Fight Aging!

The end of the year is closing in, and this is about when I usually make an annual donation to the Methuselah Foundation. I prefer the periodic lump sum donations over monthly contributions as it's a good way to force an occasional check on whether you're still making a good choice. In the years since the Foundation's inception, I've donated to the Mprize fund. The fund predates the option to directly sponsor Strategies for Engineered Negligible Senesence (SENS) research aimed at repairing the damage of aging, but I've continued to put money towards the research prize, as I consider it to be important.

Time for a change, I think. This year's donation will go towards SENS research - but not because I think the Mprize is any less worthy. At this point, it looks like the best plausible growth path for the Methuselah Foundation over the next few years is based on following through with present initiatives to establish and publicize a steady stream of modest SENS research achievements. I've long said that advocacy and tangible results have to go hand in hand for optimal progress; when one gets too far ahead of the other, it tends to slow down.

You get what you pay for in this life - so if we want to see that steady stream of research achievements, we have to fund the research. Other people hang around in the wings waiting for more confirmation and mass of support for these projects, but those of us who better understand the science and potential of SENS are the ones who must pay to start the ball rolling. My contributions aren't large, but then no one person can form a crowd. I would hope that discussing this topic moves those of you yet to donate to make that small effort to help progress towards engineered longevity.

The provision of autologous stem cell therapies in the for-profit world continues onwards, as this press release indicates: researchers "announced nine month follow up results for the first patient treated with engineered stem cells in a clinical study of primary pulmonary hypertension. The stem cells are extracted from patients' own blood and trained to become new blood vessels. ... It goes against traditional theory that we should try to fix the existing pulmonary vasculature, but we are generating new blood vessels with impressive results. ... the clinical study is a collaborative effort amongst physicians at Regenocyte Therapeutic, a Florida-based stem cell clinic; researchers from TheraVitae, a biotechnology company in Tel Aviv, Israel; and physicians from Regenocyte's Dominican Republic division. ... This is the first time medical science has successfully reversed the disease process in pulmonary hypertension, a previously untreatable condition with a very grim prognosis. Using advanced engineered stem cell technology and innovative delivery methods. We've been able to harness the regenerative power of stem cells and literally replace the damaged blood vessels in the lungs of the pulmonary hypertension patients."

Link: http://www.marketwatch.com/news/story/story.aspx?guid=%7B1B211376-C24C-4B2C-B881-7FF71EB82AAB%7D

From ScienceDaily: "Overturning a century of prevailing thought, scientists are finding that neurons in the adult brain can remodel their connections. ... [researchers] saw relatively large-scale changes in the length of dendrites - branched projections of nerve cells that conduct electrical stimulation to the cell body. Even more surprising was their finding that this growth was limited to specific type of cell. The majority of cortical neurons were stable, while the small fraction of locally connecting cells called interneurons underwent dynamic rearrangement. ... the capacity of interneurons to remodel is not predetermined by genetic lineage, but imposed by the circuitry within the layers of the cortex itself. ... Our findings suggest that the location of cells within the circuit and not pre-programming by genes determines their ability to remodel in the adult brain. If we can identify what aspect of this location allows growth in an otherwise stable brain, we can perhaps use it to coax growth in cells and regions that are normally unable to repair or adjust to a changing environment."

Link: http://www.sciencedaily.com/releases/2008/11/081124174909.htm

The Millard Foundation [UPDATE 03/08/2009: their public face on the web is now the LifeStar Institute] has been moving towards earnest funding of longevity science over the past few years: there have been initial donations, conference attendances, meetings with movers and shakers. All the normal activities and preparation by people who take investing very seriously. Much like the Glenn Foundation, which I would consider an analogous force in the philanthropic funding space, the Millard family have donated generously to the Methuselah Foundation. But where Paul Glenn opted to place his first major funding initiatives firmly in the present mainstream - calorie restriction research, understanding metabolism, and attempts to slow aging through metabolic and genetic manipulation - the Millard family is more inclined towards the Strategies for Engineered Negligible Senescence (SENS) viewpoint. This approach is to reverse aging without altering the workings of our metabolism by identifying and repairing damage: the engineering approach.

Long-time readers will know that I consider the debate over the methods used to engineer longevity in humans to be the most important scientific battle of this century. If it goes the right way - towards SENS, presently the minority viewpoint - then I believe significant results in applied longevity science will arrive decades sooner than they might, and will include therapies capable of rejuvenating the elderly. If development of metabolic manipulation therapies to slow aging continues to dominate, progress towards enhanced longevity will be much slower, and the resulting therapies will be of no use to those already aged.

From what I've seen, the Millards have money, influence, and the intelligence to use it well. That is good news for SENS-style research over the next few years. Going by the latest news from the Methuselah Foundation, things are moving forward more rapidly now:

Back in June at Aging '08 I met Barbara Logan of the Millard Foundation having previously met her father William Millard at SENS 2. ... Over the following months she became a resource for me and I introduced her to some efforts with the Alberta Government where I had proposed the development of regenerative medicine programs which are under consideration. It soon became clear that there were some strong synergies and I was invited to participate in the efforts of the Millard Foundation in developing a strategy to serve the mission. Unsurprisingly, Aubrey [de Grey] is a consultant on the project and will play an increasingly important role as we move forward - the ideas of SENS are part of the project's DNA. More than that I'm afraid I can't speak to at this time, but suffice to say, it is one of the most exciting efforts (other than the Methuselah Foundation) that I have been involved with.

Diversification in the growth of the money-bearing and money-raising side of the healthy life extension community, and the wider adoption of the ideas of SENS in that group, is a very encouraging sign. Of all the things I'd want to see in a movement primed for growth in the years ahead, diversity amongst the movers and shakers tops the list. Diversity implies competition, and competition is the way to success.

Previous studies suggest that it's never too late to gain significant health benefits by adopting a calorie restriction diet. Here is an intriguing paper that suggests there is a cut-off if you want those benefits to include an improved immune system: "We have recently shown in non-human primates that caloric restriction (CR) initiated during adulthood can delay T-cell aging and preserve naive CD8 and CD4 T cells into advanced age. An important question is whether CR can be initiated at any time in life, and whether age at the time of onset would modulate the beneficial effects of CR. In the current study, we evaluated the impact of CR started before puberty or during advanced age on T-cell senescence and compared it to the effects of CR started in early adulthood. Our data demonstrate that the beneficial effects of adult-onset CR on T-cell aging were lost by both early and late CR onset. In fact, some of our results suggest that inappropriate initiation of CR may be harmful to the maintenance of T-cell function. This suggests that there may be an optimal window during adulthood where CR can delay immune senescence and improve correlates of immunity in primates."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19032694

It is a widely held view that accumulating stochastic nuclear DNA damage is one contributer to aging. This is debated for degenerations other than cancer, however. Here is a different way of looking at DNA damage in stem cells, connected to the immortal DNA strand (IDS) hypothesis: "Cairns noted a mathematical discrepancy between predicted human tissue cell mutation rates and human cancer incidence [and predicted] the existence of IDSs as the essential elements of a mutation-defense mechanism in [stem cells]. ... several laboratories have identified IDSs in diverse mammalian [stem cells]. Past studies focused on the potential roles of IDSs as originally envisioned in [stem cell] genetic fidelity or in the maintenance of the [stem cell] phenotype. Another possible consequence of IDSs, aging, has received little attention. Herein, the potential for cumulative chemical modifications and decompositions (i.e., 'age spots') of IDSs in [stem cells] to act as a major determinant of human aging is considered. If accrued chemical alterations of IDSs prove to be essential determinants of aging, then a means to restore IDSs may yield new strategies for tissue rejuvenation."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19029623

Deuterium and engineered longevity are in the popular press again:

[The method] centres on fortifying the body's tissues and cells against attack and decay caused by free radicals, dangerous chemicals produced when food is turned into energy. Such 'attacks' on proteins are particularly damaging and have been linked to cancer, Alzheimer's and Parkinson's.

Dr Shchepinov's theory is based on deuterium, a naturally-occurring isotope, or form of hydrogen, that strengthens the bonds in between and around the body's cells, making them less vulnerable to attack.

He found that water enriched with deuterium, which is twice as heavy as normal hydrogen, extends the lifespan of worms by 10 per cent. And fruitflies fed the 'water of life' lived up to 30 per cent longer.

Heavy water is toxic to mammals at very high concentrations, and as I mentioned in response to a paper from Rejuvenation Research in 2007:

Shchepinov argues that isotopes would only be incorporated in the sites that need to be protected from oxidation. 'Ideally, they will slow down the oxidation reaction so much that they will never be released to take part in other reactions. If some of them do break free, they will only occur in small concentrations,' he said.

As for the other folk quoted in [a science press article at the time], I'm dubious - it seems to me that the level of technology required to target the isotopes reliably (and keep them targeted) would enable far more effective methdologies of repairing rather than preventing oxidative damage.

I suspect that the main benefit to come out of this research will be an increased understanding of free radical biochemistry and its interaction with degenerative aging.

UPDATE 11/27/2008: You'll find a much better article on this research at the New Scientist.

