Fight Aging!

I see that Popular Mechanics is running an article on the presently crude and early steps towards artificial vision. In comparison to work on artificial hearts and kidneys, development of artificial eyes lags far behind - it's a challenging problem and the eye is arguably a more complex system than anything else outside the brain. The present mainstream approach involves building a grid of electrodes in place of the retinal cells lost to forms of degenerative blindness; images captured by a worn camera are analyzed and the electrodes stimulated appropriately.

In the morning, a surgeon at NewYork-Presbyterian Hospital will make an incision in Barbara's left eye and lift the saran-wrap-like membrane that covers it, called the conjunctiva. He’ll then suture a small electronics package, about the size of a watch battery, to the outside wall of the eye and secure it with a piece of silicone rubber that wraps around the eye’s equator. Next, he'll thread a thin cable through an incision in the wall; the cable connects the electronics to an array of 60 electrodes. After removing the vitreous humor that fills the inside of the eye - a material that’s essentially Jell-O, minus the sugar and food coloring - the surgeon refills the eye with fluid so that he can manipulate the array onto the retina, tacking it in place with what is perhaps the world’s tiniest pushpin. The whole procedure will take 4 to 5 hours.

...

The Argus II implant that Barbara will be receiving is the second generation of the device; the first had only 16 electrodes. Information gleaned from this clinical trial will be used to improve the 60-electrode version, which will be commercialized, first in Europe, as early as December. But even as the trial continues, a much larger effort, involving six national labs, four universities and a commercial partner, Second Sight Medical Products, is developing technologies that will enable third- and fourth-generation models using as many as 1024 electrodes - which could provide enough detail to read 24-point font and recognize faces.

Progress in this model is at present a matter of making implantation safer and more reliable, greatly increasing the density of electrodes, and improving the ability to translate a camera's view into a helpful picture - a combination of medicine, electrical engineering, and computer vision research. The end result of this form of technology will never produce anything more than a detailed, glowing sketch of dots and lines for the patient: it is not true vision as experienced by those of us fortune enough to retain our sight.

Nonetheless it works - already providing a great improvement for patients over being blind - and it will serve as a foundation for later forms of artificial sight technology. An established research and development community doesn't stand still after the first products are commercialized, but rather moves onward to new breakthroughs.

The relationship between excess fat tissue and dementia is well known, and researchers continue to investigate the details: "Adipose tissue is an endocrine and paracrine organ that contributes to both metabolic and vascular homeostasis. Overweight and obesity due to excess adipose tissue, are cornerstones of vascular risk and increase risk for late-onset dementia. Vascular risk does not exist in isolation, and is accompanied by alterations in hormonal metabolism and metabolic syndromes. Thus, while vascular risk is highlighted as a primary mechanism for elevated dementia occurrence due to obesity, hormonal risk states may also precede or result from underlying dementia-related neuropathologies and direct neuronal toxicity. This is exemplified during the prodromal phase of dementia, as vascular and metabolic parameters decline in relation to dementia development, and potentially in a way that is different from 'normal' aging. In this review will be presented a review of the epidemiology of adiposity and dementia; adipose tissue biology; and two major hormones produced by adipose tissue, leptin and adiponectin, that interact directly with the brain. ... Understanding the role of adipose tissue in health of the brain is pivotal to a deeper understanding of dementia processes."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20875649

Via the Detroit News: "trials are being conducted on women with advanced stage breast cancer and attempt to target the cancer's stem cells, which are believed to be resistant to traditional therapies and the fuel behind cancer's spread. By using experimental drugs to block these cancer stem cells, doctors hope the tumors will shrink or at least stop spreading and will lead to better ways to treat - and possibly cure - the disease that is the nation's second-leading cause of death. ... We rarely use the 'C word' - cure - but the intent of research today is not to study (cancer) but to treat and ultimately to beat it. There is so much hope that we're positioned today with the information from the (human) genome, with the biologic expertise and understanding of the stem cells, I think we can be at the vanguard of treatments that hopefully will lead toward not just longer, disease-free survival but quite literally cures. That's the hope of the cancer stem cell approach. ... In breast cancer, we have very good results of getting rid of the primary cancer with surgery or radiation therapy but what is lethal to a number of women who actually die of breast cancer is the spread of the cancer. These cancer stem cells are the cells that are metastatic. That's why we had to develop new approaches to target these cancer stem cells if we are going to cure more women with breast cancer and other types of cancer."

Link: http://www.detnews.com/article/20100930/METRO/9300421/U-M-stem-cell-trial-promising

It's easy to become frustrated with the seemingly bucolic rate of progress in biotechnology and medicine: when what you really want is the medical technology of the 2040s, living in 2010 can be a cruel tease. But it's all an illusion; this is a time of tremendously rapid progress in all forms of technology. It only seems slow when you're living it one day at a time, paying close attention, and waiting for the pot to boil.

Consider that a great deal of what takes place in the laboratory today is science fiction from the perspective of the 1980s: a time in which the human genome had yet to be sequenced, and tasks that a post-grad could now knock out in a few weeks and few thousand dollars required a full laboratory and serious investments in time and money. If they were possible at all. Times change, progress happens - and it's getting faster.

To illustrate the point, have a look at these three items with the eyes of someone living in the days prior to low cost cell phones, when identifying a single genetic association and its consequences was a major triumph and work of engineering.

Rewiring a damaged brain

Scientists believe that as the brain develops, it naturally establishes and solidifies communication pathways between neurons that repeatedly fire together. Nudo and others have found that during the month following injury the brain is redeveloping, with fibers that connect different parts of the brain undergoing extensive rewiring.

"The month following injury is a window of opportunity," Mohseni said. "We believe we can do this with an injured brain, which is very malleable."

Mohseni has been building a multichannel microelectronic device to bypass the gap left by injury. The device, which he calls a brain-machine-brain interface, includes a microchip on a circuit board smaller than a quarter. The microchip amplifies signals, called neural action potentials, produced by the neurons in one part of the brain and uses an algorithm to separate these signals - brain spike activity - from noise and other artifacts. Upon spike discrimination, the microchip sends a current pulse to stimulate neurons in another part of the brain, artificially connecting the two brain regions.

Sneaking Spies Into a Cell's Nucleus

Using silver nanoparticles cloaked in a protein from the HIV virus that has an uncanny ability to penetrate human cells, the scientists have demonstrated that they can enter the inner workings of the nucleus and detect subtle light signals from the "spy." ... "The ability to place these nanoparticles into a cell's nucleus and gather information using light has potential implications for the selective treatment of disease," Gregas said. "We envision that this approach will also help basic scientists as they try to better understand what occurs within a cell's nucleus."

...

"Our ultimate goal is to develop a nanoscale delivery system that can drop off its payload -- in this case nanoparticles with other agents attached - into a cell to enhance the effectiveness of a drug treatment," Vo-Dinh said. "Theoretically, we could 'load up' these nanoparticles with many things we are interested in - for example a nanoprobe for a cancer gene - and get it into a cell's nucleus. This would provide us a warning signal of the disease at its earliest stage, thus allowing faster and more effective treatment."

'Firefly' Stem Cells May Help Repair Damaged Hearts

In his University of Central Florida lab, Steven Ebert engineered stem cells with the same enzyme that makes fireflies glow. The "firefly" stem cells glow brighter and brighter as they develop into healthy heart muscle, allowing doctors to track whether and where the stem cells are working.

Researchers are keenly interested in stem cells because they typically morph into the organs where they are transplanted. But why and how fast they do it is still a mystery. Now Ebert's cells give researchers the ability to see the cells in action with the use of a special camera lens that picks up the glow under a microscope.

Researchers forge further ahead with each passing year. Patience is a virtue, but then so is helping these researchers to move faster - and especially in the fields you yourself value.

Via EurekAlert!, signs of continued progress in understanding how to give orders to cells: "scientists have found a way to regenerate injured spinal cord and muscle by using small molecule drugs to trigger an influx of sodium ions into injured cells. The approach breaks new ground in the field of biomedicine because it requires no gene therapy; can be administered after an injury has occurred and even after the wound has healed over; and is bioelectric, rather than chemically based. ... Like human beings, who regenerate fingertips only as children, [tadpoles] lose the ability to regenerate their tail with age. Most remarkably, it was shown that [tadpoles] whose tails had been removed could be induced to make a perfect new tail by only an hour of treatment with a specific drug cocktail. The findings have tremendous implications for treating wounds ... The treatment method used is most directly applicable to spinal cord repair and limb loss, which are highly significant medical problems world-wide. It also demonstrates a proof-of-principle that may be applicable to many complex organs and tissues. ... We have significantly extended the effective treatment window, demonstrating that even after scar-like wound covering begins to form, control of physiological signals can still induce regeneration. Artificially causing an influx of sodium for just one hour can overcome a variety of problems, such as the decline in regenerative ability that comes with age and the effect of regeneration-blocking drugs."

Link: http://www.eurekalert.org/pub_releases/2010-09/tu-spk092310.php

A good demonstration of dental tissue engineering: researchers "used stem cells obtained from the periodontal ligament of molars extracted from mice, expanded them in an incubator, and then seeded them on barren rat molars. The stem cell-treated molars were reinserted into the tooth sockets of rats. After two and four months, the stem cells aligned and formed new fibrous attachments between the tooth and bone, firmly attaching the replanted tooth into the animal's mouth ... Tissue sections showed that the replanted tooth was surrounded by newly formed, functional periodontal ligament fibers and new cementum, the essential ingredients of a healthy tooth attachment. ... To verify that the ligament was formed by the transplanted stem cells and not by the animal's own cells, stem cells were labeled with green fluorescent protein prior to seeding them on the molars and re-inserting the teeth into the animal's mouth. ... Our research uncovered the code required to reattach teeth - a combination of natural tooth root surface structure together with periodontal progenitor cells. ... Our strategy could be used for replanting teeth that were lost due to trauma or as a novel approach for tooth replacement using tooth-shaped replicas."

Link: http://www.physorg.com/news204970534.html

Via Maria Konovalenko, I see that the book The Future of Aging will be published soon. It's a collection of chapters written by well known names in the field of aging and longevity science, spanning a wide range of the present field - and its goals for the next few decades.

Just as the health costs of aging threaten to bankrupt developed countries, this book makes the scientific case that a biological "bailout" could be on the way, and that human aging can be different in the future than it is today. Here 40 authors argue how our improving understanding of the biology of aging and selected technologies should enable the successful use of many different and complementary methods for ameliorating aging, and why such interventions are appropriate based on our current historical, anthropological, philosophical, ethical, evolutionary, and biological context. Challenging concepts are presented together with in-depth reviews and paradigm-breaking proposals that collectively illustrate the potential for changing aging as never before.

The proposals extend from today to a future many decades from now in which the control of aging may become effectively complete. Examples include sirtuin-modulating pills, new concepts for attacking cardiovascular disease and cancer, mitochondrial rejuvenation, stem cell therapies and regeneration, tissue reconstruction, telomere maintenance, prevention of immunosenescence, extracellular rejuvenation, artificial DNA repair, and full deployment of nanotechnology. The Future of Aging will make you think about aging differently and is a challenge to all of us to open our eyes to the future therapeutic potential of biogerontology.

A steady stream of popular science books and articles pointing out the potential of modern biotechnology is a required part of ongoing advocacy for healthy life extension. It's still very much the case that most people in the world either don't care or don't know that we stand within striking distance of true rejuvenation medicine. This is a problem, as raising funds and building a research community to create medical technologies to reverse the course of aging requires greater public support and understanding.

Michael Anissimov notes that a new cryonics support organization is starting up in Europe: "EUCRIO will officially launch on Friday, October 1st. ... EUCRIO is an organization that specializes in providing state-of-the-art standby, stabilization, and transport procedures for cryonicists in the European Union. EUCRIO is pleased to assist members of the three main cryonics storage provider organizations. ... If one of our members has an emergency we deploy our trained and well-equipped team to stand-by the patient's bedside, ready to give the best stabilization services. The patient is given stabilization medications, cooled down, and perfused with vitrification solutions before further cooling to dry ice temperatures for air-transport to the appropriate cryonics organization for long-term preservation using liquid nitrogen. Our primary mission is to improve human cryopreservation and safeguard the lives of our members. ... EUCRIO employs a wide variety of professionals: including physicians, perfusionists, emergency medical technicians, engineers and scientists, throughout the European Union. EUCRIO has staff members ready to intervene across the European Union and all are ready to respond to clients at all times." As I've remarked in the past, the support and infrastructure for conducting cryopreservation events is an area in need of both improvement and more participation. The actual provision of ongoing low temperature storage for the recently deceased, while a challenge in and of itself, is easy in comparison to managing end of life issues and a timely cryopreservation.

