The Lifespan Observations Database

Over the years a great many studies have been conducted using laboratory animals with the aim of recording changes in life span that result from drugs, genetic alterations, and environmental conditions. The shorter-lived and less costly to maintain the species, the more studies there are - probably thousands for nematode worms, for example.

If you feel like browsing through the stacks to gain an impression of the work that has taken place over the past few decades, allow me to point you to the Lifespan Observations Database, which "collects published lifespan data across multiple species." It isn't a complete reference, but contains thousands of entries. Here are counts by species:

Browsing the entries shows change in life span and other items of interest. For example, picking one at random for mice:

Species: Mus musculus

Strain: 129 SvEv

Lifespan: 815 days

Reference Lifespan: 761 days

Lifespan Change: 7.1%

Lifespan Measure: median

Lifespan Effect: increased

Significance: significant

Citation: Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. (1999). The p66shc adaptor protein controls oxidative stress response and life span in mammals.. Nature 402: 309-13. [pubmed]

Details: Mice mutant for p66shc have increased life span of 30%. Homozygous mutants are longer-lived than heterozygotes.

Other phenotypes: p66shc -/- cells are more resistant to apoptosis induced by hydrogen peroxide and UV light. p66shc -/- mice are more resistant to oxidative stress induced by paraquat,

You might compare this with some of the other online databases that have been mentioned here in the past, and are interesting to look through:

A Protein Map for Mitochondrial Function

Mitochondria and the damage they accumulate as a result of their operation are important in the process of degenerative aging. Further, declining mitochondrial function is a feature in many age-related conditions. Many researchers focus their studies on mitochondrial function, differences in mitochondria between species and how that determines life span, alterations in mitochondrial operation that occur in connection with life-extending interventions in laboratory animals, and similar areas. These days that often involves producing a great deal of data for later analysis:

In efforts to understand what influences life span, cancer and aging, scientists are building roadmaps to navigate and learn about cells at the molecular level. To survey previously uncharted territory, a team of [researchers] created an "atlas" that maps more than 1,500 unique landmarks within mitochondria that could provide clues to the metabolic connections between caloric restriction and aging.

The map, as well as the techniques used to create it, could lead to a better understanding of how cell metabolism is re-wired in some cancers, age-related diseases and metabolic conditions such as diabetes. "It's really a dynamic atlas for regulatory points in mitochondrial function - there are many interesting avenues that other scientists can follow up on. It could take years for researchers to understand what it all means, but at least now we have a list of the most important players."

[The scientists] conducted earlier research on the mitochondrial protein Sirt3, where they suggested a link between Sirt3 and the benefits of caloric restriction in situations such as the prevention of age-related hearing loss. The new research [more] broadly identifies pathways in mitochondria that could be behind the rewiring of metabolism. Their work uncovered regulatory processes that maintain mitochondrial health, control cells' ability to metabolize fat and amino acids, as well as stimulate antioxidant responses.


A Method of Determining Lobster Age

Lobsters are one of the small number of species that might be ageless, or at the very least age very slowly and exhibit little to no decline until very late life. There is little money for aging research in lobsters, however: until now researchers possessed no way to accurately determine the age of a lobster, and no good estimate as to average or maximum life span in these species. This new development should hopefully lead to a better grasp of the degree to which lobsters do or do not age, and pin down numbers for life span:

For the first time, scientists have figured out how to determine the age of a lobster - by counting its rings, like a tree. Nobody knows how old lobsters can live to be; some people estimate they live to more than 100.

Scientists already could tell a fish's age by counting the growth rings found in a bony part of its inner ear, a shark's age from the rings in its vertebrae and a scallop or clam's age from the rings of its shell. But crustaceans posed a problem because of the apparent absence of any permanent growth structures. It was thought that when lobsters and other crustaceans molt, they shed all calcified body parts that might record annual growth bands.

[Researchers] took a closer look at lobsters, snow crabs, northern shrimp and sculptured shrimp. They found that growth rings, in fact, could be found in the eyestalk - a stalk connected to the body with an eyeball on the end - of lobsters, crabs and shrimp. In lobsters and crabs, the rings were also found in the so-called "gastric mills," parts of the stomach with three teeth-like structures used to grind up food.


The Association of Reduced Thyroid Function With Longevity

The thyroid gland carries out a number of important functions, responding to changing conditions by varying its production of thyroid hormones that alter the behavior of metabolism elsewhere in the body. The behavior of the thyroid changes with age, but in a sufficiently subtle and varying manner to make its role in aging a challenging thing to study. Nonetheless, there is at this point enough data to conclude that some forms of reduced thyroid function tend to associate with increased longevity in a number of species.

This also ties in with other lines of research. Calorie restriction, for example, reduces thyroid hormone levels in the course of extending life and improving health. A predisposition to low thyroid hormone levels appear to be inherited in long-lived families. And so forth.

Here is a short and very readable open access review paper that looks at thyroid function in the context of aging and longevity:

The thyroid gland and the process of aging; what is new?

The endocrine system and particular endocrine organs, including the thyroid, undergo important functional changes during aging. The prevalence of thyroid disorders increases with age and numerous morphological and physiological changes of the thyroid gland during the process of aging are well-known.

Intriguingly, decreased thyroid function, as well as thyrotropin (TSH) levels - progressively shifting to higher values with age - may contribute to the increased lifespan. [The] most striking findings concerning potential contribution of TSH and thyroid hormones to lifespan regulation, were obtained in the studies performed on centenarians (and almost centenarians). In 2009, Atzmon et al. published the results of studies on thyroid disease-free population of Ashkenazi Jews, characterized by exceptional longevity (centenarians). They have observed higher serum TSH level in these subjects as compared to the control group. [Moreover], the authors have observed an inverse correlation between FT4 and TSH levels in centenarians and [controls], and finally, they have distinctly concluded that increased serum TSH is associated with extreme longevity

The above-mentioned inverse correlation between FT4 and TSH in centenarians may suggest a potential role of decreased thyroid function in lifespan regulation, leading to remarkable longevity. Such a hypothesis seems to have been confirmed by the findings obtained in the Leiden Longevity Study, demonstrating the associations between low thyroid activity and exceptional familial longevity.

It should be stressed that reduced thyroid function with low levels of T4 is associated with extended longevity also in animals. For example, a very severe thyroid hypofunction with reduced core body temperature, as observed in Ames dwarf (df/df) and Snell mice [is] considered to substantially contribute to remarkable longevity in these rodents. [The] findings in animals are consistent with the results obtained in humans and may confirm a relevant role of thyroid hypofunction in lifespan extension.

Kynurenine-Tryptophan Metabolism and Fly Longevity

Metabolism is a very complex set of overlapping mechanisms, feedback loops, and networks of protein interactions. So even if there are only a few core methods of extending life by altering metabolism in a species, we should expect to see scores of different ways to trigger some or all of that alteration - and with widely varying side-effects. This is one of the present challenges facing those researchers who focus on how metabolism and genes determine natural variations in longevity: mapping it all for any one species is a vast task.

Here is one example of ongoing research drawn from among the many ways to make flies live longer:

Up-regulation of kynurenine (KYN) pathway of tryptophan (TRP) was suggested as one of the mechanisms of aging and aging-associated disorders. Genetic and pharmacological impairment of TRP - KYN metabolism resulted in prolongation of life span in Drosophila models.

Minocycline, an antibiotic with anti-inflammatory, antioxidant and neuroprotective properties independent of its antibacterial activity, inhibited KYN formation from TRP. Since minocycline is the only FDA approved for human use medication with inhibitory effect on TRP - KYN metabolism, we were interested to study minocycline effect on life- and health-spans in Drosophila model.

Minocycline prolonged mean, median and maximum life span of wild-type Oregon Drosophila melanogaster of both genders [and] might be a promising candidate drug for anti-aging intervention. [The] role of TRP - KYN metabolism in the mechanisms of minocycline-effect on life- and health-span might be elucidated by the future assessment of minocycline effects in Drosophila mutants naturally or artificially knockout for genes impacting the key enzymes of KYN pathway of TRP metabolism.


Rejuvenation in the Jellyfish Turritopsis Dohrnii

Aging has evolved despite its terrible effects on the individual because over the long run it is highly effective in the evolutionary competition that takes place in most ecological niches - any amount of hardship and pain can be selected for if it means that genes are more effectively propagated. There are exceptions, however, in the form of successful species that do not appear to age; especially in the case of lower animals we can find life histories that look nothing like our own. Take the hydra, for example, or here the tiny jellyfish Turritopsis dohrnii:

[An individual Turritopsis dohrnii appears to reverse its life cycle], growing younger and younger until it reached its earliest stage of development, at which point it began its life cycle anew. ... We now know [that] the rejuvenation of Turritopsis dohrnii and some other members of the genus is caused by environmental stress or physical assault. We know that, during rejuvenation, it undergoes cellular transdifferentiation, an unusual process by which one type of cell is converted into another - a skin cell into a nerve cell, for instance.

But we still don't understand how it ages in reverse. There are several reasons for our ignorance, all of them maddeningly unsatisfying. There are, to begin with, very few specialists in the world committed to conducting the necessary experiments. ... The genus, it turns out, is extraordinarily difficult to culture in a laboratory. It requires close attention and an enormous amount of repetitive, tedious labor; even then, it is under only certain favorable conditions, most of which are still unknown to biologists, that a Turritopsis will produce offspring.


A Reminder: the Eurosymposium on Healthy Ageing Will Be Held in Brussels on December 12th

A few weeks from now, Heales, the Healthy Life Extension Society will host a Eurosymposium on Healthy Ageing in Brussels, Belgium. Heales sets its claim as the largest European longevity advocacy group:

Heales is the largest non-profit organisation in Continental Europe promoting and advocating scientific research into longevity and biogerontology (the science of aging). We are a group of biologists, biochemists, medical doctors and diverse other professions throughout Europe.

The December symposium will be a three day affair, and you may recognize some of the names in the program - noted folk from the longevity science community. The presentation abstracts make for good reading, and there is still time to register online if you plan to be in that part of the world next month.

Heales (Healthy Life Extension Society) in cooperation with the Leiden Academy on Vitality and Ageing is organizing the Eurosymposium on Healthy Ageing on December 12th to 14th in the Royal Library in Brussels. An international set of well recognized biogerontologists will discuss the latest advances in ageing research and offer pathways for future innovation.

Having followed the evolution of the European Innovation Partnership on Active and Healthy Ageing we have reached the conclusion that biology of ageing needs to be highlighted more clearly as an important solution. Innovations based on biology of ageing can contribute to improve healthy life in a very significant way and we want to address this message to the European Union through this conference.

In this conference, we will let scientists explain how their research contributes or can contribute to extend the healthy lifespan of European citizens; we will put scientists, entrepreneurs, medical doctors and other key actors together to build the business of long term health, towards a living Europe rather than a dying Europe. We hope that policy makers and people who work for the European Union will be interested and will further help biology of aging reach concrete implementations.

Visceral Fat Associated With Decreased Bone Strength

Visceral fat is strongly associated with most common age-related conditions and frailties, and mice have been shown to live longer if you remove their visceral fat. Maintaining excess fat tissue appears to be bad for you in many ways: more disability, more disease, a shorter life expectancy. So it's no surprise to see research results like this:

Visceral, or deep belly, obesity is a risk factor for bone loss and decreased bone strength in men. [Not] all body fat is the same. Subcutaneous fat lies just below the skin, and visceral or intra-abdominal fat is located deep under the muscle tissue in the abdominal cavity. Genetics, diet and exercise are all contributors to the level of visceral fat that is stored in the body. Excess visceral fat is considered particularly dangerous, because in previous studies it has been associated with increased risk for heart disease.

[Researchers] evaluated 35 obese men with a mean age of 34 and a mean body mass index (BMI) of 36.5. The men underwent CT of the abdomen and thigh to assess fat and muscle mass, as well as very high resolution CT of the forearm and a technique called finite element analysis (FEA), in order to assess bone strength and predict fracture risk. ... FEA can determine where a structure will bend or break and the amount of force necessary to make the material break.

In the study, the FEA analysis showed that men with higher visceral and total abdominal fat had lower failure load and stiffness, two measures of bone strength, compared to those with less visceral and abdominal fat. There was no association found between age or total BMI and bone mechanical properties. "We were not surprised by our results that abdominal and visceral fat are detrimental to bone strength in obese men. We were, however, surprised that obese men with a lot of visceral fat had significantly decreased bone strength compared to obese men with low visceral fat but similar BMI."


Mild Early Hypoxia Produces Life-long Benefits in Rats

Hormesis is the process by which a little stress or damage actually improves health. It spurs greater repair, growth, and regeneration than would otherwise have taken place, with the net effect being positive. This is an example with life-long benefits:

Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus.

During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity.

Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.


Exercise Versus Neurodegeneration

The brain is a machine that fails with age, as its component cells and structures become damaged in much the same way in all of us. At the high level of processes and larger masses of tissue the brain is complex enough to be able to fail in many, many different ways, however. Even though everyone ages in the same way at the level of cells, all it takes is a few small and consistent differences to create very different end points. For example, neurodegeneration conditions like Parkinson's and Alzheimer's disease might be thought of as the result of particular components or systems within the brain failing more rapidly in some people than in others. Everyone ages the same way, but not everyone loses enough dopamine neurons to be diagnosed with Parkinson's disease, or loses the ability to clear amyloid beta from the brain to a sufficient degree to suffer Alzheimer's disease.

