Fight Aging!

There should be no such thing as "I don't know what to do with my life." Scratch that statement away and erase it, as it should be "I will aid the development of life extension technology until I do know."

It should be no surprise to anyone that many, or perhaps even a majority of people at any given time have no real idea as to what they want to do with their lives. No vision, no grand dream that captures them, no burning desire to achieve a specific great work. That isn't because they are incapable - far from it, it is because they haven't found their own personal blue touch paper yet. The space of ideas and ideals is vast, and even the most aggressively autodidactic internet-addicted polymath cannot embrace more than a fraction of the sphere of human knowledge. Yet you cannot know your grand vision, the one that resonates with everything your life has led to up until that point, if you never encounter its roots.

Which is where we come back to time. We tell the younger folk that it doesn't matter if they don't know what they want to do with their lives, as that knowledge will come with time. The rituals and mythology that spring from the passage from childhood to adulthood, repeated billions of times over the course of history, are as much about expanding horizons as they are about anything else. In our comparatively wealthy modern society, that process of expansion doesn't have to stop when you stop growing in body - except for the fact that we are all limited by the realities of the human condition, and aging in particular.

Our lives have a timer, and we are all well aware of it, for all that many of us prefer not to think about it at all. The whole structure of life and society revolves around the existence of that timer, as it ticks away the freedom we have remaining in which to find and work on something worthwhile. The rush to find meaning in life? There because we don't have enough time. The need to save for retirement and medical costs? The timer again, ticking away our health and ability to fend for ourselves.

When you cannot see even the first shape of what will be your life's work, and time is ticking away, the best thing you can do is to offer a helping hand to those who work on making more time - scientists, advocates, and others who support research and development of rejuvenation biotechnologies. You can do that at the same time as you search for the cause or idea that truly speaks to you, and it beats slumping back into the grey doldrums that seem to afflict so much of our society: people who never found that fire inside, and who have no time left in which to do so.

You have an option that the older folk of previous generations did not: you can help make more time for everyone, more health, more years, and time enough to find meaning in what you do.

Artificial cells are one possible line of future biotechnology; devices built to resemble the body's building blocks, essentially nanomachines constructed of proteins. Here researchers take a modest step in that direction, by developing "a novel method of disguising nanoparticles as red blood cells, which will enable them to evade the body's immune system and deliver cancer-fighting drugs straight to a tumor. ... The method involves collecting the membrane from a red blood cell and wrapping it like a powerful camouflaging cloak around a biodegradable polymer nanoparticle stuffed with a cocktail of small molecule drugs. Nanoparticles are less than 100 nanometers in size, about the same size as a virus. ... This is the first work that combines the natural cell membrane with a synthetic nanoparticle for drug delivery applications. This nanoparticle platform will have little risk of immune response. ... Stealth nanoparticles are already used successfully in clinical cancer treatment to deliver chemotherapy drugs. They are coated in a synthetic material such as polyethylene glycol that creates a protection layer to suppress the immune system so that the nanoparticle has time to deliver its payload. ... today's stealth nanoparticle drug delivery vehicles can circulate in the body for hours compared to the minutes a nanoparticle might survive without this special coating. But in [this latest] study, nanoparticles coated in the membranes of red blood cells circulated in the bodies of lab mice for nearly two days. ... one of the next steps is to develop an approach for large-scale manufacturing of these biomimetic nanoparticles for clinical use. ... Researchers will also add a targeting molecule to the membrane that will enable the particle to seek and bind to cancer cells, and integrate the team's technology for loading drugs into the nanoparticle core so that multiple drugs can be delivered at the same time."

Link: http://www.sciencedaily.com/releases/2011/06/110620161300.htm

From the Technology Review: "The drug rapamycin has been found to reverse the effects of Hutchinson-Gilford progeria syndrome, a fatal genetic disease that resembles rapid aging, in cells taken from patients with the disease. Rapamycin, an immunosuppressant drug used to prevent rejection of transplanted organs, has already been shown to extend life span in healthy mice. Researchers hope the findings will provide new insight into treating progeria as well as other age-related diseases. Skin cells from patients with progeria show a slew of defects: deformities in their membranes, decreased growth, and early death. [Researchers] found that rapamycin could reverse these defects by enhancing the cells' ability to degrade the protein progerin, which accumulates in abnormal amounts in progeria patients. It's not yet clear whether the drug will have similar effects on animals or patients. But progeria researchers are planning a clinical trial of rapamycin. ... Researchers say the findings could be relevant beyond this rare genetic disease. Although accumulation of progerin is associated with progeria, the protein also accumulates in small amounts in normal cells, and may be partially responsible for the aging process."

Link: http://www.technologyreview.com/biomedicine/37916/

As you may know, a range of ways to extend life in nematode worms (such as the common laboratory species Caenorhabditis elegans) involve interfering in the operation of mitochondria. This is also true in a range of other lower animals - mitochondrial operation is apparently strongly coupled to the natural range of longevity enjoyed by a given species. But what are mitochondria? They are a roving swarm of tiny power plants, present inside every cell, and inside each mitochondrion there can be found an array of intricate molecular machinery that gives rise to what is called the electron transport chain. This is a critical component in the process of building stores of chemical energy - in the form of ATP - used to power the operation of the cell. It is alterations in the operation of the electron transport chain that can alter longevity for the better in many species.

A recent open access paper digs into other mechanisms that relate to this link between electron transport chain operation and life span, outlining the discovery of a gene that is necessary for that enhanced longevity:

Mitochondria have long been associated with aging and age-related diseases. Recent research has shown that a slight dampening of mitochondrial function can dramatically increase the lifespan of a wide range of organisms, suggesting that a similar mechanism likely operates in humans. The molecular basis of this observation is largely unknown, however. Uncovering the genes that allow altered mitochondrial function to impact longevity will give us important new insights into how mitochondria affect the aging process and will pave the way for future therapeutic developments aiming to improve healthy aging and to treat age-related diseases.

Here, we used an RNAi screen in the genetic model organism C. elegans, a nematode worm, to uncover how altered mitochondrial function can modulate longevity. We found that in order for mitochondria to affect lifespan, they must communicate with several unique transcription factors in the nucleus. Notably, we discovered that the putative homeobox transcription factor CEH-23, which has not previously been implicated in longevity determination, is able to respond to changes in mitochondrial function and in turn causes an extension in lifespan. ... ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background.

So it looks like some form of programmed response causes the life extension in these methods, and manipulations of the electron transport chain only trigger that response - which is interesting. Not what you might expect, given all the other ways in which mitochondria touch on aging, such as through accumulated damage to their DNA.

A long and fascinating post from Chronosphere details the extensive preparations that go into transporting the body of a cryonics patient for cryopreservation: "Many patients will be remote from the facility where cryoprotective perfusion will be carried out and will be transported by common carrier or private carrier over considerable geographical distances. In some cases it will be possible to move the patient using a specialized transport vehicle with on-going extracorporeal support. In other cases the distances will be sufficiently great that the only realistic option is iced-shipment in the absence of perfusion. It is often necessary to use a commercial air freight service to move the patient from one area of the United States to another (or from one country to another). ... Because of time constraints to get freight loaded rapidly, air freight is often not handled with care by airport personnel. ... Whenever possible, the Transport Technician should supervise the handling of the patient every step of the way, including on and off the aircraft. Due to recent terrorist acts it has become increasingly difficult for the Transport Technician to do this. Until quite recently it was usually easy for the Technician to get access to air freight facilities and the tarmac to supervise loading of the patient onto the aircraft. This is now all but impossible. However, it is still important to accompany the patient to the air freight depot and to emphasize that extra care should be used in handling the patient, and that every precaution should be taken against misrouting."

Link: http://chronopause.com/index.php/2011/06/28/commercial-air-transport-of-the-cryopreservation-patient/

You may recall that composition of cell membranes is strongly correlated to species longevity - the idea being that some membranes are more resistant to the damage of reactive oxygen species than others, and that damage resistance at the cellular level ultimately translates into a longer-lived animal. Here is more on that topic: "This review begins with the premise that an organism's life span is determined by the balance between two countervailing forces: (i) the sum of destabilizing effects and (ii) the sum of protective longevity-assurance processes. Against this backdrop, the role of electrophiles is discussed, both as destabilizing factors and as signals that induce protective responses. Because most biological macromolecules contain nucleophilic centers, electrophiles are particularly reactive and toxic in a biological context. The majority of cellular electrophiles are generated from polyunsaturated fatty acids by a peroxidation chain reaction that is readily triggered by oxygen-centered radicals, but propagates without further input of reactive oxygen species(ROS). Thus, the formation of lipid-derived electrophiles such as 4-hydroxynon-2-enal (4-HNE) is proposed to be relatively insensitive to the level of initiating ROS, but to depend mainly on the availability of peroxidation-susceptible fatty acids. This is consistent with numerous observations that life span is inversely correlated with membrane peroxidizability and with the hypothesis that 4-HNE may constitute the mechanistic link between high susceptibility of membrane lipids to peroxidation and shortened life span. Experimental interventions that directly alter membrane composition (and thus their peroxidizability) or modulate 4-HNE levels have the expected effects on life span, establishing that the connection is not only correlative but causal. Specific molecular mechanisms are considered, by which 4-HNE could (i) destabilize biological systems via nontargeted reactions with cellular macromolecules and (ii) modulate signaling pathways that control longevity-assurance mechanisms."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21708248

Type 2 diabetes is the poster child for an avoidable age-related condition: barring the worst of genetic bad luck, calorie restricted, well exercised people will not suffer from type 2 diabetes. But this is, undeniably, an age-related illness. Becoming ever more obese and sedentary will hasten the onset of diabetes into ever earlier years of life, but older obese and sedentary people are still far more likely to suffer type 2 diabetes than are equally overweight and sedentary younger counterparts. So while failing to take care of your health at any age is just another form of self-harm, there are other, less avoidable processes taking place at the level of cells and organs that make older people more vulnerable.

Here is an open access paper that reviews what researchers presently know of the decline of insulin-producing beta cells in the pancreas - which turns out to be not enough, as is still true of so much of our biochemistry. There are changes, cataloged and identified, but the chains of causation for those changes are poorly understood at best.

Type 2 Diabetes and the Aging Pancreatic Beta Cell

An increased incidence of diabetes is observed with age, and there are many possibly reasons for this. One of these is that the beta cell has reduced proliferative capacity and in diabetic individuals this is further confounded by higher rates of beta cell apoptosis. The currently known underlying mechanisms behind the reduction in beta cell proliferation observed with age include reduced expression of cell cycle activators, increased expression of cell cycle inhibitors, reduced pdx1 expression, and increased amylin aggregation. Studying aging in the non-diabetic rodent and human models is currently a developing field; therefore very few broad conclusions can be drawn. Further study in these areas is important as they could indicate targets for preventing or slowing the progression of diabetes with age.

I look on this as a good illustration of why the detailed, tissue by tissue, understand everything approach to repairing aging is doomed to take a very long time indeed. This is but one population of vital cells in one organ, one of the most studied forms of cell in past decades, and the research community remains far from a complete understanding as to how and why they fail with age.

Better strategies to deal with aging exist - such as SENS - and need to gain wider support and adoption. SENS-like approaches work around the challenge posed by the sheer complexity of human biochemistry by focusing on the known common mechanisms of aging, the root causes from which there is good reason to believe all other changes descend. Repairing these root causes is the fast path to the first generation of rejuvenation biotechnology, and that, in my eyes, is the only real shot at building viable interventions in the aging process that will arrive in time to help us.

A number of interesting studies on lithium have turned up in recent years, such as its possible association with longevity in humans. Here researchers are testing it against Parkinson's disease: "A two-year study of the effects of lithium treatment on Parkinson's disease in mice has given researchers at the Buck Institute for Research on Aging hope that the drug may halt brain damage in humans with the degenerative disorder. The research found that lithium, the Food and Drug Administration-approved drug most commonly used to treat bipolar disorder, 'profoundly prevents the aggregation of toxic proteins and cell loss associated with Parkinson's disease' in mice. ... In the last couple of years, there's been kind of a growing body of data that suggests that lithium could have some neuroprotective effects ... Other diseases lithium treatment may benefit include Alzheimer's, Huntington's and Lou Gehrig's. ... In addition, recent studies have suggested that the naturally occurring substance may extend life span. ... The group is now doing preclinical research on dose level and other issues and hopes to raise funds for a clinical trial with humans as soon as possible. ... Nonetheless, it is too early to draw conclusions, [as] medications that appear to halt Parkinson's in animals don't necessarily work the same way in humans. Lithium's potential for toxicity is also of concern, particularly because Parkinson's patients are often quite fragile, he said. In at least two known cases, toxic levels of the drug have actually caused Parkinson's."

Link: http://www.mercurynews.com/health/ci_18361882

Via EurekAlert!: researchers "have identified a new stem cell that participates in the repair of the large airways of the lungs, which play a vital role in protecting the body from infectious agents and toxins in the environment. The airways protect the body by producing and clearing mucus from the airways. The mucus is largely produced by specialized mucus glands in the airway and the mechanisms of normal and excessive mucus production are not well understood. However, this newly discovered lung stem cell for the mucus glands will likely yield new insights into this critical process. ... The study [represents] the first time anyone has found the cell of origin for the many types of cells that make up the mucus glands and that can also repair the surface epithelium. The finding, the study states, is of 'major importance to the field of lung regeneration.' ... For example, there currently are no treatments for excess mucus production, which we see in cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). But if we can understand the mechanisms of how these stem cells repair the mucus glands, then we may be able to find a way to put the brakes on the system and prevent mucus over production."

Link: http://www.eurekalert.org/pub_releases/2011-06/uoc--usc062711.php

Tissue engineering of larger blood vessels has started to move more rapidly these past couple of years - this is the sort of work in which the vessels are constructed individually for implantation, rather than the very different approaches taken for capillaries and other small vessels that are essential in building three dimensional tissue of any meaningful size. News of a recent trial of blood vessel transplantation has been in the press today, and links to a couple of representative articles follow.

Blood Vessels Grown in Lab Safely Used in Dialysis Patients

Blood vessels grown in a laboratory were safely implanted in three kidney disease patients, enabling them to have regular dialysis without relying on traditional shunts that caused complications and failed, researchers said. The foot-long vessels were engineered from donor skin cells, grown on sheets and rolled around temporary supports to form a cylindrical shape.

