ability to keep them alive will be faster than their rate of death, thus they will live into their 1000s. Still focused on the same target, but shooting from a different angle was David Sinclair, who focuses his research on a set of proteins called sirtuins."

Link: http://www.medgadget.com/archives/2009/10/tedmed_2009_day_2.html

Prospects for Brain Regenerative Medicine

Will it be possible to use patient-derived cell transplants to heal the brain in much the same way as can be done with other organs? From EurekAlert!: researchers have "found that using an animal's own brain cells (autologous transplant) to replace degenerated neurons in select brain areas of donor primates with simulated but asymptomatic Parkinson's disease and previously in a motor cortex lesion model, provides a degree of brain protection and may be useful in repairing brain lesions and restoring function. ... We aimed at determining whether autografted cells derived from cortical gray matter, cultured for one month and re-implanted in the caudate nucleus of dopamine depleted primates, effectively survived and migrated. The autologous, re-implanted cells survived at an impressively high rate of 50 percent for four months post-implantation ... Researchers found that the cultured cells migrated, re-implanted into the right caudate nucleus, and migrated through the corpus callosum to the contralateral striatum. Most of the cells were found in the most dopamine depleted region of the caudate nucleus. This study replicated in primates the success the research team had previously reported using laboratory mice."

Link: http://www.eurekalert.org/pub_releases/2009-10/ctco-rfb102809.php

Why Advocacy For Longevity Science?

Why advocacy for longevity science? Why is it important for us to be building megaphones, educating people about the scientific foundation for extended healthy life, and persuading everyone we can to help? Put simply it is because this advocacy is a necessary part of the only reliable, proven path to establishing a research community capably of getting the job done.

One of the most active Immortality Institute activists, brokenportal, sent me the text below today, which I reproduce with his permission. The dedication is a reminder to the rest of us just what it takes to make things happen in this world of ours:

Will we reach the point of Longevity Escape Velocity, and thus live on in good health for centuries, sustained by ever more effective advances in longevity medicine? Many of us ask ourselves this question, unsure of how the research community is doing: who is working on what, and how fast or slow are they moving? We think that maybe "they" can get the job done in 25 years, maybe 45, maybe 75, 100, 1,000 ... we don't know.

Here is the good news for we who wonder: WE ARE "THEY". Progress occurs at the rate at which we collectively make it happen. We are the people who build the future, not some faceless and unknown "they": if we work harder, the future arrives more rapidly. If we slack off, the future drifts away into the distance. In these early years, in which persuasion is as valuable as lab work, every volunteer hour dedicated to helping advance medical technology is priceless. Who are the volunteers? Us. It is you and I that must contribute the time and make the difference. It is our contributions that snowball over time into the determination of whether we live or die: does longevity-enhancing medicine arrive within our lifetimes, or will we just miss the boat?

If you are reading this today, then you are already like a General woken in the midst of a battle field, with one eye, in the land of the blind. You know more than most, and you can see the possibilities of longevity science - the possibilities that will only be realised if we all work towards the goal of longer healthier lives. Who else but you will do what needs to be done to rouse and guide those who are yet blind? It is our duty to use the vision that we have to benefit the rest of the world. Those people depend on us, and the length of their lives depends upon us: they need us to bring this cause to them, open their eyes, and let them make the choice to help.

Bringing this cause to the world at large is as simple as spreading the word. We can all do that! All we have to do is inform people; as a community we longevity advocates have many projects, big and small, short and tall, for one and all. You can slide in wherever you fit in, into advocacy projects that are underway or in development.

The small things are the big things at this stage in this growing movement for indefinite life extension: every little difference made now will make big waves in the years ahead. Today is a crossroads and a dawn in the age of biotechnology - a unique time filled with extraordinary opportunities for anybody to make a difference in the longevity cause. Every action we take today will have results that add up and accelerate like the penny doubling effect. If you double a penny once a month for 35 months you end up with over a billion dollars, and the earlier you start, the sooner you have that money! So the point at which you help to make those first doublings happen is very important, even though it might not look like it while you can still hold the pennies in one hand.

When the cause of longevity science is worldwide and as discussed and supported as stem cell research is today, then your modest personal contributions won't mean as much - and you if you waited until then to help out, you would have missed the opportunity to act when you could have made the greatest different. Strike now while the anvil is hot and the day is young.

I would guess that we are looking at about a five year window here to get through to the world at large. If we all put in our two cents today then the concepts of longevity science could be discussed at every dinner table in 2014, and broadly looked upon as a good thing. Think about it: new sodas, new fads, the ins and outs of stem cell medicine, and many similar things have risen from obscurity to influence the public discussion across a five year period. We can definitely do the same for the concept of extending the healthy human life span!

My recommendation to everybody is to put aside your lesser pastimes for the next 5 years or so, and make a hobby out of helping the cause of longevity research and advocacy for longer healhy human lives. Help the grassroots cause grow by devoting your energy, resources, and time. What else could you possibly find to do that will have as great an eventual payoff than this? Where else could you work towards the goal of providing yourself and everyone you know with additional decades of healthy life?

Now is the time. Not next year, not waiting around to see what the guy next to you does. But now. You won't be sorry you stepped up to help, and in years to come you'll be able to say that you took part in the greatest cause on Earth - working to save more lives than any other project mankind has ever undertaken.

TEDMED Day 1 Coverage

From MedGadget: "we heard from a series of speakers involved with regenerative medicine. Daniel Kraft (flashback: MarrowMiner) spoke of the role of stem cells in medicine and how he discovered a better way to harvest them from the pelvis. Damien Bates, the chief medical officer of Organogenesis, the company behind biologic wound healing film Apligraf, passed around a sample of their wound healing tissue for people to feel as well as talked about how the skin heals and how it can be aided by regenerative biology. Anthony Atala, from the Wake Forest Institute for Regenerative Medicine, talked about the various methods his research center is using to grow specific tissues and organs. He described much of the tissue creation process as sort of building the layers of a cake, with each tissue type placed one on top of the other. For linearly organized organs, such as arteries, this isn't so much of a problem, because you can just grow layers upon layers of tissues. However, for the more complicated, highly solid organs with lots of blood vessels, this methodology breaks down, and the scientists have to either use some sort of pre-made matrix or need to harvest tissues from other sources and de-cellularize them, leaving behind only the collagen scaffold that can be populated by cells."

Link: http://www.medgadget.com/archives/2009/10/tedmed_2009_day_1.html

The Possible is not Necessarily the Desirable

From the IEET Blog, a look at plausible outcomes in advancing computational power and biotechnology - such as being able to emulate a human brain in software. I have no doubt that this will happen within the next few decades, but is it desirable? A human mind running on software could last as a pattern for as long as civilization persists, but unless deliberately engineered for continuity it would not survive as an individual in the way we presently understand that term. For example: we are quite used to moving data from hard drive to hard drive, restoring from backups when data becomes corrupt, and constantly shifting the running of software from machine to machine. Cost-effective human emulations would likely undergo exactly these sorts of events under the hood. If you are concerned with personal continuity, as I am, this would be an existential nightmare - you would exist as a flickering series of different people, each one killed by the normal operation of computing systems, and then the next picks up where the prior left off. Yet it will be quite possible to engineer an artificial brain in software and hardware that has continuity in the same way as we do presently: a collection of nanomachines, each machine playing the role of a single neuron, for example. That strategy is probably not cost-effective in comparison to running everything in software, however - and most people won't care about the existential issues so long as everything looks good from the outside.

Link: http://ieet.org/index.php/IEET/more/3476/

The Manhattan Beach Project Longevity Summit in November

Like the Maximum Life Foundation, which I commented on in a post here not so long ago, the Manhattan Beach Project is a wrapper for entrepreneur Dave Kekich's view of longevity science and advocacy for progress in enhancing the healthy human life span.

Our first scientific anti-aging conference was held in Manhattan Beach, California over nine years ago. This was no ordinary conference. Rather, it was a high-powered brainstorm session to figure out how to reverse aging. Twelve researchers from around the world combined their genius and their levels of expertise in their specific specialties, and they laid the groundwork for what eventually evolved into a scientific roadmap for full age reversal. Each scientist represented a separate discipline. Fields such as stem cells, genomics, nanotechnology, information technology and more were represented. You see, aging is extremely complex, and each scientist contributed a piece of the puzzle.

Just as the Manhattan Project was designed in 1942 to build the atomic bomb to end WW II, the Manhattan 'Beach' Project was founded at the original conference on June 23rd, 2000 as an all-out assault on the world’s biggest killer - Aging.

It has to be said that whenever I look at Kekich's work I am struck by a strong feeling of "personally, I wouldn't go about marketing it this way." The nuclear weapons program analogy there, for example, is extended to a "Nuke Aging" logo on the Manhattan Beach Project website. But what do I know about getting people to see things my way? The clearest sign of diversity in a cultural movement is exactly my reaction to the very characteristic Kekich approach. Diversity means that the range of attempted initiatives is (fortunately) not bound by the limits of any one subculture's imagination: very different attempts will be made to convince various demographics of the merits of longevity science, which should increase the chances of success in at least one initiative.

But onwards: a Longevity Summit under the Manhattan Beach Project umbrella is scheduled for what looks to be the end of November. The Summit agenda lists a mix of well known names from the longevity advocacy and aging research communities, speaking on a range of interesting topics:

I. Intro - David Kekich
II. The Law of Accelerating Returns - Ray Kurzweil via video
III. Caloric Restriction - Stephen Spindler
IV. Evolutionary Genomics of Life Extension - Michael Rose
V. Telomere Maintenance - William Andrews
VI. Aging Genes and Manipulation - Stephen Coles
VII. Restoring Your Immune Function - Derya Unutmaz
VIII. Extracellular Aging and Regeneration - John Furber
IX. Stem Cells/Regenerative Medicine - Michael West
X.Tissue/Organ Storage - Gregory Fahy
XI. SENS/Mitochondrial Rejuvenation - Aubrey de Grey (Two topics - 30 minutes)
XII. Artificial General Intelligence - Peter Voss
XIII. Nanomedicine - Robert Freitas/Ralph Merkle
XIV. Genome Reengineering - Robert Bradbury (Multiple topics - 35 minutes)
XV. 7 Steps to Help Ensure Your Longevity - David Kekich
XVI. Cryonics - Ralph Merkle

A number of transhumanist community favorites are in the list, as you can see. The topic list more or less covers the range of plausible near future research and development paths: the directions in which, ideally, the research community will spend the next few decades moving at speed. A lot of persuasion and fundraising lies between where we stand here and now and getting that process underway, however.

An Examination of the Longevity Trend

The trend in human longevity is upward, but how much of that is due to unintended slowing of the aging process via general advances in medicine and better treatment of the diseases of aging? A paper: "The distinction between senescent and non-senescent mortality proves to be very valuable for describing and analysing age patterns of death rates. Unfortunately, standard methods for estimating these mortality components are lacking. The first part of this paper discusses alternative methods for estimating background and senescent mortality among adults and proposes a simple approach based on death rates by causes of death. The second part examines trends in senescent life expectancy (i.e., the life expectancy implied by senescent mortality) and compares them with trends in conventional longevity indicators between 1960 and 2000 in a group of 17 developed countries with low mortality. Senescent life expectancy for females rises at an average rate of 1.54 years per decade between 1960 and 2000 in these countries. The shape of the distribution of senescent deaths by age remains relatively invariant while the entire distribution shifts over time to higher ages as longevity rises."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19851933

Mechanisms of Naked Mole Rat Cancer Immunity

This seems potentially important: "Despite a 30-year lifespan that gives ample time for cells to grow cancerous, a small rodent species called a naked mole rat has never been found with tumors of any kind - and now [biologists] think they know why. ... 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 ... Like many animals, including humans, the mole rats have a gene called p27 that prevents cellular overcrowding, but the mole rats use another, earlier defense in gene p16. Cancer cells tend to find ways around p27, but mole rats have a double barrier that a cell must overcome before it can grow uncontrollably. ... It's very early to speculate about the implications, but if the effect of p16 can be simulated in humans we might have a way to halt cancer before it starts. ... We haven't come across this anticancer mechanism before because it doesn't exist in the two species most often used for cancer research: mice and humans. Mice are short-lived and humans are large-bodied. But this mechanism appears to exist only in small, long-lived animals."

