The immune system falls apart with age in ways that are as much a matter of configuration as wear and tear – it is a machine in which the programming runs awry, leading it to do the wrong things at the wrong time, or just do nothing when it should be doing something. This activity leads to damage, which in turn accelerates aging: “Immune aging is associated with loss of critical immune functions, such as host protection from infection and malignancy. Unexpectedly, immunosenescence also renders the host susceptible to inflammation, which may translate into tissue-damaging disease as the senescent immune system loses its ability to maximize inflammatory protection while minimizing inflammatory injury. On the other hand, chronic inflammation associated with immune-mediated disease represents a profound stress factor for the immune system, affecting cellular turn-over, replication and exhaustion. Immune cell longevity is tightly connected to the functional integrity of telomeres which are regulated by cell multiplication, exposure to oxidative stress and DNA repair mechanisms. Lymphocytes are amongst the few cell types that can actively elongate telomeres through the action of telomerase. In patients with the autoimmune disease rheumatoid arthritis (RA), telomerase deficiency is associated with prematurity of immune aging. Patients with RA have other defects in DNA repair mechanisms, including the kinase Ataxia telangiectasia mutated (ATM), critically involved in the repair of DNA double strand breaks. ATM deficiency in RA shortens lymphocyte survival. Dynamics of telomeric length and structure are beginning to be understood and have distinct patterns in different autoimmune diseases, suggesting a multitude of molecular mechanisms defining the interface between chronic immune stimulation and progressive aging of the immune system.”

Link: http://www.ncbi.nlm.nih.gov/pubmed/22396899

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With advancing age – and accumulating damage – the immune system moves into a state wherein it is constantly roused and on alert, exacting a toll on the integrity of tissue and cells through its signaling and activity, but also ineffective at actually tackling pathogens, senescent cells, precancerous cells, and other things that should be destroyed. So you have constant chronic inflammation and all its downsides with none of the compensatory immune activity boost that comes with short-term inflammation in the young. Researchers have given the name “inflammaging” to this progressive and increasingly harmful disarray of the immune system, and you’ll find a few introductions to inflammaging as a concept back in the Fight Aging! archives.

Below is an open access paper that gives an overview of inflammaging and how it relates to some of the forms of cellular damage that cause aging. In this paper, the researchers paint a picture of inflammaging derived from root causes that involve mitochondrial damage and progressive failure of autophagy to clear out that damage, two line items that have been examined a fair number of times here in the past – under the Strategies for Engineered Negligible Senescence (SENS) viewpoint these two are amongst the fundamental, root causes of aging.

Inflammaging: disturbed interplay between autophagy and inflammasomes

In 2000, Franceschi et al. coined the term “inflammaging” in order to refer to a low-grade pro-inflammatory status appearing during the aging process. They emphasized the role of macrophages as well as cellular stress and genetic factors in the generation of the inflammaging condition. In addition, they hypothesized that this inflammatory environment could predispose the organism to the development of several age-related diseases. During recent years, this scenario has been confirmed by a plethora of experimental evidence. … Interestingly, the aging process is simultaneously accompanied by both the features accelerating inflammaging and the counteracting, so-called anti-inflammaging characteristics. It seems that the balance between these opposite forces controls the outcome of the aging process, either leading to frailty and degenerative diseases or a healthy old age and longevity.

…

The aging process is associated with a decline in autophagic capacity which impairs cellular housekeeping, leading to protein aggregation and accumulation of dysfunctional mitochondria which provoke reactive oxygen species (ROS) production and oxidative stress.

Recent studies have clearly indicated that the ROS production induced by damaged mitochondria can stimulate intracellular danger-sensing multiprotein platforms called inflammasomes. [As a result of inflammasome activity, signaling molecules called] cytokines provoke inflammatory responses and accelerate the aging process by inhibiting autophagy.