Link: http://www.acceleratingfuture.com/michael/blog/2010/09/eucrio-good-news-for-european-cryonicists/

A paper to go along with a recent demonstration of in situ regeneration of enamel: "The regenerative capability of enamel, the hardest tissue in the vertebrate body, is fundamentally limited due to cell apoptosis following maturation of the tissue. Synthetic strategies to promote enamel formation have the potential to repair damage, increase the longevity of teeth and improve the understanding of the events leading to tissue formation. Using a self-assembling bioactive matrix, we demonstrate the ability to [induce] formation of enamel at chosen sites adjacent to a mouse incisor cultured in vivo under the kidney capsule. The resulting material reveals the highly organized, hierarchical structure of hydroxyapatite crystallites similar to native enamel. This artificially triggered formation of organized mineral demonstrates a pathway for developing cell fabricated materials for treatment of dental caries, the most ubiquitous disease in man. Additionally, the artificial matrix provides a unique tool to probe cellular mechanisms involved in tissue formation further enabling the development of tooth organ replacements."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20869764

I should remind you that the Immortality Institute conference in Brussels is coming up next month - just a couple of weeks away now - for those of you on that side of the pond who grow tired of seeing nothing by US-based conferences focused on the advancement and application of longevity science.

Many of the usual suspects from the longevity science community will be speaking or presenting, as well as a fair few faces you might not be so familiar with. Not too many of the European advocates for extended healthy life spans make it out to the US-based conferences on a regular basis, so it should be a different crowd from the circuit of the past few years.

The Institute volunteers let me know that there are sponsorship positions remaining open. If you missed the chance to fund the latest Institute research initiative - a investigation of mitochondrial uncoupling - then you might give some thought to supporting the conference:

It is because of the continued support of valuable sponsors that we have had such success with summits, conferences, research grants, fundraisers, and other diverse projects relating to the cause of defeating aging and bringing an end to involuntary death.

The Immortality Institute is currently filling the remaining sponsorship spots for our 2010 International Conference. As you know, this is the second full conference we are hosting, after co-sponsoring many others, and we hope for a repeat of the success of our 2005 event. Please Contact support@imminst.org if you would like to sponsor this event and its well-stocked program.

Sponsor logos and names are positioned in the conference program and will be included in various other promotional avenues, such as the conference page, newsletter, our YouTube channel, and other potentials avenues.

If you'd like to see more of this sort of event, it helps to offer encouragement to the folk who work hard to set it up.

Biomedical gerontologist Aubrey de Grey notes: "This October, Hannover and Detroit will host two of the year's most interesting and wide-ranging scientific conferences in the biomedical field. I'll be chairing sessions at both events, focused on the application of regenerative medicine to aging and aging-related disease - a synergy we at SENS Foundation term rejuvenation biotechnology. ... The World Stem Cell Summit - hosted this year in Detroit, Michigan from October 4th to 6th - is a wide-ranging event covering topics from basic research to social policy and ethics, and expected this year to attract more than 1,200 delegates from 30 nations. I'll be chairing a session at the summit entitled "Regenerative Medicine Against Aging - Technological, Political and Commercial Obstacles and Opportunities". Participants include Dan Perry, of the Alliance for Aging Research; Michael West, acclaimed biotechnology entrepreneur and CEO of Biotime, Inc.; and Huber Warner, former associate director of the National Institute on Aging. ... The World Congress on Preventive and Regenerative Medicine, hosted this year in Hannover from October 5th-7th, is the only international event addressing the entire regenerative medicine sector. This broad remit, similar to that of the SENS conference series, gives the meeting outstanding potential to foster interdisciplinary collaborations in research and development. I am serving as a vice-president of the Congress, and will co-chair a session entitled "Rejuvenation Biotechnologies: Applying Regenerative Medicine to Aging"."

Link: http://www.sens.org/node/1678

Eric Drexler writes on the topic of antioxidants and autophagy: "Autophagy removes cell components - including ROS-damaged proteins and organelles - by engulfing and digesting them, producing wastes and recycled nutrients. ... Upregulating autophagy [has] extraordinarily wide-ranging benefits. Interventions that extend healthy lifespan in animal models include calorie restriction, resveratrol, spermidine, and rapamycin, and in each operates, at least in part, through autophagy. Upregulating autophagy has positive effects in models of several specific neurodegenerative diseases, too ... antioxidants inhibit basal autophagy and block the induction of autophagy by calorie restriction and other means. Because this effect inhibits the central mechanism of cell repair, it helps explain why dietary antioxidants have failed to deliver their expected benefits to health and longevity." I would have said it has more to do with failing to target mitochondria, given the benefits demonstrated by mitochondrially targeted antioxidants. As Drexler notes, however, there's research to back up the antioxidant-autophagy link, which may have some relation to earlier research showing antioxidant supplementation to interfere with the processes of hormesis, and thus block beneficial effects of mild stress such as exercise.

Link: http://metamodern.com/2010/09/26/antioxidants-block-cell-repair/

Cytomegalovirus (CMV) is a herpesvirus that infects most of the population by the time they are old. Like all similar species of virus, it can remain latent in the body for long periods of time, and the immune system struggles to clear it. CMV infection appears to be an important factor in the age-related failure of the adaptive immune system: more and more naive T cells become uselessly specialized memory cells to fight CMV, leaving ever fewer T cells able to perform other vital tasks - such as destroying senescent cells, invading pathogens, and cancerous cells.

I noticed an open access paper that provides a cautious, conservative overview of where researchers stand in their investigations of CMV and immune system dysfunction in the aged. In short, these researchers believe that the damaging consequences of CMV infection are a theory in need of further proof. Additionally, there may be other significant sources of immune cell depletion that operate in the same way, and which may ultimately be shown to be more important:

Despite the widespread belief that decreased numbers of naive cells in the elderly must be a bad thing, and the certainty that CMV infection drives down the numbers of such cells even further, whether this parameter is actually associated with a measured clinical outcome has not been properly tested in humans.

...

If CMV has such an over-riding effect on immune signatures, are there likely to be any additive effects of other viruses, pathogens or different sources of "chronic antigenic stress". There is some evidence that [Epstein-Barr virus] has a minimal effect in addition to CMV, but that [other herpesvirus strains] do not. In other conditions such as rheumatoid arthritis, Alzheimer's Disease, and prostate cancer, there is some evidence consistent with CMV exacerbation; the same may be true of serious psychological stress. Evidence is sparse, but what is there suggests that there may indeed be additive immune "exhausting" effects of polypathologies.

Finding ways to clear CMV from the body doesn't solve the problem of a damaged immune system - removing CMV just stops further damage from occurring. In fact, if researchers focused on finding a way to repair and reverse this sort of immune system misconfiguration, CMV could be largely ignored in the general populace. Aside from its effects over the very long term, it is mostly harmless for anyone with a functional immune system.

In recent years, researchers have demonstrated the ability to remove autoimmune disorders - another form of immune system misconfiguration - by destroying a patient's immune system and then recreating it using stem cell technologies. As a process, this is presently crude and traumatic, as it involves the use of chemotherapy or similar approaches. It is not a therapy anyone would wish to undertake, given an alternative. The precisely targeted cell killing technologies under development in the cancer research community may soon offer that alternative, however. If the problems in a malfunctioning immune system involve too many T cells of a distinct type - e.g. specialized to cytomegalovirus - then a targeted therapy could be used to safely destroy those cells.

Sooner or later, researchers will turn up good biomarkers for aging and longevity - tools that are needed to properly evaluate therapies that aim to repair the biochemical damage of aging in humans. Here is another candidate biomarker: "Aging is a complex process resulting from, among other, dynamic non-linear interactions between genetics and environment. Centenarians are the best example of successful aging in humans, as they escaped from, or largely postponed, major age-related diseases. Ionic fluxes changes play a key role in several patho-physiological cellular processes, but their relation to human aging is largely unexplored. In the present study we have [compared] potassium (K+) current recordings from dermal fibroblasts (DF) obtained from young, elderly and centenarian donors. We found that in DF from elderly donors, but not from centenarians, K+ current amplitude is significantly smaller with respect to DF from young donors. Moreover, cell membrane capacitance of DF from elderly donors is smaller with respect to young donors and centenarians. ... The maintenance of 'young' K+ currents and the peculiar age-related remodeling of K+ channel subtypes in centenarian's DF is likely associated with successful aging and might provide a predictive marker of longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20858515

A commentary on recent research showing calorie restriction to reduce the number of senescent cells in some tissues: "The relatively short period of caloric restriction resulted in a 3.3 to 6.5% decrease in senescent cell abundance as a function of total cell number. ... As with many interesting studies, this study raises many more questions than it answers. ... Does short term caloric restriction reduce the proportion of senescent cells in other tissues, such as fat? Obesity, aging, and other conditions are associated with extensive accumulation of senescent cells in fat tissue of rodents as well as humans ... Does short term caloric restriction also reduce abundance of senescent cells and inflammation in humans? It may not, since, as the authors point out, proliferation-competent skin fibroblasts did not increase after 9 to 12 years of caloric restriction in rhesus monkeys. On the other hand, it might, since white blood cell DNA fragmentation [declines] in overweight but non-obese adult human subjects subjected to 25% caloric restriction for 6 months ... What is the cell dynamic mechanism that causes decreased senescence during short term caloric restriction? Altered rates of senescent cell formation or removal could be responsible for the effect of short term caloric restriction on abundance of senescent cells. ... Senescent cells can be removed through activation of the immune system, with the immune system being activated by factors released by senescent cells. Short term caloric restriction could enhance immune system responsiveness to senescent cells, a possibility that remains to be tested."

Link: http://www.impactaging.com/papers/v2/n9/full/100204.html

Across the near-decade of running the Longevity Meme as a resource for folk interested in healthy life extension and the science of engineering greater human longevity, a great many people have suggested that I change the name. A good name for any sort of non-profit, service-oriented, or advocacy initiative is distinctive, unambiguous, and points directly towards the initiative's goals and associations. By those standards, "Fight Aging!" is a good name. "The Longevity Meme," not so good.

The main problem with the name, as I am continually reminded, is that 95% of the populace are unfamiliar with the word "meme."

longevity: a long duration of individual life; length of life; long continuance

meme: an idea, viewpoint, behavior, style, or usage that spreads from person to person within a culture; an information pattern, held in an individual's memory, which is capable of being copied to another individual's memory

the longevity meme: the collection of ideas, viewpoints and behaviors that will enable people to lead long, healthy and extended lives

Which is all fine and well as definitions go, but if your business is a mix of information provision and persuasion then it's probably not a good thing that you have to explain the meaning of your name to everyone.

The flip side of this coin is that a meaningless name can be given meaning in the course of doing business. What does "Yahoo!" mean, or better yet, "Google?" These companies define the meaning of their own name insofar as it relates to their operations and initiatives. The Longevity Meme is a tiny minnow in the great sea of websites, but it has been around for nearly a decade. The community of readers and newsletter subscribers know what they're signed up for by now.

This stage of advocacy for engineered longevity is really all about growth, however. The present cluster of young research-funding organizations - such as the Methuselah Foundation and SENS Foundation - have come as far as they can with the resources of the initial community of supporters. Those people who were already 110% for longevity science, or were easy to reach and persuade, are now on board and giving what they are prepared to give. In order to reach the next stage in organization growth, the supporting community must grow.

Advocacy for longevity research is a balancing act informed by ongoing developments in raising funds, actual progress in the fields of interest, and the growth of the community of supporters. In an ideal world, these three factors will all advance steadily: an upward curve of success. In practice things are never that easy. A supportive community of a given size will only contribute so much in the way of resources: are those resources assigned to research, which tends to produce newsworthy results at irregular intervals in addition to actual progress, or to outreach and education? What will best grow the community so as to grow the resource pool of donations, and in turn help to achieve research goals more rapidly

Which means that the people who already know what the Longevity Meme is all about are not the people who matter when it comes to making choices about the name. It's all about outreach, and making that outreach easier.

None of which is to say that I have a new name in mind, a timeline for making this change, or that I am expecting any great bolt of inspiration to strike from the blue. But there are plenty of options regardless. I could, for example, roll the Longevity Meme into the Fight Aging! brand as "Fight Aging! News." Or keep "Longevity" - for search engine optimization and continuity reasons - and find some new longevity-related title that captures the meaning of the old but is more straightforward.

Suggestions are welcome.

This San Franscisco Business Times article looks at the future of the California Institute for Regenerative Medicine (CIRM): "The architect of Proposition 71 - the 2004 voter-approved measure that set up California's stem cell research funding agency with $3 billion in state-backed bond financing - says the California Institute for Regenerative Medicine by 2016 could seek another $3 billion to $5 billion. That may seem like a tough sell in a state smacked upside the head by a recession, but Klein is the ultimate salesman / evangelizer / patient advocate. He pulled together a powerful group of people cutting across political party lines and backgrounds to get Prop. 71 passed when most people had no scientific concept of stem cells. Strategically, what we're focused on is trying to make sure there is enough therapies advanced to Phase I or Phase II efficacy trials (where) voters of California can judge the performance and decide if they should approve another $3 billion to $5 billion. The voters are going to have to see real evidence. ... But wasn't CIRM limited to a 10-year life? No, Klein said - Prop. 71 backers simply estimated that funding would not be spent any faster than 10 years. Legal challenges delayed that another two years, he said, so funding likely won't be exhausted until late 2016 or early 2017. By then, Klein said, many clinical trials will be well under way."