Still, in part because we all age in the same way and all the varied conditions and disabilities of aging stem from the same few root forms of damage and change, some interventions can have a very broad beneficial effect. Exercise and calorie restriction are two of these, shown to produce benefits in almost every circumstance examined to date - if they were pills, the world would beat a path to the door of their manufacturer, and they would be household names. Billions of dollars are sometimes spent on commercializing therapies that do not do as well as either exercise or calorie restriction for specific groups and medical conditions.

As for many other conditions, there is a fair amount of evidence to suggest that exercise can lower the risk of neurodegeneration or slow its progression. Here are a couple of research results to illustrate the point: one association, one causation.

Active lifestyle boosts brain structure and slows Alzheimer's disease

An active lifestyle helps preserve gray matter in the brains of older adults ... The lifestyle factors examined included recreational sports, gardening and yard work, bicycling, dancing and riding an exercise cycle. The researchers used magnetic resonance imaging (MRI) and a technique called voxel-based morphometry to model the relationships between energy output and gray matter volume.

Gray matter volume is a key marker of brain health. Larger gray matter volume means a healthier brain. Shrinking volume is seen in Alzheimer's disease. After controlling for age, head size, cognitive impairment, gender, body mass index, education, study site location and white matter disease, the researchers found a strong association between energy output and gray matter volumes in areas of the brain crucial for cognitive function. Greater caloric expenditure was related to larger gray matter volumes [and there] was a strong association between high energy output and greater gray matter volume in patients with mild cognitive impairment and AD.

Exercise rate related to improvements in Parkinson's disease

People with Parkinson's disease benefit from exercise programs on stationary bicycles, with the greatest effect for those who pedal faster. ... Functional connectivity magnetic resonance imaging (fcMRI) data showed that faster pedaling led to greater connectivity in brain areas associated with motor ability.

The patients underwent bicycle exercise sessions three times a week for eight weeks. Some patients exercised at a voluntary level and others underwent forced-rate exercise, pedaling at a speed above their voluntary rate. The researchers used a modified exercise bike to induce forced-rate activity.

fcMRI was conducted before and after the eight weeks of exercise therapy and again as follow-up four weeks later. The research team calculated brain activation and connectivity levels from the fcMRI results and correlated the data with average pedaling rate. Results showed increases in task-related connectivity between the primary motor cortex and the posterior region of the brain's thalamus. Faster pedaling rate was the key factor related to these improvements, which were still evident at follow-up.

Exercise is beneficial, but that it still outperforms medical technology in any area is a sign that plenty remains to be done in the arena of research and development. Exercise cannot cure aging, and it certainly can't cure more than one or two named diseases. True longevity, additional decades of life, will only arrive from the application of near-future biotechnologies - that we can somewhat benefit from exercise is better than a poke in the eye with a sharp stick, but don't mistake taking advantage of that fact for actually getting things done.

Reducing Alzheimer's Progression By Blocking Cytokines

Researchers here demonstrate a much reduced progression of the signs of Alzheimer's disease in mice by altering immune signaling:

Alzheimer's disease is one of the most common causes of dementia. [The] accumulation of particular abnormal proteins, including amyloid-ß (Aβ) among others, in patients' brains plays a central role in this disease. [Researchers] were able to show that turning off particular cytokines (immune system signal transmitters) reduced the Alzheimer's typical amyloid-ß deposits in mice with the disease. As a result, the strongest effects were demonstrated after reducing amyloid-ß by approximately 65 percent, when the immune molecule p40 was affected, which is a component of the cytokines interleukin (IL)-12 and -23.

Follow-up experiments [showed] that substantial improvements in behavioral testing resulted when mice were given the antibody blocking the immune molecule p40. This effect was also achieved when the mice were already showing symptoms of the disease. Based on the current [study], the level of p40 molecules is higher in Alzheimer's patients' brain fluid, which is in agreement with a recently published [study] demonstrating increased p40 levels in blood plasma of subjects with Alzheimer's disease.

The significance of the immune system in Alzheimer's research is the focus of current efforts. [Researchers] suspect that cytokines IL-12 and IL-23 themselves are not causative in the pathology, and that the mechanism of the immune molecule p40 in Alzheimer's requires additional clarification.


FGF21 as Calorie Restriction Mimetic

Boosting levels of fibroblast growth factor 21 (FGF21) has been shown to extend life in mice. Here, researchers classify it as a calorie restriction mimetic treatment:

Dietary or caloric restriction (DR or CR), typically a 30-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend lifespan and healthspan in diverse organisms, including mammals. Although the lifespan benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers healthspan benefits.

A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related lifespan-enhancing protocols. Increased expression of FGF21, a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends lifespan to a similar extent as DR in a recent study.

FGF21 may achieve these effects by attenuating GH/IGF1 signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents which is a critical component of alternate day fasting, a DR-like protocol that also increases lifespan and healthspan in mammals. Various drugs have been reported to induce FGF21 [but] of these, only metformin has been reported to extend lifespan in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression.

Perhaps the most parsimonious explanation is that high, possibly unphysiological, levels of FGF21 are needed to achieve maximum life- and healthspan benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and healthspan are warranted.


A Bioprinting Infographic

Bioprinting is one of the many applications of 3D printing, a family of automation technologies for building three-dimensional structures from a blueprint. Living tissue is only different from other forms of automated fabrication by virtue of being much more complicated and somewhat more fragile. On the other hand, cells in a structure can self-assemble to some degree if the initial printed structure, chemical signals, and types of cell used are close enough to the final goal. So the challenges in printing tissue - and eventually in printing organs - are focused on trying to produce structures sufficiently close to living tissue for the cells involved to finish up on their own and close the gap. Creating a sufficiently comprehensive network of blood vessels to allow printed tissue to sustain itself is a big issue, for example.

At the end of this road, not so many years away, lies the goal of organ printing: producing complex organs for transplant on demand, grown from a patient's own cells. What effect this will have on life span remains to be seen, but on its own it is unlikely to be as large as we would like: probably incremental rather than revolutionary. You might look on it more in the way of taking conventional medicine for organ damage to the next level: expanding the number of people who can be treated, increasing the success rate of treatments, but suffering from many of the same limitations when it comes to the ability to successfully treat very elderly and frail people. There will probably be modest incidental benefits to life expectancy, just as there are for most broad improvements in medical technology. But you can have organs replaced as much as you like, and still age to death if there is no way to treat mitochondrial damage, build up of aggregates, aging in the brain, and so forth.

Surgery is never a desirable thing to have happen to you, especially if you are frail enough to need a transplant. This is one of the reasons why I suspect that stem cell medicine will ultimately gravitate to methods for inducing repair, regeneration, and rejuvenation in situ. They will either manipulate existing stem cells or infuse cultured stem cells taken from the patient, but these will be minimally invasive procedures that produce little to no trauma in the way that a transplant does.

In any case, back to bioprinting: I was recently pointed to an infographic on bioprinting, which looks at the high points of present development in the field. Click on it the thumb below for the full sized version:

Printing technology has come a long way in the 21st century, moving swiftly from two dimensional into the realm of 3D. Furniture,cars, shoes, a replica of King Tutankhamun - these are all things that have been made with 3D printing technology. However, it doesn't stop at material objects. In fact, using modified printer cartridges and extracted cells as the basis, scientists have a discovered a way in which to print human tissue. While this amazing concept is still at an early stage, the future of bioprinting (as it's commonly known) will allow for full organs and other human parts to be printed on demand for patients. Such a possibility will eventually wipe out the need for donor organs, which is a problem today considering the vast amount of patients in need of new organs.

Being ever enthusiastic about advances in print technology, our creative team at PrinterInks decided to develop an infographic about this hot topic with the help of US based start-up Organovo; who are responsible for paving the way in bioprinting. Using Organovo's expertise, we developed an infographic to portray how the process works, as well as highlight today's organ transplant figures and the importance of how much money is concentrated on research and development for drug testing each year.

Dihydrolipoamide Dehydrogenase as Longevity Gene

It's no longer remarkable for researchers to discover ways to alter genes or the level of proteins produced through gene expression that extend life in laboratory animals. Many new interventions of this sort are discovered every year, and most go largely unremarked now. With the falling cost and increasing capacity of DNA sequencing and related biotechnologies it is becoming ever easier to find new connections or poke and prod at DNA and protein machinery in living organisms. That trend speeds the pace of progress in this field, and here is a recent example:

Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong Caenorhabditis elegans lifespan. In this study we use a metabolomics approach to identify an ensemble of mitochondrial-derived α-ketoacids and α-hydroxyacids that are produced by long-lived Mit mutants but not by other long-lived mutants or by short-lived mitochondrial mutants.

We show that accumulation of these compounds is dependent upon concerted inhibition of three α-ketoacid dehydrogenases that share dihydrolipoamide dehydrogenase (DLD) as a common subunit, a protein previously linked in humans with increased risk of Alzheimer's disease. When the expression of DLD in wild type animals was reduced using RNA interference we observed [that] as RNAi dosage was increased lifespan was significantly shortened but, at higher doses, it was significantly lengthened, suggesting DLD plays a unique role in modulating length of life.


Visceral Fat Associated With Higher Mortality Rates

It is already known that both excess visceral fat and the lifestyle choices needed to gain it - being sedentary and a high calorie diet - correlate with increased risk of many age-related conditions. Going beyond associations to matters of causation, it is worth noting that animal studies have shown that surgical removal of visceral fat increases life expectancy.

These recently published open access study results add to the existing stack of reasons to care about your weight and lifestyle choices:

The purpose of this study was to determine the association between visceral adipose tissue (VAT) and all-cause mortality. The sample included 1089 white men and women 18-84 years of age from the Pennington Center Longitudinal Study, a prospective cohort of participants assessed between 1995 and 2008, and followed for mortality until 31 December 2009. Abdominal VAT was measured [using] computed tomography. There were 27 deaths during an average of 9.1 years of follow-up.

Abdominal VAT was significantly associated with mortality after adjustment for age, sex and year of examination. The association was stronger after the inclusion of abdominal subcutaneous adipose tissue (SAT), smoking status, alcohol consumption and leisure-time physical activity as additional covariates. ... Abdominal SAT was not associated with mortality, either alone or in combination with VAT and other covariates. The results support the assertion that abdominal VAT is an important therapeutic target for obesity reduction efforts.


Increased Longevity in Mice by Removing Cardiotrophin 1

Here is an question to think on while you recover from the excesses of the recent holiday: should we expect there to be, in humans, mice, or other species, many simple genetic alterations that are unambiguously beneficial for the individual, yet which evolution did not select for? Another way of looking at this question: why is it that there exist a range of ways to engineer slightly-genetically-altered mice that are stronger, healthier, and longer-lived than the standard wild variants?

The classical answer to this question suggests that these improvements come with fitness costs in the wild, or - more subtly - have the effect of dramatically reducing ability to survive under some rare combination of environmental circumstances. This is obviously the case when you look at mice lacking growth hormone, which live 60-70% longer than their peers, but are absolutely unfit for life in the wild due to their small size and, more importantly, issues with maintaining body temperature due to that small size. But for unambiguously all-round beneficial mutations like myostatin knockout, one has to think harder about how this could be a disadvantage.

Here is another example of a mutation that everyone would want for their offspring, should it turn out to work much the same way in humans:

Absence of Cardiotrophin 1 Is Associated With Decreased Age-Dependent Arterial Stiffness and Increased Longevity in Mice

Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month-old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured.

Survival rate of wild-type and CT-1-null mice was studied. ... The wall stress-incremental elastic modulus curve of old CT-1-null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1-null mice. CT-1-null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1-null mice displayed a 5-month increased median longevity compared with wild-type mice.

The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging process.

I look forward to the day on which one can take a flight across the Pacific as a medical tourist, drop into a reputable clinic, and have a few genetic alterations done: myostatin, cardiotrophin 1, and others that arise and are shown to have no downsides for people living in a society with access to modern medicine.

Vacuole Changes as a Contributing Cause of Yeast Cell Aging

The type of vacuole found in yeast cells is somewhat analogous to the lysosome that we animals possess in that it is involved in breaking down waste products and recycling broken cellular components (via the process of autophagy) that would otherwise harm the cell. It is an agent of cellular housekeeping, in other words. There the similarities end, however, as the vacuole performs many other vital tasks that the more specialized lysosome does not.

So here, researchers show that they can extend life in yeast by reversing a change that occurs in the vacuole. Because the vacuole has many more tasks than the lysosome, it's not immediately clear that this has any application to our biology of aging, however. It is still worth keeping an eye on this research as we know that decline in lysosomal function (and thus of cellular housekeeping) is important in animal aging. You might recall, for example, that researchers managed to reverse the age-related loss of liver function in mice by finding a way to keep lysosomal function running at youthful rates. Similarly, reversing the root causes of lysosomal decline is on the SENS agenda - to be achieved by breaking down the build up of metabolic waste products that accumulate in lysosomes and cause them to malfunction.

Normally, mitochondria [in yeast] are beautiful, long tubes, but as cells get older, the mitochondria become fragmented and chunky. The changes in shape seen in aging yeast cells are also observed in certain human cells, such as neurons and pancreatic cells, and those changes have been associated with a number of age-related diseases in humans.