Link: http://www.eurekalert.org/pub_releases/2009-10/uor-sdg102609.php

On Presenting the Case For Longevity Science

Opinions from a bioethicist on how researchers should present the case for longevity science in order to maximize fundraising and public support: "The medical sciences are currently dominated by the 'disease-model' approach to health extension, an approach that prioritizes the study of pathological mechanisms with the goal of discovering treatment modalities for specific diseases. This approach has marginalized research on the aging process itself, research that could lead to an intervention that retards aging, thus conferring health dividends that would far exceed what could be expected by eliminating any specific disease of aging. This paper offers a diagnosis of how this sub-optimal approach to health extension arose and some general prescriptions concerning how progress could be made in terms of adopting a more rational approach to health extension. Drawing on empirical findings from psychology and economics, 'prospect theory' is applied to the challenges of 'framing' the inborn aging process given the cognitive capacities of real (rather than rational) decision-makers under conditions of risk and uncertainty. Prospect theory reveals that preferences are in fact dependent on whether particular outcomes of a choice are regarded as 'a loss' or 'a gain', relative to a reference point (or 'aspiration level for survival'). And this has significant consequences for the way biogerontologists ought to characterise the central aspirations of the field (i.e. to prevent disease versus extend lifespan)." Personally, I'm more in favor of entirely the opposite approach - don't adapt your argument to the suboptimal cultural environment, but rather work to change that cultural environment.

Link: http://colinfarrelly.blogspot.com/2009/10/biogerontology-paper-on-framing-inborn.html

Folding@home With the Immortality Institute and Longevity Meme Team

Competition makes the world go round, and competition is what drives the continuing success of the Folding@home (or F@h) distributed computing project, as well as other similar initiatives such as Rosetta@home. Few people are naturally given to rush towards charitable giving - even when it costs them next to nothing - but how the crowds flock to donate when giving things away is presented as a contest! The F@h project uses spare processing cycles donated from volunteers' home computers to solve tough problems in protein folding, one small block of calculations at a time. These are computational simulations that would tie up a supercomputer for a very long time, and at an unfeasibly high cost, but the millions of volunteers and their spare processing cycles constitute a supercomputer in a class of its own.

With leaderboards and public ranking in place, and essentially no barrier to joining in and competing, teams and rivalries quickly formed in the early days of the F@h project. In the years since launch, an entire cottage industry has sprung up to record, inspire, and serve the community that competes to see how much processing power can be donated to this cause. Competition makes the world go round. Never forget that.

Why is protein folding important? A better understanding of how proteins fold can lead to progress in a wide range of diseases, and back in the day I started up the Longevity Meme F@h team because neurodegenerative diseases of aging, such as Alzheimer's disease (AD), were high on the F@h organizers' priority list:

AD is caused by the aggregation of relatively small (42 amino acid) proteins, called Abeta peptides. These proteins form aggregates which even in small clumps appear to be toxic to neurons and cause neuronal cell death involved in Alzheimer's Disease and the horrible neurodegenerative consequences.

We have many calculations being performed on AD. Our primary goals are the prediction of AD aggregate structure for rational drug design approaches as well as further insight into how AD aggregates form kinetically (hopefully paving the way for a method to stop the AD aggregate formation).

The Longevity Meme F@h team might have remained a small affair of a few dozen folk, just like thousands of other teams - certainly I had no world-spanning ambitions for it at that point. But a few persistent and highly effective organizers from the Immortality Institute took it upon themselves to grow the team relentlessly; in the years of their involvement, they have made a real success of this contest:

Since the humble days back in June of 2005 when Jeffery Festa suggested that life extension advocates pool their collective computing muscle and fold for The Longevity Meme team (TLM, #32641), few other folding teams have shown such persistent improvement and high level of participtation. Four years ago TLM was at rank 617 in the world, had 55 members, and was averaging 2,500 points per day (PPD). At its height in early 2009 TLM had nearly 100 contributors per day (over 400 total members), cranked out a bit over 300,000 PPD, and rose to rank 70! The team routinely had 25% of members folding on any particular day, much higher than the 10% or less of most teams. To this day TLM continues forging ahead.

The team was helped along, in part, by the establishment of the F@H Prize in early 2008. Visionaries such as Reason, The Immortality Institute, Life Extension Foundation, and Maciek Kolodziejczyk helped establish and fund the Prize. Special recognition must go out to Imminst member DNAmechanic for detailed record-keeping throughout the years and to all the Imminst volunteers who helped folders get started and set them folding to the maximum extent possible. Folding@home is a long-term project of basic science (protein folding) that requires contributions small and large from millions of volunteers. The eventual pay-off will be a greater understanding of human biology and the processes that lead to human diseases and attendant suffering. Everyone who folds should be proud of their individual and team efforts. Keep folding for the future!

That the Longevity Meme F@h team today consists of hundreds of members and is ranked 70th in the world is entirely to the Immortality Institute volunteers' credit. If renaming of teams was permitted, I would have long ago changed the name to reflect the source of its success.

What are you waiting for? Get folding!

A Look at the State of Tissue Scaffolding

Progress continues in the development of biochemically active scaffolding to sculpt and guide tissue regeneration: here, ScienceDaily looks at a scaffold "made from soluble fibers, which may help humans replace lost or missing bone. With more research, [it] could also serve as the basic technology for regenerating other types of human tissues, including muscle, arteries, and skin. ... The bioactive agents that spur bone and tissue to regenerate are available to us. The problem is that no technology has been able to effectively deliver them to the tissue surrounding that missing bone. [This] artificial and flexible scaffolding connects tissues together as it releases growth-stimulating drugs to the place where new bone or tissue is needed - like the scaffolding that surrounds an existing building when additions to that building are made. ... The [scaffold material] could be used to restore missing bone in a limb lost in an accident, or repair receded jawbones necessary to secure dental implants ... The scaffold can be shaped so the bone will grow into the proper form. After a period of time, the fibers can be programmed to dissolve, leaving no trace."

Link: http://www.sciencedaily.com/releases/2009/10/091019122844.htm

The Doom that Fell Upon Medical Progress in the US

Competition is only thing that keeps human beings striving for improvement: businessmen striving to please their customers, funds flowing to research and development. The fear of your lunch eaten by the competition and your customers deserting you is what drives people onward to build better products, and what leads to good customer service. In a competitive market, everyone operates in a constant state of anticipating the next improvement - and investors, researchers, and business owners toil to try to ensure that they themselves are the ones offering that improvement.

This is true in every market, be it shoes, computers, or medical technology. The shoe marketplace is free, cutthroat, and churning with innovation, for example - the arms race of earnest competition provides wide choice and good prices for customers. The market for medical technology is, sadly, a very different story. This is a critical time in the evolution of biotechnology and medical science. Enormous advances are possible in the years ahead, including significant extension of the healthy human life span, yet this marketplace is not open and competitive. Everywhere is the hand of government, suppressing competition, forbidding all that is not expressly permitted, and dragging the potential for progress down into the gutter.

A recent Ludwig von Mises Institute daily article consisely and clearly explains some of the more important aspects of the way in which governmental power is dooming the prospects for rapid progress in applied biotechnology. Research and development is a long connected chain of ventures, stretching from the lab to the clinic. If any part of that chain is oppressed, or has costs imposed upon it, then all the links suffer:

The problems of the American healthcare system are caused entirely by the fact that the government subjects the system to massive interventions ... by the early 1990s only about 10% of all American hospitals were private, for-profit enterprises. Socialism characterizes at least 90% of all hospitals.

...

The effect of this vast government takeover of the hospital industry, Friedman documented, is what any student of the economics of bureaucracy should expect: the more that is spent on hospital care, the worse the quality and quantity of care become, thanks to the effects of governmental bureaucratization. According to Friedman, as governments took over an ever-larger share of the hospital industry (being exempt from antitrust laws), hospital personnel per occupied hospital bed quintupled, as cost per bed rose tenfold.

...

Friedman also once suggested a syllogism to explain the bizarre spectacle on display today of responding to problems caused by healthcare socialism with even more healthcare socialism.

The syllogism goes as follows:

1. Socialism has been a failure everywhere it has been tried;
2. Everyone knows this; and
3. Therefore, we need more socialism.

...

Physicians have long enjoyed a degree of monopoly power derived from state legislatures that delegate to the American Medical Association (the doctors' union) the "right" to limit entry into medical schools through accreditation. Only graduates of accredited (by the AMA) medical schools are licensed to practice medicine. The AMA has used these state-granted privileges to limit both the number of medical schools and the number of medical-school graduates. The reduced supply of doctors drives up the price of medical care and the income of AMA members. Hundreds of other health professions limit entry with the help of occupational licensing regulation, the primary effect of which is to create monopoly profits, not to ensure quality of care.

...

Government regulation of pharmaceuticals and medical devices, primarily by the Food and Drug Administration (FDA), increases healthcare costs, denies the benefits of myriad helpful drugs and devices, and creates monopoly power. ... FDA bureaucrats are extremely risk averse: On the one hand, it costs them nothing personally to delay a life-saving drug for years, if not decades, by demanding test after test. On the other hand, if they permit a drug to enter the marketplace that turns out to be dangerous, it is a public-relations disaster for the agency, which it does not want to be associated with. Consequently, the entrance of new drugs and medical devices onto the market is often delayed by years, costing many lives and inflicting much needless pain on those already suffering, while driving up prices.

The damage done to the rate of progress in applied biotechnology is enormous - we look at what is going on in the labs under present circumstances and are impressed by progress. What we don't see is what might have been in the absence of overwhelming regulation and FDA roadblocks. If there is little or no prospect for profit at the end of the day, vast swathes of privately funded research simply don't take place. If competition is suppressed, then bad products, poor customer service, and little effort put towards improvement become the order of the day.

Think of the damage done to our prospects for longer, healthier lives; this too is considerable. I think we all see the direction the wind is blowing these days - towards worse rather than better. More controls, more regulation, less freedom, less competition, less progress. I suspect that the future of medicine will be based upon what can be salvaged - in terms of knowledge and infrastructure - from today's Western research communities and carried away to less restrictive regions for commercial development.

The Study of Centenarians and Supercentenarians

A look at some scientific studies of the present bounds of human longevity from Courant: "It's becoming clear that people who break through the 90-plus barrier represent a physical elite, markedly different from the elderly who typically die younger than them. Far from gaining a longer burden of disability, their extra years are often healthy ones. They have a remarkable ability to live through, delay or entirely escape a host of diseases that kill off most of their peers. Supercentenarians - people aged 110 or over - are even better examples of aging gracefully. ... As a demographic group, they basically didn't exist in the 1970s or '80s. They have some sort of genetic booster rocket and they seem to be functioning better for longer periods of time than centenarians. ... The average supercentenarian had freely gone about their daily life until the age of 105 or so, some five to 10 years longer even than centenarians, who are themselves the physical equivalent of people eight to 10 years their junior. This isn't just good news for the oldest old and for society in general; it also provides clues about how more of us might achieve a long and healthy old age."

Link: http://www.courant.com/health/sns-200910201351tmspremhnstr--k-h20091021oct21,0,4810521,full.story

Gregory Benford on Genescient

Here is a Google Tech Talk video of Gregory Benford discussing his latest venture, Genescient, which seems to be close to commercializing its first results: "Genescient is the world's first computational biology company founded on the use of artificial biological selection to cure the diseases of aging. Our laboratory animals have been selected for longevity through 750 generations for the equivalent of 15,000 human years. I will describe Genescient's multiple pathways toward accelerating human longevity, with parallel enhancements of vigor and function. Genescient applies 21st century genomic technology to identify, screen and develop benign therapeutic substances at precise doses, to defeat the diseases of aging. Our singular approach addresses the complex genomic networks that underlie aging and aging-associated diseases such as cardiovascular disease, Type II diabetes and neurodegenerative diseases. I shall display some results and our first product, due in 2009."

Link: http://www.youtube.com/watch?v=IuLV01iBSuc

Wars are Fought Over a Few Percentage Points of GNP

GNP is Gross National Product, more or less the sum value of all services and products produced in a year by the inhabitants of a given nation. The value is staggeringly large for the US, somewhere north of $11 trillion. Many wars and worse upheavals have been instigated by politicians - and supported by a populace - in reaction to or anticipation of change of a few percentage points of GNP. All the more reason to dislike forms of society and culture that result in this sort of thing, if you ask me, but I digress.