...

The engineered vessels had about a two-month storage life before they were implanted in the patients, he said. They have held up in mechanical and animal tests when used more than a year after they were made, he said. The grafts don't appear to trigger a response from the patients' immune systems, eliminating the need for powerful immune suppressing drugs and tests to match the cells used in the graft to the patients' tissue type, he said.

Diabetics Get Blood Vessels Made From Donor Cells

"This version, built from a master donor, is available off the shelf and at a dramatically reduced cost," estimated at $6,000 to $10,000, said Todd McAllister, chief of Cytograft Tissue Engineering Inc., the San Francisco-area company leading the work.

...

In 2005, Cytograft reported success with its first attempt at dialysis shunts using patients' own skin. Some of the early work was sponsored by the National Heart, Lung and Blood Institute. The new work, using donor cells, makes this advance more practical for wide use ... Cytograft plans a study in Europe and South America comparing 40 patients getting the lab-grown vessels to 20 getting plastic shunts. Studies also are planned on a mesh version for people with poor leg circulation.

You might compare this approach with a range of other strategies, such as the use of bioprinting technologies, or decellularization of donor blood vessels. A range of viable approaches all competing against one another is a sign of a healthy field of human endeavor.

This paper can be filed alongside those that show no benefit from the use of ingested antioxidants: "Although multivitamin/mineral supplements are commonly used in the United States, the efficacy of these supplements in preventing chronic disease or premature death is unclear. To assess the relation of multivitamin use with mortality and cancer, the authors prospectively examined these associations among 182,099 participants enrolled in the Multiethnic Cohort Study between 1993 and 1996 in Hawaii and California. During an average 11 years of follow-up, 28,851 deaths were identified. In Cox proportional hazards models controlling for tobacco use and other potential confounders, no associations were found between multivitamin use and mortality from all causes (for users vs. nonusers: hazard ratio = 1.07, 95% confidence interval: 0.96, 1.19 for men; hazard ratio = 0.96, 95% confidence interval: 0.85, 1.09 for women), cardiovascular diseases, or cancer. The findings did not vary across subgroups by ethnicity, age, body mass index, preexisting illness, single vitamin/mineral supplement use, hormone replacement therapy use, and smoking status. There also was no evidence indicating that multivitamin use was associated with risk of cancer, overall or at major sites, such as lung, colorectum, prostate, and breast. In conclusion, there was no clear decrease or increase in mortality from all causes, cardiovascular disease, or cancer and in morbidity from overall or major cancers among multivitamin supplement users."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21343248

From the SENS Foundation: "Neurofibrillary tangles (NFT -- cytoplasmic inclusions composed of phosphorylated and abnormally-cleaved species of tau protein) accumulate in the aging brain, and at higher levels in Alzheimer's disease and in vulnerable regions in a range of other neurodegenerative diseases. ... [Researchers] have tested immunotherapies targeting tau aggregates in preclinical models of neurodegeneration caused by pathological tau species. .... Vaccination with human phosphorylated tau led to the clearance of tau pathology from the brains of immunized mice [and] In turn, these reductions in abnormal tau species were clearly linked to substantial improvements in cognitive deficits. This is an impressive advance. The authors have used vaccination with a human phosphorylated tau immunogen to effect the immunologic clearance of pathological tau aggregates associated with Alzheimer's disease, in a mouse model expressing wild-type human tau. They have intervened late, months after the initial development of cognitive deficits. ... the vaccine has not only elicited a robust immunological response, and cleared pathological tau species from brain regions of relevance to human disease, but have linked such clearance to improved cognitive function on several extensively-used tests. The new work is strong support for the therapeutic importance and tractability of the removal of pathological tau species from the brain - in Alzheimer's disease, in other tauopathies, and in the 'normal' degeneration of the aging brain. And it is yet another in a mounting series of reports offering support for the therapeutic heuristic of removing the damage of aging, to effect the rejuvenation of the body - and the mind."

Link: http://sens.org/node/2207

I'm pleased to see that the Immortality Institute / Longecity has completed fundraising for their latest project, an investigation of the potential benefits of microglia transplants in the aging brain:

After months of fundraising we are now delighted to announce that the project has started! Through many donations large and small, the community has raised sufficient funds to initiate the project. Last month, we passed the 80% mark and knew that full success would only be a matter of time. Then, something amazing happened: though promoting this effort, a far sighted investor has stepped forward who can see the potential in developing this research project. The angel [committed] a substantial contribution towards a research arm that is closely aligned to the project LongeCity is funding. Thus, we have achieved something amazing together: every dollar donated to this life extension research project has not only been doubled through internal funds but multiplied manifold! Few people, especially those with very limited personal means, who want to invest in life extension would find such effective opportunities to make a real difference.

Which is good news all round. I've mentioned this effort in past months, so you can head on back into the archives for more details on the funded research. We live in an age in which a large range of meaningful early-stage work in biotechnology can be performed for comparatively little money - a few tens of thousands of dollars, or less. A single young researcher with lab access can validate theories, determine whether a line of research has promise, or make new connections in a field - and all in a matter of a few months to half a year of work, as one of a number of ongoing projects.

Most importantly, the new reality of low costs means that people of everyday means can band together in small associations to fund the research that they find important, on a project by project basis. This sort of grassroots, bottom-up organization is greatly aided by the internet, but crowdsourced philanthropy for science in detail is only just in its infancy. Projects like those undertaken by the Immortality Institute volunteers are the first signs of the true future of research funding - a detailed and glorious patchwork in which everyone can pick and choose the exact projects they wish to fund, and in doing so learn more about the science behind the causes they support.

Another sign of progress in this direction is the creation of dedicated crowdsourced scientific philanthropy initiatives like FundScience, which has actually been around for a couple of years, and will be holding a meetup on July 15th in the Bay Area:

FundScience was formed to get the public invested in science. We aim to accomplish two goals:

1. Provide a way for scientists and researchers to self fund their research by crowd funding.

2. Bring people closer to science by providing an insight into research activities done across the globe.

In addition to staying in touch with scientific activity via FundScience.org , we are launching monthly meetups to give you an opportunity to get to know your favorite researchers in person. Come find out how you can be a part of their amazing work.

I co-founded FundScience a few years ago with the hope of getting the public invested in science. We had two goals when we began. The first was to get much needed funding and guidance to young researchers. The other was to get non-scientists to interact with researchers and understand the research process. Our first round of projects was selected and posted on the site late last year. In keeping with our goal of bringing science to the masses we've decided to complement our online presence with a monthly meetup were we can get researchers to discuss their advancements and get non-scientists to come and ask questions, interact and fund some projects.

There are a fair number of philanthropic ventures that help funnel dollars from many donors to worthy causes, such as Philanthroper for example, but still very few ventures that take the next step of breaking things down into fine-grained projects. Much of the wall between the broader charitable public and the details of the work they support is, I feel, unnecessary. The faster it evaporates the better off we'll all be.

Type 2 diabetes is as close to a disease of choice as you're likely to find: provided that you adopt a sensible lifestyle of good diet and exercise then you are never going to suffer the condition, barring extremely bad luck in your genes. Similarly, if you are headed down the path towards diabetes, you can turn back by changing the way you live your life. Here's evidence that the turn can be made quite late if made aggressively enough: "An extreme eight-week diet of 600 calories a day can reverse Type 2 diabetes in people newly diagnosed with the disease .... the low-calorie diet reduced fat levels in the pancreas and liver, which helped insulin production return to normal. Seven out of 11 people studied were free of diabetes three months later. ... More research is needed to see whether the reversal is permanent, say experts. ... The 11 participants in the study were all diagnosed with Type 2 diabetes within the previous four years. They cut their food intake drastically for two months, eating only liquid diet drinks and non-starchy vegetables. ... After one week of the diet, researchers found that the pre-breakfast blood sugar levels of all participants had returned to normal. MRI scans of their pancreases also revealed that the fat levels in the organ had decreased from around 8% - an elevated level - to a more normal 6%. Three months after the end of the diet, when participants had returned to eating normally and received advice on healthy eating and portion size, most no longer suffered from the condition. ... This diet was only used to test the hypothesis that if people lose substantial weight they will lose their diabetes. Although this study involved people diagnosed with diabetes within the last four years, there is potential for people with longer-standing diabetes to turn things around too."

Link: http://www.bbc.co.uk/news/health-13887909

Lower forms of life have stages that don't exist in higher animals - such as meiosis in yeast, or the dauer stage in nematodes. Researchers have found they can manipulate longevity by manipulating the molecular machinery associated with these states, but it's generally felt that this is of lesser relevance to mammals. Here is an example of the type: "Human cells have a finite lifespan: They can only divide a certain number of times before they die. However, that lifespan is reset when reproductive cells are formed, which is why the children of a 20-year-old man have the same life expectancy as those of an 80-year-old man. How that resetting occurs in human cells is not known, but MIT biologists have now found a gene that appears to control this process in yeast. Furthermore, by turning on that gene in aged yeast cells, they were able to double their usual lifespan. ... When yeast cells reproduce, they undergo a special type of cell division called meiosis, which produces spores. The MIT team found that the signs of cellular aging disappear at the very end of meiosis. ... The researchers discovered that a gene called NDT80 is activated at the same time that the rejuvenation occurs. When they turned on this gene in aged cells that were not reproducing, the cells lived twice as long as normal. ... In aged cells with activated NDT80, the nucleolar damage was the only age-related change that disappeared. That suggests that nucleolar changes are the primary force behind the aging process." Which is an interesting conclusion, but given all the other evidence for mechanisms of aging in mammals, I'm not sure it's going to translate well into higher animals.

Link: http://web.mit.edu/newsoffice/2011/cell-aging-0624.html

I stumbled across an interesting post on life, death, and cryonics today:

A deathist is someone who tells you death is good, natural, and somehow right. If you can truly trick yourself into thinking they're correct then good luck with your funerary planning. I, for one, disagree.

...

Humans have made tremendous advances over the past twenty years. And unless you believe all progress will stop, as if nothing new can be learned, then chances are good cryonics will increasingly be a short term means to heal and repair damage instead of the long-term suspension it is today. What cryonics does is provide the time to find causes and treatments. It is a chance to continue your life. To extend your life. To improve your quality of life.

If it doesn't work you're no more dead than if you did nothing. But some chance is better than no chance. [So] don't dispair. Don't give up. Never allow anyone to bury you so they feel better. You won't be there to care. You will be forgotten.

Name any random non-famous soldier from a past war who was told they would be remembered. How many grave markers in Arlington stand in quiet solitude because no one remembers, is alive, or cares to visit? How many of these lonely markers exist in local cemeteries? Name anyone you don't know via blood, friendship, or fame who has died in the past 50 years. Chances are good you can't. We lie to ourselves and each other to feel better when what we should do is work toward never having to lie in the first place.

Funerals and monuments are made by the living for the living. The world belongs the living, and the dead are slipped from it from the very moment of their demise. There are, as the author points out above, so very many ways in which we lie to and indulge ourselves in relation to the deaths of those we know and those we never knew - and none of it helps one bit when it comes to making things better for the future.

Death, the suffering that leads up to it, and the material loss left in its wake, are horrors that we should be working harder to eliminate. We know that it is possible to build rejuvenation biotechnologies, and we know in some detail how to do it. We know that is is possible to preserve the fine structure of the brain sufficiently well to preserve the mind, and possible to do just that for near every dying person. These things are well within the laws of physics as we understand them, and economically viable projects - yet very, very few people in this world of ours are working to make these visions a reality.

A cautious popular science article on calorie restriction: "Caloric restriction as a research discipline has actually been around for ages. The first demonstration of extending lifespan and improving health in rats by cutting calories was back in 1934, and since then the finding has been repeated in numerous species up to and including non-human primates. Animals subjected to caloric restriction while maintaining adequate vitamin, mineral, and protein intakes not only live longer, healthier lives, they also maintain vitality to an older age and have fewer visible signs of aging - such as white fur - compared to better-fed siblings. It is worth noting that we are not just talking about shedding a few pounds here. Animal studies show that, almost up to the point of frank starvation, the more calorie restriction the better when it comes to extending lifespan and health. ... Virtually every animal study ever done on caloric restriction has shown benefits for health and longevity, and now we have emerging studies showing that even intermittent caloric restriction may be beneficial, so it would be almost surprising if humans turned out to be the only species to have a negative response. Unlike research animals, however, humans don't live alone in pre-paid houses with the right kind of food carefully provided by scientists, so if caloric restriction is to be a feasible strategy for maintaining health as we age it has to be feasible to implement - in other words, doable and practical in real lives in the real world." People who write about calorie restriction without having made a serious attempt at trying it invariably exaggerate the difficulty. Practicing calorie restriction is both "doable and practical," and requires no more investment of time and willpower than any modestly challenging hobby.

Link: http://www.thedailybeast.com/articles/2011/06/18/caloric-restriction-the-science-of-eating-less-and-living-longer.html

From the IEET: "The focus of the 40th annual meeting of the American Aging Association, held a few weeks ago in North Carolina, was emerging concepts in the mechanisms of aging. Most of the usual topics in aging were covered, such as dietary restriction, inflammation, stress resistance, homeostasis and proteasome activity, sarcopenia, and neural degeneration. Newer methods like microRNAs and genome sequencing were employed to investigate gene expression variance with aging and genetic signatures of longevity. Aging as a field continues to mature including by using a systems approach to tracing conserved pathways across organisms, sharpening definitions of sarcopenia, frailty, and healthspan, and distinguishing interventions by age tier (early-onset versus late-onset). A pre-conference session on late-onset intervention concluded that there are numerous benefits to deriving such interventions."

Link: http://ieet.org/index.php/IEET/more/swan20110622

You have at least two ages: your chronological age, how long you have lived, and what we might call your biological age - which is a measure of how damaged you are. Aging, meaning the process of physical degeneration, is really just a matter of damage at the level of cells and molecular machinery. The more damage, the greater your biological age. If you are 56, you might have the damage load of the average 50 year old or the average 60 year old. Or worse, or better - and in either case that will reflect in your current health and remaining life span.