There are a lot of theories of aging, some very useful, many of which overlap, and many of which are overly narrow, overly general, or otherwise unhelpful. Here's one that appears to be another way of looking at damage accumulation, or perhaps reliability theory: "Individual differences in the rate of aging are determined by the efficiency with which an organism transforms resources into metabolic energy thus maintaining the homeostatic condition of its cells and tissues. This observation has been integrated with analytical studies of the metabolic process to derive the following principle: The metabolic stability of regulatory networks, that is the ability of cells to maintain stable concentrations of reactive oxygen species (ROS) and other critical metabolites is the prime determinant of life span. ... Our studies delineate age and tissue specific patterns of transcriptional changes which are consistent with the metabolic stability-longevity principle. This study, in addition, rejects the free radical hypothesis which postulates that the production rate of ROS, and not its stability, determines life span."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19031007

The New Scientist (and some of the interviewed researchers) overhype an interesting discovery: "An overworked protein that causes yeast to age when it neglects one of its functions may trigger ageing in mice too. ... As we get older, genes can start to be expressed in the wrong body tissues - a process that is thought to contribute to diseases like diabetes and Alzheimer's. ... yeast cells [produce] a dual-function protein called Sir2 that, while being involved in DNA repair, also helps keep certain genes switched off. As yeast cells age, the protein can't do both jobs and neglects its role as a gene suppressor. Now Sinclair's team has shown that SIRT1, the mammalian version of Sir2, also begins to neglect its gene-suppressor role in mice whose DNA is damaged, and that this may contribute to ageing. ... The most exciting thing is that this work may unify in a single molecular pathway what we know about ageing in different organisms such as yeast and mammals ... It opens up the possibility of restoring youth in the elderly by re-establishing a useful pattern of gene expression." I think it will take more than restoring gene expression: there's also the matter - more important to my mind - of repairing the damage that caused those changes in gene expression.

Link: http://www.newscientist.com/article/dn16143-has-universal-ageing-mechanism-been-found.html

The message to take away from much of the research into obesity is "don't let it happen to you." Fortunately for most of us, that is well within our power: obesity is almost always a choice.

While smoking reduces life by an average of ten years, the research says being seriously overweight can cut life expectancy by as much as 13 years.

As for any complicated survey of human health, you'll find dissenting studies, or studies that show widely different results for different studied groups. Here's one that shows no real difference to life expectancy for obese versus non-obese old people:

Total, active, and disabled life expectancy in Americans aged >/=70 is estimated, with and without obesity and arthritis. Results indicate that neither obesity nor arthritis is related to the length of life for older men and women, alone or in combination. However, both conditions are significantly individually associated with increased length of disabled life in older men (1.4 years attributable to obesity; 1.2 years to arthritis at age 70) and women (1.7 years attributable to obesity; 2.1 years to arthritis at age 70). In addition, the combination of the two is significantly related to decreased active life, with nearly 50 and 60% of remaining life for 70-year-old men and women lived with disability, respectively.

I suspect there's some survivorship bias in studying people who are sufficiently inured to obesity by luck of genes or more active lifestyle to make it past 70 - despite the nasty effects that all that visceral fat has on your metabolism. Even if this you're not losing years, it certainly takes its toll in other ways. Disability and age-related disease of any sort is an unpleasant, very expensive experience, yet many people ensure they will suffering more of it by way of the lifestyle they lead and the calories they consume.

From the Telegraph: "The world's first custom-made bones that can be 'grown' in a matter of hours and fit precisely into a break could be available within three years. The new bones will replace damaged or ceramic versions that are currently used in reconstructive surgery. They are made of one of the key materials in human bone, calcium phosphate, which means they will not be rejected by the body and will be completely absorbed into the skeleton within a couple of years. ... We have just completed the investigative study and clinical trials are under way on patients. Some people have congenital defects, others have lost bone after undergoing surgery for cancer, while others have been in traffic accidents. The reactions we have had so far have been very favourable." Early days yet, along with flaws and limitations to the process, but this sort of medical engineering will improve just as rapidly as other biotechnology.

Link: http://www.telegraph.co.uk/health/3519161/Custom-made-bones-to-be-grown-within-hours.html

Advances of the sort noted here at EurekAlert! are becoming commonplace: researchers "have been able to effectively repair damaged heart muscle in an animal model using a novel population of stem cells they discovered that is derived from human skeletal muscle tissue. ... These transplanted [cells] repaired the injured muscle, stimulated the growth of new blood vessels in the heart and reduced scar tissue from the injury, thereby dramatically improving the function of the injured left ventricle ... This study confirms our belief that this novel population of stem cells discovered in our laboratory holds tremendous promise for the future of regenerative medicine. Specifically, myoendothelial cells show potential as a therapy for people who have suffered a myocardial infarction. The important benefit of our approach is that as a therapy, it would be an autologous transplant. This means that for a patient who suffers a heart attack, we would take a muscle biopsy from his or her muscle, isolate and purify the myoendothelial cells, and re-inject them into the injured heart muscle, thereby avoiding any risk of rejection by introducing foreign cells."

Link: http://www.eurekalert.org/pub_releases/2008-11/chop-chs112508.php

Damaged mitochondria accumulate in your cells with advancing age, and their malfunctions cause all sorts of further harm to your biochemistry. All in all they are a bad thing, and a strong candidate for the most important cause of degenerative aging. So it is with interest I notice that researchers working on Parkinson's disease are uncovering more of the cellular mechanisms that - when working properly - cull damaged mitochondria so that they can be replaced:

Parkin, the product of the Parkinson's disease-related gene Park2, prompts neuronal survival by clearing the cell of its damaged mitochondria.

...

Several lines of evidence suggest that Parkin loss is associated with mitochondrial dysfunction, but exactly how was unknown. To learn more about Parkin's role in cells, Narendra et al. examined the protein's subcellular location. They found that Parkin was present in the cytoplasm of most cells, but translocated to mitochondria in cells that had undergone mitochondrial damage such as membrane depolarization.

Damaged mitochondria can trigger cell death pathways; indeed, dysregulation of mitochondrial health was already thought to be a possible cause of the neuronal cell death associated with Parkinson's disease. The relocation of Parkin to damaged mitochondria, the team showed, sends these defunct organelles to autophagosomes for degradation. Parkin may thus prevent the damaged mitochondria from triggering cell death. Because neurons are not readily replicable, disposing of damaged mitochondria may be especially important in the adult brain.

I'm not so interested in the association with Parkinson's, since the cell death mechanisms for the dopamine-producing neurons that die off in Parkinson's appear to be further downstream in the chain of cause and effect than accumulation of alpha-synuclin. I am, however, very interested any mechanism that shows potential for enhancement to clear out more damaged mitochondria.

If you look back at the details of how damaged mitochondria eventually replace undamaged mitochondria in a cell, however, it isn't clear whether Parkin is involved in such a mechanism. The crucial point is whether Parkin is only involved in responding to damage to mitochondrial membranes, as the type of internal mitochondrial damage that contributes to aging leaves the membranes intact. The devil, as always, is in the details - and biochemistry has no shortage of details.

Regenerative medicine for animals is more advanced than that available for humans, as regulation is less oppressive. Here, a view of regenerative medicine for horses: "Tendon and ligament injuries in performance horses are the most common disorders currently being treated with stem cells in clinical trials ... One researcher has shown a lower recurrence rate of bowed tendons in racehorses treated with stem cells ... Clinical trials with local stem cell injection are also being performed for treatment of suspensory ligament injuries of the fore and hind limbs. ... Degenerative joint disease is a problem in performance horses and has great economic impact on the equine industry. Although there are many therapies to support joint health, the majority of these treatments are to relieve the symptoms at best. Stem cell therapy for joint disease is supported by original research performed in goats. It was shown [that] joints treated with stem cells had less arthritic changes compared with nontreated joints in the same animal. Several horses have been experimentally treated for joint injuries [using] stem cell therapy and the initial results have been positive."

Link: http://www.thehorse.com/ViewArticle.aspx?ID=13147

From Wired: "Resveratrol has proven safe in animals and early clinical trials, but much more testing is required. As a cautionary, Longo offered the example of his own research on caloric restriction and genetic manipulation of IGF-1, a cell-growth-regulating gene. In simple organisms, it's produced the most-dramatic life extension ever seen - yeast lived 10 times its normal lifespan - but a group of Ecuadorians who naturally have that mutation have severe growth deficits and other health problems. Even Longo, however, thinks resveratrol will enjoy some success in the near future, and mitochondrial approaches are being steadily embraced within the medical research community, which has been largely frustrated in its disease-by-disease, gene-centered approach. ... The approach we've taken is to go one disease at a time. We've created national institutes to go after all these major diseases, and every time we identify a new gene, or do something that lets us attack disease a little more efficiently than before, everyone jumps up and says we've succeeded and that's wonderful. Such research is important, said Olshansky, but not as promising as hitting diseases at a common root. And though he won't yet commit to resveratrol as a wonder drug, he suspects that mitochondria-targeting drugs will provide a breakthrough."