The vacuole - and its counterpart in humans and other organisms, the lysosome - has two main jobs: degrading proteins and storing molecular building blocks for the cell. To perform those jobs, the interior of the vacuole must be highly acidic. [Researchers] found that the vacuole becomes less acidic relatively early in the yeast cell's lifespan and, critically, that the drop in acidity hinders the vacuole's ability to store certain nutrients. This, in turn, disrupts the mitochondria's energy source, causing them to break down. Conversely, when [researchers] prevented the drop in vacuolar acidity, the mitochondria's function and shape were preserved and the yeast cells lived longer.

Until now, the vacuole's role in breaking down proteins was thought to be of primary importance. We were surprised to learn it was the storage function, not protein degradation, that appears to cause mitochondrial dysfunction in aging yeast cells. ... The unexpected discovery prompted [the researchers] to investigate the effects of calorie restriction, which is known to extend the lifespan of yeast, worms, flies and mammals, on vacuolar acidity. They found that calorie restriction - that is, limiting the raw material cells need - delays aging at least in part by boosting the acidity of the vacuole.


Improvements in Printed Cartilage Scaffolds

Cartilage is a deceptively complex tissue to build, due to the small-scale structure that determines its mechanical and load-bearing properties - getting that structure right has proven to be a challenge. Researchers have nonetheless been making progress towards this goal in recent years, and the lessons learned will be carried forward to other tissue engineering projects:

The printing of three-dimensional tissue has taken a major step forward with the creation of a novel hybrid printer that simplifies the process of creating implantable cartilage. [The] printer is a combination of two low-cost fabrication techniques: a traditional ink jet printer and an electrospinning machine.

In this study, the hybrid system produced cartilage constructs with increased mechanical stability compared to those created by an ink jet printer using gel material alone. The constructs were also shown to maintain their functional characteristics in the laboratory and a real-life system. The key to this was the use of the electrospinning machine, which uses an electrical current to generate very fine fibres from a polymer solution. Electrospinning allows the composition of polymers to be easily controlled and therefore produces porous structures that encourage cells to integrate into surrounding tissue.

The constructs [were] inserted into mice for two, four and eight weeks to see how they performed in a real life system. After eight weeks of implantation, the constructs appeared to have developed the structures and properties that are typical of elastic cartilage, demonstrating their potential for insertion into a patient.


Removing Large and Unnecessary Costs Imposed Upon Medicine

Insofar as politics goes, I'm against it. Both in the sense of a support for market anarchism as a desirable form of society and in the sense that what we see in the political sphere of our increasingly centralized societies today is reprehensible and destructive. There is control for the sake of control, ever-greater burdens imposed on builders of new technology, and progress in medicine is slowed for the personal aggrandizement of bureaucrats and those who line their pockets. When power accumulates to any group in society, and that group stands unopposed by peers, then it inevitably becomes corrupt.

The cartel of modern politics as practiced in countries like the US is the source of large and unnecessary costs put upon progress in medical technology - and this is a big problem for those of us who want to live longer, healthier lives. We stand at the dawn of an age in which aging might be treated as a medical condition, in which therapies could be designed to slow or reverse aging. But medicine and medical research labor beneath heavy regulation: the modern guilds like the AMA that seek to reduce supply; the agencies like the FDA that have few incentives to approve new medicines, yet seek ever-greater authority over all forms of treatment; the regulation and nationalization of medical services and insurance that severs customers from prices, and replaces markets with central planning after the Soviet model.

From a practical standpoint people of my views, being a minority, can do little but think of the vast benefits that might be realized should the present political costs imposed on progress in medicine suddenly evaporate. There are few opportunities to do more than that - we paw at the glass and stare longingly at the products on the other side, as it were. Human societies follow certain paths, and most lead away from individual freedoms of the sort needed for rapid progress in technology. Sad but true.

On this theme, here is an essay that enumerates some of the politically-imposed burdens that greatly slow progress in modern medicine and other applications of life science research, written from a far more forgiving libertarian standpoint than my own:

Political Priorities for Achieving Indefinite Life Extension: A Libertarian Approach

While the achievement of radical human life extension is primarily a scientific and technical challenge, the political environment in which research takes place is extremely influential as to the rate of progress, as well as whether the research could even occur in the first place, and whether consumers could benefit from the fruits of such research in a sufficiently short timeframe. I, as a libertarian, do not see massive government funding of indefinite life extension as the solution - because of the numerous strings attached and the possibility of such funding distorting and even stalling the course of life-extension research by rendering it subject to pressures by anti-longevity special-interest constituencies.

Rather, my proposed solutions focus on liberating the market, competition, and consumer choice to achieve an unprecedented rapidity of progress in life-extension treatments. This is the fastest and most reliable way to ensure that people living today will benefit from these treatments and will not be among the last generations to perish. Here, I describe six major types of libertarian reforms that could greatly accelerate progress toward indefinite human life extension.

We can see a modest fraction of what might be achieved by stripping away regulation, guilds, and central planning by comparing progress in medicine over the past twenty years with progress in computing and software. Consider what computers and their role in everyday life would look like if it had always been the case that introducing a new machine or new software package meant spending years and $100 million to pass a bureaucratic one-size-fits-all process - and where radical new designs required a decade of expensive lobbying to be added to the list of what is permitted.

Yet this is exactly where things stand with medicine, at a time in which it is more important than it has ever been for progress to occur as rapidly as possible. A hundred thousand lives are lost every day to degenerative aging, and we might do something about that in the years ahead - but the therapies will emerge far more slowly than they would in a society that was more free and open than ours.

Towards an Understanding of Why Dopamine Neurons Are Vulnerable in Parkinson's Disease

The most visible signs of Parkinson's disease are caused by the progressive destruction of a comparatively small population of dopamine-generating neurons in the brain. But why these cells? A full answer to that question might lead to ways to block progression of the condition:

Neuroinflammation and its mediators have recently been proposed to contribute to neuronal loss in Parkinson's, but how these factors could preferentially damage dopaminergic neurons has remained unclear until now. [Researchers] were looking for biological pathways that could connect the immune system's inflammatory response to the damage seen in dopaminergic neurons. After searching human genomics databases, the team's attention was caught by a gene encoding a protein known as interleukin-13 receptor alpha 1 chain (IL-13Ra1), as it is located in the PARK12 locus, which has been linked to Parkinson's.

IL-13rα1 is a receptor chain mediating the action of interleukin 13 (IL-13) and interleukin 4 (IL-4), two cytokines investigated for their role as mediators of allergic reactions and for their anti-inflammatory action. With further study, the researchers made the startling discovery that in the mouse brain, IL-13Ra1 is found only on the surface of dopaminergic neurons. "This was a 'Wow!' moment."

The scientists set up long-term experiments using a mouse model in which chronic peripheral inflammation causes both neuroinflammation and loss of dopaminergic neurons similar to that seen in Parkinson's disease. The team looked at mice having or lacking IL-13Ra1 and then compared the number of dopaminergic neurons in the brain region of interest. The researchers expected that knocking out the IL-13 receptor would increase inflammation and cause neuronal loss to get even worse. Instead, neurons got better.

If further research confirms the IL-13 receptor acts in a similar way in human dopaminergic neurons as in mice, the discovery could pave the way to addressing the underlying cause of Parkinson's disease. Researchers might, for instance, find that drugs that block IL-13 receptors are useful in preventing loss of dopaminergic cells during neuroinflammation.


Looking at Immune Function in Long-Lived Clk1 Mutant Mice

Reducing expression of clk1 (known as Mclk1 in mice) is one of the few known single-gene alterations that can slow aging enough to extend life in mice by as much as 30%. First impressions were that it works by altering mitochondrial function - and regular readers will know by now that mitochondria and the the pace of their self-inflicted damage is very important in aging and longevity. There is some debate as to how exactly this works in the case of clk-1, however, as the way in which it changes metabolic processes isn't self-evidently beneficial given what is known today. A fair amount of wading through complexity to gain a better understanding of mammalian biochemistry still needs to happen.

Few single gene alterations change only one thing, and clk-1 reduction has all sorts of other knock-on effects in metabolism and biological systems. Researchers here are working their way through what it does to the immune system, and how that might be beneficial even though it doesn't at first look that way:

The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1+/− mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial [reactive oxygen species] generation. Here we ask whether this phenotype is beneficial or simply tolerated.

We used models of infection [and] found that Mclk1+/− mutants mount a stronger immune response, control bacterial proliferation better, and are resistant to cell and tissue damage resulting from the response, including fibrosis and types of oxidative damage that are considered to be biomarkers of aging. Moreover, these same types of tissue damage were found to be low in untreated 23 months-old mutants. ... Mclk1+/− mutants thus display an association of an enhanced immune response with partial protection from age-dependent processes and from pathologies similar to those that are found with increased frequency during the aging process. This suggests that the immune phenotype of these mutants might contribute to their longevity. We discuss how these findings suggest a broader view of how the immune response might impact the aging process.


Some Answers in Aging Science are Not Worth the Effort

Considerations of cost versus benefit drive all human action. With this in mind, and when considering the field of aging research, I'd contend that a fair number of the better defined lines of research are not worth the time and resources likely required to reach definitive results. By better defined I mean here research that can be expressed as a concise and narrow question (e.g. "why are naked mole-rats immune to cancer?") rather than research that is as much about finding the questions in the first place (e.g. attempting to establish a coherent big picture in the progression of Alzheimer's disease), or about gathering data for later use in other people's attempts to answer questions (e.g. whole genome sequencing of various species).

The well-known difference in longevity between human genders is a good example of a constrained and defined question in aging research: why do women live longer than men? It is also, to my mind, a great example of a question with an answer that isn't worth the cost involved in obtaining it. Research to date reveals this to be an inordinately complex issue, possessing all the signs of requiring a great deal of time and money to make any headway towards definitive answers:

Sex and Life Expectancy

A sexual dimorphism in human life expectancy has existed in almost every country for as long as records have been kept. Although human life expectancy has increased each year, females still live longer, on average, than males. Undoubtedly, the reasons for the sex gap in life expectancy are multifaceted, and it has been discussed from both sociological and biological perspectives. However, even if biological factors make up only a small percentage of the determinants of the sex difference in this phenomenon, parity in average life expectancy should not be anticipated.

The examination of biological mechanisms accounting for the female-based advantage in human life expectancy has been an active area of inquiry; however, it is still difficult to prove the relative importance of any 1 factor. Nonetheless, biological differences between the sexes do exist and include differences in genetic and physiological factors such as progressive skewing of X chromosome inactivation, telomere attrition, mitochondrial inheritance, hormonal and cellular responses to stress, immune function, and metabolic substrate handling among others. These factors may account for at least a part of the female advantage in human life expectancy.

Despite noted gaps in sex equality, higher body fat percentages and lower physical activity levels globally at all ages, a sex-based gap in life expectancy exists in nearly every country for which data exist. There are several biological mechanisms that may contribute to explaining why females live longer than men on average, but the complexity of the human life experience makes research examining the contribution of any single factor for the female advantage difficult. However, this information may still prove important to the development of strategies for healthy aging in both sexes.

I should say that the last line quoted above has the sound of a quick scrabbling for relevance when the next budgetary decision comes due. Still, perhaps I'm just a cynic.

So research to date suggests that working on the gender difference in longevity with the aim of finding a definitive answer will be expensive. That is the cost side of the cost-benefit consideration. On the benefit side, we might think that the best possible benefit resulting from a definitive answer to the question "why do women life longer than men?" is something like five to seven years of life - that being the additional life expectancy enjoyed by women in wealthier regions of the world, and which might conceivably be captured by men given an exact methodology to do so. Which is not to say that this outcome could be engineered as a practical matter even if the cause of the difference was known in certainty - for example if it turns out to be, say, some many-headed web of fundamental interactions between metabolism and the genetics of being male, something that must be worked around rather than just altered.

Trying to safely alter metabolism with minimal side-effects is a complex and expensive business, a realm akin to traditional drug discovery processes, where billions can be spent with ease while only marginal benefits resulting. When it comes to slowing aging via metabolic and genetic manipulation, working through this drug discovery process, the mainstream research community believes there is little hope for significant progress towards longer human lives in the next few decades.

My point here is that a goal wherein the research community has no great hope of rapid progress, and which has every sign of being enormously expensive to pursue, and which can only at best somewhat point the way towards a possible gain of up to five years or so of healthy life in half the population is not a goal that merits a full-court press and singular attention - or at least not where better alternatives exist. Insofar as human aging goes, there is no shortage of better alternatives at this point. The aging research community should look to bolder plans, better and more beneficial ways to spend their time: work with far bigger potential gains. This is an age of revolution in the capabilities of biotechnology, a time for great leaps ahead in intervening in the aging process, not a time to be tinkering in the sandbox of fiddling questions.

Treating Spine Injury in Dogs via Stem Cell Transplant

A pleasant example of what can sometimes be achieved with even comparatively crude autologous stem cell therapies:

Scientists have reversed paralysis in dogs after injecting them with cells grown from the lining of their nose. The pets had all suffered spinal injuries which prevented them from using their back legs. The [team] is cautiously optimistic the technique could eventually have a role in the treatment of human patients. The study is the first to test the transplant in "real-life" injuries rather than laboratory animals. [The] dogs had olfactory ensheathing cells from the lining of their nose removed. These were grown and expanded for several weeks in the laboratory.