There has been some good progress in recent years in pulling things together in the big picture – and the more that we see the mechanisms of SENS featured, the better to my eyes. That ways lies increased support for rejuvenation biotechnology that will actually work to reverse aging, rather than the present mainstream course of aiming to slow down aging just a little sometime in next few decades.

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You’ll find some thoughts on incentives, politicians, and longevity science over at h+ Magazine. I don’t agree with all of them, but then my views on the state as a millstone hung upon the neck of medical progress are known: “After finding out I was an economist, [Aubrey de Grey] effectively challenged me to work out what we should want politicians to do … With over 150,000 people dying every day, I hope governments would respond to the animal experiments by accelerating our journey to [actuarial] escape velocity through massively increasing funding for longevity medical research, because the cost of dying this year goes way up if it causes you to just miss out on the chance to live long enough to live forever. But since a rational world would already make abolishing death a top priority, we can’t count on politicians automatically doing this. Still (as I will explain at the end of this article) people will likely be made aware of any inevitable approach to escape velocity which should cause at least some voters to reward politicians who increase taxpayer support for medical research. … Once we actually reach escape velocity, U.S. politicians would face enormous political pressure to make the necessary medical treatments available to all Americans, regardless of income. The U.S. government might well do this by limiting how much companies could charge for the needed medicines. Predicting this, pharmaceutical companies would have fewer incentives to develop the cures in the first place.”

Link: http://hplusmagazine.com/2012/02/28/the-politics-of-medical-immortality/

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Via EurekAlert!: “This paper reports the discovery of one of the first targeted drugs specifically developed to reverse fibrosis and regenerate the kidney. We’re optimistic about the benefits, but the real proof will come from clinical testing. … In the kidneys and other organs, fibrosis develops from normal repair mechanisms that do not stop. Scar tissue slowly builds up and replaces the working cells of the organ. In 2003, [researchers] reported that the destructive fibrosis in mice can be countered by the human protein BMP-7, originally named for its ability to spur bone growth. … However, the large protein needs to be injected or surgically implanted and, therefore, is not useful for long-term treatment protocols. Probing deeper into the biology of the kidney, they identified the protein Alk3 [and] based on the details about the molecular interaction between the BMP protein and the ALK receptor, [scientists] developed a class of small functional peptides, including THR-123, which then underwent further testing. … This receptor must be present for the new molecule to function … Working through the receptor, the molecule suppressed inflammation, cell death and fibrosis formation, as well as reversing established fibrosis and allowing kidneys to regenerate functional cells … Further experiments showed that the test drug worked even better in the mice when given in combination with ACE inhibitors, the anti-hypertensive drugs now considered a standard therapy for chronic kidney disease which work by targeting another molecular process. … Targeting the receptor not only stops fibrosis, it removes established fibrosis, and it works in combination with an existing drug used in patients. The next step is to test this molecule in the clinic.”

Link: http://www.eurekalert.org/pub_releases/2012-03/bidm-stk030712.php

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The near future of organ transplants will become very varied, as a range of different viable types of technology are presently undergoing active development. A short list looks much like this:

• Incremental progress in old-style organ transplants, such as improving the donation system, allowing organs to be stored outside the body for longer periods of time, and so forth.
• Decellularization, in which a donor organ is stripped of cells, leaving only the scaffold of the extracellular matrix. The scaffold is repopulated from the patient’s cells, removing the possibility of immune rejection and need for immunosuppressant drugs.
• Electromechanical and bioartificial organs, including hearts, lungs, and kidneys, continue to improve at a good pace. New types of small artificial organ are becoming possible thanks to advances in materials science.
• Creating organ tissue and scaffolds from scratch through a variety of methods, such as the 3-D printing pioneered by a number of groups.
• Xenotransplantation, the use of animal organs for human patients, is also becoming more viable as a near-term prospect.
• Lastly, there are the researchers who aim to rebuild damaged organs in situ through manipulation of stem cells and signaling processes in normal regeneration.