Let's look at costs for a moment. I'm sure you're all familiar with the cost of death by aging. The value of an aged human life is around $2 million, and something like 2.5 million US citizens die annually, most from the conditions of old age - which amounts to $5 trillion dollars in resources destroyed by aging each and every year.

But what about the physical effects of aging upon those still alive? Suffering from age-related diseases or frailty imposes costs, both in resources consumed and in opportunities to create wealth missed. Here is a recent open access paper looking at the cost of osteoarthritis, for example:

Osteoarthritis (OA) is a degenerative joint disease characterized by joint pain and dysfunction caused by a progressive and irreversible loss of articular cartilage. OA is the most common form of arthritis, affecting nearly 27 million Americans or 12.1% of the adult population of the United States

...

A 1997 analysis of the economic costs of musculoskeletal disorders in 5 industrialized countries (Australia, Canada, France, United Kingdom, and United States), in which OA was the most common of these disorders, found a rising trend of costs that had, by then, reached between 1% and 2.5% of the gross national product of these countries.

As I noted above, politicians and the societies that support them have inflicted great geopolitical upheavals upon themselves and their neighbors in - often useless - efforts to avert costs of this magnitude in connection to metals, oil, and economic slumps. Yet you don't see this sort of fiery urgency and upheaval happen all that often in medicine. Medical progress and costs of present disease simply fail to ignite the same intensity of interest and support as war, commodity markets, and nationalism.

This is interesting, and something to be understood regardless of your personal position on whether government interventions are to be welcomed or feared. Is talking about cost in connection with aging actually useful for advocates of longevity science and healthy life extension? Does it garner support, or does it strangely fail where other cost-based arguments in other fields of human endeavor work well?

ResearchBlogging.orgBitton R (2009). The economic burden of osteoarthritis. The American journal of managed care, 15 (8 Suppl) PMID: 19817509

Another View of Suboptimal Healing

Human biochemistry isn't as well set up for regeneration as it might be, particularly in the case of nerve damage. But medical technology will one day change all that: "The inflammatory response following a spinal cord injury appears to be set up to cause extra tissue damage instead of promoting healing ... The injury opens tissue to the external environment, increasing the potential to be exposed to pathogens. The immune system doesn't care that the spinal cord is damaged - it just wants to keep the organism alive. And neurons want to regrow, but when they try to grow their axons, they hit a wall of inflammatory cells that they can't get past or that are working against them. ... All of the responding cells in question are macrophages, but the study revealed that they have slightly different characteristics that define their functions. The research suggests that changing the balance of how these cells are activated in favor of the anti-inflammatory macrophages could be a potential treatment strategy. ... if we could minimize damage caused by inflammation, that would be helpful. Each axon that dies gets you closer to a threshold where you lose function. If we could just keep axons and neurons alive, we may have a better chance at promoting recovery."

Link: http://www.sciencedaily.com/releases/2009/10/091021133858.htm

Towards Radiation-Resistant Humans

Evolved human biochemistry is suboptimal in some intriguing ways - we don't heal as well as some other species, for example. Here, EurekAlert! notes that our biochemistry is not as radiation-resistant as it might be either: "More than half of all cancer patients are treated at least in part with radiation ... But the same radiation that kills cancer cells can also destroy healthy ones, causing side effects such as nausea and vomiting, skin sores and rashes, and weakness and fatigue. Long-term radiation exposure can lead to the scarring and death of normal tissue. [Researchers] have identified a biochemical signaling pathway that can profoundly influence what happens to both cancerous and healthy cells when they are exposed to radiation. In mouse experiments, they found that blocking a molecule called thrombospondin-1 from binding to its cell surface receptor, called CD47, affords normal tissues nearly complete protection from both standard and very high doses of radiation. ... We almost couldn't believe what we were seeing. This dramatic protective effect occurred in skin, muscle and bone marrow cells, which is very encouraging. Cells that might have died of radiation exposure remained viable and functional when pre-treated with agents that interfere with the thrombospondin-1/CD47 pathway." Given enough time, many beneficial changes to human biochemistry will be possible and affordable.

Link: http://www.eurekalert.org/pub_releases/2009-10/uops-ptf101609.php

Parkinson's Disease and the Way Exercise Slows Degeneration

Moderate regular exercise has been shown to slow many of the degenerations of aging. Like calorie restriction, exercise exerts hormetic effects on the biochemistry of mammals, wherein low levels of stress boost repair and maintenance mechanisms, which in turn leads to improved health over time. Interestingly, exercise appears to slow down the accumulation of mitochondrial damage in at least some tissues, and regular readers will know that mitochondria play a pivotal role in age-related degeneration:

Aging is associated with a reduction in muscle mass and strength, which compromises functional independence. Skeletal muscle also shows an increase in mitochondrial dysfunction and oxidative stress in older adults. ... It has been shown that resistance-exercise training increases muscle strength and function in older adults, in association with a reduction in markers of oxidative stress and an improvement in mitochondrial function.

If you look back a few years, you'll find tentative evidence that the benefits of exercise extend to slowing the advance of Parkinson's disease. This is probably a mitochondrial connection, as progressive mitochondrial dysfunction is implicated in some fraction of Parkinson's cases. Some unfortunate folk have genes that make this sort of dysfunction - and the resulting loss of vital neurons that leads to the visible symptoms of Parkinson's disease - more likely to occur earlier in life. They are less resistant to this form of biochemical wear and tear, in other words.

Here's a short article on recent research adding more weight to the exercise-mitochondria-Parkinson's connection:

"Clinical reports have implicated exercise training in improving the physical performance and mobility of people with Parkinson's disease, but no one has demonstrated, either clinically or in laboratory models, whether exercise can delay the progression of neuronal degeneration," says senior author Yuen-Sum Lau at the Univ. of Houston. "This study was aimed at investigating this possibility and at examining how exercise protects neural mitochondria."

...

At the end of the study, the exercise-trained Parkinson's mice had significantly higher brain dopamine content and exhibited greater brain mitochondrial activity than the sedentary mice. They also performed better in a test that assessed their balancing abilities.

"This research provides scientific evidence that long-term endurance exercise protects brain mitochondria and dopamine-producing neurons from undergoing progressive degeneration as demonstrated in the chronic mice model of Parkinson's disease," says Lau.

A thought to finish with: investors are presently pouring billions into research intended to capture some fraction of the benefits of exercise or calorie restriction in a pill. You'd probably pay good money for the results of that research, given that the benefits over time are far greater than any presently existing therapy targeted at common age-related diseases. So why aren't you out there getting these benefits for free, the old-fashioned way?

A Master Mechanism for Regeneration?

Researchers continue to uncover the biochemistry of regeneration: "Biologists long have marveled at the ability of some animals to re-grow lost body parts. Newts, for example, can lose a leg and grow a new one identical to the original. Zebrafish can re-grow fins. These animals and others also can repair damaged heart tissue and injured structures in the eye. In contrast, humans have only rudimentary regenerative abilities, so scientists hoping eventually to develop ways of repairing or replacing damaged body parts are keenly interested in understanding in detail how the process of regeneration works. Using zebrafish as a model, researchers [have] found that some of the same genes underlie the process in different types of tissues. Genes involved in fin regeneration and heart repair are also required for rebuilding damaged light receptors in the eye, they found, suggesting that a common molecular mechanism guides the process, no matter what body part is damaged." A common mechanism, if confirmed, would mean that the task of introducing this sort of regenerative capacity into humans will be simpler than thought.

Link: http://www.eurekalert.org/pub_releases/2009-10/uom-amm101909.php

The Prospects for Memory Enhancement

Via EurekAlert!: "Over-expressing a gene that lets brain cells communicate just a fraction of a second longer makes a smarter rat ... Dubbed Hobbie-J after a smart rat that stars in a Chinese cartoon book, the transgenic rat was able to remember novel objects, such as a toy she played with, three times longer than the average Long Evans female rat, which is considered the smartest rat strain. ... This adds to the notion that NR2B is a universal switch for memory formation ... The finding also further validates NR2B as a drug target for improving memory in healthy individuals as well as those struggling with Alzheimer's or mild dementia ... NR2B is a subunit of NMBA receptors, which are like small pores on brain cells that let in electrically-charged ions that increase the activity and communication of neurons. Dr. Tsien refers to NR2B as the 'juvenile' form of the receptor because its levels decline after puberty and the adult counterpart, NR2A, becomes more prevalent. While the juvenile form keeps communication between brain cells open maybe just a hundred milliseconds longer, that's enough to significantly enhance learning and memory and why young people tend to do both better."

Link: http://www.eurekalert.org/pub_releases/2009-10/mcog-sr101909.php

Longevity Advocacy at TEDMED 2009 and BIL PIL

TEDMED 2009 and the BIL:PIL unconference will be held at the end of this month in San Diego, California:

The fifth in a series created by Marc Hodosh and Richard Saul Wurman, TEDMED celebrates conversations that demonstrate the intersection and connections between all things medical and healthcare related: from personal health to public health, devices to design and Hollywood to the hospital.

...

The BIL:PIL 2009 Healthcare Innovation Conference will bring together over 200 entrepreneurs, health professionals, technologists, and laypeople to describe the future of healthcare. BIL:PIL will be held in the unconference format. For those unfamiliar, unconferences are free of charge, with no sponsored presentations, and the proceedings are open to all who wish to present. To ensure that the agenda is not dominated by any one interest, and to help with scheduling and room placement, registered attendees will vote online for the talks that they most wish to hear. Our goal is to make sure that every speaker is heard.

If you're in the area, you should definitely take time to drop in on BIL:PIL. I notice that folk from the LifeStar Institute will be attending both events, and biomedical gerontologist Aubrey de Grey is presenting:

He has developed a possibly comprehensive plan for such repair, termed Strategies for Engineered Negligible Senescence (SENS), which breaks the aging problem down into seven major classes of damage and identifies detailed approaches to addressing each one. A key aspect of SENS is that it can potentially extend healthy lifespan without limit, even though these repair processes will probably never be perfect, as the repair only needs to approach perfection rapidly enough to keep the overall level of damage below pathogenic levels. Dr. de Grey has termed this required rate of improvement of repair therapies 'longevity escape velocity.'

You'll find a few other interesting speakers in the TEDMED lineup, such as David Sinclair of Sirtris and Anthony Atala, the tissue engineer, who is giving a presentation entitled "Can we grow organs instead of transplanting them?"

In addition to the speakers, these conferences are a great place to network with potential movers and shakers of the next generation of the aging research community - such as the LifeStar Institute group mentioned above. Foundations are being laid and opinions shaped, spurred on by tangible progress in longevity science in the laboratory.

Newsflash: Death is Unpleasant

Matters connected with death - and a good portion of modern medical practice, such as major surgery - tend to be unpleasant and upsetting. For reasons evolutionary and cultural most people are repulsed by the details, preferring to pretend politely that such things don't exist. But if we are to make progress in branches of medicine such as cryonics, then we can't let natural repugnance hold back research and development: "Human beings are largely unaware about the gruesome nature of death. Humans also shy away from the mutilation that occurs during hospital surgery. Hollywood films portray cryonics in a glamorous high-tech manner that makes it appear that one's body can easily be placed into a capsule and frozen for future revival. Reality is that cryopreservation involves complex surgery whereby tubes are inserted into major arteries and veins in order to deliver special anti-freeze solutions into the brain. The purpose is to reduce or eliminate freezing damage and other types of damage to brain cells. The process involves introducing stabilizing drugs and a special solution in the field and a major procedure in an operating room. There's nothing pretty about human cryopreservation [or indeed any form of surgery], but as you'll read, the alternatives are truly ghastly. ... Most people are in denial about what will happen to their bodies when they die. They over react when they hear of someone's head being surgically and chemically treated to protect brain cell injury during cryo-preservation. Overlooked is that any other [course of action will result] in far more ghastly results for the victim of death."