In actual fact, biological age is probably far more complex than this. There is every reason to expect different systems in your body to suffer different rates of damage accumultion. Consider the immune system in AIDS patients for example, which is prematurely aged into exhaustion and frailty. That is an extreme example of differential rates of damage: you would expect to find smaller differences in levels of accumulated damage in the biological components of a healthy person. But the differences are there.

Recognize that a lot of what I have said above is theory. Anyone who claims to be able to measure your biological age is largely blowing smoke: there's no standard for such a thing, and not much in the way of biomarkers of aging. Biomarkers are measurable aspects of our biology that can be scaled against age or remaining life expectancy - and so might be used to determine a subject's chronological age, or how much longer they might expect to live. The absence of good biomarkers poses a strategic challenge for the ongoing development of longevity science, because in order to efficiently evaluate a potential therapy to slow or reverse aging, researchers need to rapidly understand its actual effects on healthy life span. Sitting around and waiting is the only presently foolproof strategy, and that is one of the reasons that even mouse studies of longevity therapies are very expensive. No-one wants to run an experiment for going on four years if there is a way to call a halt after a few months and some biomarker measurements.

That difference in experimental run time represents a large sum of money in every sizable study, not to mention the opportunity cost in research that might otherwise move ahead, but must wait for years for results to arrive. Further, when you stop to consider human studies, you'll see that that the present state of affairs rules out a wide range of possible trials - "wait and see" isn't viable when the time frame is decades. This is why we should all be interested in progress towards the establishment of biomarkers for aging, and today I'll point you to recent work on DNA methylation, undertaken with that aim in mind. You might recall that DNA methylation correlates with age and age-related frailty, and here researchers greatly improve upon the precision of that correlation.

UCLA scientists accurately predict age with saliva sample:

Using saliva samples contributed by 34 pairs of identical male twins ages 21 to 55, UCLA researchers scoured the men's genomes and identified 88 sites on the DNA that strongly correlated methylation to age. They replicated their findings in a general population of 31 men and 29 women aged 18 to 70. ... Vilain and his team envision the test becoming a forensic tool in crime-scene investigations. By analyzing the traces of saliva left in a tooth bite or on a coffee cup, lab experts could narrow the age of a criminal suspect to a five-year range.

Epigenetic Predictor of Age:

From the moment of conception, we begin to age. A decay of cellular structures, gene regulation, and DNA sequence ages cells and organisms. DNA methylation patterns change with increasing age and contribute to age related disease. Here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. Furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. The methylation of three sites - in the promoters of the EDARADD, TOM1L1, and NPTX2 genes - is linear with age over a range of five decades. Using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years.

There are some subtleties here. DNA methylation occurs in different regions of DNA at different rates (and probably at different rates in the same region of DNA in cells in different locations in the body). The researchers here have found a statistical model based on methylation of a few specific genes in one portion of the body that is a biomarker of chronological age. For our purposes that is the less useful biomarker: we want one that measures remaining life expectancy, or in other words a biomarker that is effectively a measure of present levels of biological damage.

We know that methylation patterns correlate with age-related frailty. There is every reason to expect that researchers will soon be able to build a range of statistical measures based on DNA methylation that will predict remaining life expectancy across most common states of health and ages. The research described above gives further weight to that expectation.

It is good to see that cryonics is now sufficiently widely known that business magazines are willing to write articles on the financial engineering and legal explorations associated with establishing a successful cryopreservation: "Financial planning, like most disciplines, generally relies on the assumption that the dead will remain that way. Some people, however, are not as willing to accept this premise. Cryonicists believe science will eventually give us the ability to reanimate the dead. In preparation for this possibility, they elect to have their bodies, or sometimes merely their heads, stored in extreme low temperatures so that, when the time comes, they can be restored to life. Some anticipate a future in which their bodies will be thawed and cured of their ailments, while others see the process as akin to data storage, preserving the organic record of their thoughts and memories until these can be downloaded onto some new medium. ... the legal and financial questions surrounding cryonics require serious believers to make plans in the present, before they start their hiatus. Since cryonics remains well outside the mainstream, most end-of-life matters have yet to be thought through as temporary-suspension-of-life concerns. Ordinarily, at death, social security numbers are cancelled and made public, and citizenship privileges such as voting are revoked (at least in most jurisdictions). What would the temporarily dead need to do to put their legal status on ice along with their bodies?" If you want a serious consideration of the details, you might look at some of Rudi Hoffman's articles on cryonics and financial planning.

Link: http://www.businessinsider.com/financial-planning-for-the-formerly-deceased-2011-5

At Forbes, a profile of one of the Thiel Fellowship recipients who focuses on longevity science: "Deming started working in a research lab when she was 12, enrolled at MIT at age 14 and last month, the now 17 year-old was awarded one of 24 $100,000 Thiel Foundation Fellowships for her work in the realm of anti-aging, specifically efforts to identify the genes that control aging and to use discoveries about age-defying therapies effective in worms to unlock the key to extending the human lifespan ... I had a fantastic childhood. Growing up, I had complete freedom to investigate whatever I was interested in, so I puzzled around with math and science, and got hooked on biology. When I was 12, Cynthia Kenyon, one of the coolest people I know, let me come to her lab. She works with a wonderful little worm called C. elegans, so I got to spend the next few years peering down a microscope at the fascinating critters. Then I went to MIT. I'm leaving as a physics major after a whirlwind couple of years spent exploring the magical properties of the quantum realm. ... 'I'd been mulling over what to do after college. The optimal scenario I came up with was exactly what the 20 Under 20 program offers; an opportunity to spend two years working to extend the human healthspan.' She will take up her award in the fall and will initially focus on identifying promising anti-aging research projects that are close to commercialization."

Link: http://blogs.forbes.com/jmaureenhenderson/2011/06/20/meet-the-teen-who-got-paid-100-000-to-drop-out-of-school/

Modern advocacy for engineered longevity and methods of preventing permanent death (such as cryonics) began in earnest in the 1970s, give or take, and has thus been around for long enough to establish a distinct and fascinating cultural past that most younger people are unaware of. The last decades of the last century are being buried rapidly indeed. The more thoughtful older folk who lived through that past there are sponsoring a growing range of initiatives to help ensure the continuation and growth of this present community of advocates, supporters, writers, and researchers. It is in everyone's interest for there to be more people working on human life extension, talking about it, and advocating for longer, healthier lives.

In this sense, the future is something that is constructed, not something that just unfolds without any effort on anyone's part - and that includes the future of communities. If there is growth it is because people planned carefully and worked hard to create that growth. Following this theme, in recent posts over at Depressed Metabolism you'll find both a little of the past and a little of the present work to build the future of the cryonics community:

Gerald Feinberg on physics and life extension

Gerald Feinberg, a Columbia university physicist who, among other things, hypothesized the existence of the muon neutrino, had a strong interest in the future of science and life extension. In 1966 he published the article "Physics and Life Prolongation" in Physics Today in which he reviews cryobiology research ... Feinberg recognized that it might be possible for people dying today to benefit from future advances in science in the absence of perfected techniques.

Teens & Twenties 2011 Gathering

On the evening of Thursday, May 19 and on Friday, May 20, I attended the 2011 (2nd annual) Teens & Twenties young cryonicists gathering which preceded the Suspended Animation, Inc. conference in Fort Lauderdale, Florida.

...

Many members of this group were impressively highly educated, mostly in computer technologies, and secondarily in biotechnologies. There were six Russians: five from KrioRus, and one from CryoFreedom. KrioRus is located near Moscow, whereas CryoFreedom is further south in Russia, closer to Ukraine. Dr. Yuri Pichugin (formerly the Cryonics Institute's cryobiologist), is associated with CryoFreedom. CryoFreedom advertises neuropreservation for $7,500. Although it currently has no human patients, two pets are in liquid nitrogen. I also learned that there is a man named Eugen Shumilov who is working to start a new cryonics company in St. Petersburg, Russia, but there was no representation of Shumilov's organization at this event.

There are two overlapping goals of the Teens & Twenties event. One is the opportunity for members of the Asset Presevation Group to meet the young cryonicists. The other is the opportunity for the widely dispersed young cryonicists to become acquainted with each other, and to build lasting networks (community building).

A little more on efforts to help build the next generation of cryonics supporters, advocates, and engineers can be found back in the Fight Aging! archives:

• The 2nd Annual Young Cryonicists Gathering
• Reports From a Youthful Cryonics Meeting

You might recall that age-related issues with the body's processing of the dietary amino acid leucine were implicated as a possible contributing cause of sarcopenia, the progressive loss of muscle mass with age. More leucine in the diet seemed to be a possible treatment - here that is tried for cancer patients, with a generally positive outcome: "Maintenance of muscle mass is crucial to improving outcome and quality of life in cancer patients. Stimulating muscle protein synthesis is the metabolic basis for maintaining muscle mass, but in cancer patients normal dietary intake has minimal effects on muscle protein synthesis. Adding leucine to high protein supplements stimulates muscle protein synthesis in healthy older subjects. The objective was to determine if a specially formulated medical food, high in leucine and protein, stimulates muscle protein synthesis acutely in individuals with cancer to a greater extent than a conventional medical food. ... . Ingestion of the experimental medical food increased muscle protein [synthesis]. In contrast, ingestion of the control medical food did not ... Conclusions: In cancer patients, conventional nutritional supplementation is ineffective in stimulating muscle protein synthesis. This anabolic resistance can be overcome with a specially formulated nutritional supplement."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21683485

A possible strategy for regrowing muscle lost to injury: "Cpl. Isaias Hernandez was 19 when he lost 70 percent of the muscles in his right thigh, and doctors initially recommended amputation ... But Hernandez worked with researchers at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, who were able to seed his remaining muscles with a cocktail of proteins and growth factors derived from pig bladders. ... [Researchers are working to] develop an implantable extracellular matrix that can re-grow tissue. The matrix is a biological scaffold, enriched with proteins and growth factors, which recruits stem cells and other cell precursors to the site of the injury. ... The therapy stimulates further tissue regeneration, essentially rebuilding the lost muscle. Skeletal muscle does not normally regenerate after an accident, so the ability to re-grow this tissue, complete with nerve branches and tendons, would be a real breakthrough. ... Before injecting the extracellular matrix, doctors had him perform a rigorous exercise regimen to build up his remaining leg muscle ... Then surgeons made an incision in his thigh and inserted the matrix. After a few weeks, Hernandez's leg began growing 'in bulk and strength.'" This is a similar strategy to that used to regenerate a fingertip some years ago - a result that hasn't been replicated to date. This may renew interest in the work in the broader research community.

Link: http://www.popsci.com/science/article/2011-06/tissue-engineers-regenerate-muscle-cells-saving-afghanistan-veteran%E2%80%99s-leg

It is not controversial to state that the practice of calorie restriction slows aging - the evidence is overwhelming, and the most important remaining open questions relate to the degree to which it slows aging in humans, and how that effect manifests in health in later life. Are you practicing calorie restriction? It is certainly something you should look into - or at least discuss with your physician.

That said, there are still a near endless series of explorations that might take place into the biology of aging and how it changes with calorie restriction. The greater the capabilities of modern biotechnology, the more that opportunities open up for further and deeper detailed examination of the way in which humans work, and the way in which we change over time. The complexity of any given system in our biology is staggering - which is one of the reasons why we should pay more attention to research strategies like SENS, which explicitly seek to work around this complexity and achieve meaningful results in healthy life extension more quickly than would otherwise be the case.

Calorie restriction slows aging in most species tested to date, so we should expect to see more or less any arbitrarily picked set of changes in biology slowed by calorie restriction in those species. Here is an example from the kidney:

Chronic kidney disease and end-stage renal disease are major causes of morbidity and mortality that are seen far more commonly in the aged population. Interestingly, kidney function declines during aging even in the absence of underlying renal disease. Declining renal function has been associated with age-related cellular damage and dysfunction with reports of increased levels of apoptosis, necrosis, and inflammation in the aged kidney. Bioactive sphingolipids have been shown to regulate these same cellular processes, and have also been suggested to play a role in aging and cellular senescence.

...

We hypothesized that alterations in kidney sphingolipids play a role in the declining kidney function that occurs during aging. ... Importantly, caloric restriction, previously shown to prevent the declining kidney function seen in aging, inhibits accumulation of [two sphingolipids examined in this study] and prevents the age-associated elevation of enzymes involved in their synthesis.

Aging is, in the broadest sense, the accumulation of damage to our cells and the molecular machinery that lies within. Calorie restriction appears, at the very least, to enhance cellular repair mechanisms - one of the strongest indications for this to be the case is the work showing that calorie restriction stops working if the most important of those mechanisms is disabled. More repair means less accumulated damage, and thus a longer life expectancy. That, at least, appears to be the easily stated high level effect of a very complex and as yet not fully understood set of evolved metabolic processes present in most species - all of which are set in motion by the simple planned action of eating less while still obtaining optimal nutrition.

No medical technology can do as much for the healthy as calorie restriction. Which is a depressing state of affairs when you stop to think about it: we stand in the midst of a revolution in biotechnology, and as yet we don't have rejuvenation medicine. A great deal of work remains to be accomplished, for all that we can clearly see the road ahead, and describe in detail the technologies capable of reversing the effects of aging.

A general interest article on immunotherapy from the Wall Street Journal: "Scientists are scrambling to develop medications that fight cancer by spurring the body's immune system, a form of treatment that some cancer specialists believe may hold the key to keeping a patient permanently disease-free. ... immunotherapy drugs are being developed for a number of other cancers, including lung, brain and kidney cancers. Unlike most traditional therapies that attack a cancer directly, immunotherapy uses the body's own internal defenses to ward off the disease, with the ultimate hope of building up a long-term resistance to the cancer. ... The growing interest in immunotherapy comes even as traditional cancer-targeting drugs have become more effective. Still, such drugs often just delay the ultimate recurrence of the disease as tumors develop resistance to the treatment, or some cancer cells survive the therapy and regrow. The hope is that the immune system's long-term activity against the cancer could stop this cycle. ... Immunotherapies can work in several ways. They can help the immune system increase its response so that it fights the cancer better; they can stop cancers from slowing down or halting the immune system's activation; or they can help the immune system find the tumor and kill it. ... The idea of using the immune system first drew significant research attention in the mid- to late-1990s, but multiple failures led to widespread discouragement ... Developments in recent years have produced the momentum that researchers believe will allow it to reach the next level of more powerful treatments and, ultimately, their combination with both traditional drugs and other immunotherapies."