Link: http://blog.wired.com/wiredscience/2008/11/two-mice-on-tre.html

From Depressed Metabolism: "One of the most neglected aspects of cryonics is that its procedures, and the research to support them, can have important practical applications in mainstream fields such as organ preservation and emergency medicine. Contrary to popular opinion, cryonics does not just involve an optimistic extrapolation of existing science but can set the standard for these disciplines. As a matter of fact, that is exactly what cryonics, and cryonics associated research, has been doing over the last 25 years. ... it is encouraging to observe that some of the procedures that are routine in cryonics stabilization protocol are starting to catch on in mainstream emergency medicine practice as well. For example, contemporary cryonics stabilization protocol has been strongly shaped by the idea that the best strategy to limit brain injury after cardiac arrest is to combine a number of different interventions: cardiopulmonary support, induction of hypothermia, and administration of circulation-supporting and neuroprotective medications. It is therefore very encouraging to learn that the Wake County EMS group in North Carolina has achieved impressive results in treating out-of-hospital cardiac arrest victims using a protocol that closely follows elements of current cryonics stabilization protocol."

Link: http://www.depressedmetabolism.com/2008/11/19/cryonics-sets-example-for-emergency-medicine/

Chris Patil of Ouroboros set down some notes earlier this week on the annual meeting of the Larry L. Hillblom Foundation, one of a number of non-profit organizations to fund research into the biochemistry of aging.

Morning session 1A:

Bob Hughes, Pankaj Kapahi, Simon Melov and Gordon Lithgow (Buck Institute) gave a group talk under the umbrella topic “Chemical biology of aging” (we heard a bit about this at last year’s meeting). Bob introduced a screen for small molecules that extend lifespan in simple model system; the goal is to screen 100,000 compounds, identify drugs that increase longevity in both yeast and worms, and then test these molecules in mice.

Morning session 1B:

Glabe’s group [has] been developing anti-amyloid antibodies, some of which [recognize] common features of amyloid aggregates formed by many different types of protein (e.g., [amyloid-beta] but also alpha-synuclein, IAPP, and other peptides involved in aggregation-based diseases [such as Alzheimer's, Parkinson's, and so forth]). These reagents will be useful in research but also potentially as therapies against multiple age-related illnesses.

Morning session 2:

Ken Nakamura (UCSF) is studying Parkinson’s disease in a refreshingly original way: he has developed ways to monitor alpha-synuclein [in] live cells, using fusion with fluorescent proteins. The pathological protein aggregates end up associating with membranes, including mitochondria - which then fragment, potentially contributing to [cell damage and death].

As you might guess from the above items, many age-related conditions are marked by a build-up of errant, damaging proteins - such as alpha-synuclein for Parkinson's and amyloid for Alzheimers. This protein aggregation may or may not be sufficiently close to the root cause of an age-related disease for removal of the protein to be a viable treatment, but we're going to find out during the next few years. The development of therapies aimed at soaking up the most common aggregates - or turning the immune system to destroy them - is advancing rapidly.

Regenerative medicine advances, step by step: "researchers have developed an unlimited number of pure insulin-producing cells from mouse embryonic stem cells (ESCs). ... These pure insulin-producing cells, which according to electron microscopy studies, have the same sub-cellular structures as the insulin-producing cells naturally found in the pancreas, were highly effective in treating diabetes in the mouse model. The transplants of pure insulin-producing cells reduced the blood glucose levels of diabetic mice with high blood glucose levels. ... None of the diabetic mice involved in the transplant experiments developed teratoma, which are a type of tumour often associated with ESCs and which could complicate their use in human therapeutic treatment. Furthermore, the pure insulin-producing cells managed to retain their insulin-production and glucose-sensing capacity over time. ... Besides providing a tool to facilitate basic research in test tubes and animals, these insulin-producing cells may be also used to replace the isolated native pancreatic cells that are hard to obtain in a large amount, for pharmacological tests."

Link: http://www.sciencedaily.com/releases/2008/11/081120130539.htm

Aging researchers are looking into ant biochemistry for much the same reasons as they look into bee biochemistry: these insects produce individuals with vastly different life spans. By comparing long-lived and short-lived specialized members of the same species, researchers may gain greater insight into the biochemical mechanisms of aging:

What can ants, not typically known for long life, tell us about human aging? Potentially much, says Liebig. Ants in a colony are genetically closely related, yet these sisters' body types, behavior and purpose can become specialized and vastly different. Queens typically arise as the single reproductive female in an ant colony, living for as long as 30 years in some species. As head of the colony they stay in the nest dedicated to perform one major task, egg-laying, for their whole life. Workers on the other hand perform brood care, colony maintenance, and complex foraging tasks. Among the workers additional behavioral and morphological differences may exist. Some individuals are larger and more robust with a focus on colony defense, which earned them the name soldiers. How can such big differences arise in each of these ant types' longevity and behavior without some real differences in their DNA?

According to Liebig and his collaborators, the answer can be found in the rising field of epigenetics - the study of inherited changes in the activity of genes - for example, when they turned on or off; changes not caused by alterations in the DNA sequence.

It is an interesting field of study, but I wouldn't hold your breath waiting for applications to human longevity. That might be decades away - by which time I would hope that more direct approaches to engineering greater human longevity are already well advanced.

From Ouroboros: "In addition the 23 chromosome nuclear genome most of us are familiar with, mitochondria contain their own, distinct genome. Each mitochondrion contains several copies of this genome, and most cell types contain hundreds of mitochondria per cell. ... [Researchers] measured the number of abasic sites [or AP sites] in the mitochondrial genome of young and aged rat brain. AP sites are positions along the DNA backbone where no adenine, guanine, cytosine, or thymine is attached; they are among the most frequent damages to DNA. The authors showed that in normally feeding animals, the number of AP sites increases with age - but calorie restricted (CR) mice did not show such an increase." Since accumulating mitochondrial DNA damage is a root cause of much age-related biochemical damage throughout the body, and since calorie restriction extends healthy longevity in laboratory animals, it makes sense that CR reduces the rate at which this damage accumulates.

Link: http://ouroboros.wordpress.com/2008/11/20/cr-counteracts-the-age-related-increase-in-mitochondrial-abasic-sites/

From EurekAlert!: researchers "have identified for the first time biomarkers of aging which are highly predictive of both chronological and physiological age. Biomarkers are biochemical features that can be used to measure the progress of disease or the effects of treatment. The research involves nematode worms, microarrays which measure changes in gene expression, and complex computer algorithms. This is the first step toward identifying similar biomarkers in humans which would provide a means of scientifically validating anti-aging therapies. ... This is the first evidence that physiological age can be predicted non-subjectively. This is a first step; our results were not perfect, but we were able to predict the ages of the animals 70% of the time, which is far better than anything that has been done before. ... Research into the biology of aging in humans has been hampered by the lack of irrefutable biomarkers that correlate with the aging process. I am confident that at some point there will be a non-subjective method of determining how old someone is with a high level of confidence."

Link: http://www.eurekalert.org/pub_releases/2008-11/bifa-but111208.php

A prodrome is an early set of non-specific symptoms that herald a particular disease. Here, researchers point to chronic inflammation as a prodrome of Alzheimer's (AD): "Recently, the term 'inflammaging' was coined [to] characterize a widely accepted paradigm that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses. Inflammaging differs significantly the from [traditional] acute inflammation in that it is characterized by a relative decline in adaptive immunity ... While the over-active innate immunity characteristic of inflammaging may remain subclinical in many elderly individuals, a portion of individuals (postulated to have a "high responder inflammatory genotype") may shift from a state of "normal" or "subclinical" inflammaging to one or more of a number of age-associated diseases. ... Although conditions of enhanced innate immune response with overproduction of pro-inflammatory proteins are associated with both healthy aging and AD, it is suggested that those who age 'well' demonstrate anti-inflammaging mechanisms and biomarkers that likely counteract the adverse immunity of inflammaging. Thus, opposing the features of inflammaging may prevent or treat the symptoms of AD."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19014446

From Reuters: "Stem cells from tiny embryos can be used to restore lost hearing and vision in animals, researchers said Tuesday in what they believe is a first step toward helping people. One team repaired hearing in guinea pigs using human bone marrow stem cells, while another grew functioning eyes in tadpoles using frog cells. ... They grew the stem cells into neuron-like cells in lab dishes and then transplanted them into the inner ears of the guinea pigs. Three months later, the animals appeared to have some hearing ... the goal was to regrow the tiny hair cells that are essential for mammals to hear, although she is not sure yet how the stem cells made this happen. They would eventually like to try something similar in humans." These are early stage proof-of-concept demonstrations. It is an illustration of progress that they do not stand out as exceptional amidst advances in the many other lines of regenerative research presently taking place.

Link: http://www.reuters.com/articlePrint?articleId=USTRE4AI02220081119

Over at Sentient Developments, George Dvorksy has a couple of posts up on the Convergence 08 unconference recently held in Silicon Valley.

Convergence08 examines the world-changing possibilities of nanotech and the life-changing promises of biotech.

A number of well known names from the healthy life extension community were there to present and exchange views.

Tanya Jones discusses Alcor, present and future:

Whole body vitrification: largely depends on the fluid which is a cryopreservant that prevents the formation of ice crystals in the body. Works particularly well for organs, which was its intended application. Automated systems are being built that are dramatically improving the perfusing process. Large animal tests are planned before it's used on a patient, giving unprecedented control over the perfusion process. It's build on bypass operations used in hospitals.