There will be a great deal of innovation and healthy competition over the next two decades before this larger cycle of technological progress in medicine settles down to a few mature and tried and tested ways of fixing broken and age-damaged organs in the body.

To add to the list of strategies, I noticed an article today on a possible middle path between old-style donor transplants (immunosuppressant drugs and all) and the near future of organs that are populated by the patient’s own stem cells. It may be possible to use the knowledge acquired by stem cell researchers to date in order to minimize or completely remove the risk of immune rejection of a donor organ:

In a standard kidney transplant, the donor agrees to donate their kidney. In the approach being studied, the individual is asked to donate part of their immune system as well. The process begins about one month before the kidney transplant, when bone marrow stem cells are collected from the blood of the kidney donor using a process called apheresis. The donor cells are then sent to the University of Louisville to be processed, where researchers enrich for “facilitating cells” believed to help transplants succeed. During the same time period, the recipient undergoes pre-transplant “conditioning,” which includes radiation and chemotherapy to suppress the bone marrow so the donor’s stem cells have more space to grow in the recipient’s body.

Once the facilitating cell-enriched stem cell product has been prepared, it is transported back to Northwestern, where the recipient undergoes a kidney transplant. The donor stem cells are then transplanted one day later and prompt stem cells to form in the marrow from which other specialized blood cells, like immune cells, develop. The goal is to create an environment where two bone marrow systems exist and function in one person. Following transplantation, the recipient takes anti-rejection drugs which are decreased over time with the goal to stop a year after the transplant.

…

Less than two years after her successful kidney transplant, 47-year-old mother and actress Lindsay Porter of Chicago, is living a life that most transplant recipients dream of – she is currently free of anti-rejection medications and says at times, she has to remind herself that she had a kidney transplant. … Doctors are hopeful that Porter will not need immunosuppressive drugs long-term, given her progress thus far.

You might look on this as creating a form of engineered chimerism. We know that some animals and humans exist with, for example, multiple blood types and genetically distinct systems in their body as a result of the fusion of two zygotes in the womb. These individuals don’t seem to suffer any great harm from being chimeric, which might be taken as a promising sign for the long-term prospects of this form of stem cell medicine.

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The Institute for Evidence Based Cryonics is hosting a symposium in Portland in July:

On Saturday July 7, 2012, the Institute for Evidence Based Cryonics and Cryonics Northwest will organize a symposium on cryonics and brain-threatening disorders in Portland, Oregon. The symposium will start at 09:00 am at the offices of Kaos Softwear. Entrance to the event is free.

Some background is provided in another post at the Institute website:

Conventional wisdom in life extension circles is that making cryonics arrangements allows one to benefit from rejuvenation technologies that are not available during one’s existing lifespan. Aside from the risk of high-impact accidents or getting lost at sea, there is one challenge that some cryonicists will face when they grow older; the debilitating consequences of brain-threatening disorders.

One of the unfortunate effects of the increase in human lifespan is a corresponding increase in late-onset identity-destroying brain disorders. We know that some patients at the existing cryonics organizations were cryopreserved after advanced Alzheimer’s disease. Some cryonics organization members who developed Alzheimer’s disease were not preserved at all, due to lapsed insurance and/or cryopreservation arrangements.

The main challenges and risks associated with low-temperature preservation of the brain after death relate to (a) overbearing regulation that prevents sensible end of life decisions and increases risk of a poor preservation, and (b) your removal from the scene as a willful actor, capable of defending your own interests. Neurodegenerative conditions like Alzheimer’s are a special case of point (b) – you are still alive, but become incapable of monitoring affairs to ensure that the course of action you desire is carried out.

All the data of your mind may still be largely intact, as appears to be the case for Alzheimer’s until late in its progression, or it may be progressively and irrevocably destroyed by a disease that will have largely consumed you by the time it kills your body. Either way, a lot of entirely disreputable things happen behind closed doors when family members are close to death and cannot look out for themselves – I’m sure we can all recall a tale or two. Which is all fine and well if it’s just an inheritance fight, but when it means the difference between your brain and the data of your mind preserved well at Alcor or rotting away to guaranteed oblivion … well, that’s a much bigger deal.