Link: http://online.wsj.com/article/SB10001424052702304778304576377892911572686.html

A good demonstrations of the promise of immune therapies, training the immune system to destroy very specific types of cell: researchers "cured well-established prostate tumors in mice using a human vaccine with no apparent side effects. This novel cancer treatment approach encourages the immune system to rid itself of prostate tumors without assistance from toxic chemotherapies and radiation treatments. Such a treatment model could some day help people to live tumor free with fewer side effects than those experienced from current therapies. ... We are hopeful that this will overcome some of the major hurdles which we have seen with immunotherapy cancer research ... Among the team's findings: no trace of autoimmune diseases in the mice. The murine T-cells attacked only cancerous prostate cells, leaving the healthy tissue unharmed. To develop this new approach, geneticists assembled snippets of genetic code from healthy human prostate tissue into a complementary DNA (cDNA) library. These bits of cDNA were then inserted into a swarm of vesicular stomatitis viruses (VSV), which were cultured and reintroduced into the test mice as a vaccine during a series of intravenous injections. Development of comprehensive cDNA libraries from healthy human prostate tissue represents the key to successful immunotherapy. All infections, allergens and tissues, including tumors, have a unique fingerprint called an antigen - a molecular protein tag that triggers a response from the body's immune system. [Researchers] deployed the human vaccine prostate cancer antigens through the mutated VSV vector to raise a full-on assault from the mice's T-cells. After exposure to the mutated viruses, the animals' immune systems recognized the antigens expressed in the virus and produced a potent immune response to attack the prostate tumors."

Link: http://www.eurekalert.org/pub_releases/2011-06/mc-mcr061411.php

Allow me to point you to an attractively blunt assessment of the human condition from the Russian end of the rejuvenation research advocacy community, tidied up a little after the automated translation made a hash of it:

Needless to say, a catastrophe - something unpleasant. Global catastrophe - unpleasant globally. And what is the most global of global catastrophes? Probably the one that leads to widespread death. And here we must note that if nothing is done, then all living people will die with 100% probability. Of aging. Therefore, it is aging that is the global catastrophe that is unfolding silently throughout the course of human history.

"Unfolding silently" because nearly everyone in the world studiously refuses to characterize the consequences of aging for what they in fact are. Everyone will die of aging - everyone! - and that is somehow removed from the normal fervor and unified efforts that greet any other form of mass death. Take the tsunamis of recent years, for example, one of which managed to kill about as many people as die of aging in any given day. There was a global outpouring of funds, support, and activity following that tsunami. Yet every day, without cease, that many people again are killed by the effects of aging - and next to no-one cares enough to do something in response to this horrible ongoing loss of life.

This is an age of biotechnology, in which we have a good grasp on the causes of degenerative aging and how to approach treating them. The goal of producing medical technologies that can rejuvenate the old and grant additional decades of life might be accomplished within a few decades, given billions of dollars in funding and and tens of thousands of researchers and supporting workers. But that support doesn't exist today. The peoples of the world think about aging little differently than they did a thousand years ago - they haven't yet woken up to see what could be accomplished through medical science within their lifetimes. As a consequence of this lack of support, many, many more people will age, suffer, and die than might have been the case - ourselves included, unless we get our act together.

From Cryonics Magazine: "As a neuroscientist whose day job is to map neural circuits, I know exactly what type of evidence is needed to convince the scientific community that cryonics preserves the neural circuits encoding our unique memories and personality. What is required is a systematic whole-brain survey with an electron microscope. Recently I, along with my colleagues John Smart and Jacob DiMare, formed the Brain Preservation Foundation (BPF) to promote new scientific research in the field of whole brain preservation for long-term static storage. The BPF has announced the Brain Preservation Technology Prize (purse currently at $106,000) for the first team to demonstrate that an entire large mammalian brain can be preserved for long-term storage such that the connectivity between neurons remains intact and traceable using today's electron microscopic imaging techniques. A complete set of rules for the prize can be found on our BPF website. ... This prize is being presented as a challenge to cryonics providers like Alcor and their research partners: 'Demonstrate the quality of your product in a rigorous, independent, and open way to the scientific community and to your customers.' The BPF is hard at work raising funds to promote this prize and to help perform the electron microscopic evaluation required, and we are recruiting a board of scientific advisors and judges that will give the prize credibility."

Link: http://www.alcor.org/magazine/2011/06/07/the-brain-preservation-technology-prize/

Researchers are making the first inroads into implanted machinery that can adjust the workings of memory, potentially leading in the years ahead to ways to restore memory function in the old: "Scientists have developed a way to turn memories on and off - literally with the flip of a switch. Using an electronic system that duplicates the neural signals associated with memory, they managed to replicate the brain function in rats associated with long-term learned behavior, even when the rats had been drugged to forget. ... Using embedded electrical probes, [scientists] recorded changes in the rat's brain activity between the two major internal divisions of the hippocampus, known as subregions CA3 and CA1. During the learning process, [CA3 and CA1] interact to create long-term memory ... experimenters blocked the normal neural interactions between the two areas using pharmacological agents. The previously trained rats then no longer displayed the long-term learned behavior. ... the teams then went further and developed an artificial hippocampal system that could duplicate the pattern of interaction between CA3-CA1 interactions. Long-term memory capability returned to the pharmacologically blocked rats when the team activated the electronic device programmed to duplicate the memory-encoding function. In addition, the researchers went on to show that if a prosthetic device and its associated electrodes were implanted in animals with a normal, functioning hippocampus, the device could actually strengthen the memory being generated internally in the brain and enhance the memory capability of normal rats."

Link: http://www.eurekalert.org/pub_releases/2011-06/uosc-rmr061211.php

Today I noticed a fairly long interview with David Gobel of the Methuselah Foundation - a lot of interesting detail in there as to the Foundation's goals and arrangements. For example:

Q: What collaborations, partnerships, or other types of relationships does Methuselah Foundation have with other longevity funding organizations, if any. One example would be the Ellison Foundation.

A: Ellison has been a donor to the Methuselah Foundation. We've had many organizations that have been supporters such as the Thiel Foundation, the Ellison Foundation, The Paul Glenn Foundation.

Q: Are there any other collaborations with any funding or research-focused organizations?

A: We are, I suppose closest to SENS foundation, we do many things together. We also co-founded the Super Centenarian Foundation which did the world's first autopsies on super centenarians to figure out not how they lived so long, but what exactly they died from, which is a question I posed during the discussion about founding that organizations so they did the autopsies and there's a paper talking about what came up and what can be done about it.

Q: What is your relation with SENS in particular?

A: We are their fiscal sponsor. They recently received their 501c3 tax-deductible exemption from the IRS but from the 2 or 3 years where they did not have that, we were their fiscal sponsor. We also continue to provide them donations from donors and they recently donated funds to help fund the NewOrgan Prize that we're producing.

Q: How far into the future do you think you and your team plan the strategy and goals of the organization?

A: We are looking at what we can accomplish and deliver to end users within 18 months and 5 years and SENS is focused on 10-15 years.

That last point is an important one, and keeping it in mind will illuminate a great deal of the thinking behind the activities of the two organizations. The Methuselah Foundation invests in technologies likely to emerge within the next few years, for example, like organ printing development by startup Organovo. The SENS Foundation, on the other hand, spends a fair amount of effort on building the foundation for the next generation of the research community - outreach amongst people who are in college now, studying life science, but who may have their own laboratories and companies in the biotech space ten years from now.

Researchers are very interested in establishing biomarkers of aging and longevity, as at present the only truly reliable way to distinguish between long-lived and not so long-lived individuals is to wait and see what happens - which isn't an efficient way to run studies of potential therapies for aging. Here's an example of one line of investigation: "Wound healing (WH) is a fundamental biological process. Is it associated with a longevity or aging phenotype? In an attempt to answer this question, we compared the established mouse models with genetically modified life span and also an altered rate of WH in the skin. Our analysis showed that the rate of skin WH in advanced ages (but not in the young animals) may be used as a marker for biological age, i.e., to be indicative of the longevity or aging phenotype. The ability to preserve the rate of skin WH up to an old age appears to be associated with a longevity phenotype, whereas a decline in WH with an aging phenotype. In the young, this relationship is more complex and might even be inversed. While the aging process is likely to cause wounds to heal slowly, an altered WH rate in younger animals could indicate a different cellular proliferation and/or migration capacity, which is likely to affect other major processes such as the onset and progression of cancer. As a point for future studies on WH and longevity, using only young animals might yield confusing or misleading results, and therefore including older animals in the analysis is encouraged."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21667230

An interview from the Scientist: "Cartilage is a firm, yet elastic, connective tissue that cushions joints and minimizes friction between bones. It is made up mostly of a matrix of collagen and proteoglycans and lacks nerve cells or blood vessels. In fact, cartilage contains only one cell type, the chondrocyte. A joint injury is often followed by progressive degeneration of cartilage, but there is hope that stem cells injected into damaged cartilage can help repair it. University Hospital Basel tissue engineer Ivan Martin discusses a recent study that sheds light on the mysterious process of cartilage regeneration by tracking labeled, implanted cells using a conventional MRI scanner ... [For treating cartilage injury] there is a very promising, relatively new technique - the use of autologous cartilage cells, or chondrocytes, which are expanded ex vivo and injected into the defective area. Even more recently, people have considered using mesenchymal stem cells, which are the progenitors of chondrocytes. ... We cannot just continue injecting cells and looking two years down the road to see if there is a change or not in the clinical results. We need to have control over the treatment we apply in order to understand the mechanisms of action and to be able to predict with better reproducibility the clinical outcome. This [MRI-based] technique would possibly contribute or provide the technical means to address this important scientific question."

Link: http://the-scientist.com/2011/05/30/cellular-salve/

Confusion is an important barrier to overcome when advocating engineered human longevity. For those folk who are not paying much attention to the topic - which is, sadly, 99.9% of the present roster of the human race - there's little apparent difference between advocacy for real, plausible scientific development and the nonsense of the "anti-aging" marketplace. It's pretty much all the same to them, and that's a big problem.

One of the long term projects for the advocacy community is to raise the general level of education and awareness, such that a far greater number of people do know that they should support SENS research and not the ramblings of the pill and potion vendors if they do have an interest in living longer. Not a small project, but we can all help.

Things become somewhat worse when we pull in religions and spirituality, however. To go along with the confusion created by the prodigious and often duplicitous output of "anti-aging" salespeople, there are entire armies of people who place immortality in the spiritual sense into the same bucket as life extension through science. They are even more confused - and you can find a good example in a recent article that shifts seamlessly between radical life extension through technology, the longevity of being famous, and Buddhist spirituality. All in the same category for that author.

Religious beliefs are, unfortunately, delusions. It's just the same as any dream of lazy immortality - such as the possibility that you are software in a simulation, a brain in a jar, or one of infinitely many copies in a universe of many parallel worlds. You shouldn't live your life banking on being a brain in a jar, and you shouldn't live your life banking on a supernatural continuation of your existence post-mortem. All that these comfortable beliefs give you is the chance to feel good while failing to achieve the material, real-world goals that will give you a greater chance at a far longer life. It's grand failure, while pretending to succeed.

While it's tempting to let the religious have their cozy refuge, that's no way to run a campaign of advocacy for scientific development, as noted at length by other authors:

As far as every experiment ever done is concerned, [the Dirac] equation is the correct description of how electrons behave at everyday energies. ... If you believe in an immaterial soul that interacts with our bodies, you need to believe that this equation is not right, even at everyday energies. There needs to be a new term (at minimum) on the right, representing how the soul interacts with electrons. (If that term doesn't exist, electrons will just go on their way as if there weren't any soul at all, and then what's the point?) So any respectable scientist who took this idea seriously would be asking - what form does that interaction take?

...

Nobody ever asks these questions out loud, possibly because of how silly they sound. Once you start asking them, the choice you are faced with becomes clear: either overthrow everything we think we have learned about modern physics, or distrust the stew of religious accounts/unreliable testimony/wishful thinking that makes people believe in the possibility of life after death. It's not a difficult decision, as scientific theory-choice goes.

We don't choose theories in a vacuum. We are allowed - indeed, required - to ask how claims about how the world works fit in with other things we know about how the world works. ... There's no reason to be agnostic about ideas that are dramatically incompatible with everything we know about modern science. Once we get over any reluctance to face reality on this issue, we can get down to the much more interesting questions of how human beings and consciousness really work.

The same goes for engineering longer lives for ourselves and our descendants. That worthy goal is fundamentally undermined by the widespread acceptance of supernatural immortality. The religious nature of your average human and human society is yet another hurdle to overcome - it won't be going away any time soon, given its origin in evolved human nature, but we have to find good ways to work around its effects.

The interesting question regarding the removal of the human heartbeat is the impact it will have on other bodily systems. Will it extend life by reducing stress on, for example, vulnerable blood vessels in the brain, or will it shorten life by also eliminating the beneficial response to that stress? Researchers are making progress in artificial hearts, so this question will likely be answered at some point over the next few decades: "The search for the perfect artificial heart seems never-ending. After decades of trial and error, surgeons remain stymied in their quest for a machine that does not wear out, break down or cause clots and infections. But Dr. Billy Cohn and Dr. Bud Frazier at the Texas Heart Institute say they have developed a machine that could avoid all that with simple whirling rotors - which means people may soon get a heart that has no beat. Inside the institute's animal research laboratory is an 8-month-old calf with a soft brown coat named Abigail. Cohn and Frazier removed Abigail's heart and replaced it with two centrifugal pumps. ... If you listened to her chest with a stethoscope, you wouldn't hear a heartbeat. If you examined her arteries, there's no pulse. If you hooked her up to an EKG, she'd be flat-lined. ... The pumps spin Abigail's blood and move it through her body. ... The doctors say the continuous-flow pump should last longer than other artificial hearts and cause fewer problems. That's because each side has just one moving part: the constantly whirling rotor. But Cohn says they will still have to convince the world that you don't need a pulse to live. ... We look at all the animals, insects, fish, reptiles and certainly all mammals, and see a pulsatile circulation. And so all the early research and all the early efforts were directed at making pulsatile pumps. ... However, the only reason blood must be pumped rhythmically instead of continuously is the heart tissue itself. ... The pulsatility of the flow is essential for the heart, because it can only get nourishment in between heartbeats. If you remove that from the system, none of the other organs seem to care much."