Of 34 pet dogs on the proof of concept trial, 23 had the cells transplanted into the injury site - the rest were injected with a neutral fluid. Many of the dogs that received the transplant showed considerable improvement and were able to walk on a treadmill with the support of a harness. None of the control group regained use of its back legs.

The researchers say the transplanted cells regenerated nerve fibres across the damaged region of the spinal cord. This enabled the dogs to regain the use of their back legs and coordinate movement with their front limbs. The new nerve connections did not occur over the long distances required to connect the brain to the spinal cord. [In] humans this would be vital for spinal injury patients who had lost sexual function and bowel and bladder control. ... This is not a cure for spinal cord injury in humans - that could still be a long way off. But this is the most encouraging advance for some years and is a significant step on the road towards it.


Telomere Length and Life Expectancy in Warblers

Researchers are making better progress of late in finding ways to use changes in telomere length that occur with aging as a marker for biological age and life expectancy - though it remains an open question as to whether telomere shortening is a cause of aging versus a secondary consequence of causes of aging. You might look at work in mice published earlier this month, for example. Or moving to birds, a few years back researchers noted that pace of telomere shortening over time correlated with lifespan differences between species. Here researchers consider telomere length in a species of warbler:

[Researchers] studied the length of chromosome caps - known as telomeres - in a 320-strong wild population of Seychelles Warblers on a small isolated island. ... Over time these telomeres get broken down and become shorter. When they reach a critical short length they cause the cells they are in to stop functioning. This mechanism has evolved to prevent cells replicating out of control - becoming cancerous. However the flip side is that as these zombie cells build up in our organs it leads to their degeneration - aging - and consequently to health issues and eventually death. Telomeres help safeguard us from cancer but result in our aging.

We wanted to understand what happens over an entire lifetime, so the Seychelles Warbler is an ideal research subject. They are naturally confined to an isolated tropical island, without any predators, so we can follow individuals throughout their lives, right through to old age. We investigated whether, at any given age, their telomere lengths could predict imminent death. We found that short and rapidly shortening telomeres were a good indication that the bird would die within a year.

We also found that individuals with longer telomeres had longer life spans overall. It used to be thought that telomere shortening occurred at a constant rate in individuals, and that telomere length could act as an internal clock to measure the chronological age of organisms in the wild. However while telomeres do shorten with chronological age, the rate at which this happens differs between individuals of the same age. This is because individuals experience different amounts of biological stress due to the challenges and exertions they face in life. Telomere length can be used as a measure of the amount of damage an individual has accumulated over its life. We saw that telomere length is a better indicator of life expectancy than chronological age - so by measuring telomere length we have a way of estimating the biological age of an individual - how much of its life it has used up.


Insufficiently Terrified of Aging or Too Terrified of Aging?

It is my hope that, if asked, most people would agree that degenerative aging is not a pleasant, beneficial thing to look forward to. It is a looming years-long tunnel of varying forms of increasing suffering, expense, loss of dignity, and disability. You wouldn't volunteer for the consequences of aging if they were optional. Everyone knows what's coming. Everyone gets a close-up preview of what will happen, in all its painful details via family, media, stories, the common currencies of education. No adult is truly ignorant of where aging leads and what its costs are.

Any yet, and yet. The masses carry on and for the most part put all thoughts of future suffering to one side - even as the young interact with old people day in and day out, and even as those old people live out their lives. The folk who look at degenerative aging and suggest, seriously, with reference to sound science, that perhaps we can and should do something about it are in a tiny minority. Further, they are often castigated for that view, as if it is something that shouldn't be brought out in polite company.

Living in fear of being dead is of debatable rationality, but living in fear of chronic pain and suffering seems eminently rational to me. You'd be terrified if a random thug could credibly threaten you with half the physical harm that aging is capable of. Fear is a great motivator, but unfortunately far from reliable in what it motivates people to do: the various shadings of fear are well characterized by a loss of analysis and control.

So people blithely walk towards degenerative aging and its suffering, and the vast majority choose to do nothing to try to fight against that future. Is that because they have too little fear of what lies ahead, or because they are too terrified to even bring out the topic for introspection, debate, and planning?

I have become perhaps one of the least qualified people to answer that sort of question. I am so far removed from the years in which I didn't think much on the topic, or had only ordinary thoughts about aging, that I have no insight left into what it was like or why I thought that way. The more I learn about rejuvenation biotechnology and the longer I spend observing the world while favoring the defeat of aging, the less I understand prevalent attitudes, and the more of a mystery it all becomes: the concurrent acknowledgement and aversion of degenerative aging; the existence of a vibrant "anti-aging" marketplace next to a lack of support for real longevity science; the signs of fear next to the signs of complacency.

Aging is Global, So Expect Correlations

The body is a web of overlapping systems, many of which depend upon one another for effective function. If one system begins to weaken, so do many others. Degenerative aging is a global affair, occurring throughout the body, and so we should not be surprised to find strong correlations between specific forms of age-related decline in many different organs. That doesn't necessarily mean that there is anything profound hiding behind such an association - cells are accumulating damage in all tissues, body-wide systems such as blood vessel elasticity and the immune system are progressively failing, and so decline is everywhere:

Decreased kidney function is associated with decreased cognitive functioning in areas such as global cognitive ability, abstract reasoning and verbal memory. [This] is the first study describing change in multiple domains of cognitive functioning in order to determine which specific abilities are most affected in individuals with impaired renal function.

[Researchers] examined longitudinal data, five years apart, from 590 people. They wanted to see how much kidney function had changed over that time period, and whether it was associated with how much cognitive functioning had changed. They were interested in the overall change, but also in specific abilities such as abstract reasoning and verbal memory.

"The brain and kidney are both organs that are affected by the cardiovascular systems. They are both affected by things like blood pressure and hypertension, so it is natural to expect that changes in one organ are going to be linked with changes in another."


An Example of Stem Cell Researchers Tackling Aging

Much of the output of the regenerative medicine and tissue engineering fields will be of greatest use to old people: repair and replacement of worn, damaged, and diseased tissue. Unfortunately the cellular environment in an old body works to suppress stem cell activity, and this seems to be a more important factor in the decline of regenerative capacity than age-related damage to stem cells themselves, or the size of the stem cell population. This is perhaps an evolved response to rising levels of cellular damage, and works to suppress cancer risk - but at the cost of an accelerated decline in organ and tissue function.

From a practical standpoint, this means that the stem cell research community must learn to control and reverse specific aspects of aging in order for their therapies to have the best possible effect. Otherwise they are throwing good stem cells into an environment that will suppress their activity. This roadblock is actually a good thing: this field of research is very well funded, and thus we all benefit as they find out that aging is in their way. Here is an example of the sort of exploratory early-stage work taking place today:

This study investigated whether cytokine enhancement of a biodegradable patch could restore cardiac function after surgical ventricular restoration (SVR) even when seeded with cells from old donors. ... SVR can partially restore heart size and improve function late after an extensive anterior myocardial infarction. However, 2 limitations include the stiff synthetic patch used and the limited healing of the infarct scar in aged patients.

We [placed cytokines onto] porous collagen scaffolds. We seeded human mesenchymal stromal cells from young or old donors into the scaffolds, with or without growth factors. The patches were characterized and used for SVR in a rat model of myocardial infarction. Cardiac function was assessed.

In vitro results showed that cells from old donors grew slower in the scaffolds. However, the presence of cytokines modulated the aging-related p16 gene and enhanced cell proliferation, converting the old cell phenotype to a young phenotype. In vivo studies showed that 28 days after SVR, patches seeded with cells from old donors did not induce functional recovery as well as patches seeded with young cells. However, cytokine-enhanced patches seeded with old cells exhibited preserved patch area, prolonged cell survival, and augmented angiogenesis, and rats implanted with these patches had better cardiac function. The patch became an elastic tissue, and the old cells were rejuvenated.


People Before Buildings

The Timeship is, frankly, an odd project. It is situated somewhere at the edge of the cryonics community, and has been floating in that nebulous space that lies between conception and work underway for nearly a decade. If I had to put money on it I'd wager it will stay that way for the foreseeable future. That said, I noticed an unlikely flicker of life in the form of a short article and a craigslist job posting for a someone with architectural skills from earlier this month:

All work will be done at the Timeship project site near San Antonio, Texas. Housing will be provided initially on site in a studio environment. Candidates will be working directly with New York architect Stephen Valentine, Prof. John Lobell, or Prof. Brent Porter (both from Pratt Institute). ... Candidates must have an exceptional sense of art of design, architecture & science. Technical skills include: highly detailed physical model making (museum quality for use in possible television documentary and museum-gallery exhibit), 3D computer modeling and AutoCAD. ... Research and investigations for the requirements of the 650-acre site for future development for Timeship at the Stasis Foundation Biotechnological Research Park.

The Stasis Foundation Biotechnology Research Park (Stasis Research Park) will be a world-class biotech facility located in Comfort, (near San Antonio), Texas. There are two parts to the primary mission to the Stasis Research Park: biotech research and the cryostorage of biological materials. The design and development of cooling systems and devices for the cryopreservation and cryostorage of human organs for transplantation purposes , materials to support fertility; tissue for regenerative medicine; DNA, including the DNA of near extinct species; whole mammalian organisms including humans after legal death for whom all medical procedures have failed.

I've talked in the past of measuring progress in a field by the number of buildings erected and conferences held. This only works as a metric if you assume rational economic motivations for building, however. Building is ruinously expensive - so you only do it when you have run out of places to put your research community, or your development groups. You only build new facilities when you are so very successful at pulling in funding and attracting workers that you cannot avoid the expense of building or buying real estate.

Thus people and their work come first and foremost, while buildings are a secondary concern. This is especially true in fields that require few specialized structures. Much of modern research can just as well be carried out in office parks and garages as anywhere else, and the field of cryonics is no exception to this rule.

The thing that strikes me most about the Timeship, and why I think it's going to remain largely a vision, is that it puts the building before the people. Cryonics is a noble field of human endeavor that has yet to find the means of growth; it remains a small industry, close to its non-profit roots. This is of course terrible, and says bad things about human nature - that a practical methodology exists to prevent people from suffering irreversible death, and we do next to nothing with it. The cryonics community is not one suffering from a lack of space to work in.

You can't follow the siren song of "build it and they will come." That is the most false of all modern sayings, and especially so given a lack of growth. Construct a building in the absence of a research and development community that is bursting forth from their existing and inadequate work spaces, and you will have constructed an empty building. A monument, in other words, and not in the good sense.

So to me, someone who measures progress in technology and service above other ends, the Timeship looks like a backwards-facing project: it is the building in advance of what that building is intended to house. When eyeing at cryonics, better to look to initiatives like 21st Century Medicine, or the ongoing work to make Alcor a better service provider, or the Brain Preservation Prize. They better reflect the cause: people doing meaningful things in office parks, building improvements one step at a time.

Astrocytes as a Potential Target for Alzheimer's Therapies

The brain is made up of far more than just neurons; its functions and complex structures require the support of a wide range of specialized cells types. Prominent amongst these supporting cells are the astrocytes. You might recall research from a few months back that indicated a role for age-related changes in astrocytes in the progression of Alzheimer's disease. Following on from that, researchers here report on the use of gene therapy to target astrocytes and potentially reduce the scope of any harmful behavior:

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes.

Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes [in] mice. AAV-Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with [a signaling pathway] shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation.

After several months of treatment with Gfa2-VIVIT, [the] mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies.


Intuition, Mortality Rate, and Life Expectancy

Here is a short post with graphs on the relationship between mortality rates and life expectancy:

I read a few weeks ago about a study where vitamin D supplementation reduced all-cause mortality rates by 6%. How many years would that add to life expectancy? I wondered. 6% of a 75-year life span would mean 4½ extra years, I thought, naïvely. I pulled up a mortality table (from the Social Security Admin) and did the calculation in a spreadsheet. The two lines were barely distinguishable. A 6% drop in mortality only increases life expectancy by 7 months.

If the death rate did not increase with age, then it would be true that subtracting 6% from mortality would add about 6% to life expectancy. That's where the intuition came from about 4½ years. But with a death rate that increases with age, you "have to work a lot harder" to get an improvement in life expectancy. And in reality, the mortality curve doesn't just rise with age - it rises at an accelerating rate.

Once I had set up the spreadsheet, it's easy enough to ask the general question: How much does life expectancy improve for a given change in mortality? The answer I found was: very slowly. ... To add just 5 years to life expectancy, we would need to slash the mortality rate by more than 40%. This is a counter-intuitive statistic - and a discouraging one.

There is another perspective: [in] medical research, we are working piecemeal to chip away at the mortality rate from one disease and another. But if the fundamental rate of aging can be slowed, this will push the curve not down but to the right. This will have as much benefit as many decades of progress in cancer and heart disease.


Evidence for α-synuclein's Central Role in Parkinson's Disease

Parkinson's disease involves a greatly accelerated loss of vital dopamine-generating neurons in the brain, leading to the characteristic symptoms in earlier stages of the condition. In recent years, scientists have focused on the role of α-synuclein in the processes that cause this cell death:

The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of α-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations.