Link: http://sanfrancisco.bizjournals.com/sanfrancisco/blog/2010/09/cirm_may_seek_up_to_5_billion_more_for_stem_cells.html

Reason Magazine interviews the author of Long for this World: "The field [of longevity research] is really badly underfunded. Even the National Institute of Aging spends a fraction of its budget on experimental gerontology. Most of the budget of the National Institutes of Health goes for fighting recognized diseases and it's much more acceptable politically to declare war on cancer than to declare war on aging. So if you want to study aging and dream of slowing it down, you've got a tough time getting funding. That worries me more now having finished the book and having spent so much time talking with the gerontology mainstream as well as Aubrey [de Grey]. We may be missing really wonderful opportunities by neglecting the sciences of aging, for instance all of those late onset diseases, not just cancer, Alzheimer's, diabetes, atherosclerosis, all of those late onset diseases become more likely [as we age]. If we want to fight cancer, the most plausible research direction may be to understand those small invisible steps leading us there. Likewise with Alzheimer's, diabetes, it may not be there is a different story with each. It may be there are common problems which we might be able to address and if we could, suddenly what sounds so futuristic and strange now might become as pedestrian and common sensical as preventive medicine. If we would just be doing the equivalent of taking out garbage, flossing the teeth, doing standard maintenance work for the body in our prime, that could postpone or even prevent disease entirely."

Link: http://reason.com/archives/2010/09/22/live-forever-or-die-trying/singlepage

A condition called TTR amyloidosis - very rare in young people - appears to cause the death of the elderly who survive or evade all of the other common age-related diseases:

TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail. "The same thing that happens in the pipes of an old house happens in your blood vessels"

This is one of many types of amyloid that build up in the body with age. If we want to repair the damage of aging, we'll have to learn how to remove these unwanted substances - and certainly find ways to reverse the course of TTR amyloidosis, which at present looks very much like the roadblock at the end of life. Finding ways to break down amyloids, such as by training the immune system to attack them, is one of the seven research themes of the Strategies for Engineered Negligible Senesence (SENS).

I notice that the SENS Foundation recently announced funding for research into developing a therapy for TTR amyloidosis:

There is already a largely-unrecognized burden of [amyloid]-related morbidity and mortality in the population today, both as a principle cause of death and disease and as a contributor to the total dysfunction of the aging cardiovascular system. And the situation will worsen globally over the course of the next 20 to 50 years, beginning in the industrialized world and the sequentially emerging in China, India, Mexico, the Middle East and beyond; ironically, this will be particularly so to the degree that other diseases are better-managed by progress in conventional medicine, or cured by rejuvenation biotechnology.

These features make the removal of wild-type TTR aggregates [a] key priority for SENS Foundation as a biomedical charity dedicated to accelerating the development of rejuvenation biotechnology. Accordingly, SENS Foundation has had an open request for proposals (RFP) for research toward the development of TTR-clearing therapies for several years now, and has approached several prominent researchers in the genetic amyloidosis field to submit applications for funding. Until recently, however, the Foundation had not received any strong proposals. But thanks to the efforts of [Supercentenarian Research Foundation's] Stan Primmer, such a proposal has recently come together and the Foundation has been given the opportunity to fund it - and I am pleased to have the privilege of announcing that the proposal has been vetted, approved, and funded, and preliminary work will soon be under way.

The first phase of the research is funded to the tune of $150,000, and will involve the development of antibodies that can safely break down TTR amyloid and thus render it harmless.

We are delighted to have such a strong project underway, in the hands of recognized experts in the field, and I am personally grateful for the critical networking done by Primmer and the Supercentenarian Research Foundation to bring the proposal together, and proud of SENS Foundation's role as funder of this promising project. TTR-based senile cardiac amyloidosis is an underdiagnosed and heretofore-untreatable disease that is prevalent in the aging population and poised to become a widespread medical problem with the aging of the global population and the improved treatment of more familiar age-related diseases. We will watch the progress of this latest funded research project with keen anticipation, and look cautiously forward to the ultimate culmination of the preclinical groundwork in a therapy for human patients.

Cytomegalovirus is one of the important contributions to immune system failure with aging: most people are infected, and it causes an ever-greater fraction of available T cells to be uselessly specialized to fight it, leaving too few naive T cells left for other jobs. Intriguingly, it seems that long-lived people have some resistance to this consequence of infection: "we analyzed long-lived families in the Leiden Longevity Study (LLS) in which offspring enjoy a 30% reduced standardized mortality rate, possibly owing to genetic enrichment. We [determined] the capacity of T cells to respond [against] CMV in a smaller group of LLS subjects and controls. CMV infection was strongly associated with an age-related reduction in the frequency of naive T cells and an accumulation [of] late-differentiated effector memory T cells in the general population, but not in members of long-lived families. The latter also had significantly lower C-reactive protein levels, indicating a lower proinflammatory status compared with CMV-infected controls. ... Our data suggest that these rare individuals genetically enriched for longevity are less susceptible to the characteristic CMV-associated age-driven immune alterations commonly considered to be hallmarks of immunosenescence, which might reflect better immunological control of the virus and contribute to their decreased mortality rate." Hopefully the basis for this resistance can be uncovered and made into a therapy.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20855876

Mutation of the WRN gene causes the accelerated aging condition Werner Syndrome. Absence of the correctly formed protein encoded by the gene impairs DNA repair, which in turn leads to the symptoms of accelerated aging. But as this research shows, gene expression of WRN appears to decline with "normal" aging as well: "The WRN gene encodes DNA helicase participating in genome maintenance. We looked for associations of natural aging with expression and methylation of this gene in blood mononuclear cells and with its common polymorphisms. Analyses were performed in ethnically homogenous Polish Caucasians. The mean level of the WRN messenger RNA was significantly lower in long-living individuals than in young and middle-aged controls. Analysis [showed] that aging might be accompanied by a slight increase of its methylation status; however, it seems to be biologically insignificant. Finally, analysis [showed] that the frequencies of the L1074F and C1367R polymorphisms were similar in all age groups tested ... We suggest that age-related decrease of the WRN expression but not its common genetic variants might contribute to human immunosenescence."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20855428

As rules go, "ignore anyone who says you can alter aging by sticking novel things in your mouth and swallowing" is a good one. The world is full of fools selling false hope to idiots, and most of this nonsense takes the form of pills, potions, and recommendations to gorge only on specific types of food. We are an orally fixed culture when it comes to anti-aging flim-flam. Had I more time, I might speculate on the deep mythological roots of this sort of thing: modern hucksterism as a direct descendant of shamanic magical thinking, drawing on core aspects of the human condition to weave a web of make-believe.

But one doesn't have to go much further than pointing out that some people are greedy and inventive, while others are gullible - or at least not paying as much attention to a given topic as they might. That is sufficient to explain much of what we see around us: if selling a $1 lump of fool's gold for $20, all you really have to do is ensure that you're selling in a place and time where it costs much more than $20 (in time or money) to fully understand the transaction. Biology is fearsomely complex, and few people are prepared to put in the time required to understand whether or not the claims made for a particular purchase or recommendation are nonsense - and the answer is rarely as simple as "yes" or "no."

A while back, I discussed the use of trust networks in this context: if you can't be informed yourself, then find informed people to listen to. But even here it is expensive to discover and use such networks, at least in comparison to the cost of individual products in the "anti-aging" marketplace.

In any case, my thoughts were swung in this direction by a semi-skeptical article on the work of Vladimir Skulachev over at Singularity Hub. Skulachev's group are developing a mitochondrially targeted antioxidant, and are somewhere in the nebulous region where lab work starts to overlap with publicity and early fundraising for commercial development. This is sound science: this is an ingested, engineered compound that slows aging in mice, and appears to have potential therapeutic uses for a range of conditions. Skulachev is far from alone in researching mitochondrially targeted antioxidants - he's just starting in on his fifteen minutes of fame as the Western press notice him for the first time.

However, for a person without any familiarity with the topic and the biochemistry involved, this sounds no different from any of the "anti-aging" nonsense out there. It's a thing you stick in your mouth and swallow, they're calling it an antioxidant - which every fellow on the street understands is a pill you buy from the stack next to the vitamins - and the press gleefully spouts the traditional nonsense with which it greets any new aging research: "Cure for aging!", "Methuselah compound!" and so on.

Back to the Singularity Hub article: the author is intelligent and well read, but not at all familiar with the biology involved. So he is on the fence when it comes a reading of Skulachev from the press. He is pulled one way by the peer-reviewed science and reputable scientists involved even as he is pushed the other by mainstream press idiocy and the superficial similarity to any number of "anti-aging" scams of past years. For example:

Skulachev’s work continues. His anti-oxidant compounds (not sure if this means a new formula or just SKQ1) are being tested in Russia on humans in clinical trials, but as a treatment for glaucoma. I’ve no idea how a mitochondrial penetrating anti-oxidant compound is supposed to cure glaucoma, but there you go. As it would be very hard to test for life extension, such trials are probably only going to confirm safety for the compound. And, of course, whether or not they can cure glaucoma.

Hold on, I just want to take a reality check here. Anti-oxidants that cure glaucoma? That sounds really weird. Most treatments are based on relieving pressure, and some experiments are being done for drugs that affect bloodflow…but antioxidants? These sort of panacea claims don’t lend credence to Skulachev’s work as a whole.

But mitochondrially targeted antioxidants do seem to have broad application: sepsis, wound healing, and so forth. A quick check of PubMed, searching for "mitochondria glaucoma" would show plenty of research on the topic of mitochondrial damage and its role in the pathology of glaucoma. The broad potential use of SkQ1 and other mitochondrial antioxidants only underscores the importance of mitochondria to our biology.

The bottom line at the end of all of this, for those who like bullet points to take away:

• We are entering an era in which it's going to be harder to tell the difference between good science and anti-aging nonsense, because researchers are soon going to be able to accomplish what the anti-aging hucksters of past years could only claim to do.
• Therefore, it is good to know more than you presently do about human biochemistry. How else are you going to be able to tell the difference between plausible research and implausible "anti-aging" scams?
• Personally, I'm not expecting SkQ1 and other mitochondrially targeted antioxidants to greatly extend life span in humans. This is for much the same reasons that other methods of extending mouse life span - such as calorie restriction - that are known to cause changes in mitochondrial metabolism are also not expected to do much for humans. As a general rule, if a way to alter metabolism extends life by 30% in mice, we shouldn't expect it to move human life span by more than a decade in the best case. This, at least, seems to be the present consensus - ever ready to be overturned, as are all consensuses in science.
• I am expecting SkQ1 and other mitochondrially targeted antioxidants to make a lot of people wealthy and produce a variety of therapies for line items other than aging: the research is far more impressive than anything to come out of calorie restriction mimetics to date, for example, and that is a multi-billion dollar undertaking.
• Targeting mitochondria with antioxidants is a patch on the underlying problem: it doesn't get rid of the biochemical damage that causes excess oxidant production in the first place. We are better served by research towards mitochondrial repair technologies that can remove that damage, and restore our mitochondria to a youthful state of operation.

There is no shortage of theories of aging: "The Reproductive-Cell Cycle Theory posits that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. ... The theory is able to explain: 1) the simultaneous regulation of the rate of aging and reproduction as evidenced by the fact that environmental conditions and experimental interventions known to extend longevity are associated with decreased reproductive-cell cycle signaling factors, thereby slowing aging and preserving fertility in a hostile reproductive environment; 2) two phenomena that are closely related to species lifespan - the rate of growth and development and the ultimate size of the animal; 3) the apparent paradox that size is directly proportional to lifespan and inversely proportional to fertility between species but vice versa within a species; 4) how differing rates of reproduction between species is associated with differences in their lifespan; 5) why we develop age-related diseases; and 6) an evolutionarily credible reason for why and how aging occurs - these hormones act in an antagonistic pleiotrophic manner via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20851172

Via EurekAlert!: "Alzheimer's disease and other dementias are exacting a massive toll on the global economy, with the problem set to accelerate in coming years. ... The worldwide costs of dementia will exceed 1% of global GDP in 2010, at US$604 billion. ... The scale of this crisis cries out for global action. History shows that major diseases can be made manageable - and even preventable - with sufficient global awareness and the political will to make substantial investments in research and care options." We see arguments for investment in research based upon the cost of inaction for all the major diseases of aging - but a distinct lack of effort in the mainstream to present the same argument for aging itself, the basis for all these diseases. The cost of degenerative aging is far, far greater than any natural disaster, war, or other medical condition. Yet at the very same time as people are prepared to listen to and be motivated by the cost of all these other horrors, aging isn't considered. This is one of the many puzzles surrounding the way in which the realities of aging and the potential for medical science to do something about it are widely ignored.

Link: http://www.eurekalert.org/pub_releases/2010-09/kcl-lrr092010.php

The Los Angeles chapter of SENS Foundation supporters will be holding a third meeting on October 2nd. I encourage you to attend if you're in the area and are interested in engineered human longevity.

On behalf of SENS Foundation I am thrilled to write to you to invite you to join Dr. Aubrey De Grey, Dr. Sarah Marr, Dr. L. Stephen Coles, and actor/director Edward James Olmos for our third SENS Foundation L.A. Chapter meeting to be held on Saturday, October 2, 2010 at the Westwood Brewing Company (1097 Glendon Avenue, Los Angeles, CA 90024-2907) from 4 PM until 8 PM and to our "after party" downstairs from 8 PM and until we are done fixing the world!