Day 2 closing panel on longevity

Gregory Benford: Benford talks about his research and its implications -- working to augment their genes in the defense of aging. Diabetes is a predictor of Alzheimer's; we share 75% of our genome with fruit flies. Fruit flies get diabetes and Alzheimer's.

Aubrey de Grey: Describes himself as being the most ambitious of the group. But he qualifies that by saying it's because he's the most pessimistic. We need a new approach that's more preventative than the geriatric approach. This has led Aubrey to the belief that we need to apply regenerative medicine to the problem of aging. He said that Terry Grossman and Ray Kurzweil recapitulated many of his views in their book."

Day 2 opening panel on synthetic biology

Benford sees benefits in the medical sciences and talks about advances in Alzheimer's and diabates -- in those fields that are somewhat stuck and not thinking about evolutionary biology in their research and development.

Benford says the European version of the precautionary principle is nothing more than, "never do anything for the first time." But if we're to make any progress about longevity, argues Benford, we need to exploit the entire suite of biology and what it has to offer.

An article on a successful transplant of a recellularized organ is doing the rounds in the mainstream press:

First a section of trachea was taken from a donor and stripped of cells that could cause an immune reaction, leaving a grey trunk of connective tissue. Stem cells were then taken from Ms Castillo’s bone marrow and grown in Professor Birchall’s laboratory. Stem cells can develop into different kinds of tissue, given the right chemical instructions, enabling researchers to cultivate cartilage and epithelial cells to cover the 7cm graft. It was then “seeded” with the new cells using a process developed in Milan. Finally the trachea, covered in cartilage and lined with epithelial cells, was cut to shape and fitted.

Professor Macchiarini said: “The probability that this lady will have rejection is almost zero. She is enjoying a normal life, which for us clinicians is the most beautiful gift.”

You might recall other news from past months on this technique for converting a donor organ into an organ built with the patient's own cells. In essence this is a clever way around the present inability to construct nanoscale scaffolds that have both the right structure and can provide the right biochemical signals to guide cell growth. The extracellular matrix left behind after the old cells are removed becomes that scaffold:

• A Recellularization Update
• A Look at More Recellularization Work

As you might guess from those two posts, much of the published recellularization work to date has focused on building new heart valves - or even complete hearts. It seems that any comparatively simple tissue structures are well within reach of present day tissue engineering, however. A decade from now, this sort of replacement for damaged organs will be commonplace.

I think this post over at Pimm might be an example of the entrepreneurial mind ("why would anyone not want this product that I believe in and toil to build?") being confused by the scientific mind ("look at what can be achieved if we go about it the right way"): "How do you interpret the following situation: we have a life extension technologist whose all endeavors is about pushing this issue to its very limits and making things possible but on the other hand this very life extensionist himself is not driven by actually living as long as he can. It seems that SENS theorist Aubrey de Grey [is] taking roughly the above position [by saying] 'I'm actually not mainly driven by a desire to live a long time. I accept that when I'm even a hundred years old, let alone older, I may have less enthusiasm for life than I have today. Therefore, what drives me is to put myself (with luck) and others (lots and lots of others) in a position to make that choice, rather than having the choice progressively ripped away from me or them by declining health. Whether the choice to live longer is actually made is not.'" I've long said that the purpose of longevity science, like most other scientific progress, is to provide new freedoms and choices - the choice to live longer in good health, and the freedom to do so.

Link: http://pimm.wordpress.com/2008/11/18/are-life-extensionists-mainly-driven-by-a-desire-to-actually-live-a-long-time/

Exercise is good for you: "A new study confirms that exercise can reverse the age-related decline in the production of neural stem cells in the hippocampus of the mouse brain, and suggests that this happens because exercise restores a brain chemical which promotes the production and maturation of new stem cells. ... One hypothesis the researchers investigated is that the age-related decline in neurogenesis is tied to a rise in corticosterone in middle age. Elevation of corticosterone has been associated with a drop in the production of new stem cells in the hippocampus. The second hypothesis is that nerve growth factors -- which encourage new neural cell growth but which decrease with age -- account for the drop in neurogenesis. ... production of neural stem cells improved by approximately 200% compared to the middle-aged mice that did not exercise. In addition, the survival of new nerve cells increased by 170% and growth by 190% compared to the sedentary middle-aged mice. ... Based on these results, it appears that nerve growth factor has more to do with these findings than the corticosterone."

Link: http://www.eurekalert.org/pub_releases/2008-11/aps-eib111708.php

A recent review paper on calorie restriction (CR) research makes the case that using smaller, short-lived animals has made it hard to see the detailed picture of CR biochemistry. Only now that larger animals - such as humans and other primates - are in longer-term CR studies is the biochemistry becoming clear.

Endocrine alterations in response to calorie restriction in humans

Prolonged CR has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats and mice. The biological mechanisms of this lifespan extension via CR are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity and functional changes in both neuroendocrine and sympathetic nervous systems.

Most of the difficulty in characterizing the systemic endocrine and neuroendocrine changes with aging and CR is due to the limited capability to collect large and multiple blood samples from small animals, which are usually shorter lived, and hence the most studied.

Ongoing studies of prolonged CR in humans are now making it possible to analyze changes in the "biomarkers of aging" to unravel some of the mechanisms of its anti-aging phenomenon. With the incremental expansion of research endeavors in the area of energy restriction, data on the effects of CR in non-human primates and human subjects are becoming more accessible. Detailed analyses from controlled human trials involving long-term CR will allow investigators to link observed alterations from body composition and endocrine systems down to changes in molecular pathways and gene expression, with their possible effects on aging.

It is interesting to consider that some degree of advances in CR knowledge stem from increasing the size of laboratory animals (and slowing down the pace of data collection) rather than the rapid advances in the tools of biotechnology taking place across the past decade.

From ScienceDaily: "Scientists examined the brains of five deceased people considered super aged because of their high performance on memory tests when they were more than 80 years old and compared them to the brains of elderly, non-demented individuals. Researchers found the super aged brains had many fewer fiber-like tangles than the brains of those who had aged normally. The tangles consist of a protein called tau that accumulates inside brain cells and is thought to eventually kill the cells. Tangles are found in moderate numbers in the brains of elderly and increase substantially in the brains of Alzheimer's disease patients. ... It was always assumed that the accumulation of these tangles is a progressive phenomenon through the aging process. But we are seeing that some individuals are immune to tangle formation and that the presence of these tangles seems to influence cognitive performance." Another type of intracellular aggregate to add to the list for removal by bioremediation.

Link: http://www.sciencedaily.com/releases/2008/11/081116142332.htm

Ouroboros weighs in on a recent demonstration of enhanced longevity via telomerase: "Telomerase is tightly repressed in most somatic cells, and for a very good reason: What do you call a cell with an unlimited division potential that's not a stem cell or germ cell? Usually 'cancer.' ... But what if cancer couldn't form for other reasons? In such a case, we could test the hypothesis that increased regenerative capacity [induced via telomerase] confers increased lifespan. ... why is the effect only on median lifespan? ...Mouse cells have really long telomeres, and telomerase expression is widespread in mouse tissues (though not usually at high enough levels to prevent some telomere shortening at every cell division) ... it makes me wonder what's going on. Could telomerase be doing something else - i.e., something other than lengthening telomeres - that is particularly important in determining median lifespan?" I'd wager on protection of mitochondria, a recently discovered secondary (but possibly more important) action of telomerase.

Link: http://ouroboros.wordpress.com/2008/11/16/telomerase-expression-slows-aging/

If you had to pick the absolute hardest, most challenging goal possible in biomedical science, I think it might be to alter the genes of adult humans so as to safely extend healthy life. Yet this is pretty much the course of the mainstream aging research community - and so I believe they are setting themselves up for maximal expense and minimal progress:

It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

Here's a paper restating that point:

Studies performed on various experimental model systems indicate that genetic interventions can increase longevity, even if in a highly protected laboratory condition. Generally, such interventions required partial or complete switching off of the gene and inhibiting the activity of its gene products, which normally have other well-defined roles in metabolic processes. Overexpression of some genes, such as stress response and antioxidant genes, in some model systems also extends their longevity.

Such genetic interventions may not be easily applicable to humans without knowing their effects on human growth, development, maturation, reproduction and other characteristics. Studies on the association of single nucleotide polymorphisms and multiple polymorphisms (haplotype) in genes with human longevity have identified several genes whose frequencies increase or decrease with age.

Whether genetic redesigning can be achieved in the wake of numerous and complex epigenetic factors that effectively determine the life course and the life span of an individual still appears to be a 'mission impossible'.

Not impossible, just far, far harder than the alternative - which is to avoid changing human genes and metabolism, rather aiming to repair the damage of aging in the biochemistry we have today, thus reversing the effects of aging. That goal allows us to skip over a great many things we don't understand about human biochemistry and avoid many challenging endeavors - and it will produce more valuable and effective therapies into the bargain.