At this point α-synuclein is taking on a similar role to beta-amyloid in Alzheimer's disease - a magnet for interest and research funds, while potential clinical intervention involves removing or other otherwise nullifying the buildup of this unwanted compound. Fairly compelling research results were recently published on this topic, wherein researchers managed to convincingly replicate the effects of Parkinson's in mice:

Misfolded protein transmits Parkinson's from cell to cell

A [team] injected a misfolded synthetic version of the protein α-synuclein into the brains of normal mice and saw the key characteristics of Parkinson's disease develop and progressively worsen. The study [suggests] that the disease is spread from one nerve cell to another by the malformed protein, rather than arising spontaneously in the cells.

Parkinson's disease has two distinct features: clumps of protein called Lewy bodies and a dramatic loss of nerve cells that produce the chemical messenger dopamine. When [the] team injected the misfolded α-synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form. This was followed by the death of dopamine neurons. Nerve cells that linked to those near the injection site also developed Lewy bodies, a sign that cell-to-cell transmission was taking place.

The study lends theoretical support to the handful of biotechnology companies that are sponsoring clinical trials of α-synuclein antibodies for Parkinson's ... At least one mystery still remains: why do the Lewy bodies appear in the first place? ... Parkinson's disease is not a disorder in which somebody injects synuclein into your brain. So what sets it in motion?

As is also the case for Alzheimer's it remains much debated as to how and why some people exhibit Parkinson's disease while others do not - which is not to say that there is any shortage of theories on how the condition progresses from its earliest stages. Just as for many other age-related conditions the commonplace correlations apply: being overweight and sedentary increases your risk, exercise and calorie restriction reduce it.

On the subject of Lewy bodies in Parkinson's disease, I noticed a couple of recently published papers suggesting that their appearance is symptomatic of a later stage of the condition, or less relevant to Parkinson's disease specifically - meaning that investigating their biochemistry may be less important than work on α-synuclein at this juncture:

The State of Bioprinting

The developing technology of bioprinting, producing tissue structures using inkjet or other print technologies, has a promising future:

Desktop 3-D printers can already pump out a toy trinket, gear set or even parts to make another printer. Medical researchers are also taking advantage of this accelerating technology to expand their options for regenerative medicine.

Researchers have made great strides in coaxing cells to grow over artificial, porous scaffolds that can then be implanted in the body to replace hard tissue, such as bone. ... But now, instead of relying on poured molds, foam designs or donated biological materials, researchers can print custom scaffold structures with biocompatible, biodegradable polymers. ... These methods have allowed us to develop very complex scaffolds which better mimic the conditions inside the body. ... Engineers can carefully control the minute, internal structures of these porous scaffolds to best promote cellular growth. And these new printing methods also allow quick and cheap experiments that test various one-off designs.

Advancing bio-printing technologies can also be used for the biological material itself. Like color printing, biomaterial printing can switch among different organic materials as well as produce gradients and blending. Inkjet printing is preferred for depositing cells themselves, and as a demonstration of this in the 1980s an unmodified HP desktop printer was used to print out collagen as well as tissuelike structures. Printing, however, is tough on cells. Some studies have successfully kept more than 95 percent of cells intact through the process, but others have not done as well - losing more than half from damaged membranes.

The future of bio-printing may be the combination of these approaches - printing both highly specific scaffolds and cell structures. Recent research has shown that stem cell fate can be controlled by the surfaces onto which the cells are printed.


Molecular Tweezers Versus Alzheimer's Disease

A range of age-related conditions are characterized by a buildup or clumping of harmful proteins, and research tends to focus first on ways to safely break down these compounds. Here researchers are testing a new candidate method of breaking down the beta amyloid and tau associated with Alzheimer's disease:

Last March, researchers at UCLA reported the development of a molecular compound called CLR01 that prevented toxic proteins associated with Parkinson's disease from binding together and killing the brain's neurons. Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau.

And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses - another target of the disease - which allow cells to communicate with one another.

Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities. ... For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease. That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease.


Arguing that AGEs Contribute to Increased Fat Tissue With Age

In this modern age people tend to grow increasingly fat with advancing age. Near any given individual can choose not to do so, but considered in aggregate the masses tend to follow the available incentives more often than not: cheap food; cheap ways to get around without walking; lots of interesting activities that don't require you to move from your chair; and so forth. For your typical fellow in a developed country advancing age means more wealth, more calories, and less exercise, and this has the inevitable effect on waistline, metabolism, long-term health, and life expectancy. With more fat and more years spent fat, the costs pile up: more money spent on medical services, more disability, frailty, and age-related disease, and more years cut from your life expectancy.

So don't get fat, don't stay fat. The weight of evidence tells us that being fat isn't good for you - and for everyone in a developed region, excepting a tiny handful of people with profound genetic disorders, whether or not you are in fact fat is absolutely a choice.

Given the ready way in which we can alter the amount of fat in our bodies through diligence - or lack of same - and the way in which lifestyle choices change with age for most people, there is no desperate need for other explanations as to why people gather more fat with advancing years. Nonetheless, I'll point out a recent open access paper (the full text is PDF only): if I'm reading it right, the researchers here argue that one of the unfortunate low-level biochemical effects of the presence of advanced glycation endproducts (AGEs) in our tissues is that it encourages the growth of fat tissue, or adipose tissue to give it the more formal name - to be fat is to have adiposity, and growth of fat tissue is adipogenesis.

Since AGE levels rise with age, even if an individual doesn't increase their ingested levels of AGEs, this mechanism for AGEs to spur fat tissue growth leaves the door open for some interesting speculation. The researchers don't put any useful numbers to the putative effect, however, and thus I'm inclined to think it small in comparison to, say, how much a person eats or exercises:

An advanced glycation end products (AGEs)-the receptor for AGEs axis restores adipogenic potential of senescent preadipocytes through modulation of p53 function

Impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction. ... We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes.

While our study is largely based on in vitro and ex vivo studies, we would predict that a chronic dietary intake of AGEs would positively contribute to adipose development during aging. ... To our knowledge, our study is the first report that AGEs are able to restore senescence-impaired adipogenic potential of aged preadipocytes. These findings implicate that AGEs-induced adipogenesis in senescent preadipocytes is likely to contribute to exacerbating aging-related adiposity.

If you look back in the Fight Aging! archives, you'll find much more information on AGEs and their role in degenerative aging - the established discussion of past years, rather than the new thoughts on fat tissue quoted above. The characteristic buildup of AGEs and similar compounds that occurs with age harms the integrity of tissue and biological systems in a number of ways:

Advanced glycation endproducts (AGEs) are a class of undesirable metabolic byproduct. The level of AGEs in the body rises with age and causes harm through a variety of mechanisms, such as by excessively triggering certain cellular receptors or gluing together pieces of protein machinery by forming crosslinks, thus preventing them from carrying out their proper function.

In past years a number of efforts were undertaken to develop drugs that can safely break down at least some forms of AGE. Early promising candidates in laboratory animals failed in humans because the most harmful forms of AGE are different for short-lived versus long-lived mammals - so what benefits a rat isn't of much utility for we humans. So far little progress has been made towards a therapy for the dominant type of AGE in humans, glucosepane, sad to say, as there is comparatively little interest in this field of research.

Eliminating Metastasis in Melanoma

Arguably metastasis is what makes cancer so dangerous: that a single malignant tumor of any size can seed further tumors throughout the body; that a diaspora of metastasized cells is exceedingly hard to eliminate once let lose. If metastasis could be blocked many forms of cancer would become tractable and far less threatening, which is a fair-sized step towards a robust cure for cancer - very much needed as a part of any package of biotechnologies aimed at greatly extending healthy human life. Thus it is promising to see signs of early progress along these lines:

In laboratory experiments, scientists have eliminated metastasis, the spread of cancer from the original tumor to other parts of the body, in melanoma by inhibiting a protein known as melanoma differentiation associated gene-9 (mda-9)/syntenin. ... With further research, the approach used by the scientists could lead to targeted therapies that stop metastasis in melanoma and potentially a broad range of additional cancers.

[Researchers] found that Raf kinase inhibitor protein (RKIP) interacted with and suppressed mda-9/syntenin. Mda-9/syntenin [was] shown in previous studies to interact with another protein, c-Src, to start a series of chemical reactions that lead to increased metastasis. ... Prior research suggests that RKIP plays a seminal role in inhibiting cancer metastasis, but, until now, the mechanisms underlying this activity were not clear.

Now that the researchers have demonstrated the ability of RKIP to inhibit mda-9/syntenin-mediated metastasis, they are focusing their attention on developing small molecules imitating RKIP that could be used as new treatments for melanoma.


Investigating a Longevity-Related Mitochondrial Polymorphism

Mitochondrial function is important in determining life span, and mitochondrial damage is one of the root causes of aging. Thus life span differences between similar species may to a large degree reflect differences in the damage resistance of mitochondria, and a number of studies in recent years have shown that some human mitochondrial haplogroups - which represent characteristic variations in mitochondrial DNA - can be correlated with increased longevity.

The way in which mitochondria become damaged involves the production of reactive oxygen species (ROS) in the course of generating fuel to power the cell that contains them. Here researchers show that a longevity-associated difference in mitochondrial DNA reduces the pace of ROS production - which fits nicely with the present understanding of the role of mitochondria in aging:

Mitochondrial DNA (mtDNA) is highly polymorphic, and its variations in humans may contribute to individual differences in function. [Researchers] found a strikingly higher frequency of a C150T transition in the D-loop of mtDNA from centenarians and twins of an Italian population.

The C150T transition is a polymorphism associated with several haplogroups. To determine whether haplogroups that carry the C150T transition display any phenotype that may be advantageous for longevity, we analyzed cybrids carrying or not the C150T transition. These cybrids were obtained by fusing cytoplasts derived from human fibroblasts with human mtDNA-less cells.

We have found no association of respiratory capacity, mtDNA level, mitochondrial gene expression level, or growth rate with the presence of the C150T transition. However, we have found that the cybrids with haplogroups that include the C150T transition have in common a lower reactive oxygen species (ROS) production rate than the haplogroup-matched cybrids without that transition. Thus, the lower ROS production rate may be a factor in the increased longevity associated with [these] haplogroups.


Mining for Longevity Genes

The intricate, reactive, self-regulating machinery of our cells is built from proteins. Those proteins are specified by the blueprints known as genes, coiled up in each cell nucleus. The operation of our metabolism proceeds as a dance of networks of related proteins, feedback loops and signaling cascades in which the amount of a given protein produced at any given time can rise and fall in response to the rise and fall of other levels of production. The full scope of how variations in metabolism and its response to environment and lifestyle can affect the pace of aging is a staggeringly complex system, and as yet poorly understood.

Still, researchers seek to fully understand metabolism and aging; this goal has broader support than any other in aging research. There are more researchers chasing that understanding at any given time than there are working on ways to intervene in the aging process. A post from last week took a look at one way in which that research can progress: given an established mutation or other single-gene or single-protein change that extends life, scientists then follow the effects of that change through the network of interactions that it impacts, in search of a greater understanding of the system as a whole.

This is a time-worn and well proven methodology in all sciences: if you want to understand how something works then change one small part of it and carefully watch what happens next. Repeat as necessary.

There are other ways in which a knowledge of protein networks and existing longevity genes can be used to further research. For example, the catalog of what is known today can be mined in order to guide the process of uncovering more of the relationship between aging and the operation of metabolism. In any given network of genes where one can be altered to increase longevity, it is to be expected that there may be others. The proteins produced by these genes existing in an interconnected system, and it is probably the case that you can change the behavior of such a system by intervening at more than one point.

Here is an example of this approach:

Prediction of C. elegans Longevity Genes by Human and Worm Longevity Networks

Intricate and interconnected pathways modulate longevity ... Because biological processes are often executed by protein complexes and fine-tuned by regulatory factors, the first-order protein-protein interactors of known longevity genes are likely to participate in the regulation of longevity. Data-rich maps of protein interactions have been established for many cardinal organisms such as yeast, worms, and humans.

We propose that these interaction maps could be mined for the identification of new putative regulators of longevity. For this purpose, we have constructed longevity networks in both humans and worms. We reasoned that the essential first-order interactors of known longevity-associated genes in these networks are more likely to have longevity phenotypes than randomly chosen genes.

We have used C. elegans to determine whether post-developmental inactivation of these essential genes modulates lifespan. Our results suggest that the worm and human longevity networks are functionally relevant and possess a high predictive power for identifying new longevity regulators. ... By combining a network-based approach with the selection of genes required for development, we identified new lifespan regulatory genes at a frequency far exceeding that achieved in genome-wide screens. Though the effect of the new [genes] on lifespan is relatively modest, one can speculate that they might function in pathways or complexes that modulate core longevity functions.

As a footnote, it perhaps something of a sign of progress that bringing to light a dozen or so longevity-associated genes comes and goes almost without mention these days. It is prosaic now, not worthy of comment in the broader scientific press: bring on the next trick.