We've put together a spectacular program for this third meeting beginning with a presentation by Dr. L. Stephen Coles (Director of the Gerontology Research Group and the Supercentenarian Research Foundation) who will give us an update on DNA Sequencing in Human Supercentenarians, starting at 5:00 PM. Following this, at around 6:30 PM, Aubrey (SENS Foundation Co-founder and CSO) and Sarah (SENS Foundation Co-founder and Executive VP) will talk about the Foundation's work and recent developments in the field, and Edward James Olmos will say a few words to our guests.

All of this again through an informal fun gathering with a full bar great for networking, mingling, socializing, and more.

The idea of these local gatherings is to create a local initiative to promote the Foundation's interests and mission by engaging a network of enthusiasts, field professionals, potential donors, sponsors, collaborators, students, etc. Also to promote educational efforts in the area, and to reach out to the Hollywood community and gain their support.

Please RSVP.

Hope to see you all there!

Maria Entraigues
SENSF Volunteer Coordinator
L.A. Chapter Coordinator
maria.entraigues@sens.org

On a related topic, I notice that a date is set for the fifth SENS conference:

The fifth Strategies for Engineered Negligible Senescence conference (SENS5) will be held at Queens' College, Cambridge, UK from August 31st to September 3rd, 2011. The SENS conferences are a unique series of events which bring together scientists and laypeople interested in research leading to the application of regenerative medicine to the problem of ageing.

You'll find links to coverage of the last SENS conference back in the Fight Aging! archives.

• SENS4 Conference Coverage from Ouroboros
• SENS4 Notes at Ouroboros, Part 2
• More SENS4 Conference Coverage

There are also a great many videos of SENS4 conference presentations published on YouTube.

The search for ways to identify cancer stem cells is a subset of the broader search for commonalities in cancer: any biochemical similarity in cancer cells that marks them as different from normal cells is a potential opening for a targeted therapy. Here is an example of the sort of investigations presently taking place: "Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. By comparison, the study of cancer stem cells is still in its infancy; so, unsurprisingly, there is great uncertainty as to the identity of these cells. ... This review assesses the utility of recognizing cancer stem cells by virtue of high expression of aldehyde dehydrogenases (ALDHs), probably significant determinants of cell survival through their ability to detoxify many potentially cytotoxic molecules, and contributing to drug resistance. Antibodies are available against the ALDH enzyme family, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these enzymes. ... For many human tumours, but notably breast cancer, cell selection based upon ALDH activity appears to be a useful marker for enriching for cells with tumour-initiating activity (presumed cancer stem cells)."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20848663

A review paper: "The immune system has the ability to recognize and kill pre-cancer and cancer cells. However, with the immune system's surveillance, the survival tumor cells learn how to escape the immune system after immunoselection. Cancer immunotherapy develops strategies to overcome these problems. Nanomedicine applications in cancer immunotherapy include the nanodiagnostics and nanobiopharmaceuticals. In cancer nanodiagnostics, it looks for specific 'molecular signatures' in cancer cells or their microenvironment by using genomics and proteomics. Nanobiopharmaceuticals is the field that studies nanotechnology-based therapeutic agents and drug carriers. DNA, RNA, peptides, proteins and small molecules can all be used as cancer therapies when formulated in nanocarriers. Currently, cancer vaccines are applied in treatments with existing cancer or to prevent the development of cancer in certain high risk individuals. Most of the non-specific immune activation agents include adjuvants which enhance immunogenicity and accelerate and prolong the response of cancer vaccines. The carriers of vaccines, such as viruses and nanoparticles, have also been in clinical studies for many years."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20821040

The klotho gene can be manipulated to either reduce or somewhat extend life in mice and nematode worms, but has not been well studied in comparison to some other aspects of longevity-associated biology. Researchers are still mapping out relationships and discovering associations; this stage of the investigation of a gene and its role in our biological machinery might last for decades, conducted at a slow and methodical pace.

Here are some examples of more recent studies involving klotho, starting with evidence that klotho extends life in nematodes by acting through two known longevity mechanisms. We would expect to see a lot of this sort of thing - that a new longevity-associated gene works by indirectly manipulating one of the known processes that can affect life span.

Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho [inhibits] Insulin/IGF1 signalling. ... Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans.

In comparison to this, there is the oxidative stress viewpoint: that klotho confers resistance to the damage caused by free radicals such as reactive oxygen species, and therefore we would expect extended life to result under the free radical theory of aging.

Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging. This emphasizes the importance of understanding the molecular mechanism(s) that link ROS production to activation of the p38 mediated promotion of aging, longevity, and resistance to oxidative stress. We examined Klotho(-/-) (elevated ROS) and Klotho overexpressing mice (low ROS and resistance to ROS) ... We propose [that] increased longevity by Klotho overexpression is linked to suppression [of] p38 MAPK activity

This view is not incompatible with the first - they are looking at different layers or areas of biochemistry. Metabolism is ferociously complex, which is one of the challenges facing those who want to safely alter its operation in humans to slow aging.

Klotho doesn't exist in a vacuum of course. Like all parts of our biochemistry, its level of expression may be altered by circumstances and other changes taking place in our biological machinery - which in turn means that it is causing further alterations. All of which has made it historically challenging to figure out where the end of the string lies. What is cause, what is contributer, and what is irrelevant - answers which may turn out to be very different for the same process when conducted under only slightly different circumstances. The study of metabolism is not for the faint of heart.

As an example, you'll find altered klotho levels showing up in this research on how to at least slow mitochondrial contributions to aging - a familiar theme for regular readers.

Angiotensin II blockade: a strategy to slow aging by protecting mitochondria?

Protein and lipid oxidation - mainly by mitochondrial reactive oxygen species (mtROS) - was proposed as a crucial determinant of life- and healthspan.

Angiotensin-II enhances ROS production [and] stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS-bl) increases survival, and prevents age-associated changes. RAS-bl reduces mtROS, and enhances mitochondrial content and function. This suggests that angiotensin-II contributes to the aging process by prompting mitochondrial dysfunction.

...

Caloric restriction - an age-retarding intervention in humans and animals - and RAS-bl, display a number of converging effects, i.e., they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease and cancer; increase body temperature; reduce body weight, plasma glucose, insulin and insulin-like growth factor-I; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H(2)O(2) production, and increase UCP-2 and sirtuin expression.

Other potential mechanisms that may underlie RAS-bl's mitochondrial benefits are TGF-beta downregulation and upregulation of Klotho and sirtuins.

Quite a list there at the end - it's worth remembering that calorie restriction moves near all biochemical processes studied to date in a beneficial direction for your long term health. But how to pick out what gene and protein is doing what when faced with an array of changes that affect near every biological subsystem known to touch on aging? It's a tough business to be in.

These researchers suggest that heat shock proteins might be used as a biomarker of aging, a way to determine biological age rather than chronological age, and hence predict life span or evaluate the effectiveness of potentially longevity-inducing therapies: "Since their discovery in Drosophila, the heat shock proteins (Hsps) have been shown to regulate both stress resistance and life span. Aging is characterized by increased oxidative stress and the accumulation of abnormal (malfolded) proteins, and these stresses induce Hsp gene expression through the transcription factor HSF. In addition, a subset of Hsps is induced by oxidative stress through the JNK signaling pathway and the transcription factor Foxo. The Hsps counteract the toxicity of abnormal proteins by facilitating protein refolding and turnover, and through other mechanisms including inhibition of apoptosis. The Hsps are up-regulated in tissue-specific patterns during aging, and their expression correlates with, and sometimes predicts, life span, making them ideal biomarkers of aging. The tools available for experimentally manipulating gene function and assaying healthspan in Drosophila provides an unparalleled opportunity to further study the role of Hsps in aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20840862

Researchers uncover details of the mechanism for the link between germline cells and longevity in lower animals, connecting it to known longevity genes: "In Caenorhabditis elegans and Drosophila melanogaster, removing the germline precursor cells increases lifespan. In worms, and possibly also in flies, this lifespan extension requires the presence of somatic reproductive tissues. How the somatic gonad signals other tissues to increase lifespan is not known. The lifespan increase triggered by loss of the germ cells is known to require sterol hormone signaling, as reducing the activity of the nuclear hormone receptor DAF-12 [prevents] germline loss from extending lifespan. In addition to sterol signaling, the FOXO transcription factor DAF-16 is required to extend lifespan in animals that lack germ cells. ... In this study, we show that the DAF-12-sterol signaling pathway has a second function to activate a distinct set of genes and extend lifespan in response to the somatic reproductive tissues. When germline-deficient animals lacking somatic reproductive tissues are given dafachronic acid, their expression of DAF-12/NHR-dependent target genes is restored and their lifespan is increased. Together, our findings indicate that in C. elegans lacking germ cells, the somatic reproductive tissues promote longevity via steroid hormone signaling to DAF-12."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930862/

Earlier this year, researchers screening potential longevity-enhancing compounds in yeast turned up the bile acid lithocholic acid:

the Titorenko laboratory [tested] the hypothesis that networks exist within cells that are not inducible, but act constitutively to extend the lifespan of cells regardless of nutrient availability ... [the study] presents an original screen designed to isolate molecules that further lengthen the life span of yeast under calorie restriction rather than imitating this effect. ... Among the chemical compounds identified, the authors focus on one group representing 6 bile acids compounds, the most efficient of them being lithocholic acid (LCA). Bile acids are mildly toxic oxidized derivatives of cholesterol that play important roles in lipid uptake by the intestine.

That screen was looking for compounds that work on top of calorie restriction - i.e. that must operate through some different and potentially new longevity-enhancing mechanism. It's a clever way of covering more ground in the study of metabolism. Here's a more readable summary from the popular science press:

"Our findings imply that LCA extends longevity by targeting two different mechanisms," says first author Alexander Goldberg, a Concordia doctoral student. "The first takes place regardless of the number of calories and involves the day-to-day or housekeeping proteins. The second system occurs during calorie-restriction and involves stressor proteins."

...

"Although we have an overall idea how LCA works to extend longevity in yeast, we still need to determine if this is the case for other species," says Titorenko. "We do know from previous studies, however, that bile acids are beneficial to health and longevity. For example, they have shown to accumulate in the serum of long living mice and play a role in improving rodent liver and pancreatic function."

On the other hand, you'll also find evidence for LCA to be a toxic cancer risk in mice:

"Lithocholic acid is highly toxic, and it builds up in a high-fat diet," Mangelsdorf said. "We don’t know how it causes cancer; but it is known to cause cancer in mice, and people with colon cancer have high concentrations of it."

So it seems a little early to be doing anything other than noting this as interesting - and in the long term, the value of this research will be to draw more attention to the biological mechanisms by which LCA works to extend life in yeast.

A great many research groups continue to investigate the biochemistry of calorie restriction, and this paper is a good illustration as to why this is the case: "It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to non-human primates, and delay the onset of numerous age-related diseases including neurodegenerative disorders. Translation of the knowledge gained from CR research in animal models to disease prevention strategies in humans should provide therapeutic approaches for these diseases. Signaling pathways induced by CR are therefore potentially new therapeutic targets for neurodegenerative diseases. This review summarizes the evidence on key biological mechanisms underlying the beneficial effects of CR based on our current understanding, with particular emphasis on the recent impact of CR on neuroprotection, and on the emerging development of pharmacological agents that target signaling pathways induced by CR. We focus in particular on recent findings on sirtuins for prevention of neurodegenerative diseases." Even outside the context of aging, there is potentially much to learn about human biochemistry by following the effects of calorie restriction.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20840070

The process of declaring parts of aging as a disease is driven by regulation: the FDA does not permit treatments for aging, only for named diseases. Since there is little funding for research that cannot be legally commercialized, the incentive is to carve off chunks of the process of aging and go through the process of having government employees add it to the list of diseases - which can take years and millions of dollars. Sarcopenia, for example, is still not recognized by the FDA, meaning that no potential treatment can be commercially developed in the US. Here is an example of this process at work for memory loss: "Simply getting older is not the cause of mild memory lapses often called senior moments, according to a new study ... even the very early mild changes in memory that are much more common in old age than dementia are caused by the same brain lesions associated with Alzheimer's disease and other dementias. ... The very early mild cognitive changes once thought to be normal aging are really the first signs of progressive dementia, in particular Alzheimer's disease. The pathology in the brain related to Alzheimer's and other dementias has a much greater impact on memory function in old age than we previously recognized. ... dementias are the root cause of virtually all loss of cognition and memory in old age. They aren't the only contributing factors; other factors affect how vulnerable we are to the pathology and to its effects. But the pathology does appear to be the main force that is driving cognitive decline in old age."

Link: http://www.rush.edu/webapps/MEDREL/servlet/NewsRelease?ID=1420

Antioxidant compounds can extend life in mice provided they are localized to the mitochondria - which doesn't happen for anything you can presently buy in a bottle. Near all antioxidants that can be ingested, injected, or otherwise introduced into the body do nothing of any great significance to healthy life span, and may even be detrimental by interfering in the processes of hormesis that help to maintain and improve health.