These are challenges, given that the best we can do today is to try change the laws that prevent voluntary euthanasia, support research into biotechnologies that can repair the brain, and live an exceedingly healthy life. Many of these issues relating to the brain and cryopreservation could be dealt with if Western governments didn’t force people to live to the bitter end, no matter the personal cost. On the general health side of things, it is true that fit older folk don’t tend to suffer Alzheimer’s, which appears to be just as much a lifestyle disease as type 2 diabetes for most people. There are still any number of other degenerations, however, and even the best kept body and brain deteriorate progressively until death.

So, as people tend to point out, support of cryonics is not a complete alternative to support of medical biotechnology – people who will not live to see the advent of true rejuvenation biotechnologies should still be very interested in medical progress in regenerative medicine and other fields likely to support therapies and methods of preventation for the degeneration of the brain with aging.

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Via EurekAlert!: “Alzheimer’s disease is characterized by abnormal deposits in the brain of the protein Amyloid-ß, which induces the loss of connections between neurons, called synapses. Now, scientists [have] discovered that specific antibodies that block the function of a related protein, called Dkk1, are able to completely suppress the toxic effect of Amyloid-ß on synapses. … Dkk1 is elevated in the brain biopsies of people with Alzheimer’s disease but the significance of these findings was previously unknown. Scientists [have] found that Amyloid-ß causes the production of Dkk1, which in turn induces the dismantling of synapses (the connections between neurons) in the hippocampus, an area of the brain implicated in learning and memory. … scientists conducted experiments to look at the progression of synapse disintegration of the hippocampus after exposure to Amyloid-ß, using brain slices from mice. They were able to monitor how many synapses survived in the presence of a specific antibody which targets Dkk1, compared to how many synapses were viable without the antibody. The results show that the neurons that were exposed to the antibody remained healthy, with no synaptic disintegration.”

Link: http://www.eurekalert.org/pub_releases/2012-03/ucl-sdt030512.php

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If you’ve been reading Fight Aging! for a while, you’ll recall that I’ve discussed organized crowdsourcing of funding of life science research – and longevity science in particular – for a few years now. This is a concept whose time has come: the Internet is providing great transparency and insight into all fields of endeavor, the cost of biotechnology has fallen rapidly to the point at which graduate students and a few tens of thousands of dollars can accomplish meaningful novel research, and crowdsourcing is achieving critical mass in other markets.

So we have ventures like Kickstarter, which is making a name for itself in art, publishing, and manufacturing projects. That is an example of a successful marketplace, where workers and funders can come together to raise sums comparable to pre-angel investments in start up companies – but on their own terms, and usually far better terms.

If you can raise money for books, art projects, and widgets, why not for discrete life science research projects with determined goals? The LongeCity (previously the Immortality Institute) crowd have been trying this for some years, with a great deal of success considering the limited audience of this community in comparison to the audience available through Kickstarter. It is sad but true that far more people are brought to a state of excitedly opening their wallets for the development of an iPhone widget than for any sort of biotechnology project, even one that will contribute to the reversal of aging.

But regardless, the groundwork is laid – this is the time for growth in crowdsourced funding. For the scientific community, the remaining piece of the puzzle at this time would seem to be a viable first marketplace, some Kickstarter-for-science that captures an audience and replicates the success of Kickstarter in this field. Once that is done a single time, then the idea will be accepted by the public and many such ventures can blossom.

Today, I see a fairly professional offering is put forward as a contender: Petridish:

Petridish lets you fund promising research projects and join first hand in new discoveries. World famous researchers post projects and expeditions that need your help to get off the ground. Each project has a minimum threshold it must hit in pledges, or it will not be funded. Backers in successful projects join the team and get insider rewards such as: Early access to news about progress and findings, souvenirs from the field, acknowledgements in journals, naming rights for new discoveries, or the ability to join an expedition in person.