Injectable, Compressible, Shaped Tissue Scaffold

Biodegradable scaffolds are an important part of tissue engineering, providing a way to hold cells in place and shape their growth in three dimensions, breaking down gradually as the new tissue builds its own supporting extracellular matrix. Here an intriguing advance in scaffold technology is noted:

Bioengineers [have] developed a gel-based sponge that can be molded to any shape, loaded with drugs or stem cells, compressed to a fraction of its size, and delivered via injection. Once inside the body, it pops back to its original shape and gradually releases its cargo, before safely degrading.

"The simplest application is when you want bulking. If you want to introduce some material into the body to replace tissue that's been lost or that is deficient, this would be ideal. In other situations, you could use it to transplant stem cells if you're trying to promote tissue regeneration, or you might want to transplant immune cells, if you're looking at immunotherapy."

Consisting primarily of alginate, a seaweed-based jelly, the injectable sponge contains networks of large pores, which allow liquids and large molecules to easily flow through it. [Researchers] demonstrated that live cells can be attached to the walls of this network and delivered intact along with the sponge, through a small-bore needle. [The] team also demonstrated that the sponge can hold large and small proteins and drugs within the alginate jelly itself, which are gradually released as the biocompatible matrix starts to break down inside the body.

Normally, a scaffold like this would have to be implanted surgically. Gels can also be injected, but until now those gels would not have carried any inherent structure; they would simply flow to fill whatever space was available. [Researchers] pushed pink squares, hearts, and stars through a syringe to demonstrate the versatility and robustness of their gel.


Humanity+ 2012 Conference, December 1st in San Francisco

This year's Humanity+ conference is near:

The Humanity+ conference in San Francisco takes place on December 1-2, 2012 at Seven Hills Conference Center at San Francisco State University. ... Revolving around the theme "Writing the Future", the conference will explore the world of media and communicating Transhumanism. ... Speakers include multi-award winning science fiction author Kim Stanley Robinson, acclaimed biomedical gerontologist Aubrey de Grey, designer and theorist Natasha Vita-More, futurist Jamais Cascio, science fiction author David Brin, philosopher and proactionary principle advocate Max More, national best selling author Sonia Arrison, artificial general intelligence researcher Ben Goertzel, and more.

"Writing the Future" focuses on communicating how emerging and converging sciences and technologies are the tools for designing our future, based on the advances in robotics, nanotechnology, artificial intelligence, human enhancement, brain-computer integration, regenerative medicine, and radical life extension.

The future and its many narratives, both written and spoken, are is created by people of the present. In many cases, notably the biomedical realm, the intrinsic costs of pioneering technological research mean that the rate of progress is strongly influenced by public enthusiasm for its goals. This creates a dilemma, in that the public are often ambivalent (at best) concerning such goals, even when by any rational standards they should not be. Should those involved in such work therefore understate their goals when writing proposals and addressing a general audience, making them less "scary" and thereby attracting funds to make initial progress?


Investigating the Agelessness of Hydra

Hydra are one of the few ageless species, or at least a good candidate for such: researchers have watched populations age for years with no signs of increased mortality rates or declining pace of reproduction. One might view these creatures as an incremental step up from bacteria or yeast: multicellular animals that can reproduce asexually via budding, and which are extremely proficient at regeneration.

One line of thought regarding the agelessness of hydra is that they simply consistently and relentlessly renew all the tissues in their body, which is accomplished by having very many stem cells that don't decline over time. Hydra might follow a strategy of eliminating the inevitable buildup of malformed proteins, aggregate waste products, and similar damage in individual cells by (a) sacrificing and then replacing damage-bearing cells, and (b) using the bacterial approach of moving as much damage as possible into one of the two daughter cells produced in any cell division. Since a hydra has no brain, any cell can be sacrificed at any time so long as it is replaced with an equivalent new cell - the whole organism can be replaced completely over any arbitrarily short period of time provided it can find the metabolic resources to do so.

There's nothing magical about making cell lineages last essentially forever. All bacteria do it, and even complex organisms like we humans are capable of it. There is, for example, the process that ensures that the first cells of a human child are biologically young and free from damage even though the parents bear decades worth of accumulated damage in their cells. It's also possible that hydra use an aggressive repair and renewal process of this nature, either when they bud or on an ongoing basis.

Aging doesn't happen because it has to, aging happens because it's almost always advantageous from an evolutionary perspective - that we age is an example of the success of the gene built upon the pain, suffering, and death of the individual who bears it. Though apparently this isn't the case for hydra, and many other types of life that are closer to what we might think of as self-replicating machines rather than populations of individual entities. One might argue that the big downside of individual entityhood is the need for brain cells that store data, and thus cannot simply be replaced at arbitrary times. Or perhaps one might argue that a necessary precondition for individual entityhood is a loss of the processes of aggressive regeneration and tissue replacement such that a thing like a brain might be able to evolve in the first place.

In any case, not everything that the aging research community works on is both interesting and potentially useful when it comes to intervening in human aging. Ongoing research into the biology of hydra is certainly interesting, but I'm dubious that we'll find anything that can inform us of a way out of our present predicament, the one in which we are aging to death. We and the hydra live in very different worlds, with very different requirements for success.

Here, for example, is a paper that steps into the stem cell biology of the hydra, but I don't think it tells us all that much in the end. The interesting matter to my mind is not really stem cell population size, or the ability to manipulate it by some genetic manipulation, but rather damage over time - breaking hydra agelessness by removing an aspect of their biology doesn't necessarily say anything meaningful about aging in general. Further, the release materials for this work overly stretch the case for the relevance of this work to human aging:

FoxO is a critical regulator of stem cell maintenance in immortal Hydra

"Surprisingly, our search for the gene that causes Hydra to be immortal led us to the so-called FoxO gene", says Anna-Marei Böhm, PhD student and first author of the study. The FoxO gene exists in all animals and humans and has been known for years. However, until now it was not known why human stem cells become fewer and inactive with increasing age, which biochemical mechanisms are involved and if FoxO played a role in ageing. In order to find the gene, the research group isolated Hydra's stem cells and then screened all of their genes.

The Kiel research team examined FoxO in several genetically modified polyps: Hydra with normal FoxO, with inactive FoxO and with enhanced FoxO. The scientists were able to show that animals without FoxO possess significantly fewer stem cells. Interestingly, the immune system in animals with inactive FoxO also changes drastically. "Drastic changes of the immune system similar to those observed in Hydra are also known from elderly humans", explains Philip Rosenstiel of the Institute of Clinical Molecular Biology at UKSH, whose research group contributed to the study.

"Our research group demonstrated for the first time that there is a direct link between the FoxO gene and ageing", says Thomas Bosch from the Zoological Institute of Kiel University, who led the Hydra study. Bosch continues: "FoxO has been found to be particularly active in centenarians - people older than one hundred years - which is why we believe that FoxO plays a key role in ageing - not only in Hydra but also in humans". However, the hypothesis cannot be verified on humans, as this would require a genetic manipulation of humans. Bosch stresses however that the current results are still a big step forward in explaining how humans age. Therefore the next step must be to study how the longevity gene FoxO works in Hydra, and how environmental factors influence FoxO activity.

I would say certainly and by all means do more work on the biology of hydra agelessness, but I don't think that these researchers have made any great leap of relevance to human aging here.

Digging Deeper into Zebrafish Brain Regeneration

Zebrafish, like a number of lower animals, are far better at regenerating lost tissue than mammals. In recent years, researchers have been investigating the mechanisms by which this superior regeneration works. It is possible that mammals such as we humans still have the necessary machinery, but it is turned off - or if we have lost it, that there is a way to recapture some of that loss through genetic engineering or other advanced medicine. But first, far more must be learned of the way in which regeneration proceeds in species like the zebrafish:

The secret to zebrafish's remarkable capacity for repairing their brains is inflammation ... Neural stem cells in the fish's brains express a receptor for inflammatory signaling molecules, which prompt the cells to multiply and develop into new neurons.

Zebrafish, like many other vertebrates, are able to regenerate a variety of body tissues, including their brains. In fact [mammals] are the ones that seem to have lost this ability - they are kind of the odd ones out. [Given] the therapeutic potential of neuron regeneration for patients with brain or spinal injuries, [we'd] like to figure out if we can somehow reactivate this potential in humans.

Last year, [researchers] discovered that radial glial stem cells are responsible for producing new neurons during brain regeneration in zebrafish. But they didn't know what prompted these cells to spring into action. Inflammation seemed a good candidate, [as] it arises as an immediate response to injury.

[Researchers] introduced Zymosan A - an immunogenic factor derived from yeast - into the brains of zebrafish to induce inflammation in the absence of injury. They found that, just like brain injury, Zymosan A induced significant glial cell proliferation and new neuronal growth. In fish with suppressed immune responses, however, brain injury did not induce regeneration, further suggesting a role for inflammation.


SENS Foundation Hiring a Telomere Biology Research Lead

OncoSENS is the cancer-related project in the Strategies for Engineered Negligible Senescence (SENS). In typically ambitious fashion the plan is to remove the ability of humans to generate cancer by blocking all processes that can lengthen telomeres, as telomere lengthening is a function that all cancers must abuse in order to bypass normal limits on cell replication.

No other commonality between all cancers is presently known, and this blocking of telomere lengthening looks very likely to work, but for my money I'd prefer a more traditional approach to building robust cancer therapies - or perhaps adapting the mechanisms by which mole rats render themselves immune to cancer. The reason for this preference is that a person unable to lengthen telomeres would, at a minimum, require replacement of all stem cell populations once a decade or so - and if you miss that procedure, you will decline pretty quickly with many of the symptoms of an accelerated aging condition.

The SENS Foundation is presently hiring for a research group lead position in the OncoSENS project; pass it on to anyone you know who might be interested:

SENS Research Foundation is hiring for our research center located in Mountain View, CA. We are seeking a team lead for our OncoSENS group to work both on established projects and new independent research geared towards understanding the genetic mechanisms of telomerase-independent telomere elongation; for example, see the project Identifying and Disrupting Mediators of ALT. Research is focused on developing therapies against cancers that maintain their replicative potential using alternative lengthening of telomeres (ALT), and more generally the mission of the Foundation, toward overcoming the diseases and disabilities of aging.

Qualified candidates will have a Ph.D. in the chemical/biological sciences. Duties will include bench work, management of a small team of lab researchers, the preparation of grant proposals, internal and external progress reports, individual and collaborative publication. The project lead will develop, interpret and implement standards, procedures, and protocols for the OncoSENS research program and may collaborate on determining strategic directions in the research program.


More Thoughts on Regenerative Medicine Timelines

By way of following on from Friday's post on timelines for the next decade in regenerative medicine and organ regrowth, here is another commentary on much the same subject:

Regenerative medicine may transform transplants

Dr. Brooks Edwards [is the] deputy director of the Mayo Clinic Center for Regenerative Medicine and director of the Mayo Transplant Center. [His] goal, before retiring from Mayo, is to be able to treat most of those patients with regenerative strategies, so they don't have to wait for a catastrophe to happen to a healthy person to become an organ donor, he said.

"We're going to have strategies to repopulate cells in the heart for patients with heart failure to restore them to normal cardiac function, we're going to have regenerative medicine strategies to be able to restore diseased liver to healthy liver by re-growing a liver from the recipient," he said. "We're going to have regenerative medicine strategies for patients with chronic lung disease that could avoid lung transplant."

Those treatments are not available now, said Edwards, who is 55. "But I think when you talk about five- and ten-year horizon, I think some of these things are going to become reality and we're going to look back at the current era and say, 'can you imagine that they had to wait for a deceased donor to treat that patient with heart failure?'" he said.

It seems that the research community is fairly bullish on prospects for the next ten years of development - the process of moving new regenerative therapies from laboratory demonstrations to readiness for clinical tests. We should listen to these voices; they form an important signal for those of us who watch the pace of progress. As always, however, this doesn't much account for the roadblock of the FDA, which might well add an additional and very unnecessary decade of delay for any new advance on its way towards widespread clinical application.

Nonetheless, I think it's clear that we live in exciting times. A great deal of money is funneled into applications of stem cell science, and a great deal of progress is occurring: this is a large, active, and enthusiastic research community, racing ahead towards clearly envisaged goals. I do not think it unreasonable to expect to see a range of complex inner organs grown from cells in the laboratory by fifteen to twenty years from now. The challenges are largely those of control and knowledge: figuring out the chemical signals that instruct cells to do the right thing at the right time, building better growth environments to provide cells the right cues, and so forth. This area is exactly where much of the research in the field is focused, so a fair pace of progress should be expected.

That said, I do think it unreasonable to expect the shiny new biotechnologies of 2030 to become widely available very soon after their development, or at least not in the US and Europe, as the present direction for regulation in medicine is to pile costs, requirements, and interference ever higher. That, unfortunately, also slows down the research itself by stifling investment and business development - we can only imagine how rapidly this field would be moving if it didn't take a decade and tens of millions of dollars to push a new therapy through the onerous process of regulatory approval.

"Successful Aging" Seems a Little Ridiculous as a Concept

As I've pointed out in the past, the concept of "successful aging" looks more and more awkward and ill-thought the closer you examine it. At the high level the idea is connected to compression of morbidity, pushing disability and frailty further out into old age without extending life - but are these things even possible as goals for medical science?