As I'm sure you know by now, mitochondria are the cell's powerplants, converting food into the chemicals used by cells to store and transport energy. They also generate damaging free radicals - such as reactive oxygen species - as a consequence of their operation. These free radicals in turn tend to damage mitochondria in ways that eventually snowball towards larger and larger consequences in the body: this mitochondrial damage is in fact one of the important root causes of aging.

In the field of targeted antioxidants, researchers have gene engineered mice to generate more natural antioxidants in their mitochondria. A group in Russia has been quite active in working on SkQ1, an ingested compound that targets mitochondria, and Australian researchers have a similar chemical under development. Out of these lines of work, a number of studies show healthy life extension and other benefits in mice.

Unfortunately, raising funds to develop any sort of longevity enhancing therapy for humans - even one with a probably small effect, and which looks exactly like run of the mill drug discovery and evaluation - runs right into the roadblock of the FDA. Since the FDA bureaucrats don't recognize aging as a medical condition, they will not approve any commercial application sold to that end. Since there can be no selling, and hence no potential for profit, no-one will fund the research and development. All potential approaches to extending longevity are instead sidelined into becoming just another therapy for the late stages of an age-related condition like diabetes. Wasted time, wasted effort.

From where I stand, the preferable ways forward are to tear down the FDA (for all that this once grand country seems very lacking in revolutionary spirit these days), or take the commercial development overseas, which may force much the same end result in the fullness of time. But many groups choose to stay within the US regulatory straitjacket.

For the targeted antioxidant development, two potential lines of within-the-system development spring to mind. Firstly, as a therapy for sepsis:

Bench-to-bedside review: Targeting antioxidants to mitochondria in sepsis

Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. Under normal circumstances, complex interacting antioxidant defense systems control oxidative stress within mitochondria. However, no studies have yet provided conclusive evidence of the beneficial effect of antioxidant supplementation in patients with sepsis. This may be because the antioxidants are not accumulating in the mitochondria, where they are most needed. Antioxidants can be targeted selectively to mitochondria by several means. This review describes the in vitro studies and animal models of several diseases involving oxidative stress, including sepsis, in which antioxidants targeted at mitochondria have shown promise, and the future implications for such approaches in patients.

Secondly, it appears that wound healing, and especially in the old, may benefit from mitochondrially targeted antioxidants:

It is shown that the novel mitochondria-targeted antioxidant SkQ1 [stimulates] healing of full-thickness dermal wounds in mice and rats. Treatment with nanomolar doses of SkQ1 in various formulations accelerated wound cleaning and suppressed neutrophil infiltration at the [early steps] of inflammatory phase. SkQ1 stimulated formation of granulation tissue and increased the content of myofibroblasts in the beginning of regenerative phase of wound healing. Later this effect caused accumulation of collagen fibers. Local treatment with SkQ1 stimulated re-epithelization of the wound. Lifelong treatment of mice with SkQ1 supplemented with drinking water strongly stimulated skin wounds healing in old (28 months) animals. In an in vitro model of wound in human cell cultures, SkQ1 stimulated movement of epitheliocytes and fibroblasts into the 'wound'. Myofibroblast differentiation of subcutaneous fibroblasts was stimulated by SkQ1.

It is suggested that SkQ1 stimulates wound healing by suppression of the negative effects of oxidative stress in the wound and also by induction of differentiation. Restoration of regenerative processes in old animals is consistent with the 'rejuvenation' effects of SkQ1, which prevents some gerontological diseases.

Either of these uses is probably sufficiently large to support a fair-sized research and development effort in the US, should the present lines of research continue to show promise and benefit. But it won't be work on slowing aging any more - which is perhaps the most pernicious effect of the FDA roadblock on applied longevity science.

Galley HF (2010). Bench-to-bedside review: Targeting antioxidants to mitochondria in sepsis. Critical care (London, England), 14 (4) PMID: 20804578

Demianenko IA, Vasilieva TV, Domnina LV, Dugina VB, Egorov MV, Ivanova OY, Ilinskaya OP, Pletjushkina OY, Popova EN, Sakharov IY, Fedorov AV, & Chernyak BV (2010). Novel mitochondria-targeted antioxidants, "Skulachev-ion" derivatives, accelerate dermal wound healing in animals. Biochemistry. Biokhimiia, 75 (3), 274-80 PMID: 20370605

Calorie restriction has been shown to slow down almost every measure of degenerative aging examined to date. Here is another such open access study: "Dietary restriction (DR) extends the lifespan of a wide variety of species and reduces the incidence of major age-related diseases. Cell senescence has been proposed as one causal mechanism for tissue and organism ageing. We show for the first time that adult-onset, short-term DR reduced frequencies of senescent cells in the small intestinal epithelium and liver of mice, which are tissues known to accumulate increased numbers of senescent cells with advancing age. This reduction was associated with improved telomere maintenance without increased telomerase activity. We also found a decrease in cumulative oxidative stress markers in the same compartments despite absence of significant changes in steady-state oxidative stress markers at the whole tissue level. The data suggest the possibility that reduction of cell senescence may be a primary consequence of DR which in turn may explain known effects of DR such as improved mitochondrial function and reduced production of reactive oxygen species." The telomere maintenance line item above might suggest that the shortest-telomere cells - i.e. senescent cells - are being destroyed and recycled, thus raising the average amongst remaining cells.

Link: http://www.impactaging.com/papers/v2/n9/full/100196.html

There are interesting intermediate destinations on the road to tissue engineered replacement organs. This is one of them: researchers have "invented the first artificial human ovary, an advance that provides a potentially powerful new means for conducting fertility research and could also yield infertility treatments for cancer patients. The team has already used the lab-grown organ to mature human eggs. ... An ovary is composed of three main cell types, and this is the first time that anyone has created a 3-D tissue structure with triple cell line. ... the ovary not only provides a living laboratory for investigating fundamental questions about how healthy ovaries work, but also can act as a testbed for seeing how problems, such as exposure to toxins or other chemicals, can disrupt egg maturation and health. ... To create the ovary, the researchers formed honeycombs of theca cells, one of two key types in the ovary, donated by reproductive-age (25-46) patients at the hospital. After the theca cells grew into the honeycomb shape, spherical clumps of donated granulosa cells were inserted into the holes of the honeycomb together with human egg cells, known as oocytes. In a couple days the theca cells enveloped the granulosa and eggs, mimicking a real ovary."

Link: http://www.sciencedaily.com/releases/2010/09/100914102108.htm

The advance of medical science would proceed far faster if not for certain attitudes pervasive in the research community, and the heavy shroud of regulation that drapes every human endeavor in our modern societies. I've written on these topics in the past, on the cost of central control of medical research in particular: under a regime in which all that is not permitted is forbidden, we should not be surprised to see that barely a fraction of the potential of each new discovery's is utilized.

This is a critical time in the evolution of biotechnology and medical science. Enormous advances are possible in the years ahead, including significant extension of the healthy human life span, yet this marketplace is not open and competitive. Everywhere is the hand of government, suppressing competition, forbidding all that is not expressly permitted, and dragging the potential for progress down into the gutter.

I am far from the only person to see the present state of affairs as it is. A recent interview with James Watson, for example, is on the topic of cancer research, but his comments could equally well be applied to all of medicine and biotechnology:

the Nobel Laureate bemoaned some pessimistic cancer researchers who he said were more interested in merely researching cancer and didn't realise that they had an obligation to cure people and save lives.

"I got real annoyed with someone … at the end of his talk he said, 'we're going to get somewhere over the next ten to twenty years'. He could have said twenty to forty or why didn't he say five to ten?"

"We should try and cure cancer now, not ten to twenty years from now," Watson warned. "It would be sort of irresponsible to all those people who would die of cancer if we don't try and do it now."

...

Watson told journalists that he was in favour of less regulation for clinical trials as this could speed up the process of finding a cure for cancer: "We're terribly held back on clinical tests by regulations which say that no one should die unnecessarily during trials; but they are going to die anyway unless we do something radical. I think the ethics committees are out of control and that it should be put back in the hands of the doctors. There is an extraordinary amount of red tape which is slowing us down. We could go five times faster without these committees."

Nothing is more important to progress than freedom. The simple freedom for patients to collaborate with researchers as they see fit, and take the risks they want to take - not to have the terms of their lives and deaths dictated by uncaring, unaccountable government employees. At the present time, we live in a sick society, one in which it is considered normal and appropriate for people to be blocked from their own considered medical choices by threat of fines and jail, and for vast swathes of research and development to be forbidden outright.

Why, despite the great range of potential applicable biotechnology, do we not see hundreds of millions of dollars invested in startups attempting to address the aging process? The answer is buried in this New York Times article on Sirtris: "Dr. Westphal and Mr. Sinclair stress that they are not working to 'cure' aging, a condition that, so far at least, is common to all humanity and that most physicians do not consider a disease. 'Curing aging is not an endpoint the federal drug agency would recognize,' Dr. Westphal says dryly.

An open access paper: "The enthesis, which attaches the tendon to the bone, naturally disappears with aging, thus limiting joint mobility. ... Tendons and ligaments are fibers made up of dense connective tissue and they are critical for physiological movement and the stability of joints because of their attachment to bone. Injury to these structures can significantly destabilize joints, resulting in the development of degenerative joint diseases, especially in the upper limbs ... Surgery is frequently needed but the clinical outcome is often poor due to the decreased natural healing capacity of the elderly. This study explored the benefits of a treatment based on injecting chondrocyte and mesenchymal stem cells (MSC) [in rats] ... damage was repaired by classical surgery without cell injection (group G1) and with chondrocyte (group G2) or MSC injection (group G3). ... The spontaneous healing rate in the G1 control group was 40%, close to those observed in humans. Cell injection significantly improved healing (69%) ... A new enthesis was clearly produced in cell-injected G2 and G3 rats, but not in the controls. Only the MSC-injected G3 rats had an organized enthesis with columnar chondrocytes as in a native enthesis 45 days after surgery. ... Cell therapy is an efficient procedure for reconstructing degenerative entheses. MSC treatment produced better organ regeneration than chondrocyte treatment. The morphological and biomechanical properties were similar to those of a native enthesis."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923611/

Researchers continue to delve into the root causes of sarcopenia: "It is well known that the human aging process is associated with a progressive loss of muscular strength. Characteristic of this decline in muscle performance is the loss of skeletal muscle mass (sarcopenia) that occurs even in the healthy elderly. Indeed, humans can lose as much as 40% of their muscle mass from age 20 to 60. ... investigators used a combination of experimental approaches to phenotypically compare wild type old mice with mature mice lacking a novel muscle specific inositide phosphatase (MIP/MTMR14) that plays an important role in muscle calcium homeostasis. Interestingly, the mature MIP/MTMR14 knockout mice displayed phenotypes that closely resembled the muscles of old animals. Indeed, these relatively young knockout mice displayed impaired muscle calcium homeostasis, depressed muscle contractile force production and a loss of muscle mass that is commonly observed in senescent animals. Interestingly, the old wild type mice also displayed impaired muscle calcium homeostasis and decreases in muscle size and contractile function. Importantly, these old mice also possessed reduced muscle levels of MIP/MTMR14. The authors concluded that these findings were consistent with the hypothesis that an age-related loss in MIP/MTMR14 may be a contributory factor to sarcopenia."

Link: http://www.impactaging.com/papers/v2/n9/full/100193.html

For the past few years, researchers have been following the trail of biochemistry in the accelerated aging condition Hutchinson-Gilford Progeria Syndrome (HGPS or progeria). This research started with the discovery that progeria patients had a mutant form of the lamin A protein, involved in the mechanics of cell structural stability amongst other things, and continues today. This is of interest because the same harmful processes that drive progeria appear to operate over the course of "normal" aging, albeit to a far lesser degree:

Malformed lamin A proteins lie at the root of the accelerated aging condition progeria. ... In cells taken from the elderly, the nuclei tend to be wrinkled up, the DNA accumulates damage, and the levels of some proteins that package up DNA go askew ... This mirrors the same changes that they previously observed in cells from [Hutchinson-Gilford progeria syndrome (HGPS)] children. ... The team suggests that healthy cells always make a trace amount of an aberrant form of lamin A protein, but that young cells can sense and eliminate it. Elderly cells, it seems, cannot. Critically, blocking production of this deviant protein corrected all the problems with the nucleus.

If your memory is very good, you'll recall that aberrant lamin A also appears to damage the ability of stem cells to maintain tissue. Interestingly, the Wnt signaling pathway appears to be somehow involved here - and you'll find an introduction to Wnt and aging back in the Fight Aging! archives:

• Thoughts on Wnt and Aging Stem Cells
• More Thoughts on Wnt, Aging, Regeneration and Cancer

Wnt has a great deal to do with regulation of regeneration, and its operation changes with age. Researchers have shown that altering the Wnt pathway may restore youthful levels of regenerative capability - but may well also increase the risk of cancer. This is one small part of the well known evolutionary trade-off between aging and cancer: regenerative capacity shuts down with age to reduce the risk of damaged cells involved in the healing process running amok.

In any case, a few years ago, researchers had this to say:

Specific mutations in the human gene encoding lamin A [cause] premature aging. New data on mice and humans suggest that these mutations affect adult stem cells by interfering with the Notch and Wnt signaling pathways.