Link: http://www.depressedmetabolism.com/2009/10/16/death-is-gruesome/

Suitably Framing the Future of Medicine

Now this is what we'd like to see more of in the press: there's nothing new in this BBC article insofar as science and technology goes, but the way it is presented is all in terms of lengthening health life and repairing the damage of aging. That is still fairly novel. When this way of looking at things becomes widespread, half the battle is won: "Half of babies now born in the UK will reach 100, thanks to higher living standards, but our bodies are wearing out at the same rate. To achieve '50 active years after 50', experts at Leeds University are spending £50m over five years looking at innovative solutions. They plan to provide pensioners with own-grown tissues and durable implants. New hips, knees and heart valves are the starting points, but eventually they envisage most of the body parts that flounder with age could be upgraded. ... The concept is to make transplantable tissues, and eventually organs, that the body can make its own, getting round the problem of rejection. So far they have managed to make fully functioning heart valves using the technique. ... experts elsewhere [are] also working on similar regenerative therapies, but grown entirely outside of the body, to ensure that people can continue being as active during their second half-century as they were in their first."

Link: http://news.bbc.co.uk/2/hi/health/8314442.stm

Attacking Cytomegalovirus With RNAi

Cytomegalovirus (CMV) is one of the herpesvirus group, viruses that are extremely hard or impossible for the body to clear. They lurk and return time after time. CMV doesn't cause immediate issues in healthy people, but over time it becomes one of the principle causes of the characteristic failure of the immune system with aging:

Your immune system is capped in its use of resources; it can only have a set number of T cells in operation at one time. ... chronic infections by the likes of cytomegalovirus (CMV) cause too many of your immune cells to be - uselessly - specialized. ... because you cannot clear it from your system, its presence chews up more and more of your limited immune resources with time.

Immune cells dedicated to remembering and attacking the many biochemical signatures of CMV are not available to fight new threats - and that starts to be a real issue in later life. Your immune system simply cannot mount an effective response when so much of it is tied up in uselessly awaiting the next emergence of CMV.

Many research groups are investigating ways to effectively destroy herpesviruses like CMV, and thus clear them from the body. As a strategy this might be compared to using metabolic manipulation to slow aging, insofar as (a) to have the best effect the methodology must be applied early in life, and (b) it's of little use to those already old. The damage is already done by the time you are old, and clearing out CMV doesn't do anything to free up the errantly specialized immune system resources.

A better strategy for reversing this immune system issue might be to use targeted cell destruction methods under development in the cancer research community to kill CMV-specialized immune cells and so free up space. There it doesn't matter that CMV is in your system, because the cull of specialized cells restores this aspect of your immune system to a more functional state. This type of treatment could then be repeated whenever necessary.

Like the mainstream of aging research, however, the bulk of work on CMV is focused on clearance (i.e. slowing the rate of damage) rather than immune system repair (i.e. restoration by removing damage). This is unfortunate, and yet another aspect of the most important debate over strategy in longevity science - do researchers continue to largely focus on slowing aging, or do they instead try to reverse and repair aging?

With that in mind, let me point out a recent paper on the use RNA interference to attack CMV by disabling its vital mechanisms - a strategy which you will notice is not all that different in complexity to the targeted cell destruction method mentioned above. Reversing aspects of aging and slowing aspects of aging will often enough require a similar level of resources to put into play, despite the fact that reversal is far more beneficial. This is why the choice of strategy is so important.

In order to develop a gene therapy to human cytomegalovirus (HCMV), RNA interference (RNAi) was employed to inhibit the expression of HCMV UL122 gene in vitro. ... it may be concluded that plasmids encoding siRNAs targeted to UL122 is able to in vitro reduce markedly the expression of [UL122].

Previous studies have shown that CMV without the UL122 gene is effectively disabled and cannot infect a host. This sort of work is very cutting edge, and it represents the beginning of the end for viruses as a threat to humanity. When medical technology and the research community can rapidly identify and disable lynchpin genes that are unlikely to rapidly evolve substitutes, then the common virus is pretty much out of luck.

This is all good news for those of us who intend a long and healthy life - the risk of death or serious illness due to pathogens will diminish greatly in the decades ahead. But for our generation, this sort of work is not the key to reversing the immune system damage we already suffer. We'll need a different approach there.

ResearchBlogging.orgDuan QJ, Tao R, Hu MF, & Shang SQ (2009). Efficient inhibition of human cytomegalovirus UL122 gene expression in cell by small interfering RNAs. Journal of basic microbiology PMID: 19810036

Aubrey de Grey's Big Think Videos

Aubrey de Grey's videos at Big Think made it onto the Independent's website recently: "At a certain point in time - perhaps sooner than most people think - the ever-increasing average human lifespan will begin accelerating faster than people age. This moment, according to anti-aging expert Aubrey de Grey, will be more important than the Singularity - when the human race achieves this 'longevity escape velocity,' we will essentially become immortal. And de Grey, who is in his mid-40s, argues that this moment has a 50/50 chance of occurring in time for him to live forever. Crazy talk? Maybe not - de Grey shared with Big Think some surprising aging research and explained why there are no more major breakthroughs necessary for us to defeat aging for good. He even provided a vision of how we might defeat cancer. De Grey's optimistic vision brings up some interesting questions; most importantly, wouldn't an ageless society present a logistical nightmare? Aubrey de Grey is confident that arguments about economic difficulties and overpopulation in an ageless society are unwarranted; he does, however, believe that society would change dramatically, but mostly for the better."

Link: http://www.independent.co.uk/life-style/health-and-families/features/big-think-is-the-human-life-span-accelerating-faster-than-people-age-1805536.html

Watching Stem Cell Infrastructure

Advances in infrastructure drive the pace of research: making tools better, cheaper, and faster means that established research groups can do more, and more new research groups can afford to enter the field. Here is some good news on that front: researchers have "developed a method that dramatically improves the efficiency of creating stem cells from human adult tissue ... The new technique, which uses three small drug-like chemicals, is 200 times more efficient and twice as fast as conventional methods for transforming adult human cells into stem cells (in this case called 'induced pluripotent stem cells' or 'iPS cells'). ... In developing the improved method, Ding drew on his knowledge of biology. He decided he would focus his efforts on manipulating a naturally occurring process in cells, in particular in a type of adult cell called fibroblasts, which give rise to connective tissue. This naturally occurring process - called MET (mesenchymal to ephithelial cell transition) - pushes fibroblasts closer to a stem-cell-like state. If he could manipulate such a fundamental process to encourage MET and the formation of stem cells, Ding reasoned, such a method would be both safer and more direct than hijacking other aspects of biology, for example those directly involved in cancer. ... the safety profile of the new method is highly promising. Not only is the method based on natural biological processes, [but] also the type of molecules used have all been tested in humans."

Link: http://www.sciencedaily.com/releases/2009/10/091018141615.htm

Russian Metabolic Manipulation Research in a Nutshell

The community of Russian researchers interested in engineered longevity bears many resemblances to the English-speaking longevity research community more familiar to you or I. You'll find ties to transhumanist pro-longevity advocacy groups and cryonics organizations, for example. Both communities have been largely working on metabolic manipulation to slow aging for the past ten years, and the older scientists have been involved in the field of aging research for decades - well back into the depths of the cold war, in fact.

These days - days in which a great deal of investment is flowing into metabolic manipulation research and development in the US - I am seeing more English language publications from the Russian longevity science community. Here, for example, is a review that aptly summarizes their efforts of the past decade:

The review comprises the results of author's long-term investigation in the mechanisms of aging and a role of peptide bioregulators in prevention of age-related pathology. A number of small peptides have been isolated from different organs and tissues and their analogues (di-, tri-, tetrapeptides) were synthesized from the amino acids. It was shown that long-term treatment with some peptide preparations increased mean life span by 20-40%, slow down the age-related changes in the biomarkers of aging and suppressed development of spontaneous and induced by chemical or radiation carcinogens tumorigenesis in rodents.

Its worth noting that one of the authors here, Vladimir Anisimov, shares space on the scientific advisory council of the Science Against Aging initiative with Vladimir Skulachev, whose work on extending life in mice I've discussed in the past, and with Aubrey de Grey, a figure you should all recognize by now.

Metabolism and longevity are easily changed though wide variety of methods, researchers have found - up to a point. It is interesting that diverse research communities chasing entirely different methods on different continents are extending the lives of mice by about the same amount. Why do so many metabolic manipulations discovered to date result in something near to a 30% life extension in mice? The outliers above this level are few - a couple of 50% methods and one 60-70% method, the latter of which produces mice unlikely to survive in the wild.

ResearchBlogging.orgAnisimov VN, & Khavinson VK (2009). Peptide bioregulation of aging: results and prospects. Biogerontology PMID: 19830585

More Engineered Heart Muscle

Another example of progress in tissue engineering from the Boston Globe: "researchers have created a strip of pulsing heart muscle from mouse embryonic stem cells, a step toward the eventual goal of growing replacement parts for hearts damaged by cardiovascular disease. ... I think over the last five years or so, we've made great progress in being able to guide stem cells into whatever cell type we want, in this case the heart ... For years, scientists have been able to turn embryonic stem cells into a variety of heart cells, producing dramatic videos of cells beating in a dish. In the new work, [biologists] first isolated a progenitor cell that would only give rise to ventricular muscle cells - the working muscle that drives blood around the body, and the tissue that is damaged during a heart attack. Then, collaborating with biomedical engineers, they seeded those cells on a thin film that had been engineered in such a way that it encouraged them to begin to form cardiac muscle." This doesn't seem quite as far along as some other groups, and it's still far behind what can be done with decellularization and a donor organ - but progess is underway.

Link: http://www.boston.com/news/local/massachusetts/articles/2009/10/16/harvard_team_grows_heart_muscle_from_mouse_stem_cells/

Natural Healing is not Optimal

If you look at research into the fundamental biological mechanisms of healing, you'll quickly see that we mammals are not optimally evolved. There are all sorts of changes and tweaks that may allow far greater regeneration in specific circumstances, such as nerve injury. Here is one example: "Scars can serve as double-edged swords in spinal cord injuries ... The scar forms a wall around the wound, preventing the injury from spreading, but [releases] molecules that keep severed nerve fibers from passing the damaged tissue, so they cannot connect with their original targets to restore motor and sensory function. ... [researchers have] identified where these potent molecules - called chondroitin sulfate proteoglycans (CSPGs) - bind to the surface of neurons, exposing a novel therapeutic target. ... This discovery suggests that we might be able to treat central nervous system injuries with a pill in the future ... It's hard to overcome CSPGs in the human body, but receptors may offer an easier target ... follow-up experiments in culture dishes on neurons missing the receptor - called PTP sigma - and studies in mice confirmed the connection. ... [researchers] observed unprecedented levels of growth in the neurons of injured mice missing the PTP sigma receptor. In fact, motor neurons sent extensions all the way through the scar and well beyond the wound."

Link: http://www.eurekalert.org/pub_releases/2009-10/hms-rip101209.php

The False Expectation of a Gentle Upward Slope

People generally expect the future to be much like the present, but with shinier toys. They expect their lives to look like the lives of their parents, albeit with those shinier toys, and are deeply skeptical of predictions of radical change. At one and the same time, these folk take for granted the radical change that has taken place across their lives to date, and that was neither forseen nor expected by their parents:

While going through old SF magazines, I found mention of Atlantic Richfield's ad campaign requesting vision statements from Americans of what life might be like in the Tricentennial [in 2076]. ARCO received some 60,000 responses and in 1977 published an 80-page booklet summarizing those visions. The SF reviewer stated that most of the visions listed therein would have seemed old-hat to SF fans in the 70s. As in 20 to 30 years out of date.

...

In short, [people predicted that] life would be like 1976 in 2076, only more so.

No hint of the telecommunications revolution that was already well underway in 1976. No hint of the things young men named Gates and Jobs were up to. Nor any discussion about what that then newfangled computer network, the Arpanet, might grow into.

Curiously enough, when discussing the idea of a Technological Singularity on most public discussion boards today, I find most participants wear the same blinders the American people did 1/3 of a century ago.

The present day US stands a world and a culture away from from the US of 40 years ago. It is a profoundly transformed society, capably employing the technologies that enabled that transformation - such as ubiquitous, next-to-free instant communication and mass publishing, or more low-cost computing power than most people seem to know what to do with.

Today the trajectory of biotechnology is arguably more obvious than the trajectory of computer hardware and software in 1976. It's in many ways more of the same: bigger and better hardware driving ever greater capabilities in an information-based field. Yet people expect the past gentle trends in life expectancy or the introduction of new medical therapies to continue much as they have. This is, on the face of it, ridiculous, but convincing folk that other futures are possible and plausible if they'd just pitch in and help remains an uphill battle.