Link: http://www.npr.org/2011/06/13/137029208/heart-with-no-beat-offers-hope-of-new-lease-on-life

If the level of interest the public has in their gray hair could only be transferred to an interest in practical work to repair aging, how much better off we'd be. Here is more research into the biological causes of loss of hair pigmentation with aging: "Wnt signaling, already known to control many biological processes, between hair follicles and melanocyte stem cells can dictate hair pigmentation. ... We have known for decades that hair follicle stem cells and pigment-producing melanocycte cells collaborate to produce colored hair, but the underlying reasons were unknown. We discovered Wnt signaling is essential for coordinated actions of these two stem cell lineages and critical for hair pigmentation. ... The study suggests the manipulation of Wnt signaling may be a novel strategy for targeting pigmentation such as graying hair. The research study also illustrates a model for tissue regeneration. ... Using genetic mouse models, researchers were able to examine how Wnt signaling pathways enabled both hair follicle stem cells and melanocyte stem cells to work together to generate hair growth and produce hair color. Research also showed the depletion (or inhibition or abnormal) Wnt signaling in hair follicle stem cells not only inhibits hair re-growth but also prevents melanocytes stem cell activation required for producing hair color. The lack of Wnt activation in melanocyte stem cells leads to depigmented or gray hair."

Link: http://www.sciencedaily.com/releases/2011/06/110614115046.htm

"Should we treat aging?" is a rhetorical question here, but sadly it remains a straightforward open question for much of the world - when it is asked, they are quite serious in asking it. People expect there to be good reasons as to why aging should be left as it is, the cause of death for more than 100,000 people each and every day, and scientists restrained from working on therapies of rejuvenation. This is one of the uphill struggles taking place in the patient advocacy community for aging research, that most people don't consider themselves patients exhibiting the symptoms of degenerative aging, have little inclination to do anything about it, and are in fact initially hostile to the whole idea.

Here's an American Scientist article from researcher David Gems that asks the rhetorical question in the title of this post, and answers it for those who don't see things the way we do:

I am a scientist working in the growing field of biogerontology - the biology of aging. The cause of aging remains one of the great unsolved scientific mysteries. Still, the past decade has brought real progress in our understanding, raising the prospect that treatments might one day be feasible. Yet aging is not just another disease. And the prospect of treating aging is extraordinary in terms of the potential impact on the human condition. So, would it be ethical to try to treat it?

...

I argue for the recognition of an imperative to seek treatments that decelerate aging in order to alleviate late-life diseases. But at what point would such an imperative be fulfilled? Although decelerating aging would postpone the illnesses of aging, it would not make them any less awful. This means that achieving decelerated aging would not lessen the imperative. We would only be compelled to decelerate aging further, and then further still. Here the ethical calculus seems to set us inexorably on a road to ever-greater life extension. Could any sane authority ever opt to force others to forego treatment and suffer from avoidable age-related disease? Surely not.

So it is that decelerated aging would force a dilemma upon us. Should we alleviate suffering on a large scale and accept life extension? Or should we allow an immensity of avoidable suffering in order to avoid extending life? To my mind, the only reasonable course is the first. In fact, we should pursue it energetically, and begin to prevent illness as soon as is feasible. If not, we risk the fury of future generations for dithering. As for life extension, we will just have to take that on the chin. If we can prepare for it socially, politically and institutionally, and if we keep birth rates low, we should be able to ensure long, healthier, happier lives for our children and for our children's children.

In reading this, one must understand there there are a great many people in the world whose first, instinctive reaction to extending healthy human life is to reject it. For them, life extension is indeed a bad thing. Various strains of environmentalism are one of the main culprits here: so many minds are poisoned by the false ideas that spread from environmentalist and related Malthusian ideologies: that there are too many people, that people are intrinsically bad, that wealth and longevity are intrinsically bad, that economics is a zero-sum game, and so forth.

There's nothing wrong with liking trees and wild places enough to spend your hard-earned resources on helping to maintain them. But environmentalism has a way of veering off into the worship of death and destruction, a sort of modern penitent movement focused on the mortification of society as a whole. It's so widespread and embedded in our cultures now that even mild-mannered, everyday folk declare their support for shorter and fewer human lives, for abandonment of technologies that improve the quality of human life, and for relinquishment of technological development that will greatly improve life in the future.

In the long run, these are the ideas we must defeat and bury if we are to build the level of understanding and support required to speed the advent of rejuvenation biotechnology.

Researchers are making progress in changing cells directly from one type to another: "A research breakthrough has proven that it is possible to reprogram mature cells from human skin directly into brain cells, without passing through the stem cell stage. The unexpectedly simple technique involves activating three genes in the skin cells; genes which are already known to be active in the formation of brain cells at the fetal stage. ... By reprogramming connective tissue cells, called fibroblasts, directly into nerve cells, a new field has been opened up with the potential to take research on cell transplants to the next level. ... We didn't really believe this would work, to begin with it was mostly just an interesting experiment to try. However, we soon saw that the cells were surprisingly receptive to instructions. ... In experiments where a further two genes were activated, the researchers have been able to produce dopamine brain cells, the type of cell which dies in Parkinson's disease. The research findings are therefore an important step towards the goal of producing nerve cells for transplant which originate from the patients themselves. The cells could also be used as disease models in research on various neurodegenerative diseases. Unlike older reprogramming methods, where skin cells are turned into pluripotent stem cells, known as IPS cells, direct reprogramming means that the skin cells do not pass through the stem cell stage when they are converted into nerve cells. Skipping the stem cell stage probably eliminates the risk of tumours forming when the cells are transplanted. "

Link: http://www.sciencedaily.com/releases/2011/06/110609084815.htm

Progerin is the mutant form of lamin-A implicated in the accelerated aging condition progeria. It also shows up in normal aging, to a much lesser degree, and here researchers make progress towards understanding why: "Telomeres wear away during cell division. When they degrade sufficiently, the cell stops dividing and dies. The researchers have found that short or dysfunctional telomeres activate production of progerin, which is associated with age-related cell damage. As the telomeres shorten, the cell produces more progerin. ... This study highlights that valuable biological insights are gained by studying rare genetic disorders such as progeria. Our sense from the start was that progeria had a lot to teach us about the normal aging process and clues about more general biochemical and molecular mechanisms. ... the mutation that causes progeria strongly activates the splicing of lamin A [or LMNA] to produce the toxic progerin protein, leading to all of the features of premature aging suffered by children with this disease. But modifications in the splicing of LMNA are also at play in the presence of the normal gene. The research suggests that the shortening of telomeres during normal cell division in individuals with normal LMNA genes somehow alters the way a normal cell processes genetic information when turning it into a protein, a process called RNA splicing. To build proteins, RNA is transcribed from genetic instructions embedded in DNA. RNA does not carry all of the linear information embedded in the ribbon of DNA; rather, the cell splices together segments of genetic information called exons that contain the code for building proteins, and removes the intervening letters of unused genetic information called introns. This mechanism appears to be altered by telomere shortening, and affects protein production for multiple proteins that are important for cytoskeleton integrity. Most importantly, this alteration in RNA splicing affects the processing of the LMNA messenger RNA, leading to an accumulation of the toxic progerin protein."

Link: http://www.sciencedaily.com/releases/2011/06/110613121956.htm

SENS, the Strategies for Engineered Negligible Senescence, is detailed plan for development of the biotechnologies needed to reverse the effects of aging - to repair the biological damage that causes age-related degeneration and disease, and thereby eliminate the frailty and increasing risk of death that comes with it. Strangely, SENS has gone from valid but fringe idea rejected by the mainstream of aging research to an accepted and supported, albeit small, research program over a handful of years without much in the way of widely published and debated critiques. There was the SENS challenge, a couple of scientific op-ed exchanges in the journals (some of which were quite entertaining), and that was pretty much that. In the early days, no-one would take the time to engage, and the switch from outsider concept to insider concept with a well-connected non-profit foundation backing it happened fairly rapidly as such things go.

Not that I'm complaining: there are worse outcomes. But publicity is important when it comes to expanding the support available for any field of research, and well constructed critiques - and the debates that follow - are a good basis for that publicity. With that in mind, you'll recall that a previous issue of Cryonics magazine contained a critique of SENS from long-standing advocate and activist Ben Best. In the latest issue, Aubrey de Grey of the SENS Foundation responds:

SENS, my proposal for combating aging with regenerative medicine, was first formulated in 2000 and first published in 2002. In 2005 and 2006, the first scientific critiques of SENS appeared that were worthy of the name - in other words, that focused squarely on the scientific details of SENS rather than speaking in generalities. Both featured many profound flaws, as outlined in my replies, but I was under no illusion that this meant that SENS will definitely work. Accordingly, it has been a source of disappointment to me that the subsequent five years have not seen better-informed and better-founded critiques, even though an undercurrent of intuitive pessimism about SENS undoubtedly survives. I am therefore gratified that Cryonics Institute CEO Ben Best has published a careful analysis of what he sees as deficiencies in SENS, in the previous issue of CRYONICS.

I'm not going to quote the bulk of it - you should go and read the whole article, which is a series of point by point discussions, and which provides some insight into ongoing and currently unpublished work taking place at the SENS Foundation and in allied laboratories. It is exactly the sort of thing I'd like to see more of out in the public sphere. Now that the SENS Foundation is a going concern, perhaps it's time to start arranging debates on SENS that will be seen by a wider audience once again. After all, now we can say, "and if you liked the pro-SENS position, here is an ongoing and internationally recognized research program you can support, where the participants and advisors are a who's who of modern longevity and aging science."

More reasons to be exercising - many aspects of the biology of an exercising older mammal are improved over one that is sedentary, and the bugbear of inflammation is one of them: "We tested the hypothesis that regular aerobic exercise reverses arterial inflammation with aging. Compared with young controls, old male B6D2F1 cage-restricted mice demonstrated increased arterial activation of the pro-inflammatory transcription factor, nuclear factor κB (NFκB) ... Similarly, aortic expression of the pro-inflammatory cytokines [were] greater in the old mice. Macrophage and T lymphocyte abundance was unchanged with age in the aortic intima and media, but was markedly increased in the adventitia and perivascular fat tissue of old mice. This pro-inflammatory arterial phenotype with aging was associated with vascular endothelial dysfunction, as reflected by impaired nitric oxide-mediated endothelium-dependent dilation (EDD). Voluntary wheel running (10-14 weeks) in old mice normalized [all of these age-altered features]. Short-term voluntary wheel running started late in life reverses arterial inflammation with aging in mice possibly via 'outside-in' actions. These anti-inflammatory effects may play an important role in the amelioration of age-associated vascular dysfunction by regular aerobic exercise."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21622824

An op-ed on perpetual trusts aimed at preserving wealth for cryopreserved individuals can be found at h+ Magazine: "Rudi Hoffman is an insurance salesman specializing in cryonics-related insurance policies. He's also a deep thinker about cryonics and life extension, and an incredibly funny guy. So, we thought it would be interesting to have Rudi tell our readership about cryonics trusts - the notion of setting up a trust to fund your own revival and post-resuscitation life. He put together a few words on some of the misconceptions he encounters when talking to people about the concept of cryonics trusts. ... Cryonics trusts and planning for wealth upon revival is not a new idea. Questions about cryonics estate and trust planning were being asked and explored by pioneers as early as the 1980s. These questions were also asked to me, as well as by me as early as early 1994 when I signed up with Alcor. The history of cryonics back to early days is an series of lessons in real world finance, in many cases hard lessons like the Chatsworth cryonics tragedy, a function of unrealistic funding structure for maintenence of cryonics patients. Out of these funding tragedies, real world experience has emerged. The cool thing about this is that you and I can benefit from the work that has gone before us. The underbrush has been cleared and a smoother path is now available for us to travel regarding cryonics trusts. ... While there are significant challenges in setting up a viable and effective cryonics trust, the 'Rules against perpetuities' are pretty much a non-issue. These laws have been abolished by statute in states including Alaska, Idaho, New Jersey, and South Dakota. ... Most cryonics model or prototype trusts available utilize a "dynasty trust" format. This basically sidesteps the question of whether someone pronounced dead and currently in biostasis is well and truly, permanently 'dead.' This format, used by wealthy folks seeking to control their assets even after traditional death, has been used for many decades. Basically, you direct a trustee to act in your behalf to carry out the terms of the trust. This does not require new law be made determining whether you are 'dead enough' or even 'too dead to have rights.'"

Link: http://hplusmagazine.com/2011/06/10/seven-silly-superstitions-about-cryonics-trusts/

Open Cures is an initiative that aims to accelerate the development of existing longevity-enhancing biotechnologies demonstrated in the laboratory, but which are not being developed for commercial use in humans - largely due to regulatory barriers.

Open Cures is a volunteer initiative, open to everyone willing to help, that aims to speed the advent of biotechnologies that can slow down or repair aspects of the biological damage of aging and thus extend healthy human life. Our primary long-term goal is to bring together (a) promising but undeveloped biotechnologies of longevity and (b) the developers who can bring them to the clinic.

A fellow named Allen is one of the folk whose interest in the Open Cures vision convinced me that I needed to do more than just talk about it: you can see his comments on the old Vegas Group posts here at Fight Aging!, which contain the ideas that led to Open Cures.

The first phase of the Open Cures initiative aims to produce detailed documentation of existing forms of longevity biotechnology from the laboratory, as that documentation is a necessary precursor to bringing these potential foundations for future therapies to a wider audience. One of these nascent-but-demonstrated biotechnologies is mitochondrial protofection: a way to introduce new and undamaged mitochondrial DNA (mtDNA) into mitochondria in an attempt to repair the accumulated defects they bear - defects which contribute meaningfully to aging. You'll want to look back in the Fight Aging! archives for an introduction to that topic.

Mitochondria go bad as a natural consequence of their operation, and if enough go bad in the right way, and manage to escape the natural recycling mechanisms of the cell, then they take over that cell - causing it to malfunction, damage its surroundings, and release harmful reactive molecules that are carried throughout the body. Given enough cells doing this, you will become frail and eventually die as vital systems in your body become too damaged to operate correctly.