Crowdsourced funding is a tremendously powerful tool for minority research fields – such as the rejuvenation biotechnology of the SENS Foundation. This is true for exactly the same reasons that make it a powerful tool for indie publishers and other entities largely removed from the traditional funding sources in their industry. In fact, the history of the SENS Foundation and Methuselah Foundation has been one long crowdsourced funding effort, launched by the early interest of the transhumanist community and carried onward by a broader community of people who value longer lives enough to do something about it.

What an organization like Petridish can bring to the table, if successful, is a larger audience and a formalism of the crowdsourced funding process that enables it to proceed much more smoothly – and more successfully. There are economies of scale that emerge quite quickly if you want to break down your fundraising into ten small programs rather than one big one, but it takes something like a Petridish or a Kickstarter to make this work well.

I believe that the SENS Foundation folk should contact the Petridish folk and set something up: there is no shortage of discrete, interesting projects that the Foundation would like to undertake, and I think this would be an excellent test of the waters. This is the future of small to mid-sized project funding, both in the sciences and elsewhere: if you want enthusiastic, knowledgeable supporters, then you have to get them more involved in the nuts and bolts of your work – in the small victories and accomplishments that are the foundation of the bigger picture. This is the best way to do that.

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Most known cancer suppression genes and mutations shorten life in laboratory mice, as they suppress the mechanisms of cell replication needed to maintain tissues. There are exceptions that have emerged as researchers find more sophisticated methods of genetic engineering to work around these limitations, but this life-extending example of gene engineering seems to be more straightforward than most: “Mice with an extra dose of a known anti-cancer gene lose weight even as their appetites grow. Not only that, but [the] animals also live longer, and that isn’t just because they aren’t getting cancer, either. … One of the animals’ youthful secrets is hyperactive brown fat, which burns energy instead of storing it. The findings add to evidence that tumor suppressors aren’t designed only to protect us against cancer, the researchers say. They also point to new treatment strategies aimed to boost brown fat and fight aging. … Tumor suppressors are actually genes that have been used by evolution to protect us from all kinds of abnormalities. … In this case, the researchers studied a tumor suppressor commonly lost in human cancers. Mice with an extra copy of the gene known as Pten didn’t get cancer, but that’s not the half of it. Those mice were also leaner, even as they ate more than controls … That suggested that the animals were experiencing some sort of metabolic imbalance – and a beneficial one at that. Cancer protection aside, the animals lived longer than usual. They were also less prone to insulin resistance and had less fat in their livers. Those benefits seem to trace back to the fact that those Pten mice were burning more calories thanks to overactive brown fat.”

Link: http://www.sciencedaily.com/releases/2012/03/120306131252.htm

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Here is one of many clear signs to show that chronic inflammation is something to be avoided: “Inflammation, oxidative damage, and platelet activation are hypothesized biological mechanisms driving the disablement process. The aim of the present study is to assess whether biomarkers representing these mechanisms predicted major adverse health-related events in older persons. … Data are from 2,234 community-dwelling nondisabled older persons enrolled in the Health Aging and Body Composition study. Biomarkers of lipid peroxidation, platelet activation, and inflammation (serum concentrations of interleukin-6) were considered as independent variables of interest and tested in Cox proportional hazard models as predictors of (severe) mobility disability and overall mortality. … The sample’s (women 48.0%, whites 64.3%) mean age was 74.6 (SD 2.9) years. During the follow-up (median 11.4 years), 792 (35.5%), 269 (12.0%), and 942 (42.2%) events of mobility disability, severe mobility disability, and mortality occurred, respectively. … Only interleukin-6 showed significant independent associations with the onset of all the study outcomes. … The inflammatory marker interleukin-6 is confirmed to be a robust predictor for the onset of negative health-related events.”

Link: http://www.ncbi.nlm.nih.gov/pubmed/22389462

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