Gene Therapy to Boost Dopamine in Parkinson's

A fairly cautious article here on current work to stimulate the production of dopamine in Parkinson's patients: "Macaque monkeys that received gene therapy for symptoms of Parkinson's disease saw a significant improvement in their motor function without the side effects associated with current standard therapy ... For the past 40 or so years, the treatment of choice for Parkinson's has been so-called dopamine replacement therapy, which uses drugs to increase dopamine levels in the brain. The approach helps, but because the infusion of dopamine takes place in fits and bursts, not continuously, people often develop involuntary movements. Scientists have thus been focused on finding ways to deliver dopamine to the brain more continuously. Simultaneous insertion of three genes allowed certain cells in the brain to take over production of the neurotransmitter dopamine. ... But even if this gene therapy approach were to someday produce good results in humans, it still would not solve many of the myriad other problems associated with Parkinson's. ... the gene therapy would be considered a treatment rather than a cure because it 'corrects only dopamine-related symptoms.' ... an early-phase clinical trial in humans is in progress. ... So far, six Parkinson's disease patients have been treated - no serious adverse events, encouraging results so far. [But] the study is not ended, so still no final results."

Link: http://news.yahoo.com/s/hsn/20091014/hl_hsn/genetherapyshowspromiseforparkinsons

Manipulating Microglia to Remove Amyloid

Via EurekAlert!: researchers have made "the unexpected finding that when the brain's immune cells (microglia) are activated by the interleukin-6 protein (IL-6), they actually remove plaques instead of causing them or making them worse. The research was performed in a model of Alzheimer's disease established in mice. ... [Researchers] initially set out to prove that the activation of microgila trigger inflammation, making the disease worse. Their hypothesis was that microglia would attempt to remove the plaques, but would be unable to do so, and in the process cause excessive inflammation. To the surprise of the researchers, when microglia were activated by IL-6, they cleared the plaques from the brains. ... researchers then set out to determine exactly how IL-6 worked to clear the plaques and discovered that the inflammation induced by IL-6 directed the microglia to express proteins that removed the plaques. This research suggests that manipulating the brain's own immune cells through inflammatory mediators could lead to new therapeutic approaches for the treatment of neurodegenerative diseases, particularly Alzheimer's disease."

Link: http://www.eurekalert.org/pub_releases/2009-10/foas-sra101509.php

Is Epigenetic Disarray a Cause of Aging?

Your DNA is a blueprint for the protein components of the machinery of your metabolism and structure as a living organism. Gene expression is the process by which a part of the DNA blueprint is interpreted into instructions to build a protein, and epigenetics is the study of ways in which things other than changes in DNA can cause changes in gene expression. The blueprint may be the blueprint, but the execution of that blueprint is a shifting and very complicated process.

Epigenetics, it has to be said, is an unfolding and early-stage field. It's poorly understood. People are still arguing over whether accumulated nuclear DNA damage is significant in human aging, so of course it should be taken as read that there are also debates over whether epigenetic changes are significant in aging. Yes, the blueprint is getting smudged, and yes, the interpretation of that blueprint looks like it's changing - but is that actually important in comparison to the other known forms of age-related biochemical damage?

Here's a review:

Of all the proposed causes of ageing, DNA damage remains a leading, though still debated theory. Unlike most other types of age-related cellular damage, which can hypothetically be reversed, mutations in DNA are permanent. Such errors result in the accumulation of changes to RNA and protein sequences with age, and are tightly linked to cellular senescence and overall organ dysfunction.

Over the past few years, an additional, more global role has emerged for the contribution of DNA damage and genomic instability to the ageing process. We, and others have found that DNA damage and the concomitant repair process can induce genome-wide epigenetic changes, which may promote a variety of age-related transcriptional and functional changes. Here, we discuss the link between DNA damage, chromatin alterations and ageing, an interplay that explains how seemingly random DNA damage could manifest in predictable phenotypic changes that define ageing, changes that may ultimately be reversible.

With the present speed of progress, I doubt we'll be left hanging on a resolution to this debate for decades, awaiting data. Data is abundant in the life sciences nowadays. See this recent publication, for example:

Although the human genome sequence faithfully lists (almost) every single DNA base of the roughly 3 billion bases that make up a human genome, it doesn't tell biologists much about how its function is regulated. Now, researchers at the Salk Institute provide the first detailed map of the human epigenome, the layer of genetic control beyond the regulation inherent in the sequence of the genes themselves.

...

Being able to create high resolutions maps of the human epigenome, Ecker's group will now begin to examine how it changes during normal development as well as examining a variety of disease states. "For the first time, we will be able to see the fine details of how DNA methylation changes in stem cells and other cells as they grow and develop into new cell types," he says. "We believe this knowledge will be extremely valuable for understanding diseases such as cancer and possibly even mental disorders. Right now we just don't know how the epigenome changes during the aging process or how the epigenome is impacted by our environment or diet."

What interesting times we live in. You might recall the circus of triumph that surrounded the Human Genome Project at the turn of the century, but less than ten years later, mapping large segments of the epigenome merits a minor press release and little notice. How fast things do move, thanks to the ferociously competitive market for computing power.

ResearchBlogging.orgSinclair DA, & Oberdoerffer P (2009). The ageing epigenome: damaged beyond repair? Ageing research reviews, 8 (3), 189-98 PMID: 19439199

A View of the Power of Prevention

Many diseases, such as cancer, are curable - or at least treatable - using today's technology if they can be detected in their very earliest stages. Therein lies the challenge, of course. Here, a glance at one initiative emblematic of present research and development efforts in this direction: Leroy Hood of the Institute for Systems Biology "has secured $30 million in venture capital for a startup that aims to detect cancer and neurodegenerative diseases like Alzheimer's in their earliest and most treatable stages. ... It will make it possible for doctors to diagnose diseases much earlier; it will open the door to more individually tailored therapies that will have much greater odds of success; and it will allow doctors to follow up with patients to see if treatments they prescribe are really working at the molecular level ... My view is that P4 medicine - predictive, preventive, personalized, and participatory - will emerge over the next five to 20 years, and this is the first step. This is going to be the platform in the initial days ... We are optimistic that systems biology will become a critical tool in the development of personalized medicine." You might recall that Hood has said he thinks an additional decade or two of healthy life is possible through use of this sort of technology platform.

Link: http://www.xconomy.com/seattle/2009/10/14/lee-hoods-new-company-snags-30m-to-spot-cancer-and-alzheimers-in-early-days/

Incentives to Repair the Aged Immune System

As immune therapies are developed further, researchers will be increasingly incentivized to find ways to repair and restore age-damaged immune systems to youthful effectiveness. Most work on immune therapy is aimed at cancer and other diseases of the old, after all: "Elderly cancer patients need a combination of treatments tailor-made to their specific needs to successfully combat the disease. The challenge is to boost their immune response to cancer vaccines, because like the rest of our organs, our immune system ages and gradually becomes less efficient as we get older. ... Aging of the immune system coincides with higher rates of cancer in the elderly. There is a wealth of research on the effects of harnessing the power of the body's own immune defences to recognize and destroy tumors (immunotherapy), yet very little of this work takes into account the effects of aging on the immune system. Older individuals do not respond to vaccine therapy as well as younger adults. ... The immune system of the elderly is very different from the young and it is difficult to extrapolate results obtained in the young, for use in the old. Our job in the next few years is to figure out how to robust the old immune system by understanding, at a molecular level, its intrinsic defects to properly stimulate antitumor responses. Only then can we successfully customize tumor vaccines to be effective for the treatment of tumors in the old."

Link: http://www.sciencedaily.com/releases/2009/10/091008113301.htm

Alternate Day Fasting Continues to Look Promising

Alternate day fasting, or intermittent fasting in general, is known to produce similar health and longevity benefits to the practice of calorie restriction. Intermittent fasting isn't as well researched as calorie restriction - by which I mean to say the evidence for health benefits is "only" very good rather than overwhelming, as in the case of calorie restriction. It's worth noting that there exist intriguing hints that the underlying biological mechanisms by which these benefits are conferred are different for these two strategies, despite the basic similarity: eating less while still obtaining all the necessary nutrients.

Over at the Longevity Meme I recently remarked upon a study showing improvement in heart function and overall health with age as a result of suppressing one gene involved in the calorie restriction response:

researchers compared aged mice with a functional p110alpha to aged mice with suppressed p110alpha and found that mice with the suppressed gene had: improved cardiac function; less fibrosis (fibrosis causes the heart to lose flexibility); fewer biological markers of aging; and a pattern of cardiac gene expression like that of younger mice.

By way of comparison, here is another study showing much the same result, but achieved through alternate day fasting rather than genetic engineering:

The free radical theory of aging is currently one of the most popular. In parallel, many studies have demonstrated the association of fibrosis and increased oxidative stress in the pathogenesis of some chronic human diseases, and fibrosis is often characteristic of aging tissues. One of the few interventions that effectively slows aging is calorie restriction and the protection against the age-associated increase of oxidative stress remains one of the foremost hypotheses to explain this action.

As an alternative to traditional calorie restriction, another dietary regimen, termed alternate-day fasting, has also been tested, whose anti-aging mechanisms have not been explored so much extensively. We thus studied the effects of alternate-day fasting, started at 2 months of age, on oxidative stress and fibrosis in the heart during aging. In the left ventricle of the heart of elderly (aged 24 months) versus young (aged 6 months) male rats we found a significant increase in oxidative stress paralleled by increased fibrosis. In parallel there was a significant increase in inflammatory cytokine levels and in NF-kB DNA binding activity with advancing age. Alternate-day fasting protected against all these age-related phenomena.

These data support the hypothesis that this kind of dietary restriction protects against age-related fibrosis, at least in part by reducing inflammation and oxidative damage, and this protection can thus be considered a factor in the prevention of age-related diseases with sclerotic evolution.

While researchers toil away with the goal of capturing some of the benefits of eating less in a drug, it's nice to know that you can be well ahead of the game if you so choose. Why not practice calorie restriction or intermittent fasting? It's not like there's a better game in town today for those of us who'd like to live long enough to see medical technologies capable of reversing aging rather than just slowing it down. You can alter your own metabolism through diet and exercise, and you can help to make the future of medicine arrive faster. If you're doing neither of those ... well, you'll only have yourself to blame for the years and health you miss out on.

ResearchBlogging.orgCastello L, Froio T, Maina M, Cavallini G, Biasi F, Leonarduzzi G, Donati A, Bergamini E, Poli G, & Chiarpotto E (2009). Alternate-day fasting protects the rat heart against the age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation. Free radical biology & medicine PMID: 19818847

2009 Humanity+ Summit in December

The humanity+ transhumanist advocacy group - the new face of the old World Transhumanist Association - will be holding their yearly meeting in December: "Humanity will be radically changed by technology in the (possibly quite near) future. We foresee the feasibility of redesigning the human condition, including such parameters as the inevitability of aging, limitations on human and artificial intellects, unchosen psychology, suffering, and our confinement to the planet earth. The possibilities are tremendously broad and exciting - and the H+ Summit will provide a venue to discuss them with like-minded individuals, and hear exciting, presentations by the leaders of the ongoing H+ r/evolution." There are many of the same speakers and topics on the program as for the recent Singularity Summit, so coverage of that event should give you a good idea as to what to expect. I see that open source medicine makes an appearance - the more of that the better. It's an important concept for the future of medical research; as the cost of biotechnology plummets, the field of those who can contribute meaningfully broadens, and if we're luckly we will see a research culture that looks a lot like - and is as productive as - today's vibrant open source software community.

Link: http://www.humanityplus.org/read/2009/10/2009-h-summit/

Gene Engineering a Longer Lasting Heart

Manipulating the insulin/IGF-1 signaling system is known to promote longevity in lower animals, and here is a demonstration of specific benefits to heart tissue: researchers "studied elderly mice genetically engineered to suppress the activity of one form of the PI3K gene, which is a part of the insulin/IGF-1signaling system that helps regulate the lifespan of cells. A variation of PI3K, known as the p110alpha isoform, plays an important role in tissue aging. Suppressing the isoform's activity in the roundworm C. elegans extends its life. And in fruit flies, suppression prevents the age-dependent decline of heart function. ... researchers compared aged mice with a functional p110alpha to aged mice with suppressed p110alpha and found that mice with the suppressed gene had: improved cardiac function; less fibrosis (fibrosis causes the heart to lose flexibility); fewer biological markers of aging; and a pattern of cardiac gene expression like that of younger mice. ... This study showed that aging of the heart can be prevented by modifying the function of insulin and paves the way to preventing age-associated susceptibility to heart failure."