Here is news from a more recent investigation:

Progeria is caused by a mutation in the gene for lamin A that leads to production of "progerin", a truncated form of the lamin A protein that causes the cell nucleus to become misshapen. ... a progerin-like truncation of lamin A [causes] post-natal connective tissue cells to stop producing an extracellular matrix. The lack of this surrounding matrix then causes the cells to stop dividing and to die.

...

The researchers [show] that the defects in the extracellular matrix in mouse and human progeria cells are due to abnormalities in a protein network called the Wnt signaling pathway. "Our results provide support for the hypothesis that progeria is a disease of the connective tissue extracellular matrix which manifests as abnormalities in the skeleton, teeth, skin and vasculature," concludes Dr. Stewart. "If these failures are due to defective Wnt signaling and/or cytoskeletal-extracellular matrix function, they suggest possible new routes of intervention that may help in treating this disease."

As there is also evidence for defective lamin production in the vascular system during the normal aging process, the researchers are keen to explore potential implications of their new findings in these and other aspects of both progeria and normal aging.

No-one ever said that biology was simple. Fortunately, the contribution to degenerative aging of bad forms of lamin A is likely small when compared to, say, the forms of biochemical damage outlined in the Strategies for Engineered Negligible Senescence.

Aggregates of unwanted proteins are important in aging, and researchers continue to investigate why it is that aggregates appear in the first place. Here, researchers "have solved a long-standing mystery of how cells conduct 'quality control' to eliminate the toxic effects of a certain kind of error in protein production. ... The new study suggests how cells in eukaryotic organisms, like humans, sense and destroy 'non-stop' proteins that remain stuck in the ribosome, the protein manufacturing plant of the cell. ... DNA is used to make RNA, which, in turn, is used to make proteins. In healthy cells, the ribosome translates the code carried by a messenger RNA (mRNA) to link together protein building blocks (amino acids) in a particular order to form specific proteins. But errors happen - which is why the body has a host of different quality control mechanisms to ensure that the proteins that emerge from this process are flawless. When aberrant proteins escape these surveillance mechanisms, they accumulate and form 'aggregates' that can be toxic to certain neuronal types, and disorders such as Alzheimer's and Parkinson's diseases can result. ... For some 15 years, scientists have understood the mechanism that identifies and destroys these problematic non-stop proteins in bacteria. In these organisms, non-stop proteins are tagged by a marker known as tmRNA or ssrA, which then leads to their destruction. In more complex eukaryotic organisms, which range from yeast to humans, though, the mechanism for identifying and eliminating such dangerous non-stop errors has remained a mystery - until now."

Link: http://www.eurekalert.org/pub_releases/2010-09/sri-srs090910.php

A press release from Tengion: "rodents with chronic kidney disease (CKD) were treated with healthy kidney cells to catalyze the regeneration of functional kidney tissue and delay disease progression, as evidenced by extended survival, improved kidney filtration, and reduced severity of kidney tissue pathology. The published data demonstrate that delivery of a selected population of kidney cells to the kidney significantly extended long-term survival and improved kidney function in rodents with chronic kidney disease during six months of follow-up. Further, the therapeutic effects reported in this study were more pronounced and more durable than have been previously reported with this animal model. ... Chronic kidney disease is a serious medical condition affecting millions of Americans and can lead to kidney failure requiring the need for transplant or lifelong dialysis. A treatment approach that can increase kidney tissue and improve function would be a significant advancement in the care of these patients. The scientific community has historically considered that CKD develops from an imbalance between tissue damage and the kidney's ability to repair and regenerate itself. These preclinical data provide clear evidence that regeneration of functional renal tissue can delay progression of CKD."

Link: http://www.prnewswire.com/news-releases/regenerative-cellular-therapy-in-chronic-kidney-disease-extends-survival-tengion-preclinical-study-published-in-american-journal-of-physiology-renal-physiology-102766104.html

As the tools of genetic analysis improve by leaps and bounds, the cost falling with each advance, more and more research is taking place into genetic influences on human longevity. This is an enormously complex area of study, and has little to no relevance to any repair-based methodology for lengthening human life. Outside the field of regenerative medicine, most aging researchers do not work on repair strategies such as SENS, however. Meanwhile there is plenty of funding for genetic studies of all sorts - compared with comparatively little available for initiatives to repair the biochemical damage of aging.

This is a sad state of affairs, but it is what it is: one of the numerous things we must help to change in the years ahead if we are to see significant progress towards engineered longevity in our lifetimes.

In any case, here is a good (and open access) example of the sort of genetic longevity studies presently taking place: detailed associations and commonalities are being uncovered in the genomes of long-lived people, and there is a lively debate over just how important any individual longevity-associated genetic variants are likely to be.

Centenarians often reach old age with delayed onset or absence of geriatric diseases ... This correlation between exceptional longevity and healthy aging suggests that common genetic factors may underlie both traits.

...

Estimates of the heritability of normal human lifespan range from 10% to 58%, averaging about 25%. The genetic contribution to lifespan grows markedly after age 60, indicating the heritability of exceptional longevity may be substantially higher than these estimates. The relative survival probability for siblings of centenarians increases steadily with age, until male and female siblings have a 17-fold and 8-fold increased chance, respectively, of reaching age 100 compared to others from their birth cohort. Moreover, while natural lifespan is likely a complex trait controlled by many genes with small effect sizes, extreme longevity may be determined by fewer genes of stronger effect.

...

To map the [genetic] loci conferring a survival advantage, we performed the second genomewide linkage scan on human longevity and the first using a high-density marker panel of single nucleotide polymorphisms. By systematically testing a range of minimum age cutoffs in 279 families with multiple long-lived siblings, we identified [multiple longevity-associated loci].

The present phase of research is producing mountains of data, and there will likely be thousands of combinations of gene-variants that have statistically significant effects on human longevity. But none of this will have the slightest impact on how long you and I live: if our lives are made longer, it will be through the use of technologies to repair and reverse the known biochemical changes that drive degenerative aging, not through genetic manipulation.

Boyden, S., & Kunkel, L. (2010). High-Density Genomewide Linkage Analysis of Exceptional Human Longevity Identifies Multiple Novel Loci PLoS ONE, 5 (8) DOI: 10.1371/journal.pone.0012432

Recent research: "Aging has many different causes, says Jessica Tyler, a molecular biologist at the University of Texas MD Anderson Cancer Center in Houston. Now, Tyler and her colleagues think they have uncovered yet another way cells age - by losing histones. Histones are important proteins that form a spool upon which DNA is wound. This spooling allows yards of DNA to fit inside a cell and also helps control how genes are turned on and off. Tight winding helps keeps genes off, while loosening the packaging allows genes to be turned on. As yeast cells age they make fewer histone proteins, Tyler's team found. ... Exactly how histones determine how long yeast will live is still unknown. The researchers think falling levels of histones during aging may loosen DNA and allow many genes to be turned on inappropriately. That excess gene activity may zap a cell's energy reserves. Making extra histones may help old yeast keep tighter control of gene activity. ... the team found that the histone life-extension process is likely independent of other known mechanisms for increasing life-span. For instance, histones appear to work differently from the well-known antiaging sirtuin protein Sir2. ... Yeast on restricted-calorie diets live longer. So do yeast with more histones. If the two mechanisms are entirely independent of each other, combining the two treatments should add up to make yeast live longer than either manipulation alone. Instead, combining the treatments in the new experiments led to a life-span extension somewhere in between the solo effect of either treatment. The finding serves as a reminder that biological processes are complicated and intertwined."

Link: http://www.sciencenews.org/view/generic/id/63244/title/A_cellular_secret_to_long_life

From the Telegraph: "The negative effects of an aging population may have been exaggerated because people are staying healthier for longer, according to a new study. ... The two factors tend to balance each other out, the researchers found, suggesting that Governments may have overestimated the future costs of demographic changes. For instance, standard measures assume that over 65s are likely to need carers, whereas healthy elderly people are often themselves able to look after an even older relative, the report's authors said. ... If we apply new measures of aging that take into account increasing life-spans and declining disability rates, then many populations are aging slower compared to what is predicted using conventional measures based purely on chronological age. ... Their calculations show that in the United Kingdom, for example, while the old age dependency ratio is increasing, the disability ratio is remaining constant. What that means, according to the authors, is that [although] the British population is getting older, it is also likely to be getting healthier, and these two effects offset one another." Any "negative effects" of greater human longevity are entirely imaginary, or the product of broken regulatory systems that should be scrapped. Longer lives produced by modern medical technology are an unambiguously good thing.

Link: http://www.telegraph.co.uk/finance/personalfinance/pensions/7991505/Costs-of-aging-population-have-been-overestimated.html

"Atomic medicine": a phrase to inspire optimism, awe, or uneasy fear, depending on which decades of the 20th century you spent being young. The word "atomic" has a great deal of weight and a long and changing legacy. As a recent essay at H+ Magazine argues, however, isn't all medicine atomic medicine? We are collections of atoms, and the ills we suffer - aging included - are all, ultimately, caused by atoms being out of place. The medicines of today and all of history are nothing more than very crude and many-times-removed attempts to put errant atoms back where they belong.

Today, when we speak of manipulation, what we seek is manipulation at the atomic level, while working at a sub-atomic resolution. As Drexler and others have pointed out, to date we have worked with atoms only in bulk. We have shaped them with stones, pounded them with hammers, milled them by computer control. The manipulation of individual atoms, in a deft and dexterous fashion, would fulfill a contemporary definition of mastery over fabrication. The field of medicine also falls into the above category.

...

While the notion that we would one day possess the ability to treat maladies at the molecular level may seem absurd, it should be noted that what I have done while simply writing this article - broadcasting 22,092 copies of a 4 megabyte text - would have required several hours of effort just ten years ago. It took centuries to go from months of work to replicate a single book to minutes, and a decade to go from minutes to fractions of a second. As we master the observation and manipulation of matter, we can look forward to similar changes in medicine.

The leading edge of the age of molecular manufacturing is not far away: a matter of a couple of decades, I'd say.

Systems that can identify, manage and place trillions of molecules accurately are not a pipe dream; after all, we are already surrounded by examples. You, for example, are just such a system, albeit somewhat slow at self-assembly to full size. There's nothing in the laws of physics that jumps out and says we can't do this. It's just a matter of time.

If you have the technology base to build a nanoforge to assemble a brick, then you also have the technology base capable of simultaneously assembling and controlling a hundred million medical nanorobots of arbitrary design and programming. Or an artifical lung better than the real thing, or replacements for immune cells that never get old or worn. You get the idea. A brick is just as complex as any portion of the human body if you have to build the thing molecule by molecule; more fault-tolerant, but just as complex.

The future will becoming increasingly interesting as this century advances: one of many reasons to want to live in good health to see as much of it as possible. That goal will become ever easier as the boundaries of medical technology are pushed outward. In the long run, radical extension of the healthy human life span is a given. It's the short term of the next few decades that will be a challenge, and where every additional effort to accelerate the deployment of the first longevity medicine will save countless lives - perhaps your own included.

Researchers uncover a potentially important lead: "Elimination of a molecular gatekeeper leads to the development of arthritis in mice ... The newly discovered gatekeeper is a protein that determines the fate - survival or death - of damaging cells that mistakenly attack the body's own tissues and lead to autoimmune disorders such as arthritis. ... An added bonus is that this finding may help in the search for new treatments for other autoimmune disorders, such as lupus. ... The protein at the center of the new finding, known as G alpha q, is part of a larger signaling pathway that Lund and collaborators from across the United States and China investigated in mice. G alpha q regulates B cells, one type of immune cell that the body maintains to fight off invaders like bacteria, viruses and parasites. While most B cells help defend the body, some B cells are autoreactive - they turn against the body's own tissues. ... Several new studies expanding on the current finding are in the works, including testing whether drug compounds that alter the expression or activity of G alpha q in mice can slow the development of autoimmunity. Beyond preclinical testing in mice, researchers also hope to start screening G alpha q levels in patients to learn more about how the protein works in humans."

Link: http://www.sciencedaily.com/releases/2010/09/100908121923.htm

This CNN article demonstrates the sort of willful persistence required to learn about and gain access to newer medical technologies that are not yet widely available: "The doctor who was on call at the emergency room told me there was no way he could reattach [the tip of] my pinky. I didn't like that, so I asked to see a specialist ... Eventually, Kulkarni made an appointment with Dr. Michael Peterson, an orthopedic surgeon in Davis. At first, [he] was hesitant to try tissue regeneration since he hadn't done it before, but she gave him some research materials, and she says eventually he agreed to try it.
The therapy involved cleaning out the finger and removing scar tissue - a process called debridement - and then dipping her finger into MatriStem wound powder. After seven weeks of treatment, her fingertip grew back. ... What I found out is that even though I like my doctors, I don't have to take every recommendation they give me. I can do my own research. ... Some doctors are more out-of-date or up-to-date than others. ... Imagine if I hadn't pursued other options because I was worried about what other people think - I didn't want to live with that regret." Fingertips are known to sometimes regenerate in very young children, but only in recent years has any methodology been shown to work in at least some adults.