Why take the hard path to extend longevity a little by slowing aging when there is an easier and more direct path towards reversing aging? The debate over the approach to aging research in the next few decades is vitally important to progress in engineered longevity: the presently dominant strategy is an inefficient path forward, and it will eventually produce therapies that do little to help those of us who have grown old waiting for them. That has to change.

An article of quotes from various noted aging reseachers: "Aging is caused by the gradual, lifelong accumulation of a wide variety of molecular and cellular damage ... The free radical theory is the most widely accepted theory of aging. But the idea that aging is caused by one thing is naive. One general theory can never fit all. Clearly, it's the combination of genes that your parents dealt you and the lifestyle choices you make and the environmental toxins one is exposed to. One need only count the number of ways a car will fail to start to appreciate that aging can be caused by a large number of problems. Like any machine, it's going to wear out ... about 25 percent of how a person ages is due to inherited genes. Certain genes control a cell's ability to repair damaged DNA. If those genes are defective, they can't do their job. ... Not everybody will be susceptible to diseases like Parkinson's or cancer as they age. But each one of us will lose muscle mass and muscle strength. That's why this research is so important. Frailty affects all of us."

Link: http://www.mcclatchydc.com/226/story/55835.html

From Science News: "the enzyme telomerase can extend the lifespan of mice by about 24 percent. ... Telomerase lengthens telomeres - the 'caps' on the end of chromosomes that protect DNA from damage. Like burning fuses, telomeres normally get shorter each time that most body cells divide. ... While the enzyme enables cells to keep dividing, it also takes cells one step closer to growing and proliferating out of control - that is, becoming cancerous. Lab animals with extra genes for telomerase often die young from tumors. ... [researchers] engineered mice to have not only an extra copy of the gene for telomerase, but also extra anti-tumor genes to combat the enzyme's cancer-causing potential. In the altered mice, signs of aging such as poor coordination or degraded tissue health were delayed compared to mice that had only the extra copies of anti-tumor genes." Most interesting; you might also want to look at recent research that suggests telomerase operates by protecting mitochondria, and less damaged mitochondria means better preservation of telomeres - but, more importantly for life span, less oxidative stress.

Link: http://www.sciencenews.org/view/generic/id/38552/title/Telomere_enzyme_a_likely_key_to_longevity

From In Search of Enlightenment:

The inborn aging process is now the major risk factor for disease and death after around age 28 in the developed countries

...

Aging is not immutable. The lifespan of organisms such as worms, flies, and mice can be extended by restricting food intake.

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Despite the fact that the vast majority of the world's 6.5+ population will die from age-related causes, aging research is underfunded.

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Even a modest deceleration in human aging could be this century’s most important medical intervention. Furthermore, there is a sound scientific basis for believing this could be achieved. We are closer to this goal than we are to eliminating cancer or heart disease. Furthermore, age retardation could yield health dividends far greater than those that would be achieved by the elimination of any specific disease of aging.

Despite the fact that progress is very visible in advocacy for longevity science, members of the healthy life extension community can't go far wrong in continuing to hit on the basic concepts - like those expressed above.

• Aging isn't written in stone: it can be addressed by future medical science
• Living longer means living in good health for longer, not being older for longer
• Longevity science is plausible and underway, but very underfunded
• We could live much longer in good health, but we have to work to make that goal a reality

It is still the case that comparatively few people think this way, or realize the potential of the next few decades for engineered human longevity. Much more public support, fundraising, and applied medical research will be required to realize this potential - which all starts with a large number of people saying "I want to see this come to pass."

From ScienceDaily: "Until now, creating synthetic cartilage was complex but not impossible. The problem was that it was impossible to imitate the perfection of human cartilage due to the difficulty in orienting the collagen nanofibers [in] a particular configuration: in parallel, in a circle, or crossed. The fibers that form the cartilage that protects the knee are aligned in parallel. ... [Researchers have now] achieved this using the electrospinning method. ... collagen nanofibers are obtained by exposing the collagen to electrical discharges. The collagen is extruded, in the form of a nanofiber thread, through a fine needle and is deposited on an electric collector consisting of two grounded plates. The student placed a nonconductive material between the two conducting plates. The nanofibers aligned on top of each other perfectly in parallel lines between the two conducting plates." Innovations in engineering the simpler forms of human tissue have been arriving more rapidly of late - more scientists are involved, the tools are improving, and the cost of research is falling. This is all groundwork for the next decade and tissue engineering of complex replacement organs.

Link: http://www.sciencedaily.com/releases/2008/11/081113075959.htm

Discovering a stem cell population is the first step to regenerating the tissue they support: "A novel protein marker has been found that identifies rare adult liver stem cells, whose ability to regenerate injured liver tissue has the potential for cell-replacement therapy. ... In the future, this marker will allow for the isolation and expansion of these stem cells, which could then be used to help patients whose livers can no longer repair their own tissue. ... In a healthy liver, proliferation of mature liver and bile-duct lining cells is sufficient to maintain the necessary size and function of the organ. This even works when the liver is confronted with mild and acute injury, but the situation changes when injury to the liver is chronic and severe ... For chronic injury, the liver uses a back-up system that stimulates stem cells to proliferate and eventually differentiate into new liver cells. [Researchers] found that these dual-potential stem cells can be identified and potentially isolated from other liver cells."

Link: http://www.uphs.upenn.edu/news/News_Releases/2008/11/liver-stem-cell-marker.html

You might recall that age-related thinning of the myelin that insulates nerves strongly correlates with declining brain function. Researchers investigating MS are making progress into the mechanisms by which this happens: the protein netrin-1 "is known to guide and direct nerve cell axons to their targets. ... blocking the function of netrin-1 and one of its receptors in adult neural tissue causes the disruption of myelin. ... We've known for just over 10 years that netrin is essential for normal development of the nervous system, and we also knew that netrin was present in the adult brain, but we didn't know why. ... the new findings show that netrin-1 and its receptor are needed to hold paranodal junctions in place, and thereby maintain the structure of myelin. The paranodal junction is a highly specialized region of contact where an oligodendrocyte cell attaches itself to the nerve cell's axon. This juncture acts as a molecular fence, which organizes and segregates the distribution of key proteins along the nerve cells axon and plays an imperative role in the proper conduction of electrical signals along the length of the nerve cell. When the function of netrin-1 and its receptor is disrupted, the organization of this adhesive junction comes apart, disrupting the function of nerve cells in the brain and spinal cord."

Link: http://www.eurekalert.org/pub_releases/2008-11/mnia-itw111208.php

From the Economist: "a second generation of nanoparticles has entered clinical trials. Some are so good at hiding their contents away until they are needed that the treatments do not merely reduce side-effects; they actually allow what would otherwise be lethal poisons to be supplied to the tumour and the tumour only. Others do not depend on drugs at all. Instead, they act as beacons for the delivery of doses of energy that destroy cancer cells physically, rather than chemically. ... To get them to the cancer, you whip up a batch of, say, 80 trillion of them and inject it into the patient's bloodstream. The particles end up in the tumour, rather than in healthy tissue, because tumours have abnormal blood capillaries. The pores in these vessels are larger than those in healthy tissues. Make your nanoshells the right size, then, and they can pass through the capillary pores and lodge in a tumour, but not in a normal organ. Twelve to 36 hours later, when enough shells have accumulated, you insert an optical fibre into the tumour, and deliver an appropriate blast of infra-red. That heats the particles up and cooks the tumour."

Link: http://www.economist.com/science/displayStory.cfm?story_id=12551598

A post at Reddit on predictions for (and arguments against) engineered longevity has been the subject of a long discussion over the past couple of days - a long time for any Reddit post to remain far high enough in the lists to be actively discussed. I think you'll find it an interesting exercise to wander through the hundreds of comments, some of which are reproduced below. The ratio of positive to negative in these sorts of online discussions is growing, I think:

How about this: those who are for living longer, can do so, and those against, can ignore the treatments?

...

Obviously entirely new systems would come into play. We can't see what they will be now, but they will be self-evident once they evolve. To extrapolate current systems into extremely long lives, where people could keep their health and strength and work at what they want far longer than they do now, is bootless. Maybe with a greater time span of non-age-ossified brains people would have time to emotionally mature more than they do now, and make better decisions. Certainly there would be time to use the power of compounding interest to far greater advantage than is possible now. With youth and vigor extended, the expansion of life-possibilities would be immense, and would extend into spaces we can't even see.

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I think that once we defeat aging, we can work on those other problems which are an order of magnitude less bad.

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Other definitions that would change are old person and young person. The idea is to lengthen that period of life where you both can and wish to do things, not extend fogeyhood into forever. So if someone looks thirty but is far older, what does that do to our current paradigm of the stages of life? We'll make up a new one, gradually and fitfully. Probably it won't be comfortable, but change seldom is.

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Who cares about advantage to our species? I only care about advantage to actual, living people. If there were no more humans, ever, but everyone alive today had a better life, I would consider that a net positive.

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Leon Kass, the former head of Bush's Council on Bioethics, insists that 'the finitude of human life is a blessing for every human individual' ... He's just confused. Obviously, the finitude of his life is a blessing for all of us, but that's not true for everyone.