Link: http://americanheart.mediaroom.com/index.php?s=43&item=839

The Prospects for Liver Tissue Created on Demand

It is interesting that heart and bladder tissue engineering have been consistently ahead of work on liver tissue these past years, because the liver is the vital organ most capable of regeneration in humans - as much as three quarters of a lost liver can grow back. In theory, then, the additional effort needed to spur full liver regrowth is less than for other internal organs. From a position of knowledge a decade ago, one might have wagered money on progress in liver tissue engineering leading the pack - but that was not to be.

The advent of induced pluripotency is in the process of leveling the tissue engineering playing field, however. In the past year research groups have demonstrated the creation of all sorts of tissue through genetic reprogramming of commonly available cells. The latest in line are liver cells, and the natural regenerative capacity of the liver means that a low-cost source of unlimited numbers of liver cells might be put to good clinical use more rapidly than other types of engineered tissue:

The Medical College research team generated patient-specific liver cells by first repeating the work of James Thomson and colleagues at University of Wisconsin-Madison who showed that skin cells can be reprogrammed to become cells that resemble embryonic stem cells. They then tricked the skin-derived pluripotent stem cells into forming liver cells by mimicking the normal processes through which liver cells are made during embryonic development. Pluripotent stem cells are so named because of their capacity to develop into any one of more than 200 cell types in the human body.

At the end of this process, the researchers found that they were able to very easily produce large numbers of relatively pure liver cells in laboratory culture dishes. "We were excited to discover that the liver cells produced from human skin cells were able to perform many of the activities associated with healthy adult liver function and that the cells could be injected into mouse livers where they integrated and were capable of making human liver proteins," says Dr. Duncan.

...

The liver may be particularly suitable for stem-cell based therapies because it has a remarkable capacity to regenerate. ... It is possible that in the future a small piece of skin from a patient with loss of liver function could be used to produce healthy liver cells, replacing the diseased liver with normal tissue.

Onwards and upwards, cell type by cell type. The sooner that a general biotech repair-and-replacement kit for human organs is established, the sooner we will all benefit from that technology.

An Interview With Rudi Hoffman

Most people who sign up with a cryonics provider fund the cost of their future suspension using a life insurance policy. Rudi Hoffman is a long-standing member of the cryonics community and one of the few insurance agents to specialize in this type of policy: "The general feeling of the uninformed populace is that 'Cryonics is only for rich guys.' It is my passion, as well as my profession, to dispel this pernicious and potentially deadly lie. Cryonics is AFFORDABLE for most people who are in good health living in a developed country. This is because of the magical leverage of life insurance, in which a few dollars a day can create a fund of literally hundreds of thousands of dollars exactly when these funds are needed. ... Cryonics trusts exist to enable your funds to grow at a rate somewhat higher than taxes and inflation, and compound and grow. These funds are earmarked to both enable the cryonics resuscitation process, and enable you to have funds to provide you with enhanced options in the astounding future that you may be revived in. ... The bad news is that legitimate cryonics estate planning is not cheap. The better news is that some groundwork has been laid out by pioneers of this idea to make it more affordable than it used to be. And the actual funding of the cryonics trust can come from the leverage of life insurance."

Link: http://www.depressedmetabolism.com/2009/10/10/interview-with-cryonics-funding-specialist-rudi-hoffman/

Temporomandibular Joint Bone Grown From Stem Cells

From the BBC: "Scientists have created part of the jaw joint in the lab using human adult stem cells. They say it is the first time a complex, anatomically-sized bone has been accurately created in this way. It is hoped the technique could be used not only to treat disorders of the specific joint, but more widely to correct problems with other bones too. ... The joint has a complex structure which makes it difficult to repair by using grafts from bones elsewhere in the body. The latest study used human stem cells taken from bone marrow. These were seeded into a tissue scaffold, formed into the precise shape of the human jaw bone by using digital images from a patient. The cells were then cultured using a specially-designed bioreactor which was able to infuse the growing tissue with exactly the level of nutrients found during natural bone development. ... he availability of personalised bone grafts engineered from the patient's own stem cells would revolutionise the way we currently treat these defects. ... he new technique could also be applied to other bones in the head and neck, including skull bones and cheek bones, which are similarly difficult to graft."

Link: http://news.bbc.co.uk/2/hi/health/8290138.stm

Steady Advances in Tissue Engineering

Tissue engineers are, as one might expect, steadily becoming better at building comparatively simple forms of human tissue - not that any tissue is actually simple. Even straightforward muscle like heart tissue is formed of layered types and laced with tiny blood vessels. A great deal of money and expertise is involved these days, however, and challenges will be overcome step by step:

University of Washington (UW) researchers have succeeded in engineering human tissue patches free of some problems that have stymied stem-cell repair for damaged hearts. The disk-shaped patches can be fabricated in sizes ranging from less than a millimeter to a half-inch in diameter. Until now, engineering tissue for heart repair has been hampered by cells dying at the transplant core, because nutrients and oxygen reached the edges of the patch but not the center. To make matters worse, the scaffolding materials to position the cells often proved to be harmful.

...

Stevens and her fellow researchers added two other types of cells to the heart muscle cell mixture. These were cells similar to those that line the inside of blood vessels and cells that provide the vessel's muscular support. All of the heart muscle cells were derived from embryonic stem cells, while the vascular cells were derived from embryonic stem cells or a variety of more mature sources such as the umbilical cord. The resulting cell mixture began forming a tissue containing tiny blood vessels.

"These were rudimentary blood vessel networks like those seen early in embryonic development," Murry said.

In contrast to the heart muscle cell-only tissue, which failed to survive transplantation and which remained apart from the rat's heart circulatory system, the pre-formed vessels in the mixed-cell tissue joined with the rat's heart circulatory system and delivered rat blood to the transplanted graft.

This isn't as flashy as demonstrations of entire tissue-matched hearts created using decellularizing techniques and stem cells, but you should pay attention to progress in straightforward construction of tissue sections from scratch - especially progress in solving the blood vessel issues. The odds are good that you'll have pieces of fabricated tissue working away inside you thirty years from now, replacements for areas where age got the better of your standard issue physiology.

ALS as Accelerated Immune System Aging

From ScienceDaily: "Premature aging of the immune system appears to play a role in the development of amyotrophic lateral sclerosis (ALS) ... CD4+ T cells, which grow and mature in the thymus before entering the bloodstream, are reduced in number in patients who have ALS as the thymus shrinks and malfunctions. ... The thymus gland, where immune cells called T lymphocytes mature before entering the bloodstream, normally reaches its peak in size and production in childhood. It then slowly shrinks, becoming virtually nonexistent in the elderly, but the lifespan of newly produced T cells ranges from three to 30 years. This study found that the thymus glands of mice and patients with the disease undergo accelerated degeneration. ... The findings are consistent with evidence collected over a decade [suggesting] that a well-functioning immune system plays a pivotal role in maintaining, protecting and repairing cells of the central nervous system. Studies conducted in animals have shown that boosting immune T-cell levels may reduce symptoms and slow progression of certain neurodegenerative diseases. ... If T-cell malfunction is confirmed to be a contributing factor to ALS, as we propose, therapeutic strategies may be aimed at overcoming this deficiency through rebuilding, restoring or transplanting the thymus."

Link: http://www.sciencedaily.com/releases/2009/10/091008192737.htm

A Trial For Granulocyte Cancer Therapy

A cancer therapy trial based on the work of Zheng Cui is presently underway in Florida: "About 75% of US population living today will not die of cancer. It is not uncommon that some people remain cancer-free into their 80s and 90s, even if they are regularly exposed to environmental carcinogens such as air pollutants, cigarette smoking, etc. A frequently asked but unanswered question is why these individuals do not get cancer. There has been a recent report of a colony of cancer-resistant mice developed from a single male mouse that unexpectedly survived challenges of lethal cancer cell injections. In these so-called spontaneous regression/complete resistant (SR/CR) mice, cancer cells are killed by rapid infiltration of leukocytes, mainly of innate immunity. This highly effective natural cancer immunity is inherited and mediated entirely by white blood cells. Moreover, this cancer resistance can be transferred to wild type mice through the transfer of various immune cell types including granulocytes. This observation raises the possibility that infusion of white blood cells, particularly cells of innate immunity, is a viable anticancer therapy in humans as well. This proposed trial will test whether white blood cell infusions from healthy unrelated donors can be used to treat cancer. The trial is designed to determine whether responses can be seen in cancer patients after infusion of HLA-mismatched white cells from healthy donors."

Link: http://clinicaltrials.gov/ct2/show/NCT00900497

Another Method of Increasing Autophagy to Enhance Longevity

Autophagy seems to be the topic of the week, and here's another example of research demonstrating enhanced longevity in laboratory animals through increased autophagy:

Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice [and] led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells.

Those of you who like your research a little more preprocessed than the original papers will no doubt prefer this article from the science press:

It seems that spermidine exerts its influence at the level of the cell's mechanism for dealing with damaged internal components. Throughout a cell's life, proteins and other molecules become damaged by exposure to environmental factors such as UV light or oxidants. This debris is swept up and deposited into a biochemical recycling bin. However, as cells age this clean-up process, called autophagy, becomes less efficient and ultimately the accumulation of this waste causes the cell to trigger its own suicide.

Autophagy is ultimately controlled by genes being switched on and off. It appears that spermidine inhibits a protein in the cell's nucleus that is involved with controlling the genes for autophagy.

Richard Faragher, an expert on cellular ageing at the University of Brighton in the UK, says that the new work 'is interesting because it adds to the growing body of data suggesting that ageing is caused by a general failure of recycling.'

You might compare this with another recent attempt at increasing autophagy in mammals, which also showed positive changes in biochemistry. While assessing end results is comparatively rapid in short-lived worms and flies, it takes much more time to establish that a mechanism also holds in mammals. Mouse or rat life span studies take a good number of years to complete, which is why we'll probably be waiting a while longer to learn to what degree their lives are extended by methods of boosting autophagy.

ResearchBlogging.orgEisenberg, T., Knauer, H., Schauer, A., Büttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., Ring, J., Schroeder, S., Magnes, C., Antonacci, L., Fussi, H., Deszcz, L., Hartl, R., Schraml, E., Criollo, A., Megalou, E., Weiskopf, D., Laun, P., Heeren, G., Breitenbach, M., Grubeck-Loebenstein, B., Herker, E., Fahrenkrog, B., Fröhlich, K., Sinner, F., Tavernarakis, N., Minois, N., Kroemer, G., & Madeo, F. (2009). Induction of autophagy by spermidine promotes longevity Nature Cell Biology DOI: 10.1038/ncb1975

New York Times on CALERIE

A look at present human studies of the health benefits of calorie restriction at the New York Times: "As Americans become fatter and fatter - a study published in July revealed that obesity rates increased in 23 states last year and declined in none - a select group of men and women under the watchful care of medical professionals have spent the past few years becoming thinner and thinner. There are 132 of them, located in and around Boston, St. Louis and Baton Rouge, La. All are enrolled in a large clinical trial that is financed by the National Institutes of Health and known as Calerie, which stands for Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy. ... the Calerie project [is] that it is not meant to study weight loss or if one type of diet is better than another. Instead, Calerie is investigating how (and if) a spartan diet affects the aging process and its associated diseases. To the Calerie researchers, these are quite distinct. The aging process, which researchers sometimes call 'primary' or 'intrinsic' aging, refers to the damage that ordinarily accumulates in our cells as we grow older, a natural condition that seems to have limited the maximal lifespan of humans to 120 years. Diseases that accompany the aging process - often called 'secondary aging' - are those afflictions increasingly prevalent in the elderly, like cancer, diabetes and cardiovascular disease."