Link: http://www.cnn.com/2010/HEALTH/09/09/pinky.regeneration.surgery/

Accumulated damage to mitochondrial DNA is an important component of aging. Mitochondria are the cell's powerplants, and their DNA, separate from that contained in the cell nucleus, is vulnerable to the reactive by-products of mitochondrial operation. Intricate DNA repair processes exist, but eventually they become outmatched, and broken mitochondria dominate in a small but significant fraction of our cells. These cells become very active exporters of harmful, reactive biochemicals, which in turn causes progressively greater damage to biological processes throughout the body - and in the fullness of time this helps to kill you.

What we would like to see happen in the near future is for any one of the several lines of research into mitochondrial repair to advance to completion. Whole body repair of mitochondrial DNA damage conducted once every two or three decades would eradicate this important contribution to degenerative aging.

In the meanwhile, here's an open access paper that looks more closely at mitochondrial damage over time in the eyes, a process that contributes to the formation of catacts:

Oxidative damage resulting from reactive oxygen species (ROS) is considered to be a major risk factor in the pathogenesis of both age-related and diabetic cataract. ROS is mostly generated within the mitochondria in lens epithelium and the superficial fiber cells, which are highly reactive and can damage macromolecules in living cells, [causing] mutagenesis and cell death. Mitochondrial DNA (mtDNA) is highly susceptible to the damage produced by ROS because of its close proximity to ROS generation through the respiratory chain.

...

The 'mitochondrial theory of aging' suggests that aging results from declining mitochondrial function, due to high loads of damage and mutation in mtDNA. Oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases, in cancer, and in aging . Under normal growth conditions, ROS leads to a low level of mtDNA and nuclear DNA (nDNA) damage, which is rapidly repaired, and most oxidative DNA lesions are repaired by the base excision repair (BER) pathway

...

The purpose of the study presented here was to determine if there is an increased mtDNA [damage] in the lens with age.

...

The gene expression [of] key BER enzymes decreased with age, which caused a decrease in the repairing capability of the mtDNA and the accumulation of mtDNA damage. The increased mtDNA damage and decreased expression of BER enzymes may cause a "vicious cycle" of oxidative stress that contributes to the accumulation of mtDNA mutations and age-related cataract pathogenesis.

As hinted at here, the growth of mitochondrial damage, like most aspects of biology, is a very dynamic process. Human biology strives to maintain itself, and most of its self-repair systems are very effective indeed - in the young, at least. Aging is as much a progressive failure of biological repair mechanisms as it is an accumulation of damaged and misplaced machinery.

Antagonistic pleiotropy is the tendency for a gene that is advantageous in youth to cause problems in later life - evolution selects for it despite the later cost. The trade-off between fertility and longevity might be thought of in this way, as the delayed cost of mechanisms that increase youthful fertility: "Aromatase (CYP19) and estrogen receptor-alpha (ESR1) are involved in the metabolism of estrogens, which have a relevant role in female and male aging. Moreover, due to their influence on fertility, both genes may be part of the longevity-fertility trade-off mechanism. This investigation examines the association of [ESR1 and CYP19 polymorphisms] with longevity. A sample of 258 individuals (mean age = 83.1 +/- 5.7 years) was recruited in 2000. Based on mortality data collected in 2009, the sample was divided into two groups of participants surviving more than 90 years or not. The analysis showed that ESR1 PP and CYP19 genotypes carrying the T allele were significantly associated with longevity (survival to age more than 90 years). As the ESR1 PP genotypes were found associated with reduced fertility in the same sample, we may infer that ESR1 genotypes could exert an antagonistic pleiotropic effect on longevity and fertility."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20819792

An open access paper on one of the causes of aging: "In neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease, specific proteins escape the cell's quality-control system and associate together, forming insoluble aggregates. Until now, little was known about whether proteins aggregate in a non-disease context. In this study, we discovered that the aging process itself, in the absence of disease, leads to the insolubilization and increased aggregation propensity of several hundred proteins in the roundworm Caenorhabditis elegans. ... We asked if this inherent age-dependent protein aggregation impacts neurodegenerative diseases. We found that proteins similar to those aggregating in old worms have also been identified as minor components of human disease aggregates. In addition, we showed that higher levels of inherent protein aggregation aggravated toxicity in a C. elegans Huntington's disease model. Inherent protein aggregation is a new biomarker of aging. Understanding how to modulate it will lead to important insights into the mechanisms that underlie aging and protein aggregation diseases."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919420/

Science is as much about investigating what we do not see as it is about investigating what we do see. For example, from a recent open access paper:

Small rodents in captivity routinely reach ten times their mean life span in the wild. Why is it then that in human populations with an average life span of 40 to 80 years nobody has ever lived to 400 years old or more?

This is a fine and valid question. Why do we see little variation in human life span in comparison to that of smaller and more short-lived mammals?

The authors of this paper performed an analysis of mortality statistics across different species of mammal, the results of which lead into a very interesting and readable discussion on the interaction between evolutionary pressures and age-related frailty. This is all part of the larger question of why we age, and why we age in the way we do.

In particular, these researchers argue that the end stages of frailty in aging - senescence - do not result from a lack of evolutionary pressure later in life. But the fact that senescence still exists despite pressure for increased evolutionary fitness is telling us something important about the nature of mammalian biochemistry. From the paper:

A clear implication of our study, therefore, is that long-lived mammals are more likely than short-lived mammals to reach an age when their lives are affected by senescence (that is, an age closer to their maximum life span). In other words, our analysis suggests that senescence occurs at a much younger age, relative to the mean natural life span, in longer lived mammal species.

...

An age when senescence retards survival (i.e. near to the maximum life span) is reached by a higher proportion of individuals, and therefore remains under increasingly high selection pressure, in natural populations of longer lived mammal species ... This implies a minimum rate of senescence has been unavoidable in the evolution of mammals and could place a limit on their maximum life span, preventing humans from [naturally] reaching Methuselah-like ages. Because senescence affects survival in long-lived species despite relatively strong opposing selection pressure, they have probably evolved mechanisms to delay its negative effects. Retarding senescence further seems to be unavailable to natural selection.

This sort of theorizing is a sideline to the real work of extending healthy human longevity. We don't need to know how aging came to exist in its present form in order to be able to repair the biochemical damage that causes aging and thus reverse its effects. But it is nonetheless very interesting.

Turbill, C., & Ruf, T. (2010). Senescence Is More Important in the Natural Lives of Long- Than Short-Lived Mammals PLoS ONE, 5 (8) DOI: 10.1371/journal.pone.0012019

There will likely be a great many genetic contributions to human longevity, as this open access paper suggests, which in turn means that the genetics of longevity will be a very complex morass of a field: "The results of genome-wide association studies of complex traits, such as life span or age at onset of chronic disease, suggest that such traits are typically affected by a large number of small-effect alleles. Individually such alleles have little predictive values, therefore they were usually excluded from further analyses. The results of our study strongly suggest that the alleles with small individual effects on longevity may jointly influence life span so that the resulting influence can be both substantial and significant." Bear in mind that this may mean thousands or tens of thousands of potentially important interactions, which may differ significantly by population or individual. This is one of the many reasons that slowing down aging will likely be harder to accomplish than repairing the effects of aging: a repair strategy such as SENS doesn't depend on understanding genetic contributions to longevity. Researchers already know enough about the varied forms of biochemical damage that cause aging to make a start on repair technologies, were they so minded.

Link: http://www.impactaging.com/papers/v2/n9/abs/100191a.html

A novel way to assembled a targeted cancer therapy: "Cancer is a difficult disease to treat because it's a personal disease. Each case is unique and based on a combination of environmental and genetic factors. Conventional chemotherapy employs treatment with one or more drugs, assuming that these medicines are able to both 'diagnose' and 'treat' the affected cells. Many of the side effects experienced by chemotherapy patients are due to the fact that the drugs they are taking aren't selective enough. ... But what if we had cancer treatments that worked more like a computer program, which can perform actions based on conditional statements? Then, a treatment would kill a cell if - and only if - the cell had been diagnosed with a mutation. Only the defective cells would be destroyed, virtually eliminating unwanted side effects. ... researchers [have] created conditional small RNA molecules to perform this task. Their strategy uses characteristics that are built into our DNA and RNA to separate the diagnosis and treatment steps. ... Here's how it works: Treatment involves two different small RNAS. The first small RNA will open up if - and only if - it finds the cancer mutation. A positive 'diagnosis' exposes a signal that was previously hidden within the small RNA. Once this small RNA is open, a second small RNA binds to it, setting off a chain reaction in which these RNA molecules continue to combine to form a longer chain. The length of the chain is an important part of the 'treatment'. Longer chains trick the cell into thinking it has been invaded by a virus, tripping a self-destruct response."

Link: http://www.eurekalert.org/pub_releases/2010-09/nsf-tcw090310.php

A great deal of medical research into aging is built upon a foundation of correlation studies: what can we identify as more often occurring for patients who suffer from a particular age-related condition? Are there environmental factors, lifestyle choices, or genetic differences that are statistically linked to the occurrence of this condition? The next step that follows from the identification of such correlations is to pick them apart looking for commonalities. Why do these many correlations exist, and do they exist because of one underlying mechanism?

For example, see this open access paper that proposes chronic inflammation as the causative process for a range of correlations:

Tobacco smoking, physical inactivity and resulting obesity are established risk factors for many chronic diseases. Yet, the aetiology of age-related diseases is complex and varies between individuals. This often makes it difficult to identify causal risk factors, especially if their relative effects are weak. For example, the associations of both obesity and air pollution with several age-related diseases remain poorly understood with regard to causality and biological mechanisms. Exposure to both, excess body fat and particulate matter, is accompanied by systemic low-grade inflammation as well as alterations in insulin/insulin-like growth factor signalling and cell cycle control.

These mechanisms have also been associated in animal and some human studies with longevity and ageing in more general terms. In this paper, it is therefore hypothesised that they may, at least in part, be responsible for the adverse health effects of obesity and air pollution.

Inflammation is very much a bugbear, and in recent years a great deal of research has focused on just how chronic inflammation and the failing immune system contributes to degenerative aging. Researchers are also making good progress on understanding exactly how excess fat tissue produces chronic inflammation and damages the immune system in the process.

Nicole M. Probst-Hensch (2010). Chronic age-related diseases share risk factors:
do they share pathophysiological mechanisms and why does that matter? Swiss Medical Weekly DOI: 10.4414/smw.2010.13072

The same genes in different people can produce different metabolisms, and this is largely due to epigenetics: the way in which genes express themselves to form proteins. Studies of epigenetic differences are gathering pace: "One of the most ambitious large-scale projects in Human Genetics has been launched today: Epitwin will capture the subtle epigenetic signatures that mark the differences between 5,000 twins on a scale and depth never before attempted, providing key therapeutic targets for the development of drug treatments. ... Epigenetics [explores] how the actions of genes can be temporarily modified by chemical reactions that may occur either at random or by lifestyle or diet. This effect may last several generations. The plan is to look at the methylation patterns of 20 million sites (called CpG islands) in the DNA of each twin and compare them with the patterns in the co-twin. Rather than looking at similarities as in previous studies, the team will be looking for differences that explain why many identical twins don't develop the same diseases. Initially the team will focus on obesity, diabetes, allergies, heart disease, osteoporosis and longevity, but the method can be applied to every common trait or disease. ... So far this type of study has only been attempted on a handful of twins, so we want to scale it up - one thousand fold."

Link: http://www.eurekalert.org/pub_releases/2010-09/kcl-lee090310.php

You might recall that centenarian studies in the Ashkenazi population showed an association betweeen lipid metabolism and longevity. Here is another study that shows similar correlations in a different population: "Mechanisms underlying the variation in human life expectancy are largely unknown, but lipid metabolism and especially lipoprotein size was suggested to play an important role in longevity. We have performed comprehensive lipid phenotyping in the Leiden Longevity Study ... only LDL size and triglyceride levels were associated with offspring from long-lived families. Sex-specific backwards regression analysis revealed that LDL particle sizes were associated with male longevity. Triglyceride levels, but not LDL particle size, were associated with female longevity. Due to the analysis of a comprehensive lipid profile, we confirmed an important role of lipid metabolism in human longevity, with LDL size and triglyceride levels as major predicting factors." That different populations and the two genders have noticeable differences in the correlations between longevity and aspects of lipid metabolism is an indication of complexity: many factors at work under the hood.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20811950

Metformin is one of the known calorie restriction mimetics amongst drugs presently in use by the medical establishment. A calorie restriction mimetic is a drug that can reproduce some of the beneficial changes to metabolism exhibited during the practice of calorie restriction, which hopefully in turn leads to improved health and extended healthy life span.

Metformin has been shown to modestly increase maximum life span in mice, though by much less than is possible through calorie restriction:

chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice.

In human medicine, metformin is primarily used as an anti-diabetic treatment, which has led to speculation as to just how much of the calorie restriction effect on health and longevity is due to changes in insulin metabolism - such changes made directly in genetically engineered laboratory animals have been shown to significantly affect longevity as well.