It seems likely not: either you extend life or you don't; either you treat aging by slowing its progression or reversing it or you don't. Aging itself is by definition a degenerative medical condition that causes pain, suffering, and death - so the idea of aging successfully seems a contradiction in terms at best, and at worst a sort of propaganda intended to deliberately cloud the issue of what should be done by the medical research community:

Increasing longevity is one of the great achievements of our civilization, but it has also given rise to discussion about good and successful aging. The concept of successful aging has attracted much debate, but there is still no universally accepted definition or standard measurement tool for it. The Encyclopedia of Aging defines successful aging as survival (longevity), health (lack of disabilities), and life satisfaction (happiness). It appears that the main sources of difficulty lay in the ambiguity of the meaning of "success," in the complexity of the aging process, the rapid changes taking place in society, and the changing characteristics of the older population.

Discussions on successful aging have taken two main perspectives: one defines successful aging as a state of being, while the other understands it as a process of adaptation, described as doing the best with what one has. Studies taking the adaptation approach have often found that older people themselves feel they are aging successfully, even though traditional quantitative models say otherwise. Successful aging as a state of being, then, is an objective measurable condition at a certain point in time, demonstrating the positive extreme of normal aging. The most influential model of successful aging as a state of being was introduced by Rowe and Kahn, who characterize "success" as absence of disease and disability, maintained physical and mental functioning, and active engagement with life. Many studies and definitions take the view that successful aging is possible only among individuals without disease and impairment.

Obviously such categorizations are likely to exclude most older people, typically the oldest-old, from the possibility of successful aging.


The Goal of Lifelong Perfect Health

A short Slate article here looks at some comments made by Aubrey de Grey on the goals and outcomes of rejuvenation biotechnology research:

"I do not like to use the word immortality. It gives a very bad, a wrong impression about my work. I work on health. I am interested in ensuring that people will stay completely youthful, like young adults, for as long as they live," he said at a press conference at Ciudad de las Ideas, an annual conference about big ideas held in Puebla, Mexico.

de Grey is the founder of the SENS Foundation, a nonprofit that, among other things, is funding projects intended to cure aging, if not dying. His goal: that everyone may stay a health 29 for as long as they may live. "It is quite likely that there will be a big side effect of doing that, which is that people will live a lot longer, but that is just a side effect," he says.

Let's say that de Grey's research pans out - whether it's in the next 20 years, as he hopes may be possible; in the next 40, which he thinks is likely; or not for the next 100, which could happen "if we are unlucky or if we do not try hard enough." How would lifelong health change the way we live? ... "I think that actually society will be very different but ... mostly in ways that it is already moving as a result of technology, including health technologies, that are happening already," he says. "We see today many more people having multiple careers, moving from one to another; having multiple long-term partnerships one after another; generally much more equality between ages; people having partners that are very far distance from them in age. These things I think will simply continue to progress."


Regenerative Medicine Timelines from Anthony Atala

Anthony Atala is one of the present luminaries of tissue engineering, or at least that part of the field focused on building replacement organs and pseudo-organs - the latter being tissue structures that are not exactly the same as what they replace, but still get the job done, such as the substitute bladder tissue manufactured by Tengion. Atala is also on the SENS Foundation research advisory board, and so can be seen to look favorably on the agenda of engineering longer healthy human life spans.

I notice that a recent article has Atala giving some thoughts on timelines for organ regrowth, which you might compare to similar thoughts from another figure in the field, and to speculative timelines for the use of animal organs, such as those grown in engineered chimeras. Researchers are usually fairly reticent to put times and timelines on the table in public, for all the obvious reasons, so I think it worth taking note when they do:

How Close Are We to Making Like Salamanders and Regenerating Our Own Organs?

Right now, more than 116,000 people are on the U.S. organ transplant waiting list. But what if they could just regrow their own livers, hearts, and kidneys, even 3-D print them? Anthony Atala, the director of the Wake Forest Institute for Regenerative Medicine, is working to make that a reality. Speaking today at Ciudad de las Ideas, an annual conference about big ideas held in Puebla, Mexico, and sponsored by Grupo Salinas, Atala asked, "If a salamander can do it, why can't we?"

So how long until regenerative medicine can make the agonizingly long transplant waiting list a thing of the past? Within the next decade, Atala predicts, "we will see partial replacements of [some] organs - not the entire replacement, but many times that's all we need." Of course, the very necessary regulatory process will have to be carried out before there is widespread use of regenerated organs. Atala notes that the average drug takes 15.5 years to be approved in the United States, and regenerative medicine is neither drug nor medical device, but a combination thereof, which makes approval even more complicated.

"Very necessary" is complete nonsense when describing the enormously restrictive and costly regulatory straightjacket fastened around modern medicine. The FDA is an ever-increasing dead weight that does little but slow down - or block entirely - important progress in medical science. Its existence makes every new medical technology vastly more expensive to develop, and in many cases regulators have closed the door entirely on lines of development because there is no way that benefits could be profitably realized.

Worse, regulators can declare entire potential fields of medicine forbidden, as is the case for applications of longevity science. Aging is not a defined disease for the FDA, and all that is not explicitly permitted is forbidden in their regulatory rubric - so there is no path to legally commercialize a therapy for aging in the US, even when it becomes technically possible to do so. Thus there is little to no funding for such development.

The medicines that might have been and the progress that might have happened is all invisible, of course, so few people pay any attention to it - the broken window fallacy again, where the harm done and costs incurred are swept under the carpet, so people can suggest that we are all better off for it. How much further might medical science have advanced if the ruinous cost of clinical trial after trial after trial, under far more onerous requirements than existed even a few decades ago, were instead funneled into more research?

To explain the seeming gap between accelerating progress in the laboratory and lagging slowness in clinical medicine, one only has to point to the regulators. They are to blame, and the rest of us for not doing something about this squalid situation.

Work on Better Understanding Oxidative Damage in Aging

Oxidative stress is a term you'll see a lot when reading the literature of aging research. The more reactive oxidant compounds there are in a cell, the more they will react with important proteins, modifying them and thus causing cellular machinery to run awry or require repair. Aging is characterized by rising levels of oxidative stress, caused by things such as increased presence of metabolic byproducts that are ever more inefficiently removed, accumulating damage to mitochondria, and so forth.

This is still something of a high level picture, however, and there is still a lot of room left for researchers to expand the understanding of how exactly oxidative damage progresses, or how it contributes to specific manifestations of aging, such as increased cellular senescence. Hence we see work of this nature:

Protein damage mediated by oxidation, protein adducts formation with advanced glycated end products and with products of lipid peroxidation, has been implicated during aging and age-related diseases, such as neurodegenerative diseases.

Increased protein modification has also been described upon replicative senescence of human fibroblasts, a valid model for studying aging in vitro. However, the mechanisms by which these modified proteins could impact on the development of the senescent phenotype and the pathogenesis of age-related diseases remain elusive.

In this study, we performed in silico approaches to evidence molecular actors and cellular pathways affected by these damaged proteins. A database of proteins modified by carbonylation, glycation, and lipid peroxidation products during aging and age-related diseases was built and compared to those proteins identified during cellular replicative senescence in vitro.

Common cellular pathways evidenced by enzymes involved in intermediate metabolism were found to be targeted by these modifications, although different tissues have been examined. ... An important outcome of the present study is that several enzymes that catalyze intermediate metabolism, such as glycolysis, gluconeogenesis, the citrate cycle, and fatty acid metabolism have been found to be modified. These results indicate a potential effect of protein modification on the impairment of cellular energy metabolism. Future studies should address this important issue by combining metabolomics and targeted proteomic analysis during cellular and organismal aging.


Towards Tissue Engineered Large Intestines

Last year a research group demonstrated that they could build tissue engineered sections of small intestine in mice. That same group is also working on producing structures of the large intestine using human cells, and here is an update on their progress:

[Researchers] have for the first time grown tissue-engineered human large intestine. ... Our aim is exact replacement of the tissue that is lacking. There are many important functions of the large intestine, and we can partially compensate for that loss through other medical advances, but there are still patients for whom this technology might be revolutionary if we can cross the translational hurdles. This is one of the advances that brings us toward our goal.

The human tissue-engineered colon includes all of the required specialized cell types that are found in human large intestine. The research team grew the tissue-engineered large intestine from specific groups of cells, called organoid units that were derived from intestinal tissue normally discarded after surgery. The organoid units grew on a biodegradable scaffold. After 4 weeks, the human tissue-engineered colon contained the differentiated cell types required in the functioning colon, and included other key components including smooth muscle, ganglion cells, and components of the stem cell niche. ... This proof-of-concept experiment is an important step in transitioning tissue-engineered colon to human therapy.


The Greatest Instance of the Broken Window Fallacy

We as a species are defined by our ability to create: given time we will build new wonders from all the matter we can lay our hands on. The true legacy of every generation is the new advances they create in technology - that progress in creation is the only thing likely be recalled in the distant future. Yet despite a history of creation piled upon creation, the urge to destroy is also strong; a certain love of destruction seems a hardwired part of human nature. See the broken window fallacy, for example, which is the 19th century formulation of an ancient truth: that people look upon the consequences of destruction selectively, and call it beneficial.

Suppose it cost six francs to repair the [window broken by a child], and you say that the accident brings six francs to the glazier's trade - that it encourages that trade to the amount of six francs - I grant it; I have not a word to say against it; you reason justly. The glazier comes, performs his task, receives his six francs, rubs his hands, and, in his heart, blesses the careless child. All this is that which is seen.

But if, on the other hand, you come to the conclusion, as is too often the case, that it is a good thing to break windows, that it causes money to circulate, and that the encouragement of industry in general will be the result of it, you will oblige me to call out, "Stop there! Your theory is confined to that which is seen; it takes no account of that which is not seen."

It is not seen that as [the owner of the window] has spent six francs upon one thing, he cannot spend them upon another. It is not seen that if he had not had a window to replace, he would, perhaps, have replaced his old shoes, or added another book to his library. In short, he would have employed his six francs in some way, which this accident has prevented.

The lesson of the broken window is that destruction is never beneficial. It is a cost, and that cost must be paid at the expense of some other benefit. This lesson is needed: the broken window fallacy was widespread two centuries ago and remains so now. You will hear commentary after every natural disaster suggesting that the resulting expenditures on repair will benefit the economy, for example.

What is the greatest ongoing disaster, the cause of the greatest destruction? The answer is degenerative aging. Aging destroys human capital: knowledge, skills, talents, the ability to work, the ability to create. It does so at a ferocious rate, a hundred thousand lives a day, and all that they might have accomplished if not struck down. If translated to a dollar amount, the cost is staggering - even shifts in life expectancy have gargantuan value. And why shouldn't they? Time spent alive and active is the basis of all wealth.

It is unfortunate, but many people advocate for the continuation of aging, for relinquishment of efforts to build medicines to extend health life. Among these are people who welcome aging and death because to their eyes it gives a young person the chance to step into a role vacated by an older person. This is another form of the broken window, however: the advocate for aging looks only at the young person, and dismisses what the older person might have done were they not removed from the picture by death or disability. So too, any apologism for aging based on clearing out the established figures because it provides a greater opportunity for younger people to repeat the same steps, follow the same paths, relearn the same skills, redo the same tasks ... these arguments are the broken window writ large.

Vast wealth and opportunity bleeds into the abyss on a daily basis, destroyed because the people who embody that wealth and opportunity decay and die. We would all be wealthier by far given the medical means to prevent these losses. In your thoughts on aging, don't ignore the vast invisible costs - the work never accomplished, the wonders never created, because those who could have done so never had the chance. The enforced absence of the age-damaged, the frail, the disabled, and the dead is in and of itself a form of damage; the loss of their skills and knowledge is something that must be repaired. That requires work and resources that might have gone to new creations, rather than catching up from loss.

So this continues, and the perpetual devotion of resources to repair and recover from the losses of death and disability is a great ball and chain shackled to our ability to create progress. But most people don't think of at all - it is invisible to them. Nonetheless, the costs of aging that we labor under are so vast that the introduction of ways to rejuvenate the old will lead to an blossoming of wealth and progress the likes of which has never before been seen.

Lower Vitamin D Levels Correlated to Human Longevity

This research result is noted because it stands in opposition to the present consensus on vitamin D and long term health in humans; the evidence to date supports a correlation between higher levels of vitamin D, a lower risk of age-related disease, and a longer life expectancy. But here we see the opposite result. This sort of outright contradiction is usually indicative of some greater complexity under the hood yet to be outlined and understood - and there's certainly no shortage of complexity in metabolism:

Low levels of 25(OH) vitamin D are associated with various age-related diseases and mortality, but causality has not been determined. We investigated vitamin D levels in the offspring of nonagenarians who had at least one nonagenarian sibling; these offspring have a lower prevalence of age-related diseases and a higher propensity to reach old age compared with their partners.

We [assessed] vitamin D levels, [dietary] vitamin D intake and single nucleotide polymorphisms (SNPs) associated with vitamin D levels. We included offspring (n = 1038) of nonagenarians who had at least one nonagenarian sibling, and the offsprings' partners (n = 461; controls) from the Leiden Longevity Study.

The offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L), independent of possible confounding factors. ... Compared with controls, the offspring of nonagenarians who had at least one nonagenarian sibling had a reduced frequency of a common variant in the CYP2R1 gene, which predisposes people to high vitamin D levels; they also had lower levels of vitamin D that persisted over the 2 most prevalent genotypes. These results cast doubt on the causal nature of previously reported associations between low levels of vitamin D and age-related diseases and mortality.