Link: http://www.nytimes.com/2009/10/11/magazine/11Calories-t.html?pagewanted=print

h+ Magazine on Anti-Cancer Nanotechnology

A look at the state of the art in cancer therapies under development from h+ Magazine: "Nanomedicine, an offshoot of nanotechnology, refers to highly specific medical intervention at the molecular scale for curing disease or repairing damaged tissues, such as bone, muscle, nerve, or brain cells. Nanoparticles - anywhere from 100 to 2500 nanometers in size - are at the same scale as the biological molecules and structures inside living cells. ... Titanium dioxide is not the only nanoparticle that shows promise in cancer therapy. Gold nanospheres - nearly perfectly spherical nanoparticles that range in size from 30 to 50 nanometers - are being used to search out and 'cook' cancer cells. The cancer-destroying nanospheres show promise as a minimally invasive future treatment for malignant melanoma, the most serious form of skin cancer. ... The hollow gold nanospheres are equipped with a special peptide that draws the nanospheres directly to melanoma cells, while avoiding healthy skin cells. After collecting inside the cancer, the nanospheres heat up when exposed to near-infrared light, which penetrates deeply through the surface of the skin."

Link: http://hplusmagazine.com/articles/nano/targeting-cancer-cells-nanoparticles

Don't Feed the Trolls

Those of you who pay attention to the media will have noticed the present disquiet in the cryonics community brought on by a former employee of Alcor: a renewed round of unpleasant and entirely unrealistic accusations of misconduct, made in the mass media echo chamber with intent to damage Alcor and produce profit for said former employee. I won't link to the recent press, not wishing to feed the trolls any more than is necessary, but you can find it easily via Google News or similar.

This should be looked on as a lesson in just how easy it is to make a terribly wrong hire, and just how much damage such a hire can do should they turn out to be irrational. This is why small companies and ventures must always be very cautious - though I fail to see what Alcor could have done differently to avoid this particular hire. Ultimately, the responsible party is the one who sets out to do bad things, not everyone else.

I will point you to Alcor's recent press releases on the matter:

Alcor Life Extension Foundation Granted Temporary Restraining Order Against Larry Johnson

Merkle said that Johnson’s main area of responsibility during his tenure at Alcor in 2003 was the supervision of the cryopreservation of Alcor members. According to Merkle, "Johnson expressed none of his lurid and sensationalistic concerns during his employment -- when preventing and correcting any such alleged mistakes would have been a major part of his duties. Only afterwards, when he could profit from exaggerations and misrepresentations, did he start to complain about how Alcor performed cryopreservations."

Alcor Response to ABC Nightline and Larry Johnson Allegations

Alcor condemns the gross insensitivity of news media in presenting Johnson’s stories as newsworthy, desecrating the memory of Ted Williams to the great upset of his family, who were devastated in a New York courtroom on Monday when learning sales of Johnson’s book would go forward. This was particularly heinous since the publisher apparently knowingly accelerated release of the book in order to preclude the Temporary Restraining Order requested by Alcor and the Williams family. The situation sadly demonstrates how easy it is for one malicious individual to taint the memory of a great man, emotionally crush a family, and damage decades of work by others. That this is presented as wrong-doing on Alcor's part is incomprehensible.

From my distant vantage point, I'll say this: this whole affair has the look of what becomes of those grade-school creators of drama when they grow up and become capable of causing real harm. It is very unfortunate that Alcor became the target of this particular individual. Alcor's volunteers and employees work hard at what they believe in: using technology to give people a chance at a longer life in the future, and ensuring that each new cryopreservation is as good as it can be under the always difficult end of life circumstances. They have been doing this for decades, to little applause, but it seems there's always some idiot ready and waiting to trample the hard-won gains of others for no better reason than he can.

The Pursuit of Cryonics as Medicine

From Depressed Metabolism: "The biggest obstacle to the acceptance of cryonics is medical myopia; the idea that someone who has been pronounced dead by contemporary medical criteria will still be considered dead by future criteria. Advocates of human cryopreservation strongly argue against this. There are few things more discomforting than the idea that medical professionals of the future will look back in horror and wonder why we gave up on people who still possessed the neuroanatomical basis of their identities and memories. But there is another kind of myopia in the public discussion of cryonics that warrants consideration. It is taken for granted by some critics of contemporary cryonics that cryonics has always been framed as a form of medicine. Nothing could be further from the truth. The history of cryonics is replete with debates between advocates of the medical model and those who believe that timely transport of the patient to a cryonics facility for low temperature storage should be adequate for future resuscitation by advanced nanotechnology. It is only because cryonics advocates with medical and research backgrounds such as Mike Darwin and Jerry Leaf vigorously argued for adopting conventional medical techniques and protocols that today's cryonics organizations can even be criticized for falling short of these criteria."

Link: http://www.depressedmetabolism.com/2009/10/06/the-pursuit-of-cryonics-as-medicine/

Singularity Hub on the Mprize

The Singularity Hub here looks at the Mprize for longevity research: "If living forever isn't enough motivation to get scientists to study longevity, maybe $3.8 million will work instead. That's the current size of the Mprize, a special fund put forth by the Methuselah Foundation that seeks to encourage research into extending healthy human life. The prize is awarded to those scientists who can increase the lifespan of lab mice in the hopes that work performed on that species can be readily applied to humans. Can we live longer? Do we even want to? When will the average human life expectancy start to increase by more than a year each year? The Methuselah Foundation's answers are yes, yes, and much sooner than you might think. ... offering a cash prize to help motivate research has a long and successful history. Mariners were finally able to determine their longitude at sea thanks to the aptly named Longitude Prize offered by the British government. Lindbergh's transatlantic flight was in direct response to the Orteig prize. The modern day Xprize is inspiring new achievements in genomics, space flight, lunar exploration, and transportation efficiency. With the Mprize, the Methuselah Foundation may very well bring about a surge in the interest in increasing human lifespans within the next generation."

Link: http://singularityhub.com/2009/10/06/mprize-your-children-could-be-immortal/

Attention Paid to Autophagy

Autophagy is good for you. You should be doing more of it.

Autophagy is, put simply, the process by which cells recycle damaged components. Of course like all cellular processes the reality on the ground is anything but simple, and autophagy interacts with all sorts of other processes in ways that can produce counter-intuitive results. But the weight of evidence points to more and better autophagy as beneficial overall, most likely because it leads to fewer lingering damaged components inside a cell. Repeated throughout all your cells, this should result in better functioning tissue, fewer errant biological systems, and a longer life - remember that aging itself is nothing more than accumulated damage and the thrashing of systems trying to adapt to that damage.

Research into autophagy and its significance to longevity has been picking up breadth and pace in the past few years. This has no doubt been helped by the rising level of interest (and potential commerical profit) in the biochemistry of calorie restriction - autophagy appears to be very important to the benefits derived from calorie restriction. So we shouldn't be too surprised to see the mainstream science press start to cover autophagy research in much the same way as it covers research into the mechanisms of calorie restriction. Here's an example from today's New York Times:

Unfortunately, as we get older, our cells lose their cannibalistic prowess. The decline of autophagy may be an important factor in the rise of cancer, Alzheimer’s disease and other disorders that become common in old age. Unable to clear away the cellular garbage, our bodies start to fail.

If this hypothesis turns out to be right, then it may be possible to slow the aging process by raising autophagy. It has long been known, for example, that animals that are put on a strict low-calorie diet can live much longer than animals that eat all they can. Recent research has shown that caloric restriction raises autophagy in animals and keeps it high. The animals seem to be responding to their low-calorie diet by feeding on their own cells, as they do during famines. In the process, their cells may also be clearing away more defective molecules, so that the animals age more slowly.

Some scientists are investigating how to manipulate autophagy directly. Dr. Cuervo and her colleagues, for example, have observed that in the livers of old mice, lysosomes produce fewer portals on their surface for taking in defective proteins. So they engineered mice to produce lysosomes with more portals. They found that the altered lysosomes of the old experimental mice could clear away more defective proteins. This change allowed the livers to work better.

"These mice were like 80-year-old people, but their livers were functioning as if they were 20," Dr. Cuervo said. "We were very happy about that."

Methods of enhancing human levels of autophagy will almost certainly emerge from the broader field of metabolic research, and likely on much the same timescale as such line items as calorie restriction mimetic drugs that can capture most of the benefits of actual calorie restriction, mitochondrially targeted antioxidants, and other similar manipulations.

The "Yuck Factor" and Cryonics

As pointed out at Depressed Metabolism, people don't like to contemplate most medical procedures in any detail: "In sensationalized accounts of cryonics, explicit descriptions of cryonics procedures, and that of neuropreservation in particular, are used to invoke a negative response in the reader. ... In some [other and undesirable aspects of human activity], such as senseless violence, this is not necessarily an unreasonable approach because it may reflect a preserved instinct against behavior that is harmful to the individual or group. ... Where such an appeal to gut feelings is less fruitful, however, is in the context of medicine and forensics. The daily activities of many medical professionals and morticians consist of activities that would produce a strong negative gut response in most people who would observe them in all their detail. ... The 'yuck factor' that is produced in many people when they read about the details of cryonics procedures is not evidence of pseudo-science or mistreatment. As a matter of fact, the procedures that are routinely performed in cryonics labs are designed to preserve life, not to destroy it. In this sense, the practice of cryonics can claim the moral high ground over prevailing methods of dealing with 'human remains,' where [people presently considered dead and gone in the mainstream view] are buried or burned because contemporary medicine has not yet found a way to treat [or restore] them. If anything, it is this kind of medical myopia that should trigger the yuck factor."

Link: http://www.depressedmetabolism.com/2009/10/05/the-yuck-factor-and-cryonics/

Methuselah Foundation Newsletter, September 2009

The latest Methuselah Foundation newsletter is out: "This month we are introducing the last of the four newest Mprize competitors. Significant cash Prizes are awarded for Longevity, breaking the world record for the oldest-ever mouse, and Rejuvenation, the most successful late-onset rejuvenation of a mouse. The amount won is in proportion to the size of the fund and to the margin by which the previous record is broken. ... Bruce Teter is optimistic about the possibility that curcumin, which is the element of the spice turmeric that gives it its color, will extend the life of mice. ... In addition to the mice at Steve Spindler's lab, three other labs are conducting tests. Those three labs are funded through ITP, the Interventions Testing Program of the National Institute on Aging ... The ITP labs started with 3 month old mice to determine if curcumin intervention mimics the effects of Calorie Restriction in extending life. Steve's lab started with 12 month old mice and will measure the effects of a unique preparation of curcumin to extend maximal lifespan with late-life treatment."

Link: http://blog.methuselahfoundation.org/2009/10/methuselah_foundation_newslett_5.html

Coverage of This Year's Singularity Summit

As I noted in the latest Longevity Meme newsletter, this last weekend saw the Singularity Summit event held in New York.

The Singularity Institute is pleased to host the Singularity Summit 2009, a rare gathering of thinkers to explore the rising impact of science and technology on society. The summit has been organized to further the understanding of a controversial idea - the singularity scenario.

While the technological singularity is ostensibly about the creation of self-improving artificial intelligence and consequences thereof, you will find a great many advocates for longevity science mixed in with the AI crowd. Indeed, there has long been significant overlap between these two fields: shared luminaries (e.g. Ralph Merkle), shared funding sources (e.g. the Thiel Foundation), and even shared workers and researchers (e.g. Aubrey de Grey, who worked on an attempt at commercial AI development back in the day).

I see that the Summit garnered an impressive array of coverage - a good job of preparation there on the part of the busy bees at the Singularity Institute and the other Summit backers, and something that we longevity advocates need to work on harder for our events. But take a look at what's out there; here's a selection of links from various mainstream perspectives that include the usual level of fact-mangling:

What Does a Beer Taste Like After the Singularity?

You can see how believable and even plausible a technological singularity seems once you take a few things for granted. If it were possible to improve your memory with a digital device, for example, then everybody would want one, because not having such a device would put you at a disadvantage to those who had such technology. Then an escalation of biodigital enhancement would naturally occur until some people were walking around with more microchips than neurons. At some point the hand off between human intelligence and machine intelligence would have occurred. And that's just one possible singularity scenario.

Man vs. Machine: The Singularity Summit 2009

Kurzweil looks forward to living in an age in which human intelligence is enhanced by brain implants that extend our memories, enhance our senses, and allow us to solve problems faster and with greater accuracy. There is only a small population of people who are more optimistic about the future than Kurzweil. He believes that futurism is about thinking exponentially, not linearly, and points to technology’s history of rapid acceleration. When we reach the Singularity, Kurzweil believes that by using technology like nano-sized blood cells that swim through our body, zapping cancer and bad cholesterol, humans will be able to live forever.