Since the launch of Open Cures, Allen has been looking into the published papers on mitochondrial protofection and writing up an outline for a protocol - the detailed step by step instructions that allow a technique in biotechnology to be replicated. The work to date can be found in the Open Cures wiki:

"Protofection" is a word coined by a group of scientists at the University of Virginia. It is the name they have given to a procedure they were developing which could possibly become a way to rejuvenate malfunctioning mitochondria by providing them with a new, undamaged genome.

I have been attempting to write a detailed set of instructions that would allow someone with sufficient knowledge and means to reproduce their work. So far I've come up with a bare-bones skeleton or scaffolding upon which a more experienced and better writer can build - adding detail, correcting errors, and making it more understandable. ... Corrections, additions, improvements, and comments are very welcome.

The next stage in this documentation project, one of many to come, is to find writers - such a grad-level life science students willing to freelance at reasonable rates - to flesh it out into as full a protocol document as can be built from the present state of published scientific work on protofection.

Two of the interesting items we discovered in the course of researching protofection more closely are that (a) a number of research groups attempted to replicate mitochondrial protofection over the past five years but met with no success, and (b) the scientists who initially demonstrated protofection have not yet published a clear explanation of the transcription factor used as a tool when introducing replacement DNA into mitochondria:

TFAM refers to human mitochondrial transcription factor A. This protein plays several roles in the mitochondria. It participates in mtDNA transcription, replication and maintenance. It also non- specifically binds to mtDNA which is the property we want to exploit as we attempt to pull pristine mtDNA into mitochondria which contains damaged DNA

[Missing details: We need to provide the DNA sequence in the format used by DNA synthesis machines. The DNA sequence must be verified as accurate. If we make a mistake here, which would be easy to do, the entire experiment is useless. The amino acid sequence is provided in the 2008 paper and the DNA sequence could be deduced from that, but there are some complications.

A. The published amino acid sequence may not be accurate. For one thing, a ")" symbol appears in the sequence and I have no idea what that means. Also the sequence contains an unusual repeated chain of amino acids which I suspect was not really part of the protofection protein.

B. The DNA will also have to be modified by adding a short sequence to each end of it. These two short sequences must each contain a site that can be cut by EcoI, the restriction endonuclease that will be used to prepare the DNA to be spliced into the bacterial plasmid that will be used later.

C. We also have to carefully check the DNA sequence to be sure that another EcoI restriction site is not found somewhere in the middle of the sequence.]

This second point, the missing definition, doesn't matter as much as you might think for the purposes of producing a good protocol document. When we do eventually find out the correct DNA sequence for the modified TFAM, it will be the work of moments to update the published document, and none of the other materials need to change.

I see this missing information as one good example as to why an initiative like Open Cures is both necessary and helpful: there are gaps that need filling in all these scientific publications and procedures, left there (intentionally and otherwise) because these works are not intended for a wider audience. Yet in order to accelerate progress, that wider audience is absolutely essential.

What are the effects of a large and energetic open development community on an industry? What happens when tens of thousands of people start making their products available for free, sharing data, designs, and improvements openly, and making money for services and expertise rather than through selling protected secrets? Fortunately we don't have speculate on this topic: we know. Look at the software industry, which is presently more vibrant and accomplished than it has ever been, whilst a large proportion of the most important software used around the world is open, freely shared, and constructed by a mix of professional and amateur contributors. Open source software is big business and that community gets things done.

Why is this relevant? It is relevant because what happens in software today will happen in biotechnology tomorrow. The tools and techniques of biotechnology continue to fall in price, and the knowledge of how to use them is already spread widely beyond the ivory towers in which it originated.

Another example of simultaneously boosting life span and reducing cancer in mice in the laboratory - not maximum lifespan, however, or the paper would be much more triumphant. This is the first I've seen of this particular mechanism, so your guess is as good as mine as to what is going on under the hood. Once thing I'm pleased to note is that the researchers controlled for calorie restriction, and considered it important enough to state as much in the abstract. That's progress: "Sulfate (SO(4)(2-)) plays an important role in mammalian growth and development. In this study, hyposulfatemic NaS1 null (Nas1-/-) mice were used to investigate the consequences of perturbed SO(4)(2-) homeostasis on longevity. Median life spans were increased (by ≈25%) in male and female Nas1-/- mice when compared with Nas1+/+ mice on identical food intakes. At 1yr of age, serum SO(4)(2-) levels remained low in Nas1-/- mice (≈0.16mM) when compared to Nas1+/+ mice (≈0.96mM). RT-PCR revealed increased hepatic mRNA levels of Sirt1 (by ≈60%), Cat (by ≈48%), Hdac3 (by ≈22%), Trp53 and Cd55 (by ≈36%) in Nas1-/- mice, genes linked to ageing. Histological analyses of livers from 2yr old mice revealed neoplasms in >50% of Nas1+/+ mice but not in Nas1-/- mice. This is the first study to report increased lifespan, decreased hepatic tumours and increased hepatic expression of genes linked to ageing in hyposulfatemic Nas1-/- mice, implicating a potential role of SO(4)(2-) in mammalian longevity and cancer."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21651971

Here another study of the long-lived confirms the common wisdom: "Objectives: To identify predictors of extraordinary survival. Design: Longitudinal study of a cohort of elderly people followed up until almost all have died. Setting: Two counties in Iowa; a part of the Established Populations for Epidemiologic Study of the Elderly. Participants: Two thousand eight hundred ninety community-dwelling citizens aged 65 to 85 at baseline and surviving at least 3 years. Measurements: Data relating to age, sex, birth order, parental longevity, marital status, education, family income, social support, self-reported health, chronic diseases, blood pressure, body mass index, physical ability, exercise, life attitude and mental health were obtained. Extraordinary survivors (ESs) were defined to include approximately 10% of the longest survivors in their sex group. Results: The 253 ESs were far more likely never to have smoked. In models adjusted for age, sex, and smoking, the earlier-life factors such as parental longevity, being earlier in the birth order (in women only), and body mass index at age 50 were associated with extraordinary survival. In similar models for predictors at age 65 to 85, extraordinary survival was associated with excellent self-reported health, fewer chronic diseases, better physical mobility and memory, and positive attitude toward life, but it was not associated with depression, anxiety, or sleep quality. In multivariable models, attitude toward life was not an independent predictor. Women in the top third of a cumulative score of independent predictors were 9.3 times as likely to reach extraordinary survival as those in the bottom third. Conclusion: ESs had fewer 'classical' risk factors and were in better health than their contemporaneous controls. Possibly genetic factors such as parental longevity and birth order appear to be less predictive in men than in women."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21649635

A good interview can be found at h+ Magazine, in which Aubrey de Grey and Ben Goertzel discuss a range of topics. Goertzel is an artificial intelligence researcher who strongly supports the goal of achieving radical life extension, so the interaction between the two fields is one of his interests:

Ben:

On a different note - I wonder how much do you think progress toward ending aging would be accelerated if we had an AGI system that was, let's say, roughly as generally intelligent as a great human scientist, but also had the capability to ingest the totality of biological datasets into its working memory and analyze them using a combination of human-like creative thought and statistical and machine learning algorithms? Do you think with this sort of mind working on the problem, we could reach the Methuselarity in 5 or 10 years? Or do you think we're held back by factors that this amazing (but not godlike) level of intelligence couldn't dramatically ameliorate?

Aubrey:

I think it's highly unlikely that such a system could solve aging that fast just by analysing existing knowledge really well; I think it would need to be able to do experiments, to find things out that nobody knows yet. For example, it's pretty clear that we will need much more effective somatic gene therapy than currently exists, and I think that will need a lot of trial and error. However, I'm all for development of such a system for this purpose: firstly I might be wrong about the above, and secondly, even if it only hastens the Methuselarity by a small amount, that's still a lot of lives saved.

My take on it is that the researchers working on strong artificial intelligence are stretching the point when they discuss the relevance of their work to rejuvenation research - but this is based on my own particular estimate of how the near future of of artificial intelligence development will likely play out. Any and all systems that help biologists manage information will do their part in accelerating progress towards interventions in aging - but the next two decades don't look likely to see much more than incremental advances in expert systems. Better expert systems and knowledge management tools are a good thing, but they aren't strong AI.

I think that the first strong AI will most likely emerge from emulation and simulation of the human brain, and the computing hardware powerful enough to enable that to happen will only just be emerging twenty years from today. Meanwhile, those twenty years between now and 2030 are a vitally important time for longevity science: either we get our act together and build (a) a meaningful, funded, supported research community and (b) the scientific basis for all the necessary biological repair technologies in that time frame, or rejuvenation biotechnology will not arrive in time for those of us heading into middle age today.

So for us, I don't see that strong AI development has an enormous relevance to the future of human longevity - no more so than any line of development likely to spin off incrementally better knowledge management tools. For our descendants, strong AI will absolutely reshape the world. But we're in a far worse position than they will be when it comes to time to wait and the tools at hand - not a hopeless position, but one that requires a great deal more work right here and right now.

Transhumanism is in many ways the urge to self-improvement taken to its logical conclusion - that in addition to improving in ways that are presently possible, we should carry out the foundational work in technology that creates new ways for us to improve ourselves. So it all starts with simple, available tools to improve health, per this post at Sentient Developments: "there are a number of things we can do to extend our capacities and optimize our health in a way that's consistent with transhumanist ideals - even if it doesn't appear to be technologically sophisticated. While the effects of these interventions are admittedly low impact from a future-relativistic perspective, the quest for bodily and cognitive enhancement is part of the broader transhumanist aesthetic which places an emphasis on maximal performance, high quality of life, and longevity. ... Sure, part of being a transhumanist involves the bringing about of a radical future, including scientific research and cheerleading. But it's also a lifestyle choice; transhumanists actively strive to exceed their body's nascent capacities, or, at the very least, work to bring about its full potential. In addition to building a radical future, a transhumanist is someone who will, at any time in history, use the tools and techniques around them to maximize their biological well-being." Which is a slightly different take on the utilitarian considerations of keeping in shape so as to have the best chance of living into the era of rejuvenation biotechnology - with the pace of technology, a few years may matter. The decade or more of change you can exert on your life expectancy via lifestyle choices may make the difference between missing the boat or living a life of centuries. Or longer.

Link: http://www.sentientdevelopments.com/2011/06/primal-transhumanism.html

A review paper notes a number of lines of research aimed at introducing new DNA into mitochondria or new mitochondria into cells. Although discussed in the context of introducing specific types of damage to study, the much more important prospect is for repairing mitochondria - and thus the possibility of removing the significant contribution to aging caused by damaged mitochondria: "Maintenance of the mitochondrial genome is a major challenge for cells, particularly as they begin to age. Although it is established that organelles possess regular DNA repair pathways, many aspects of these complex processes and of their regulation remain to be investigated. Mitochondrial transfection of isolated organelles and in whole cells with customized DNA synthesized to contain defined lesions has wide prospects for deciphering repair mechanisms in a physiological context. We document here the strategies currently developed to transfer DNA of interest into mitochondria. Methodologies with isolated mitochondria claim to exploit the protein import pathway or the natural competence of the organelles, to permeate the membranes or to use conjugal transfer from bacteria. Besides biolistics, which remains restricted to yeast and Chlamydomonas reinhardtii, nanocarriers or fusion proteins have been explored as methods to target custom DNA into mitochondria in intact cells. In further approaches, whole mitochondria have been transferred into recipient cells. Repair failure or error-prone repair leads to mutations which potentially could be rescued by allotopic expression of proteins. The relevance of the different approaches for the analysis of mitochondrial DNA repair mechanisms and of aging is discussed."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21645537

I noticed a recent open access paper (in PDF format) that explains in a very readable fashion how the last few years of new research into mitochondria may imply changes for a few important details in the mitochondrial free radical theory of aging.

Mitochondria are organelles of eukaryotic cells that contain their own genetic material and evolved from prokaryotic ancestors some 2 billion years ago. They are the main source of the cell's energy supply and are involved in such important processes as apoptosis, mitochondrial diseases, and aging. During recent years it also became apparent that mitochondria display a complex dynamical behavior of fission and fusion, the function of which is as yet unknown. In this paper we develop a concise theory that explains why fusion and fission have evolved, how these processes are related to the accumulation of mitochondrial mutants during aging.

If you look back in the Fight Aging! archives, you'll find a layman's explanation of how degenerative aging is caused in part by accumulating mitochondrial mutations. Mitochondria go bad as a natural consequence of their operation, and if enough go bad in the right way, and manage to escape the natural recycling mechanisms of the cell, then they take over that cell - causing it to malfunction, damage its surroundings, and release harmful reactive molecules that are carried throughout the body. Given enough cells doing this, you will become frail and eventually die as vital systems in your body become too damaged to operate correctly.

In this, we're all in the same boat. The interesting part of this process is that mitochondria swarm around a cell in bacteria-like herds, but the real damage only starts after a cell is completely taken over by clones of one particular mutant form of mitochondrion - a different dysfunctional clone army for each dysfunctional cell, each based on a particular random set of mutations. The question all along has been how that clonal takeover happens, and here the researchers propose that fusion is the culprit:

Another important finding of recent years is that individual mitochondria do not exist as permanently distinct entities, as has long been believed, but instead form a dynamic network within which the mitochondria regularly exchange proteins, [mitochondrial] DNA, and lipids by rapid fusion and fission processes ... The fact that mitochondrial fusions do occur revives an earlier idea that the selection advantage of deletion mutants is their reduced size, which allows them to replicate faster ... we propose that mitochondrial fusion is the underlying mechanism that opens the door for the clonal expansion of mitochondrial deletion mutants.

Does this view, if accurate, change any of the existing approaches to dealing with mitochondrial mutation and its considerable consequences to our health and life span? Not really, though one might argue that it complicates the question of what actually happens under the hood during the delivery of new, undamaged DNA into a cell's mitochondria. The problem remains the damaged DNA, and the resulting absence of necessary protein cogs in the mitochondrial machinery of energy generation and other functions - so either deliver fixed DNA, or deliver the needed proteins, and the problem is solved.