Here, however, I will point you towards a paper that shows much of the effect of metformin to reside in the mitochondria, the cell's power plants. Regular readers will by now know that our mitochondria are very important determinants of aging and longevity, and the accumulated damage suffered by mitochondria - caused by the reactive oxygen species they produce as a consequence of their operation - produces some fraction of the aging process. These reactive oxygen species include hydrogen peroxide, H2O2, and, as it turns out, metformin reduces the rate at which H2O2 is produced by mitochondria without otherwise impairing their operation:

In conjunction with improved glycemic control, metformin treatment reduced H(2)O(2) emission in muscle from obese rats to rates near or below those observed in lean rats ... Surprisingly, metformin treatment did not affect basal or maximal rates of O(2) consumption in muscle from obese or lean rats. ... These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H(2)O(2) emission by blocking reverse electron flow without affecting forward electron flow or respiratory O(2) flux in skeletal muscle.

Since I'm not greatly in favor of efforts that only slow aging, I see this sort of research as more in the way of a confirmation of the importance of mitochondrial damage - and the need to put more resources towards mitochondrial repair with the aim of reversing the effects of aging.

Kane DA, Anderson EJ, Price JW 3rd, Woodlief TL, Lin CT, Bikman BT, Cortright RN, & Neufer PD (2010). Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free radical biology & medicine, 49 (6), 1082-7 PMID: 20600832

Via EurekAlert!: "Scientists have devised a method for coaxing mouse embryonic stem cells into forming a highly specific motor neuron subtype. The research [provides] new insight into motor neuron differentiation and may prove useful for devising and testing future therapies for motor neuron diseases. ... The existence of dozens of muscle groups in the limbs of most mammals demands an equivalent diversity of motor neuron pool subtypes ... During normal development, motor neurons settle into specific sections of the spinal cord (called columns), which correspond to the muscles that they will innervate. For example, cells in one area link up with muscles in the limbs, while cells residing in another region innervate muscles in the body wall. Although previous studies have shown that mouse and human embryonic stem cells can be converted into motor neurons, it was not clear whether these were 'generic' neurons or whether they could acquire characteristics of the specific specialized subtypes. In the current study, [researchers] showed that removing a key differentiation factor allowed cultured embryonic stem cells to form motor neurons with molecular characteristics corresponding to a limb innervating subtype, without the need for genetic manipulation or added factors. Importantly, when this stem cell-derived subtype was transplanted into embryonic chick spinal cords, the motor neurons settled in the expected columnar position within the cord and had projections that mimicked the trajectory of limb innervating motor neurons."

Link: http://www.eurekalert.org/pub_releases/2010-09/cp-fmn082510.php

Ray Kurzweil in h+ Magazine: "There has been recent disappointment expressed in the progress in the field of genomics. In my view, this results from an overly narrow view of the science of genes and biological information processing in general. ... To reverse-engineer biology we need to examine phenomena at different levels, especially looking at the role that proteins (which are coded for in the genome) play in biological processes. In understanding the brain, for example, there is indeed exponential progress being made in simulating neurons, neural clusters, and entire regions. This work includes understanding the 'wiring' of the brain (which incidentally includes massive redundancy) and how the modules in the brain (which involve multiple neuron types) process information. Then we can link these processes to biochemical pathways, which ultimately links back to genetic information. But in the process of reverse-engineering the brain, genetic information is only one source and not the most important one at that. So genes are one level of understanding biology as an information process, but there are other levels as well, and some of these other levels (such as actual biochemical pathways, or mechanisms in organs including the brain) are more accessible than genetic information. In any event, just examining individual genes, let alone SNPs, is like looking through a very tiny keyhole."

Link: http://hplusmagazine.com/editors-blog/new-era-health-and-medicine-information-technology-broader-individual-genes

The future of our organs is as much artificial as it is fleshy. In the competition to develop a source of replacement organs built from scratch, the biotechnology-focused materials science researchers will give the tissue engineers a run for their money. Viable artificial hearts are in trials at the present time, for example, at the same time as decellularization of donor heart values is employed to build replacement parts for injured hearts. Neither path ahead is quite ready for prime time, but a wide range of trials are underway for early stage products, and an even wider range of work is taking place in the laboratory.

So to the future of bioartificial organs. A computer doesn't look much like a brain, a slide-rule, or a typewriter. The bioartificial pancreas of the future won't look a whole lot like the pancreas you're carrying around with you at the moment. In parallel to work on regenerative medicine and repair of aging - aiming to maintain the body we have - we will see a great breadth of development in semi-organic prostheses and other functional replacements, and the growth of support infrastructure for that technology.

At the end of the day, some decades from now, it'll all be nanotechnology of course: fully artificial all the way down to the carefully tuned cell-substitute nanomachines. But in the meanwhile, and in the early days of this biotechnology revolution, competition is good for progress. On this subject, I see that matters are moving ahead for the kidney:

UCSF researchers today unveiled a prototype model of the first implantable artificial kidney, in a development that one day could eliminate the need for dialysis. The device, which would include thousands of microscopic filters as well as a bioreactor to mimic the metabolic and water-balancing roles of a real kidney, is being developed in a collaborative effort by engineers, biologists and physicians nationwide. ... [The] goal is to apply silicon fabrication technology, along with specially engineered compartments for live kidney cells, to shrink that large-scale technology into a device the size of a coffee cup. The device would then be implanted in the body without the need for immune suppressant medications, allowing the patient to live a more normal life.

...

The two-stage system uses a hemofilter to remove toxins from the blood, while applying recent advances in tissue engineering to grow renal tubule cells to provide other biological functions of a healthy kidney. The process relies on the body's blood pressure to perform filtration without needing pumps or an electrical power supply.

Cast your mind back and recall what a mobile phone looked like in 1980, 30 years ago now. Consider, in turn, what a bioartificial kidney, pancreas, or liver will look like in 2040, 30 years from now. The same forces of progress are at work.

Excess fat tissue in your body actively works to change your metabolism, and largely for the worse. Here's a reminder of that fact: "Scientists are reporting new evidence that the fat tissue - far from being a dormant storage depot for surplus calories - is an active organ that sends chemical signals to other parts of the body, perhaps increasing the risk of heart attacks, cancer, and other diseases. They are reporting discovery of 20 new hormones and other substances not previously known to be secreted into the blood by human fat cells and verification that fat secretes dozens of hormones and other chemical messengers. ... [Researchers] note that excess body fat can contribute to heart disease, diabetes, cancer and other diseases. Many people once thought that fat cells were inert storage depots for surplus calories. But studies have established that fat cells can secrete certain hormones and other substances much like other organs in the body. Among those hormones is leptin, which controls appetite, and adiponectin, which makes the body more sensitive to insulin and controls blood sugar levels. However, little is known about most of the proteins produced by the billions of fat cells in the adult body."

Link: http://www.kurzweilai.net/new-evidence-that-fat-cells-are-not-just-dormant-storage-depots-for-calories

The mainstream press notices sarcopenia: "Bears emerge from months of hibernation with their muscles largely intact. Not so for people, who, if bedridden that long, would lose so much muscle they would have trouble standing. Why muscles wither with age is captivating a growing number of scientists, drug and food companies ... Comparisons between age groups underline the muscle disparity: An 80-year-old might have 30 percent less muscle mass than a 20-year-old. And strength declines even more than mass. Weight-lifting records for 60-year-old men are 30 percent lower than for 30-year-olds; for women the drop-off is 50 percent. With interest high among the aging, the market potential for maintaining and rebuilding muscle mass seems boundless. Drug companies already are trying to develop drugs that can build muscles or forestall their weakening ... In addition, geriatric specialists, in particular, are now trying to establish the age-related loss of muscles as a medical condition under the name sarcopenia. ... But with sarcopenia still not established as a treatable condition, 'there is no real defined regulatory path as to how one would get approved in this area.'" When you live under a regime in which all that is not permitted is forbidden, it should be no surprise that progress is slow and expensive. One of the best things that could be done for medicine in this modern age is to tear down the FDA and other similar regulatory bodies.

Link: http://www.nytimes.com/2010/08/31/health/research/31muscle.html

The SENS Foundation recently teamed up with InnoCentive to spur movement in the development of AGE-breakers for human use. I'd mentioned this over at the Longevity Meme, but the initiative seems worth more time and attention than just a link. So here we are: but what is an AGE-breaker, and why should we care? In short, it has been known for some time that one of the unpleasant changes that takes place with aging is the accumulation of advanced glycation endproducts, or AGEs, in our biochemistry:

Your body needs certain proteins in order to work properly; the creation of AGEs involves taking two or more of these proteins and sticking them together with chemical gunk, preventing them from doing their jobs. This is known as crosslinking; day in and day out, it is taking place in your body. Some AGEs are short-lived but common, growing or declining in population in response to your diet and metabolic peculiarities. Others are very long-lived or impossible for the body to break down; they build up over the years, and eventually there's enough of this gunk to seriously damage you. Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

You can read more on the topic at the SENS Foundation: dealing with AGE crosslinks is one of the seven facets of the SENS program.

A few earnest efforts to establish drugs capable of safely breaking down AGEs have taken place in past years, such as the development of ALT-711 or alagebrium. This sort of treatment has great promise: if medical science can clear out AGEs on a regular basis, then their contribution to the aging process can be eliminated entirely. Unfortunately the only meaningful progress resulting from work to date is the discovery that AGEs in laboratory animals are quite different from those in humans: age-breakers like ALT-711 that showed results in rats have gone nowhere in human trials.

However, researchers have identified the most important AGE in humans, a chemical called glucosepane:

In the extracellular matrix of the skin of a non-diabetic 90-year-old, glucosepane accounts for about 50 times the protein cross-linking as all other forms of protein cross-linking.

Sadly, very few scientists are working in any way on an AGE-breaker for glucosepane. The only group I know of is Legendary Pharmaceuticals, which is a very small outfit indeed. This is a state of affairs very familiar to anyone who spends much time looking into the science of human aging and the potential for engineered longevity: a great deal is known about what needs to be done, but, aside from the field of regenerative medicine, next to nothing is being done.

This is where non-profits like the SENS Foundation or Methuselah Foundation enter the picture: working to raise awareness, spur interest, persuade scientists, and generate research funding. In the case of glucosepane, the SENS Foundation has branched out to work with InnoCentive, a company with an interesting business model: they are a marketplace for people in search of cost-effective solutions to specific problems in life science development, biotechnology, and engineering (amongst other areas of endeavor). This, I imagine, works for these fields because (a) any laboratory is capable of a wide range of tasks touching upon its specialty, (b) the state of play is so dynamic and broad that someone outside a particular specialty is going to find it hard to dig up the right connections for a very specific need. A marketplace of this sort allows laboratory managers and experts to find new buyers for their talents and products, and buyers to find what they need at a better price - or at all, in some cases.

So if you look through the InnoCentive challenges, you'll see things ranging from speculative RFPs to prizes offered for processes yet to be developed by biotechnologists - but which could be, sometime soon.

The SENS Foundation has dipped into this marketplace in search of the development path to an AGE-breaker for glucosepane, and a kick in the pants for the research and development community who should already be working on the problem:

As a biomedical charity, SENS Foundation's usual method for tackling research problems is to provide direct grants for expert researchers to do critical-path work in rejuvenation science. So we have long had an open Request for Proposals (RFP) for qualified researchers to tackle this problem, addressing specifically the most important of those crosslinks - a stubborn AGE called glucosepane. To date, we've had no takers.

That's why we've launched this $20,000 Theoretical Research prize - not to demonstrate the breakage of glucosepane in the lab, but to give us a clear enough roadmap for the project that we can attract the further financial and scientific resources needed for a full-scale research and development project. ... SENS Foundation is reaching out to InnoCentive's network of more than 200,000 Solvers: in the next 60 days, give us a detailed working plan to develop a drug to give aging arteries their youthful spring, and averting age-related disease and pathology.

To be a supporter of engineered human longevity is to be frustrated by the large difference between what might be and what is. We'd like to see a small army of researchers working to develop repair technologies for issues such as glucosepane buildup, and there is no good reason as to why that army doesn't yet exist. But it doesn't exist. At least regenerative medicine and stem cell research is a going concern, and far beyond needing our help, but still: the present state of longevity science is a long, long way from where we'd like it to be.

There is a great deal of work left to do, and initiatives like the SENS Foundation/InnoCentive effort are a step in the right direction.

The mainstream view of aging in the adaptive immune system is that too many memory T cells exist, uselessly specialized and using up limited resources that should be devoted to the naive T cells needed to tackle new threats. An alternative (and not mutually exclusive) theory is presented in this paper: that memory cell populations are failing in old age, meaning that acquired immunity vanishes. "Evidence is accumulating that old individuals are more susceptible to infection with organisms to which they were previously immune, indicating that there might be a limit to the persistence of immune memory. The prevailing concept is that defects in memory T-cell populations result from inexorable end-stage differentiation as a result of repeated lifelong antigenic challenge. We discuss here mechanisms that might constrain the persistence of memory T cells and consider whether humans will suffer from memory T-cell exhaustion as life expectancy increases." Whether or not this in fact occurs, the proposed therapies would look much the same as for other immune system issues known to occur with aging: destroy the old, misconfigured, damaged immune cells and replace them with new cells grown from the patient's stem cells.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20795550

As researchers peer more deeply, the accelerated aging condition progeria continues to look very much like one aspect of "normal" aging run amok: "Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. ... We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year in coronary arteries. ... Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in the cardiovascular aging of the general population."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20798379