Methuselah Speaks

De Grey is running through the standard gamut of life-extension medical technology. Gerontology, he says, is becoming an increasingly difficult and pointless pursuit as it attempts to treat the inevitable damage of old age. But if we reverse the damage, he says, we might be able to extend our biological age at a rate approaching the pace of time.

...

There are some interesting implications of his calculations. One of them, he notes, is that once we increase average longevity past the current maximum (about 120 years), the hardest part is over (since LEV will steadily decrease). This means that, he says, the first thousand-year-old will probably be not much more than twenty years older than the first 150-year-old.

The Quest to Recreate Regeneration in Higher Animals

A somewhat meandering article from the Boston Globe looks at the state of regenerative medicine: "Cut an arm off a starfish, and an exact duplicate emerges. The salamander, upon losing a tail, sprouts another. The conventional thinking has been that we, along with all other mammals, lost the ability to regrow entire organs and limbs. Yet there are exceptions. Deer show off new antlers every year. Even children retain vestiges of regenerative capacity: Up to an age of between 7 and 11, if a child loses the top third of a finger, that tip will reemerge. How can we, [like] starfish and salamanders, harness the power of regeneration? ... Each and every cell has an electric flow across its membrane ... researchers have known for some time that the site of a wound produces an electrical field. But only recently have research instruments allowed this flow to be investigated at the molecular level. ... electrical signals tell cells what to repair and how to re-create what was lost. Levin deciphered one of those cues, a protein in a tadpole that creates a flow of protons, which produces an electric field at the site of a lost tail, starting a voltage flow. ... If you block that flow, the tail won't grow back. ... Levin took a tadpole that matured past the ability to regenerate a lost tail. He removed the tail, then manipulated proteins to turn on the switch. [This] triggers tail regeneration and stops the tail growth when it's complete. The tadpoles end up with perfectly sized tails like their siblings. Levin is now working with tissue engineer David Kaplan to develop [a] bioreactor, which could encourage the same regeneration in mammals, starting with rats."

Link: http://www.boston.com/bostonglobe/magazine/articles/2009/10/04/need_a_new_heart_grow_your_own?mode=PF

A Special Mprize Award

Via the Methuselah Foundation Blog: "Methuselah Foundation will award Z. David Sharp, Ph.D. the Special Mprize Lifespan Achievement Award for the first pharmaceutical intervention to successfully extend the life of laboratory mice. The study, published this summer in the journal Nature, showed that when aging mice were given the drug rapamycin, they lived longer than other mice. Methuselah Foundation will present this special MPrize for Rejuvenation to Sharp at a ceremony on Thursday, October 8th in New York City. Presenters will include Dave Gobel, CEO Methuselah Foundation, Roger Holzberg, CEO My Bridge 4 Life, Huber Warner, University of Minnesota and Keith Murphy, CEO Organovo. Dr. Max Gomez, broadcast Journalist, will serve as emcee for the event." I should note that the Mprize website has recently been redesigned and a lot of new video content added, especially around the competitors list. If you'd like to learn more about the more than a dozen teams and different longevity-inducing methodologies competing in the Mprize, that would be a good place to start.

Link: http://blog.methuselahfoundation.org/2009/10/scientist_to_be_awarded_specia.html

A Very Safe Prediction

This, I think, is a very safe prediction by Vaupel et al.:

If the pace of increase in life expectancy in developed countries over the past two centuries continues through the 21st century, most babies born since 2000 in France, Germany, Italy, the UK, the USA, Canada, Japan, and other countries with long life expectancies will celebrate their 100th birthdays.

Although trends differ between countries, populations of nearly all such countries are ageing as a result of low fertility, low immigration, and long lives. A key question is: are increases in life expectancy accompanied by a concurrent postponement of functional limitations and disability? The answer is still open, but research suggests that ageing processes are modifiable and that people are living longer without severe disability.

There's also plenty of mainstream press attention:

James Vaupel of the Max Planck Institute in Germany and colleagues in Denmark examined studies published globally in 2004-2005 on numerous issues related to aging. They found life expectancy is increasing steadily in most countries, even beyond the limits of what scientists first thought possible. In Japan, for instance, which has the world's longest life expectancy, more than half of the country's 80-year-old women are expected to live to 90.

"Improvements in health care are leading to ever slowing rates of aging, challenging the idea that there is a fixed ceiling to human longevity," said David Gems, an aging expert at University College London. Gems was not connected to the research, and is studying drugs that can lengthen the life span of mice, which may one day have applications for people.

If you look back in the Fight Aging! archives, you'll find more of Vaupel's views on aging and enhanced longevity through medical science:

Plasticity of Aging:

So the progress [in life expectancy prior to 1950] was largely due to saving lives below age sixty-five, especially children.

But after 1950 the improvements to life expectancy have largely been due to saving lives after age sixty-five, to this extension of life, to this [adding] years to the life of older people.

A Short Quote:

"But 125, 130 years is not unreasonable to expect soon," said James Vaupel, the institute's expert on ageing. "Really, the potential to live even beyond this time is there."

From my perspective, for present trends in longevity to continue unchanged would be the least likely of outcomes. We live in an age of revolution in computing and biotechnology, of vast and ever-increasing gains in our knowledge of human biochemistry. Only by utterly failing to put this knowledge to practical use could we avoid some form of greatly increased life span. The open questions, the important open questions, all revolve around how fast this future will arrive - fast enough to help us, or slow enough to help only our children?

Exploring the Mechanisms of Protein Restriction

Lowered dietary protein leads to a longer life, acting in much the same way as calorie restriction. Here researchers delve more deeply into the underlying mechanisms: "Mitochondria act as the 'powerhouse' of the cells. It is well known that mitochondrial function worsens with age in many species ... Our study shows that dietary restriction can enhance mitochondrial function hence offsetting the age-related decline in its performance ... The researchers report the unexpected finding that while there is a reduction in protein synthesis globally with the low protein diet, the activity of specific genes involved in generating energy in the mitochondria are increased ... That activity, which takes place at the level of conversion of RNA to protein, is important for the protective effects of dietary restriction ... There have been correlative studies that show mitochondria change with dietary restriction, this research provides a causal relationship between diet and mitochondrial function ... mitochondrial genes are converted from RNA to protein by a particular protein (d4EBP). Flies fed a low protein diet showed an uptick in activity of d4EBP, which is involved in a signaling pathway that mediates cell growth in response to nutrient availability called TOR (target of rapamycin). ... d4EBP is necessary for lifespan extension upon dietary restriction. When the activity of the protein was genetically 'knocked out' the flies did not live longer, even when fed the low protein diet. When the activity of d4EBP was enhanced, lifespan was extended, even when the flies ate a rich diet."

Link: http://www.eurekalert.org/pub_releases/2009-10/bifa-lp092409.php

On Reversible Cryopreservation

From Depressed Metabolism: "I think in the next 20 years more small animal organs, and perhaps some human organs, may be reversibly cryopreserved. The best scenario for cryonics would be improved, and possibly demonstrably reversible, cryopreservation of animal brains. It has been long observed that if reversible solid-state brain preservation could be demonstrated, then cryonics revival becomes a purely technical problem (albeit very complex one) of tissue regeneration. There would be no remaining doubt about whether the preservation itself was viably preserving human beings ... Reversible solid-state cryopreservation of whole mammals is a very difficult problem with existing technology. This is why when asked about it people will often defer to nanotechnology. References to nanotechnology as a solution to a medical problem basically say, 'We have no idea how to solve this problem with existing tools, but future abilities to completely analyze and repair tissue at the molecular level will be implicitly sufficient.' It's a valid argument, but saying that a medical problem will be solved when someday technology exists to solve every medical problem is not very illuminating about time lines or nature of the problem."

Link: http://www.depressedmetabolism.com/2009/10/01/reversible-cryopreservation/

And Now a Female-Only Longevity Mutation in Mice

Back in June, I pointed out a longevity mutation that only extends healthy life span in male mice. By way of a bookend to that discovery, here is a mutation that extends healthy life span by 20% or so in female mice only.

Researchers have identified a genetic tweak that can slow aging in mice:

Caloric restriction has long been known to extend lifespan and reduce the incidence of age-related diseases in a wide variety of organisms, from yeast and roundworms to rodents and primates. Exactly how a nutritionally complete but radically restricted diet achieves these benefits has remained unclear. But recently several studies have offered evidence that a particular signaling pathway, involving a protein called target of rapamycin (TOR), may play a pivotal role. This pathway acts as a sort of food sensor, helping to regulate the body's metabolic response to nutrient availability.

Withers and colleagues noticed that young mice with a disabled version of the protein S6 kinase 1 (S6K1), which is directly activated by TOR, bore strong resemblance to calorie-restricted mice: they were leaner and had greater insulin sensitivity than normal mice.

UC Development Aids Longevity Research

Armed with this knowledge and an appropriate mouse model for further testing, Withers and his team hypothesised that S6K1 could play a role in mammalian longevity. He began studying this hypotheses using UC’s S6K1 "knock-out" mouse models - those without S6K1.

The team determined that female S6K1 knock-out models were hyperactive and actually consumed more calories, but those calories were quickly used or "burned up," which naturally lowered levels of ATP (energy) within the cell. Decreased ATP levels in S6K1 knock-out mice increased levels of the protein kinase AMPK, resulting in a restriction of anabolic processes and an increase in longevity.

You might recall that manipulation of AMPK has also been shown to produce some of the same benefits as calorie restriction - many of the genes and proteins in these pathways have been worked on by research groups over the past five years or so. Back in 2004, manipulation of S6K1 itself was shown to produce changes that might be expected to enhance long-term health, centering around insulin signaling:

Here, we report that S6K1-deficient mice are protected against [some of the biochemical consequences of obesity]. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance.

The more recent results in S6K1 knockout mice are one small part of the flurry of research into the biochemistry of calorie restriction. Scientists are racing to explore pathways and mechanisms gene by gene and protein by protein, seeking the best place to intervene using designed drugs. The goal is to capture all the benefits of calorie restriction, or even do better, whilst minimizing or eliminating unwanted side-effects. Give it another ten years and the new scientific industry of metabolic manipulation will rival that of stem cell research, I'd wager. It certainly seems set for that sort of growth, starting from calorie restriction biochemistry and working its way outward.

SENS Research Wins the 3banana Contest

I see that, thanks to the vigorous response of the pro-longevity community, the SENS Foundation has won $5,000 for longevity research: "The challenge, launched this September, was sponsored by 3banana as a philanthropic crowdsourcing contest helping health, environment and education-focused non-profit organizations raise money and exposure for their respective causes while testing the sharing features of the company's online and mobile note-taking software. ... 'We are very honored to accept this prize. This contest has really opened our eyes to the possibilities of furthering our cause using social networks,' said Dr. Aubrey de Grey, Chief Science Officer for the SENS Foundation. 'Thousands of our supporters shared their words of encouragement for our mission, and this effort has created more dialog between our organization and our supporters.'" As the cost of biotech research falls, I think we're going to see much more grassroots fundraising of this nature - see, for example, the laser ablation of lipofuscin research that was funded earlier this year via online efforts.

Link: http://www.prweb.com/releases/2009/09/prweb2968404.htm

Towards the Restoration of Aged Muscles

Via ScienceDaily: "adult muscle stem cells have a receptor called Notch, which triggers growth when activated. Those stem cells also have a receptor for the protein TGF-beta that, when excessively activated, sets off a chain reaction that ultimately inhibits a cell's ability to divide. The researchers said that aging in mice is associated in part with the progressive decline of Notch and increased levels of TGF-beta, ultimately blocking the stem cells' capacity to effectively rebuild the body. This study revealed that the same pathways are at play in human muscle, but also showed for the first time that mitogen-activated protein (MAP) kinase was an important positive regulator of Notch activity essential for human muscle repair, and that it was rendered inactive in old tissue. ... For old human muscle, MAPK levels are low, so the Notch pathway is not activated and the stem cells no longer perform their muscle regeneration jobs properly ... When levels of MAPK were experimentally inhibited, young human muscle was no longer able to regenerate. The reverse was true when the researchers cultured old human muscle in a solution where activation of MAPK had been forced. In that case, the regenerative ability of the old muscle was significantly enhanced. ... In practical terms, we now know that to enhance regeneration of old human muscle and restore tissue health, we can either target the MAPK or the Notch pathways. The ultimate goal, of course, is to move this research toward clinical trials."

Link: http://www.sciencedaily.com/releases/2009/09/090930084602.htm