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I, for one, would like to live as long as I want. For those of you who would insist I die, what's wrong with you? You actually want people to die? You want to lose the people you love? Really?

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I saw a comment somewhere that said that it is new generations that bring change, and that people need to die. WRONG. Just think about living more than ten times longer than your current expectancy. One person can learn for much longer, work for longer, and continue to better him or herself. A thousand [years]. You could get alot done, and teach alot of other people, without leaving the next generation to pick up where you left off every 50-80 years.

The tide of educated opinion on engineered longevity has come a long way in the seven years I've been writing on this topic. A great deal of work remains to be accomplished in laying the foundations for truly massive research and development fundraising for longevity science, but the signs of progress exist - matters are further ahead than they were.

Autoimmune conditions such as rheumatoid arthritis result from errant cellular behavior in the immune system - immune cells are instructed to attack healthy tissue rather than performing beneficial tasks such as hunting down cancerous or senescent cells. As researchers become better at controlling cellular behavior, reprogramming cells for desired tasks by sending the right chemical signals, this type of disease will become a treatable nuisance rather than a life-destroying condition. Here is an example of the sort of work presently taking place:

Normally, immune cells develop to recognise foreign material - antigens; including bacteria - so that they can activate a response against them. Immune cells that would respond to 'self' and therefore attack the body's own cells are usually destroyed during development. If any persist, they are held in check by special regulatory cells that provide a sort of autoimmune checkpoint. A key player in these regulatory cells is a molecule called Foxp3.

...

Dr. Alexander Betz, Group Leader at the MRC laboratory, explains: "We have generated a modified form of Foxp3 which can be introduced into immune cells using genetic engineering techniques and then activated by a simple injection. When administered to and activated in animal models of arthritis, the modified cells inhibit or even reverse the disease process."

Further work is now aimed at elucidating the detailed molecular mechanisms involved in Foxp3 function, and transferring the experimental approach to human cells.

It's a road of a decade or more in the present over-regulated environment to move from a promising therapy in mice to human therapy in late clinical trials. But many groups are working on the reprogramming of immune cells: it is a broad field of endeavor, and advances in the state of the art made by any one group benefit all the others.

The fifth Hourglass blog carnival on the science of aging and longevity is hosted at psique: "It seems that prohibiting olfaction pharmacologically, by ablation of olfactory regions or genetic manipulation can result in an extension of life span, at least in C. elegans and Drosophila. Interestingly, [calorie restriction (CR)] and blocking olfaction appear to act in synergy, increasing life span most effectively when applied together, while exposure to food odours is capable of reducing the positive effects of CR to some extent. The obvious question is whether losing the sense of smell could also extend life span in humans. Failing the possibility of clogging up people's noses, Plunet proposes a straightforward test - one could compare the life span of anosmics, who are people that have chronically lost their ability to smell for a variety of reasons, to carefully matched controls."

Link: http://psiqueii.blogspot.com/2008/11/hourglass-v.html

Via the Daily Galaxy: biomedical gerontologist "Aubrey de Grey has famously stated, 'The first person to live to be 1,000 years old is certainly alive today ... whether they realize it or not, barring accidents and suicide, most people now 40 years or younger can expect to live for centuries.' Perhaps de Gray is way too optimistic, but plenty of others have joined the search for a virtual fountain of youth. In fact, a growing number of scientists, doctors, geneticists and nanotech experts - many with impeccable academic credentials - are insisting that there is no hard reason why ageing can't be dramatically slowed or prevented altogether. Not only is it theoretically possible, they argue, but a scientifically achievable goal that can and should be reached in time to benefit those alive today. ... But not everyone thinks ageing can or should be cured. Some say that humans weren't meant to live forever, regardless of whether or not we actually can." From there the piece leads into a rogue's gallery of quotes from pro-death advocates who want to see us all age, decay, and slowly, painfully die.

Link: http://www.dailygalaxy.com/my_weblog/2008/11/can-humans-live.html

Under at least some circumstances, the practice of calorie restriction appears to increase regenerative capacity - in addition to the range of other benefits it brings to health and longevity. It makes you wonder just how many other ways we harm and hinder ourselves by eating more than is necessary. From a recent paper (for which the full PDF version is freely available):

Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, the functional roles of CR in regulation of [regrowth of blood vessels] in response to ischemia have not been examined. Here, we investigated whether CR modulates vascular response.

By examining varying strains of mice, the researchers demonstrated that calorie restriction greatly improves regrowth of blood vessels - and also identified components of the biomechanisms which drive this improvement. The enzyme AMPK - already known to increase with CR and to be important in the benefits provided by exercise - is one of the biochemicals involved in this increased regenerative capacity.

Based on that evidence, calorie restriction mimetic drugs might turn out to have many more diverse applications in medicine than first suspected.

A very readable overview of recent research from PLoS Biology: "When resources are short, growing organisms face an existential choice: should you ignore the shortage and hope for better times soon, or scale back and live within your limited means? And if you do scale back, will there be any payoff later in life? For animals, these choices are played out hormonally, with environmental fluctuations leading to internal rearrangements in endocrine signal and response throughout the growing body. In mammals, two principal hormones - growth hormone (GH) and insulin-like growth factor 1 (IGF-1) - promote growth. Remarkably, inhibiting one or both of these two not only retards growth, but also extends lifespan, not just in lab animals, but possibly also in people: mutations that reduce the function of the IGF-1 receptor have recently been discovered in centenarians (who are also short). Growth occurs throughout the body, and receptors for IGF-1 are found in every organ on virtually every cell. But [researchers have now shown] that it is the IGF-1 receptors in the brain that set the pattern for growth and lifespan."

Link: http://dx.doi.org/10.1371/journal.pbio.0060274

An interesting, if flawed, article on the singularity and engineered longevity via the Korean OhmyNews: "Amidst the rapid changes of society ranging from general advances in science and technology to politics and social policy, with respect to knowledge, there is an emergent issue that promises to radically change our lives and our reality. It is predicted that within less than 20 years, the human lifespan will be extended to perhaps 150 or more years. Scientists and futurists on the cutting edge of thought about science and society believe that the increase in lifespan is one step towards what will be known as the Singularity, at which time, life might be extended indefinitely depending upon environmental conditions. The Singularity is the term used for a technological integration unheard of; it is a theoretical future point of unprecedented technological progress, caused in part by the ability of machines to improve themselves using artificial intelligence. ... it was just over a hundred years ago, when the human lifespan began to double to what it is today. It is possible that most people who lived only to 35 years of age thought that to live to 72 years would be too long and that they would be too tired. Nevertheless, we have adjusted and found life to be meaningful, even in our current 'long' life of 72 years."

Link: http://english.ohmynews.com/ArticleView/article_view.asp?menu=A11100&no=384115&rel_no=1

You might recall the links drawn between the protein alpha-synuclein and development of Parkinson's disease:

Patients with Parkinson's disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.

It looks possible that the reason behind all this clumping synuclein is chronic inflammation - that catch-all bugbear that appears to contribute to all the major diseases and degenerations of aging. As we get older, our immune system slips into faulty states that lead to rising levels of inflammation, damaging our biochemistry in many different ways such that we degrade that much faster. This might be one of those ways:

Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats:

The Lewy body is a pathological hallmark of Parkinson's disease. It has been revealed that the Lewy body contains nitrated alpha-synuclein which is prone to [forming aggregates]. We tested the hypothesis that aging may enhance nitration of alpha-synuclein due to an exaggerated neuroinflammatory reaction ... greater nitration of proteins like alpha-synuclein occurs in the substantia nigra of 16-month-old rats versus 3-month-old rats ... These results imply that an exaggerated neuroinflammatory response that occurs with aging might be involved in the increase in prevalence of neurodegenerative diseases like Parkinson's disease.

Whether or not this particular linkage is established beyond doubt, there is more than enough evidence demonstrating chronic inflammation to be bad for your health and longevity. Making sensible life choices to minimize inflammation as best you can is a sensible response to the research findings amassed to date.

From the Exchange Morning Post, a statist, public funding viewpoint on longevity science: "Learning how to turn back time - or at least how to slow the aging process - may be more important for improving our overall health than the discovery of a cure for cancer ... there are real, tangible benefits, for society as well as individuals, to slowing down the aging process. 'By extending the life span, people would remain in the workforce longer, personal income and savings would increase, age entitlement programs would face less pressure from shifting demographics, and national economies would flourish' ... almost half of the current population over 75 years old is limited in their activity by chronic conditions, with costs to society set to rise dramatically ... Given the current predicament we face, we can't ignore the call to tackle aging more aggressively. To those who ask: 'Can we really afford to invest more in such research?' we can reply: 'Can we really afford not to tackle aging?' ... the greatest obstacle will be convincing the general public that slowing the aging process is both feasible and deserving of a larger share of the funds available for scientific research."