In a self-repairing system, a little damage is actually a good thing - it wakes up the repair mechanisms and sets them to work, producing an overall net benefit. Thus a given form of damage may be good or bad for system longevity, depending on its degree, where it happens, and whether it is noticed by the repair mechanisms. This is why you'll see superficially contradictory research papers on reactive oxygen species, the damaging oxidant molecules emitted by mitochondria, and their impact on aging. See this, for example: "researchers have identified a pathway by which reactive oxygen species (ROS) molecules, which are usually implicated in the aging process due to their damage to DNA, can also act as cellular signaling molecules that extend lifespan. ... Increased ROS, and their effects at the cellular level, can lead to oxidative stress, which is involved in many diseases and aging. But ROS are also necessary for the proper functioning of the immune system and other biological functions. ... Inhibiting a signaling pathway called Target of Rapamycin (TOR), which is involved in sensing nutrients and cell growth, increases lifespan in yeast, as it does in mice. ... a key way this occurs is by altering the function of cellular powerhouses called mitochondria so that they produce more signaling ROS. ... The concept that ROS are important cellular signaling molecules, and not just agents of damage and stress, has grown to be widely accepted. Remarkably, in this study, we show that their purposeful production by mitochondria can even provide an adaptive signal that can delay aging. ... Trials targeting the TOR pathway as an anti-cancer strategy in humans are already underway. Our study suggests that carefully augmenting mitochondria and ROS production in humans may also be beneficial in combating aging and associated diseases." Note that "carefully augmenting mitochondria and ROS production" is a fair description of the results of exercise, and is one of the ways in which exercise works to improve long-term health. You may recall that researchers demonstrated that antioxidants applied generally tend to block this effect by mopping up the ROS that act as signals to the body's repair systems.

Link: http://opac.yale.edu/news/article.aspx?id=8625

It is known that centenarians - and their immediate families - tend to have better immune systems, a capability that is increasingly important in old age as people become more vulnerable to infections. Here is more research to illustrate this fact: "Aging is characterized by a progressive alteration of homeostatic mechanisms modulated by environmental and genetic factors. It is associated with a pro-inflammatory status. In centenarians, an increase of pro-inflammatory cytokine production balanced by anti-inflammatory immune response that would promote longevity is observed. Cytokine dysregulation is believed to play a key role in the proposed remodeling of the immune-inflammatory responses accompanying old age. IL-22 is a pro-inflammatory cytokine belonging to the IL-10 family and represents an important effector molecule of activated [T cells]. We recruited 17 healthy centenarians (4 males, 13 females, range 100-105 years). All ultralongeval subjects were living at home or in a nursing home. Sixteen healthy, sex-matched individuals (4 males, 12 females, range 60-95 years) were also recruited as controls. Centenarians displayed significantly higher circulating IL-22 levels compared to control population. It's well known that IL-22 is a pro-inflammatory cytokine produced by activated T lymphocytes and NK cells. IL-22 stimulates the production of acute phase reactants and promotes the antimicrobial defense. The results of the present study show, for the first time, that there is an increase of IL-22 in healthy centenarians. This pro-inflammatory condition probably is protective against infection, promoting the longevity of these subjects."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21640395

What I'll here call hyperactivism is a poisonous sort of dysfunction that you'll find in activist and advocate communities associated with struggling industries or long-standing initiatives that have failed to fulfill early visions of growth. It comes about because the early supporters in any new field tend to be passionate, driven, ornery, and focused: if they didn't have these characteristics, they wouldn't be up for the job of fighting over and again to persuade people to see things their way. If you are trying to build a new venture, then you need these people: they are worth their weight in gold, and they will help you succeed.

When an initiative does succeed attracting broad support and a large community, the energy and quirks of the early activists are tempered by a sea of more sedate, everyday folk. Sometimes the pioneers are quietly airbrushed out of the official histories - once an initiative becomes large enough for its leaders to want it to look like a shiny, official, professional machine, then the original barnstormers and larger than life personalities start to be seen as a liability. Justifiably or not, they are shuffled to one side of the growing crowd. In this way, the ultimate accolade of success is to be made irrelevant in the movement you helped found: accepting that likelihood up front is the way to peace of mind for activists and advocates.

But when things don't go according to plan, and what was intended to be great fails to achieve its original promise, or moves too slowly, then the problems start. Some of the early activists, untempered by large numbers of new volunteers and supporters, become poisonous. Their hyperactivism manifests itself in perfectionism, attacks on members of the community, and other displays of frustration or bitterness: to their eyes, failure was avoidable, and the problem must be the other people involved.

You see some of this going on in the cryonics community, an example of success on the small scale amidst a failure to achieve the grand goals originally envisaged for the movement. Which is to say that the few people who choose to be cryopreserved have a good chance of successfully achieving that goal, thanks to decades of largely volunteer efforts, but the vast majority of people in the world don't know, don't care, and go to the grave and oblivion just as they always have. So, understandably given human nature, you'll find a degree of hyperactivism amongst the long-standing members of the cryonics community. I noticed a perfectly passive-aggressive example of the type from Cryosphere the other day - which is disappointing, given the normally useful output there. It prompted a response in Alcor CEO Max More in his latest update, which I think is somewhat more useful.

Outside of pure mathematics and logic, perfection is not attainable in the real world. Even the flawless achievement of one goal means giving up another goal of inferior but substantial value (the economists' concept of "opportunity cost"). And achieving some aspects of a desired goal will mean giving up others. You may want a car that gets excellent gas mileage, but that will probably mean giving up the level of performance you hoped for. You may want to delay having children until you've accumulated more wealth and experience, but your fertility level may decline.

Tradeoffs clearly exist in cryonics, although you wouldn't know it by listening to most critics. We would all like cryonics to be perfect, but we know that gains come at a cost. We would like the costs of membership dues and cryopreservation charges to be lower. We would like the quality of cryopreservations to be higher. We would like everything to be run by medical professionals at low cost and with total commitment.

You can't have everything, no matter how much a hyperactivists might wish for it. Hyperactivism is something that we're all prone to, being human as we are, and it is also something to watch for when we support our favored organizations. It is important to keep the community honest, to criticize what should be criticized, and help other members of the community achieve success where possible - but if you have come to the point at which you feel that attacking other parts of the community is helpful, then somewhere you crossed the line.

I'm of the mindset that the right response - when you find yourself at that point of frustration with an existing initiative or organization - is to channel your passion into support for an existing alternative, or start such an alternative yourself. It is better to build than to tear down, and if your frustrations are in fact based on a meaningful or useful point then you have a shot at irrefutably demonstrating that point by building a better initiative, a better product, a better community. Many people in the cryonics community have worked on doing just that over the last decade - and progress springs from this impulse to achieve better results, not the impulse to attack those who are somehow not doing things your way.

The nature of medical research is that it is an uncertain business - sometimes the practical applications just don't work: "GDNF first showed promise as a treatment for Parkinson's patients when scientists discovered that it could boost the survival of dopamine-producing neurons - cells that degenerate in the disease - back in 1993. But so far, the results in humans have not borne out those hopes. Early trials involving injecting the protein directly into the brain showed some promise, but a second, more comprehensive trial subsequently showed no benefit. Another recent trial that used a gene therapy approach to deliver a similar compound, neurturin, showed some signs of benefit but failed in its primary goal of improving symptoms after one year. [Researchers] believe that other attempts failed because they didn't target the right tissue precisely enough. The first attempts, he said, injected the GDNF protein into the spaces near the brain regions of interest, where it failed to diffuse far enough into the brain. Infusing the treatment directly into the relevant brain tissue, he says, caused leakage into the surrounding fluid. ... They all turned out to be negative, because the delivery was never controlled ... The new trial will introduce the gene encoding GDNF into the putamen, a brain area involved in Parkinson's disease. The gene will be carried by a virus, and will be injected directly into the brain using a technique called convection-enhanced delivery, which uses positive pressure to drive fluid deep into targeted regions. The injection will include an MRI contrast agent, and the researchers will use an MRI-based imaging system to track the distribution of the treatment during delivery. ... the imaging system will allow the team to make sure the gene gets to where it's needed. ... It still remains to be seen whether GDNF really is something that helps people with Parkinson's disease."

Link: http://www.technologyreview.com/biomedicine/37708/

A long piece from Chronosphere covers a fair amount of ground, and holds up the AIDS patient advocacy of the 80s and 90s as a model of success that could be and should be emulated for longevity science advocacy: "[It is plausible that] maturation of the technologies required to extend lifespan indefinitely for most people now living who are aged 30 or older will not be developed with sufficient rapidity to prevent their being cryopreserved. ... [For example], mature, clinically available, and FDA-approved therapies to slow or halt brain cell loss are a decade, and likely closer to two decades, away. And when clinical application does come, it will likely be only for the most serious disease states, such as [Alzheimer's disease], Huntington's Disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Even in these conditions, access to treatment may be limited by many factors, including high cost and government regulation. Thus, for many of us, even another decade of waiting will be too long. ... One of the hardest things for people to understand is that it is possible to do good, without doing good enough; and nowhere is this more the case than in medical research. ... [Looking at the history of AIDS], by 1983 demonstrations, peaceful and otherwise, had begun, and those men who found themselves or loved ones dying of AIDS decided to take both research and treatment into their own hands. Broadly, this effort took two forms: intense lobbying and application of pressure within the system to obtain government money at every level to support research and provide care for the dying, and the creation of the 'AIDS Underground': a guerrilla effort to find or to develop treatments that would do anything to improve the situation for those ill with or dying of the disease. Those efforts ranged from finding more effective ways to manage symptoms, to a full blown effort to find a definitive cure. Importantly, any advance in treating the illness and extending the lives of patients suffering from it, was the subject of underground research efforts. ... If you want graphic proof of just how miraculously effective their efforts were, all you need to do is look at [the present mortality data, and the fact that AIDS is now a largely controllable condition]. We cryonicists are in exactly the same position today [with respect to aging]. The question is, are we smart enough to realize it, and courageous enough to take the necessary action?"

Link: http://chronopause.com/index.php/2011/05/31/going-going-gone-part-3/

A novel take on the immediate biological consequences of cancer can be found in a recent research brief:

"People think that inflammation drives cancer, but they never understood the mechanism," said Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center. "What we found is that cancer cells are accelerating aging and inflammation, which is making high-energy nutrients to feed cancer cells."

In normal aging, DNA is damaged and the body begins to deteriorate because of oxidative stress. "We are all slowly rusting, like the Tin-man in the Wizard of Oz," Dr. Lisanti said. "And there is a very similar process going on in the tumor's local environment." Interestingly, cancer cells induce "oxidative stress," the rusting process, in normal connective tissue, in order to extract vital nutrients.

Dr. Lisanti and his team previously discovered that cancer cells induce this type of stress response (autophagy) in nearby cells, to feed themselves and grow. However, the mechanism by which the cancer cells induce this stress and, more importantly, the relationship between the connective tissue and how this "energy" is transferred was unclear.

"Nobody fully understands the link between aging and cancer," said Dr. Lisanti, who used pre-clinical models, as well as tumors from breast cancer patients, to study these mechanisms. "What we see now is that as you age, your whole body becomes more sensitive to this parasitic cancer mechanism, and the cancer cells selectively accelerate the aging process via inflammation in the connective tissue."

You might look back at a recent post on the immune response and aging: increased cancer risk is one of the consequences of a lot of immune system activity and infection throughout life. Likewise, chronic inflammation is a bad thing - it is probably a strong contributing cause to long-term health issues that come with a lot of fat tissue, for example.

Aging itself is no more than accumulated damage of various forms and the flailing of systems trying to adapt to that damage - this realization and the models that result from it are useful. But I think that there is a point at which it stops being useful to talk about accelerated aging, and this is a good example. If you have a strong understanding of a specific process involved in causing damage, then you should be talking about the details and how to use that knowledge to build repair biotechnologies. Aging is far more than just oxidative stress, for example, and labeling this now better understood effect of cancer as accelerated aging just clouds the issue.

The counterpoint to that argument is that talking about accelerated aging caught my eye and made me think about this research and what it might mean. So job well done on the part of Jefferson public relations. I do think that it is in many ways a promising sign that someone in the well-funded field of cancer research is willing to adopt the terminology of aging research and use of accelerated aging as a model in describing their research. It shows that the field of aging research is losing the stigma it had up until comparatively recently - and hopefully in the process becoming exciting once more for younger scientists.

From EurekAlert!: "transplantation of adult stem cells enriched with a bone-regenerating hormone can help mend bone fractures that are not healing properly. ... stem cells manufactured with the regenerative hormone insulin-like growth factor (IGF-I) become bone cells and also help the cells within broken bones repair the fracture, thereby speeding the healing. ... A deficiency of fracture healing is a common problem affecting an estimated 600,000 people annually in North America. ... This problem is even more serious in children with osteogenesis imperfecta, or brittle bone disease, and in elderly adults with osteoporosis, because their fragile bones can easily and repeatedly break, and bone graft surgical treatment is often not successful or feasible. ... Fractures that do not mend within the normal timeframe are called non-union fractures. Using an animal model of a non-union fracture, a 'knockout' mouse that lacks the ability to heal broken bones, Spagnoli and her colleagues studied the effects of transplanting adult stem cells enriched with IGF-I. They took mesenchymal stem cells (adult stem cells from bone marrow) of mice and engineered the cells to express IGF-I. Then they transplanted the treated cells into knockout mice with a fracture of the tibia, the long bone of the leg. Using computed tomography (CT) scanning, the researchers showed that the treated mice had better fracture healing than did mice either left untreated or treated only with stem cells. Compared with controls left to heal on their own or recipients of stem cells only, treated mice had more bone bridging the fracture gap, and the new bone was three to four times stronger."

Link: http://www.eurekalert.org/pub_releases/2011-06/uonc-sct060111.php

Via EurekAlert!: "The world's first clinical trial for the treatment of patients with torn meniscal cartilage has received approval from the UK regulatory agency, the MHRA, to commence. The current treatment for the majority of tears is the removal of the meniscus, a procedure that often results in the early onset of osteoarthritis. The Phase I trial, one of the first in the UK to be approved using stem cells, will treat meniscal tear patients with a cell bandage product, seeded with the patient's own, expanded, stem cells. The cell bandage, produced by Azellon Ltd, a University of Bristol spin-out company, is focused on the research, development and commercialisation of an adult autologous (patient's own) stem cell technology which in vitro (tissue culture) has shown great promise for the healing of meniscal tears. The trial is designed primarily to test the safety profile of Azellon's cell bandage in ten meniscal tear patients, but some information on whether or not it works will also be obtained. The bandage, containing the patient's own stem cells will be implanted in a simple surgical procedure using a specially designed instrument that helps to deliver the cells into the injured site as a first-line treatment in place of removal of the meniscus. Patients will be closely monitored for safety over a five-year follow-up period."