Link: http://www.exchangemagazine.com/morningpost/2008/week45/Friday/1107018.htm

A good article on cryonics from Engineering and Technology: "The field of cryonics, which made its debut in the 1960s, continues to push the envelope and search for a solution to death. The process consists of preserving legally dead humans or pets at very low temperature (below -130C) in the hope that future science can restore them to life, youth, and health. ...The advancement of medicine and science is so much faster than it used to be. Science fiction is becoming science fact on a daily basis. All of a sudden, cryonics doesn’t look quite so far-fetched. ... Most cryonicists believe reanimations will occur within 50 to 100 years for those currently being cryopreserved. ... Within that time frame, virtually all current diseases should be curable and elderly people can probably be rejuvenated to a youthful condition. ... With full disclosures and signed consent, [cryonics] is highly ethical. When you think about the grand scheme of things, cryonics is a lot more conservative than burial or conventional cremation. ... Tissue preserved at the temperature of liquid nitrogen does not deteriorate, even after centuries of storage. Therefore, if current medical technology can’t keep us alive, we can instead choose to be preserved in liquid nitrogen, with the expectation that future medical technology should be able to reverse any cryopreservation injury and restore good health. If sceptics don’t want to pursue this area, that’s fine, but I ask them not to interfere with my own efforts to save the lives of myself and the people I love."

Link: http://kn.theiet.org/magazine/issues/0819/science-without-deadline.cfm

Another modest advance in stem cell science is noted in a Japanese paper, one of many on the way to developing a comprehensive repair kit for the aging human body:

Researchers have created cerebral tissue from human embryonic stem [ES] cells, an achievement thought likely to lead to a breakthrough in tackling Alzheimer's disease as well as pave the way for new regenerative treatments and other drugs, The Yomiuri Shimbun has learned.

Yoshiki Sasai, a group director of the RIKEN Center for Developmental Biology, said the tissue also can be created using induced pluripotent stem (iPS) cells. ... Sasai's group solidified about 3,000 human ES cells into balls 0.2 millimeter in diameter, added material that helped them develop into nerve cells, and cultured them for 50 days. The balls grew into mushroomlike objects one millimeter to two millimeters in diameter. Four types of nerve cells arranged in layers, which appeared very similar to those found in the cerebral cortex of a fetus, were observed inside each of the mushroom-shaped objects. The nerves also sent out electrical signals and showed other functional capacity.

Sasai said brain tissue can be created in the same way using human iPS cells. He said he planned to attempt to create six-layered tissue, far closer in structure to adult brain tissue. "This achievement will enable us to forge ahead with research into the adverse reactions caused by drugs as well as develop new vaccines," Sasai said. "It will lead to treatment capable of regenerating cerebral nerves."

There is much that could be done to lengthen life with the fully developed technology to generate new, undamaged tissue as needed. For all that, it is far from the be-all and end-all of longevity science - just one necessary technology of many - but it is encouraging to see the pace of development accelerating in the tissue engineering field in recent years.

The possibilities of bioengineering are endless, and one of the most energetic branches of the research community is involved in developing methods of precisely targeting therapies: "MIT engineers have outfitted cells with tiny 'backpacks' that could allow them to deliver chemotherapy agents, diagnose tumors or become building blocks for tissue engineering. ... The polymer backpacks allow researchers to use cells to ferry tiny cargoes and manipulate their movements using magnetic fields. Since each patch covers only a small portion of the cell surface, it does not interfere with the cell's normal functions or prevent it from interacting with the external environment. ... researchers worked with B and T cells, two types of immune cells that can home to various tissues in the body, including tumors, infection sites, and lymphoid tissues - a trait that could be exploited to achieve targeted drug or vaccine delivery. ... The researchers found that T cells with backpacks were able to perform their normal functions, including migrating across a surface, just as they would without anything attached. By loading the backpacks with magnetic nanoparticles, the researchers can control the cells' movement with a magnetic field."

Link: http://www.eurekalert.org/pub_releases/2008-11/miot-mct110508.php

One approach to the issue of declining naive T-cells with age - and consequence failure of the immune system - is to boost production by manipulating the thymus: "a key gene may be crucial to maintaining the production of the thymus and its disease-fighting T-cells after an animal's birth. The discovery could help scientists find out how to turn the thymus back on so it could produce T-cells long after it normally shuts down most of its function, which, for humans, occurs by early adulthood. If the finding leads to further ways to manipulate the gene, the result could be a new avenue for the body to fight disease more effectively as the body ages. ... Such things as infectious diseases, inflammation and heart problems are all related to immune response. You don't have to think far to see how understanding the effect of this gene could affect the quality of life for older people and others as well. ... If [physicians] were able selectively to turn T-cell production back on, then many diseases that currently afflict older people could become manageable if not, in cases, entirely absent."

Link: http://www.uga.edu/news/artman/publish/081106_Manley_Research.shtml

An interview with one of the pillars of that nebulous and hard to define thing, the transhumanist community:

I'd make a distinction between the "Transhumanist movement" and a larger group of people - many of whom probably read io9 (and Boing Boing, Slashdot, Wired, and on and on). There are lots of people out there who are fully cognizant of transhumanist views, and who are interested in - and possibly supportive of, or ambiguously curious about - say, cyborg body enhancements, or memory enhancement, or ending aging. And in fact, my friend Ramez Naam argues that anybody who wears glasses or takes birth control pills is a transhumanist and so he refuses the label as sort of banal.

If you look around at the serious efforts to make progress in longevity science or other means of postponing permanent death, you'll find members of the transhumanist community involved and amongst the most vocal supporters: the Methuselah Foundation; Alcor and the Cryonics Institute; the Immortality Institute. Similarly in the fields of strong artificial intelligence and advanced nanotechnology - organizations like the Singularity Institute, the Future of Humanity Institute and the Center for Responsible Nanotechnology are outgrowths of the transhumanist community of the 80s and 90s. Collectively these organizations and others have raised tens of millions of dollars over the years.

The transhumanist community that was - once upon a time - clearly defined at the edges, and largely in the business of talking rather than doing, actually attained its immediate goals. This is to say its members and the general progress of technology brought the transhumanist view to a much broader audience. Ideas once strange and unthinkable became accepted as plausible extrapolations of present trends; which was always the case, but some people can see farther ahead than others. During this process, the transhumanist community became diffuse at the edges and no longer ahead of its time; most of the core ideas and goals spread into the mainstream, changing along the way. That's the best end possible for any subculture, a victory in the sense that all of these ideals - bioengineering, the defeat of aging, enormously lengthened healthy life spans, artificial beings, molecular manufacturing, and much more - will come to pass. Too many people are thinking about these goals now for any but the impossible to vanish from the horizon.

It's just a question of when it all comes to pass - which is a very big question when it comes to the development of medical technologies that can rescue us from aging to death. Soon enough, or too late? What are you doing to help things along?

Many research groups are working on ways to boost the effectiveness of an exhausted immune system - due to either chronic viral infection or aging - without necessarily aiming to address the root causes: "In contrast to most normal somatic cells, which show little or no telomerase activity, immune cells up-regulate telomerase in concert with activation. Nevertheless, during aging and chronic HIV-1 infection, there are high proportions of dysfunctional [immune cells] with short telomeres ... exposure of CD8(+) T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) modestly retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity. The enhanced antiviral effects were abrogated in the presence of a potent and specific telomerase inhibitor, suggesting that TAT2 acts primarily through telomerase activation. Our study is the first to use a pharmacological telomerase-based approach to enhance immune function."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18981163

Chronic inflammation, a source of age-related cellular and molecular damage, is linked to most of the common age-related conditions. It might be thought of as a form of rust that hastens the failure of the machinery. Here, researchers show how inflammation causes one specific form of cancer: "evated levels of a single proinflammatory cytokine, an immune system protein called interleukin-1 beta (IL-1beta), can start the progression towards stomach cancer. ... accumulation of IL-1beta, which is induced by infection with the bacterium Helicobacter pylori (H. pylori) in the gastrointestinal tract, is a significant contributor to the onset of stomach cancer ... We show in this study that IL-1beta works by activating a type of white blood cell known as myeloid derived suppressor cells (MDSCs), which in our study appeared to be strongly pro-inflammatory. Blocking IL-1beta or the myeloid (MDSCs) cells may represent a potential strategy to prevent stomach cancer ... these findings help to explain why only a small percentage of those with H. pylori infection go onto develop stomach cancer - a genetic predisposition for high expression levels of proinflammatory cytokines." So a ugly feedback loop of accelerating inflammation and damage is kicked off by an initial event and predisposition to reach the threshold that will activate that loop.

Link: http://www.eurekalert.org/pub_releases/2008-11/cumc-rdh110508.php

In recent years researchers have been sketching a convincing picture of causal links between shortened telomeres, damaged mitochondria, rising oxidative stress, and the degenerations of aging. This is important because researchers are on the verge of being able to both manipulate telomere length and repair or replace damaged mitochondria. Here are some introductory posts from the archives:

• Linking Telomere Shortening and Mitochondrial Damage?
• More On Telomere Shortening and Mitochondrial Dysfunction
• Filling in the Gaps Between Telomeres and Mitochondria in Aging

Following on from that, a paper that adds a little more to the pile of evidence by demonstrating a correlation between different forms of genes associated with oxidative stress, shortened telomeres, and measurable symptoms of aging:

Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey

Telomere shortening is a biomarker of cellular senescence and is associated with a wide range of age-related disease. Oxidative stress is also associated with physiological aging and several age-related diseases. Non-human studies suggest that variants in oxidative stress genes may contribute to both telomere shortening and biological aging. We sought to test whether oxidative stress-related gene polymorphisms contribute to variance in both telomere length and physical biomarkers of aging in humans.

Telomere lengths were calculated for 190 (82 men, 108 women) participants aged 79 years and associations with 384 SNPs, from 141 oxidative stress genes, identified 9 significant SNPS, of which those from 5 genes [had] robust associations with physical aging biomarkers, respiratory function or grip strength. Replication of associations in a sample of 318 (120 males, 198 females) participants aged 50 years confirmed significant associations for two of the five SNPs on telomere length.

These data indicate that oxidative stress genes may be involved in pathways that lead to both telomere shortening and physiological aging in humans. Oxidative stress may explain, at least in part, associations between telomere shortening and physiological aging.

Which leads nicely into the role of mitochondrial damage in rising levels of oxidative stress with age, thereby reinforcing the evidence for accumulated mitochondrial damage as the important root cause of telomere shortening. All the more reason to support research aimed at repairing that damage.

From EurekAlert!: "A drug designed to specifically hit a protein linked to the life-extending benefits of a meager diet can essentially trick the body into believing food is scarce even when it isn't .. SRT1720, which acts through the protein SIRT1, enhances running endurance in exercised mice and protects the animals against weight gain and insulin resistance even when they eat a high-fat diet, the researchers report. The drug works by shifting the metabolism to a fat-burning mode that normally takes over only when energy levels are low. ... It also helps lay to rest a long-standing controversy in the scientific world over the metabolic benefits of [resveratrol]. Resveratrol also acts on SIRT1, but its influence on other metabolic actors had left room to question exactly how it works. .. There has been a lot of controversy in the field about resveratrol action. We find that the majority of the biology of resveratrol can be ascribed to SIRT1. ... While SIRT1 might not explain all of resveratrol's effects, the new results suggest that the central metabolic protein is responsible for about '80 percent of the picture.'" Which suggests that resveratrol and SRT1720 are not capturing all of the biochemical benefits of calorie restriction.

Link: http://www.eurekalert.org/pub_releases/2008-11/cp-dml102808.php

The fifth Hourglass blog carnival on aging and longevity science draws near - remember to send in your submissions. "Hourglass is a monthly blog carnival devoted to biogerontology. Its main purpose is to provide a regular showcase for the growing number of excellent blog posts about the biology of aging. We are soliciting entries in the general subject area of aging and biogerontology: Topics of posts should have something to do with the biology of aging, broadly speaking - including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway. ... Just about the only sorts of things we'll turn away are quackery and promotions of commercial products (including brazenly for-profit websites of no redeeming scientific value). So, no growth hormone commercials or glowing reviews of your own book, please. ... Submissions should be emailed to [hourglass.host][at][gmail][dot][com]."

Link: http://ouroboros.wordpress.com/2008/11/03/hourglass-v-submissions-wanted/

Mitochondria are the power plants of your cells: they toil to turn food into ATP, used as fuel by the cell. In recent years, the eye of the research community has turned towards the process of mitochondrial uncoupling, whereby the processing of food is uncoupled from the generation of ATP. The result is less ATP and more energy in the form of heat - this is a part of the temperature regulation process in mammals, for example. It also appears to be important in calorie restriction, and therefore possibly important to longevity and aging.

Research is still in full swing, however, and the vision of how mitochondrial uncoupling fits into the big picture of metabolism and aging is present incomplete. A number of natural uncoupling proteins (such as UCP1, UCP2, and UCP3) as well as manufactured uncoupling drugs like DNP have been investigated with contradictory results. The following items provide a sampling of the confusion.

Mitochondrial Uncoupling and Tissue Aging:

Mitochondrial uncoupling is much as it sounds; a feedback mechanism in which processing is disconnected from ATP production; energy from food goes elsewhere, as heat for example. Because this affects free radical production, it seems to be important in tissue aging: "Faster aging is predicted in more active tissues and animals because of greater reactive oxygen species generation. Yet age-related cell loss is greater in less active cell types, such as type II muscle fibers. Mitochondrial uncoupling has been proposed as a mechanism that reduces reactive oxygen species production and could account for this paradox between longevity and activity. ... These results reject respiration rate as the sole factor impacting the tempo of cellular aging. Instead, they support mild uncoupling as a mechanism protecting mitochondrial function and contributing to the paradoxical longevity of the most active muscle fibers.

More Building of Better Mice:

We were a little bit disappointed because we had hoped uncoupling in muscle would slow aging, but maximum lifespan didn't increase. However, the odds of reaching that maximum lifespan did improve in the uncoupled mice. ... mice with [increased UCP1] were more likely to live longer, presumably because they were able to avoid age-related diseases. One result appeared in all of the experiments: Decreasing body fat and inflammation in the animals by accelerating muscle metabolism with uncoupling protein delayed death and diseases, including atherosclerosis, diabetes, hypertension and even cancer.

Ouroboros On Mitochondrial Uncouplers:

The DNP treated mice ate the same amount of food as control mice but had lower body mass [and] showed many phenotypes observed in calorie restricted mice. Like CR mice, DNP treated mice had higher rates of respiration with lower production of ROS. ... Most importantly, DNP treated mice showed an extended lifespan. This study suggests that mitochondrial uncouplers are an effective mimic of calorie restriction and might be a realistic therapeutic intervention for delaying aging and extending lifespan.

Uncoupling extends life, except that it doesn't - depending on how you go about it, which suggests that greater complexity is, as always, hidden under the hood. I noticed a paper today that adds weight to the negative side, though in a way that leaves the door open for further ambiguity:

Characterization of survival and phenotype throughout the life span in UCP2/UCP3 genetically altered mice:

In the present investigation we describe the life span characteristics and phenotypic traits of ad libitum-fed mice that overexpress UCP2/3 (Positive-TG), their non-overexpressing littermates (Negative-TG), mice that do not express UCP2 (UCP2KO) or UCP3 (UCP3KO), and wild-type C57BL/6J mice (WT-Control). We also included a group of C57BL/6J mice calorie-restricted to 70% of ad libitum-fed mice in order to test partially the hypothesis that UCPs contribute to the life extension properties of CR.

Mean survival was slightly, but significantly, greater in Positive-TG, than that observed in Negative-TG or WT-Control; mean life span did not significantly differ from that of the UCP3KO mice. Maximal life span did not differ among the ad libitum-fed groups. Genotype did not significantly affect body weight, food intake, or the type of pathology at time of death.

Calorie restriction increased significantly mean and maximal life span, and the expression of UCP2 and UCP3. The lack of difference in maximal life spans among the Positive-TG, Negative-TG, and UCP3KO suggests that UCP3 does not significantly affect longevity in mice.

So, to summarize that last paper: calorie restriction increases UCP2 and 3 - which is one of the reasons that aging researchers become interested in the uncoupling process - but getting rid of UCP2 or UCP3 entirely doesn't seem to do much. There is an agreement that more uncoupling helps resist age-related degeneration to some degree without extending maximum species longevity. Questions remain as to whether uncoupling is important in calorie restriction, and how DNP is extending longevity if uncoupling proteins have no effect in that regard.

From the MIT Technology Review: "Engineering heart tissue presents particularly tough problems for researchers, since the heart is an active organ ... scaffolds designed for other kinds of tissues did not have the right mechanical properties for heart tissue. Heart tissue must be flexible enough to change shape as the heart contracts, but also strong enough to withstand the intense forces generated by these contractions. ... The researchers designed the scaffold to encourage cells to align themselves in the same direction to better mimic this property of natural heart muscle tissue. Using a laser cutting technique, they created a pattern of oblong holes in the polymer; the result is a flexible, honeycomb-like structure that is stiffer in one direction than another. ... just as rowers line up in one direction to propel a boat forward, 'all the heart muscle cells in a given region have to be lined up and contracting in the same direction' in order for the heart to beat efficiently. The honeycomb-like scaffold [represents] a 'substantial jump' toward that goal ... If we had a biodegradable biomaterial, which had beating heart cells, we might be able to return function to [damaged parts] of the heart."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=21625&channel=biomedicine§ion=

As the science advances, these articles get more positive. Recall the ridicule heaped upon the practice of calorie restriction even just a few years ago. "Some people are doing it strictly to enhance longevity. Others do it to avoid age-related disease, or because they already have diabetes, high cholesterol or clogged arteries and want to clean up their bodies by using diet. ... In rich countries, 90 percent of the population probably eats, on average, about 50 percent too much. ven if they were to reduce their calorie intake by half, they would still only be at baseline ... A wealth of scientific evidence has confirmed that maintaining that balance helps prevent type-2 diabetes, cardiovascular disease and cancer. But experiments with both animals and humans have also shown that pushing one's calorie intake 10 to 20 percent below that baseline threshold -- without lowering nutrients -- may provide additional health advantages. ... Will this add 10 years to your life? Nobody knows. But one thing is sure -- calorie restriction will help you reach your maximum lifespan potential, which is different for all of us depending on our genetic profile."

Link: http://afp.google.com/article/ALeqM5i8eh2v_zPiht03CZWKvVulsaPYqA