Link: http://www.eurekalert.org/pub_releases/2011-06/uob-psc060311.php

The activity and changing configuration of the immune system is intimately connected with aging in a number of ways. In early life, exposure to infections that require an energetic immune response in effect burns your candle faster by generating more biochemical damage to your body in the process of defending it from the effects of disease. In later life, when the immune system runs beyond its evolutionary warranty, it falls into a state of constant, futile activation and damage - and that damage also adds up.

When you look at the reliability theory of aging, or any like consideration of aging as the consequences of accumulating damage to a complex system, it becomes clear that the immune system is an important component in the model. For example, it is generally accepted that much of the improvement in life expectancy over past centuries stems from a reduction in infectious disease - a process that is by no means complete, given what we still suffer from quiet, persistent infections like cytomegalovirus. But fewer infections mean less activation of the immune system in early life and less damage carried into later life. That leads to both improved health, a physiologically younger body at a given chronological age - and an immune system that declines more slowly, and later in life.

Here is an open access paper in which researchers directly demonstrate (in insects) the principle that early immune activity means a shorter life expectancy:

The pathology of many of the world's most important infectious diseases is caused by the immune response. Additionally age-related disease is often attributed to inflammatory responses. Consequently a reduction in infections and hence inflammation early in life has been hypothesized to explain the rise in lifespan in industrialized societies.

Here we demonstrate experimentally for the first time that eliciting an immune response early in life accelerates ageing. We use the beetle Tenebrio molitor as an inflammation model. We provide a proof of principle for the effects of early infection on morbidity late in life and demonstrate a long-lasting cost of immunopathology.

Like many investigations into the roots of aging, this is more a pointer towards areas where future development of rejuvenation biotechnology should focus than something of direct and immediate use. Results like this add more weight to work on reversing damage in the immune system, and preventing the immune system from falling into a chronic inflammatory state. There isn't anything we can do about our past exposure to infection and persistent agents like cytomegalovirus, but we can help to accelerate the development of ways to fix the resulting damage that we carry with us.

The BBC here looks briefly at the study of aging in varying animal species - it mangles the scientific details in the usual fashion, but covers much of the territory: "From the moment they are born into the dense jungle of Central Africa, the biological clock is ticking for baby bonobos. A recent study, published in the journal Science, revealed that all primates - from men to monkeys - roughly age in the same way, with a high risk of dying in infancy, a low risk of dying as juveniles and then an increasing risk of dying as they aged. Some species though, have found a few tricks to help them play the aging game and extend their natural lifespans. By doing so, they can live for hundreds of years. While a select few, by some definitions, may already have become immortal. ... some species of bat [can] live for decades [and] the explanation may lie in the way bats protect themselves from protein damage, using special molecules called protein chaperones. ... Studies of the American lobster (Homarus americanus), have shown that its extreme longevity might be related to the expression of telomerase ... High concentrations of telomerase are found in cells that need to divide regularly such as organs and embryonic stem cells. Access to an elevated supply of telomerase would equip this crustacean with the ability to rebuild cells damaged by aging. The ability to repair cells in this way may help to explain why lobsters can live up to 100 years and are able to regrow limbs even at an 'old age'. ... Another oceanic resident, the quahog clam (Arctica islandica), is thought to be one of the longest lived metazoans of all. A recent study on this ancient clam, [which] lives more than 400 years, shows it has an increased resistance to oxidative stress. ... The reasons for the exceptional longevity in Arctica may have little to do with resistance to oxidative stress though. ... Instead, like in naked mole rats, it may be the integrity of the animal's proteins that may be the key, rather than damaging free radicals or antioxidants used to defend against them."

Link: http://www.bbc.co.uk/nature/12733853

An example of the how advances in biotechnology are allowing medicine to move closer towards intervening in first causes at the biochemical level: researchers "have developed a new approach for identifying the 'self' proteins targeted in autoimmune diseases such as multiple sclerosis, diabetes and rheumatoid arthritis. ... errant immune responses which mistakenly target the body's own proteins rather than foreign invaders can now be examined in molecular detail. Further research could lead to new insights into the exact causes of these debilitating autoimmune disorders. ... The immune system, the body's main line of defense against disease, has a critical responsibility to distinguish self-derived proteins from those of invaders like viruses and bacteria. Autoimmune diseases arise when a person's immune system fails to make that critical distinction and mistakenly attacks a normal tissue, such as nerve, joint, or insulin-producing pancreatic cells. ... Knowledge of the self-antigens involved in autoimmune processes is important not only for understanding disease etiology, but also for developing diagnostic tests. In addition, physicians may someday use antigen-specific therapies to destroy or disable auto-reactive immune cells. ... But looking through the haystack of cellular complexity for those single-needle self-antigens targeted by the immune system has proved daunting, to say the least. Ideally, scientists would be to develop some kind of biological magnet that could pull these fine needles out of the mass. In this report, the researchers describe an approach which does just that."

Link: http://www.eurekalert.org/pub_releases/2011-06/hms-apn060211.php

Aging research is the poor cousin of the life science field, despite the fact that the overwhelming majority of the harm brought to humanity through disease, frailty, and death is basically caused by aging. Work on extending life or reversing aging is in turn the poor cousin in the aging research family. This situation must change for the better if we are to see meaningful progress in our lifetimes.

A recent article puts some numbers to the picture, here for the Buck Institute, which is one of the largest mainstream laboratories specializing in aging research.

In this fiscal year, the institute will receive about $23 million in government grants, about 66 percent of its $35 million budget. The institute will also get about $5.6 million from the Marin Community Foundation - down from close to $8 million before the economic downturn - and about $5 million from individual and corporate donations.

Compare that with the SENS Foundation, which is currently running a with a yearly budget of a little over $1 million, and is completely reliant on philanthropic donations.

These are small numbers when considered against the broader field of medical research and development. They reflect a society that has not yet woken up to decide that repair of aging is in fact both a possibility and a priority. The feedback loop of education from scientists to the public and support from the public to scientists isn't yet running well for longevity science - it is running better than it was a decade ago, but clearly there is much work to be done.

From the SENS Foundation: "For Max, working at the [SENS Foundation Research Center (SENSF-RC)] has been the culmination of years of dedicated study and preparation. Before he first heard about SENS in early 2005, he wasn't a scientist at all; in fact, he was a 23-year-old cost accountant. When he wasn't studying for his MBA, he was counting other people's money. He knew that he wanted more out of life, though: specifically, he wanted to change the world in a way that would benefit society. As soon as he found and read Aubrey de Grey's Ending Aging, he settled on human health as the area he would strive to impact - and on SENS as the way to make that impact. Over the next few years he committed himself to working in finance, at one point teaching at a local community college, always with the intention of saving his money so that he could return to school to learn about science and laboratory work. During this period he studied whenever he had the time, reading articles relevant to health and aging in scientific journals. In 2008, Max went back to school full-time at the University of Toledo to study chemistry, math, and biology. He was interested in taking an active role in SENS research as quickly as he could, so he contacted the predecessor of the SENS Foundation Academic Initiative, MFURI. As a member of the Initiative, he performed a literature review on the harm caused by iron and aluminum accumulation in the body, citing well over a hundred journal articles. Max's paper was accepted by the journal Rejuvenation Research and published in April 2010, just as he was completing his coursework at Toledo. As his next step, Max opted to join the RC staff rather than pursue a PhD opportunity so that he could continue to make as direct and immediate of a contribution to SENS as possible. Max has now been working at the SENSF-RC for one year, and will be staying on to continue his work on the A2E degradation project. In the long term, he hopes to see the LysoSENS project through all of its pre-clinical stages. It is his wish that this work will lead to therapies that can effectively reverse, or at the least greatly slow, the pathology of age-related macular degeneration."

Link: http://www.sens.org/node/2036

An interesting discovery: "Reprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency-associated transcription factors. This seminal work was followed by numerous studies reporting alternative (non-insertional) reprogramming methods, and various conditions to improve the efficiency of reprogramming. These studies have contributed little to an understanding of global mechanisms underlying reprogramming efficiency. Here we report that inhibition of the mTOR (mammalian target of rapamycin) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF-1 signaling pathway, which like mTOR is involved in control of longevity, also enhances reprogramming efficiency. In addition the small molecules used to inhibit these pathways also significantly improved longevity in Drosophila melanogaster. We further tested the potential effects of six other longevity-promoting compounds on iPSC induction, including two sirtuin activators (resveratrol and fisetin), an autophagy inducer (spermidine), a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), an antioxidant (curcumin) and an AMPK (activating adenosine monophosphate-activated protein kinase) activator (metformin). With the exception of metformin, all of these chemicals promoted somatic cell reprogramming, though to different extents. Our results show that the controllers of somatic cell reprogramming and organismal lifespan share some common regulatory pathways, which suggests a new approach for studying aging and longevity on the basis of the regulation of cellular reprogramming."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21615676

I had an artistic vision, a long time back, shortly after I had my initial realization with regard to engineered longevity, of the path to radical life extension as a sort of vertical ascension. I recall describing the vision of flight through darkness years ago, to my partner at the time - the rest of that conversation lost, along with much else, to failing memory. A room is packed with thousands of people, waiting. The walls and ceiling then unfold to reveal a void beyond, and the assembled masses begin to ascend towards some distant goal - arms spread and looking up in anticipation, as they fly upward, empowered by their own sheer force of will. The energies of their passage glow blue in the darkness, a thousand, thousand trails of light. But with each moment, some falter, and fall away into the abyss, their light-trails vanishing into the surrounding darkness - and the crowd thins and thins the further they ascend.

I am not an artist, needless to say, and so that vision will never make it much beyond the confines of my head. But it is an ugly reality of the human condition that only a fraction of us will have the opportunity to live through into the age of rejuvenation biotechnology - even under the most optimistic timelines, billions will die. The alternatives are far worse, of course, but this is far from the best of worlds. Intellectually we can grasp this scale of death and destruction, but the ape within filters it out. He only cares about the people we associate with - and there aren't all that many of them, even allowing for the artificial and strange relationships of celebrity or much-loved fiction. The rest of the world? Just numbers.

That memory of people in flight through darkness is with me again because I learned today that my former partner died a few weeks ago, unexpectedly. As though the expectedness or the delay in learning of it should change anything of the meaning, but the ape within feels - strongly - that the details of tragedy are important. If we felt even a minuscule fraction of what we do under such circumstances for the vast crowds who fall from the flight each and every day, aged to death ... well, we'd be better than human, and aging would be much further along the path to a solution.

More than a hundred people have died since I started to write this post, most of them from aging or the complications of aging. All just as much individuals as my former partner, just as much people with attachments, potential, things to do, desires and regrets. So very many regrets. But I feel only intellectual loss for that hundred, and not much of it at that - this is what it is to be built on top of a foundation of ape prehistory, to be able to put the terrible fates of countless others easily from our minds, but to be deeply troubled by the loss of one.

To make the best of being human, we have to do the important work, even though it will not reward us, even though the ape inside doesn't really give a damn. Being human is about not letting the ape drive, even though it's always far easier just to let him take the wheel. So no obituary and no talking to the dead to say things that perhaps should have been said one day - and now can't be. Hard as it may be. The only person who would be listening here is the ape inside, and talking to him is a pointless exercise.

The world, meanwhile, is lived in by the living - who are falling from the flight in great numbers, day after day, while too little is being done about it. When whatever happens to me eventually happens to me, I would hope that someone takes a few minutes to write exactly the same thing, and mean it.

Hormesis is the process by which a little damage or stress to our biology can lead to a longer life span, as it wakes up the repair mechanisms and makes them do a better job than they otherwise would - a net gain in resiliency. Here is a review that summarizes the implications for much of mainstream research into aging and longevity: "Various nutritional, behavioral, and pharmacological interventions have been previously shown to extend life span in diverse model organisms, including Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, mice, and rats, as well as possibly monkeys and humans. This review aims to summarize published evidence that several longevity-promoting interventions may converge by causing an activation of mitochondrial oxygen consumption to promote increased formation of reactive oxygen species (ROS). These serve as molecular signals to exert downstream effects to ultimately induce endogenous defense mechanisms culminating in increased stress resistance and longevity, an adaptive response more specifically named mitochondrial hormesis or mitohormesis. Consistently, we here summarize findings that antioxidant supplements that prevent these ROS signals interfere with the health-promoting and life-span-extending capabilities of calorie restriction and physical exercise. Taken together and consistent with ample published evidence, the findings summarized here question Harman's Free Radical Theory of Aging and rather suggest that ROS act as essential signaling molecules to promote metabolic health and longevity." ROS can of course be acting both as useful signals and sources of damage in different circumstances - the fact that life can be extended by antioxidants specifically targeted to mitochondria, coupled with the evidence mentioned above, suggests that much.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21619928

A review paper: "Aging is a gradual process during which molecular and cellular processes deteriorate progressively, often leading to such pathological conditions as vascular and metabolic disorders and cognitive decline. Although the mechanisms of aging are not yet fully understood, inflammation, oxidative damage, mitochondrial dysfunction, functional alterations in specific neuronal circuits and a restricted degree of apoptosis are involved. Physical exercise improves the efficiency of the capillary system and increases the oxygen supply to the brain, thus enhancing metabolic activity and oxygen intake in neurons, and increases neurotrophin levels and resistance to stress. Regular exercise and an active lifestyle during adulthood have been associated with reduced risk and protective effects for mild cognitive impairment and Alzheimer's disease. Similarly, studies in animal models show that physical activity has positive physiological and cognitive effects that correlate with changes in transcriptional profiles. According to numerous studies, epigenetic events that include changes in DNA methylation patterns, histone modification and alterations in microRNA profiles seem to be a signature of aging. Hence, insight into the epigenetic mechanisms involved in the aging process and their modulation through lifestyle interventions such as physical exercise might open new avenues for the development of preventive and therapeutic strategies to treat aging-related diseases."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21624506