Hypothesizing a Link Between Taste Receptors and Longevity

Since calorie intake has a comparatively large impact on natural variations in life expectancy, any genetic difference that systematically reduces calorie intake in some way should be correlated with increased longevity. So how about differences in the genes that determine taste? Here researchers search for signs of that correlation:

Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process.

Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy.

We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics.

Given the broad role of this gene, the correlation with longevity may or may not have anything to do with a tendency to reduce calorie intake through differences in food preference.


Many Longevity Manipulations Seem to Work Through Insulin Signaling

There are many ways to manipulate a single protein or gene in lower animals in order to modestly slow aging and extend life, and new ones are discovered on a regular basis. This process of discovery tends to proceed more rapidly for short-lived laboratory species like flies and nematode worms, where evaluating alterations in life span requires less time and fewer resources. Thus more and more diverse studies can be conducted within a given budget in comparison to, say, work in mice.

So: genes can be mutated via genetic engineering, or removed, or doubled up. An individual protein produced from a genetic blueprint can be created more rapidly so as to boost its presence in cells or its production dialed back to lower levels. This is not an exhaustive list. Any of these possibilities can be targeted to specific cell types or portions of anatomy, if so desired. There are far more combinations to tinker with than the research community has capacity for, so researchers tend to work in areas that have already demonstrated some promise, or where the maps of function and interaction between protein machinery are better understood.

Even seemingly trivial functions in the metabolism of lower animals are enormously complex in their details. Anything of the subsystems involved in how food is converted into something that cells can use for energy, for example, or how body temperature is regulated. These evolved systems make use of overlapping feedback loops that might involve dozens or hundreds of proteins, and any given protein might be promiscuously involved in several quite different systems; if our biology teaches us anything it is that evolution favors the reuse of existing materials. A great example is p53, which shows up as a player in many of the central, crucial processes of cellular biology.

Alter the amount of a protein in circulation and that ripples out through all the networks of protein machinery that it is in involved with. You can't flip any switch in isolation. This diversity of components in every biological system is one of the reasons why there are seemingly so many different ways to alter life span in lower animals. There might be only a few important networks of proteins tightly coupled to determination of life span, such as that involved in the calorie restriction response, but within each network there are possibly dozens of proteins that can be tweaked to produce some form of beneficial effect on the whole - and of course varying degrees of side-effects.

So when researchers uncover yet another life extending methodology, they must then chase cause and effect through networks of interacting protein machineries until they get to something that looks familiar - which they usually do. One very well studied area is the network of insulin and insulin-like growth factor (IGF) signaling, and as is the case for increased autophagy, many diverse longevity enhancing alterations touch on this machinery.

Here is an example of the way in which researchers proceed from a single manipulation that extends life in flies, go on to explore the networks that it influences, and find their way to IGF signaling, as is often the case. By doing this they shed a little more light on how metabolism can operates to somewhat change the pace of aging:

Modulation of Methuselah Expression Targeted to Drosophila Insulin-producing Cells Extends Life and Enhances Oxidative Stress Resistance:

Ubiquitously reduced signaling via Methuselah (MTH), a G-protein coupled receptor (GPCR) required for neurosecretion, has previously been reported to extend life and enhance stress resistance in flies. Whether these effects are due to reduced MTH signaling only in specific tissue(s) and through with signaling effects reduced MTH might produce these phenotypes remains unknown.

We determined that reduced expression of mth targeted only to the insulin-producing cells (IPCs) of the fly brain was sufficient to extend life and enhance oxidative stress resistance. Paradoxically, we discovered that overexpression of mth targeted to the same cells has similar phenotypic effects to reduced expression due to MTH's interaction with β-arrestin, which uncouples GPCRs from their G-proteins.

We confirmed the functional relationship between MTH and β-arrestin by finding that IPC-targeted overexpression of β-arrestin alone mimics the longevity phenotype of reduced MTH signaling. As reduced MTH signaling also inhibits insulin secretion from the IPCs, the most parsimonious mechanistic explanation for its longevity and stress resistance enhancement might be through reduced insulin/IGF signaling (IIS). However, examination of phenotypic features of long-lived IPC-mth modulated flies as well as several downstream IIS targets implicates enhanced activity of the JNK stress resistance pathway more directly than insulin signaling in the longevity and stress resistance phenotypes.

A great deal of present day research into aging and longevity is exactly like this: shining narrow beams onto a very complex system, establishing and following maps of gene and protein relationships, and gradually filling out information on how it all fits together. The answers obtained from any individual study are rarely as comprehensive or certain as would be the case in a perfect world, alas. It's a slow process.

This is interesting work, but ultimately of limited utility when it comes to our health and life span: slowing aging by adjusting human metabolism certainly lies in the future, but we'll be old by the time that work reaches any sort of meaningful fruition. Ways to slow aging are of little use to people already bowed and damaged by that process. This isn't to say that the knowledge generated here is useless; all knowledge is useful in the fullness of time. This just isn't a part of the road to lengthening human life any time soon - it's a part of the road to fully understanding the biology of living organisms. Which is not the same thing at all.

Some Visible Signs of Aging Reflect Biological Age

As one might expect, some of the easily measurable, more visible signs of aging tend to reflect a correspondingly greater risk of age-related conditions. Aging is a body-wide process, after all. Different people age at modestly different rates, predominantly due to lifestyle choices involving diet and exercise these days, now that the burden of infectious disease is greatly reduced. Genetic differences do contribute to some degree, but appear to be more important in survival at old age. The aim of any meaningful advance in longevity science is to make all of these natural differences irrelevant, washed out by the benefits of therapies that can slow or reverse various aspects of degenerative aging:

In a new study, those who had three to four aging signs - receding hairline at the temples, baldness at the head's crown, earlobe crease, or yellow fatty deposits around the eyelid (xanthelasmata) - had a 57 percent increased risk for heart attack and a 39 percent increased risk for heart disease. ... "The visible signs of aging reflect physiologic or biological age, not chronological age, and are independent of chronological age."

Researchers analyzed 10,885 participants 40 years and older (45 percent women) in the Copenhagen Heart Study. Of these, 7,537 had frontoparietal baldness (receding hairline at the temples), 3,938 had crown top baldness, 3,405 had earlobe crease, and 678 had fatty deposits around the eye. In 35 years of follow-up, 3,401 participants developed heart disease and 1,708 had a heart attack.

Individually and combined, these signs predicted heart attack and heart disease independent of traditional risk factors. Fatty deposits around the eye were the strongest individual predictor of both heart attack and heart disease. Heart attack and heart disease risk increased with each additional sign of aging in all age groups and among men and women. The highest risk was for those in their 70s and those with multiple signs of aging.


Quantifying Gains in Life Expectancy Correlated With Exercise

In recent years a number of studies have tried to put numbers to the gains in life expectancy that might accompany exercise. Here is another:

In pooled data from six prospective cohort studies, the researchers examined associations of leisure-time physical activity of a moderate to vigorous intensity with mortality. They analyzed data from more than 650,000 subjects and followed subjects for an average of ten years - analyzing over 82,000 deaths.

Participation in a low level of leisure time physical activity of moderate to vigorous intensity, comparable to up to 75 min of brisk walking per week, was associated with a 19 percent reduced risk of mortality compared to no such activity. Assuming a causal relationship, which is not specifically demonstrated in this research, this level of activity would confer a 1.8 year gain in life expectancy after age 40, compared with no activity. For those who did the equivalent to 150 min of brisk walking per week - the basic amount of physical activity currently recommended by the federal government - the gain in life expectancy was 3.4 years.

Participants faring best were those who were both normal weight and active: among normal weight persons who were active at the level recommended by the federal government, researchers observed a gain in life expectancy of 7.2 years, compared to those with a BMI of 35 or more who did no leisure time physical activity.

You might compare these results to those obtained from a study of highly trained athletes and work examining jogging and life expectancy.


A Look at the Camp of Slowing Aging via Metabolic Alteration

As I'm sure the regular readers know by now, researchers interested in extending human life span form a minority community within the broader medical research establishment. In that small community, most scientists see the best path ahead as a slow, incremental, and challenging process of finding ways to safely alter metabolism in order to modestly slow down the aging process. They don't expect significant progress in anything other than fundamental research and discovery of mechanisms any time soon. The alternate approach of reversing the known forms of damage that cause degenerative aging, so as to aim for rejuvenation, remains as yet a minority position - sadly, because it is the only plausible chance at radical life extension of decades and more within our lifetimes.

For today, let us look at the metabolic alteration camp, however. What are their aims in greater detail? To begin with, a lot of research has spiraled out from investigations of calorie restriction - which is, after all, an evolved way to shift the operation of metabolism such that aging is slowed and life span extended. Billions of dollars have been funneled into trying to understand how this works, in search of ways to replicate some of the same effects.

Understanding in this context means building a map of the various signals, proteins, epigenetic alterations, and so forth: knowing how they flow from one to another and act as a network in unison. The work accomplished to date is just a beginning, even billions of dollars and more than a decade down the line, however. Metabolism is very, very complex, and thus at this point there is little of practical worth to show for all this time and money. Sufficient understanding to produce even moderately effective and safe calorie restriction mimetic drugs still lies in the future.

Other lines of research are underway: metabolic alteration is not just a field focused on calorie restriction these days. Below you will find a couple of open access publications that give some insight into how the researchers focused on metabolic manipulation to slow aging presently see the state of play. It is very similar to that landscape of drug discovery and development for complex and only partially understood diseases like Alzheimer's: a matter of uncovering new information that proceeds hand in hand with the evaluation of classes of protein that might be manipulated with designer drugs to achieve some beneficial effect with hopefully minimal side-effects. Indeed, one of the reasons that this hard, inefficient approach to extending healthy life does presently dominate over other, superior approaches - such as the goal of periodic repair for cellular and other biological damage - is that it can be treated as an extension of existing drug discovery programs. The power of inertia in the culture of research shouldn't be underestimated: we humans don't like change, even when beneficial.

Epigenetic drugs: a novel anti-aging strategy?

In this Opinion, we present arguments that the development of specific drugs which target epigenetic pathways could be a highly promising anti-aging strategy. Epigenetic factors including DNA methylation, histone modifications, and alteration in microRNA expression play key roles in controlling changes in gene expression and genomic instability throughout the human lifespan. Epigenetic modifications are finely balanced and highly reversible in normal tissues.

Histone deacetylases (HDACs) are global transcriptional regulators; [the] therapeutic effects of HDAC inhibitors are based on their ability to affect the transcription of various genes ... Overall, as a major mechanism of transcriptional regulation, protein acetylation is a key controller of many physiological processes essential for the maintenance of homeostasis and a healthy lifespan. Consequently, it is believed that the development of specific drugs which target HDAC activity could be a highly promising anti-aging strategy.

Notwithstanding all doubts, in recent years, experimental research has emerged on the life-extending potential of synthetic HDAC inhibitors. A substantial increase in both mean and maximum survival by up to 30-50% without diminution of locomotor activity, resistance to stress, or reproductive ability was observed by feeding Drosophila melanogaster the HDAC inhibitor, PBA (4-phenylbutyrate), throughout adulthood.

In conclusion, understanding the molecular mechanisms underlying the protective role of HDAC inhibitors and other modulators of epigenetic processes could bring us closer to the development of novel drug targets for age-associated chronic diseases. In our opinion, this approach may also provide a new way for the development of efficient anti-aging treatments.

The spatiotemporal dynamics of longevity-defining cellular processes and its modulation by genetic, dietary, and pharmacological anti-aging interventions

Aging of multicellular and unicellular eukaryotic organisms is a highly complex biological phenomenon that affects a plethora of processes within cells. ... The focus of this Frontiers Special Topic Issue is on an important conceptual advance in our understanding of how cells integrate and control these numerous processes and how genetic, dietary, and pharmacological anti-aging interventions extend longevity by altering their functional states and spatiotemporal dynamics.

Collectively, the articles in this Issue highlight the various strategies used by evolutionarily diverse organisms for coordinating these longevity-defining cellular processes in space and time, critically evaluates the molecular and cellular mechanisms underlying such coordination, and outlines the most important unanswered questions and directions for future research in this vibrant and rapidly evolving field.

There is plenty of reading material to found by diving in to follow the links embedded in the second item above.

Compression of Morbidity Through Physical Activity

Compression of morbidity is a hypothesis suggesting that advances in medical science are causing, or will cause, a compression of the terminal period of frailty, illness, and disability at the end of life, squeezing it into an ever-shorter fraction of the overall human life span. In colloquial use compression of morbidity is often spoken of as a practical goal by medical researchers who do not wish to talk openly about extending human life for political or funding reasons.

There is data to support the existence of compression of morbidity with respect to the effects of lifestyle choices on longevity, such as exercise. When it comes to advances in medical science, however, it seems unlikely that gains in life expectancy will forever lag behind gains in health. Consider aging in terms of accumulated damage, for example: if we find ways to repair that damage, then the overall life expectancy will increase, just as it does for any complex machine that is better maintained.

In any case, here is an example of present data supporting a compression of morbidity through increased physical activity:

"Active aging" connotes a radically nontraditional paradigm of aging which posits possible improvement in health despite increasing longevity. The new paradigm is based upon postponing functional declines more than mortality declines and compressing morbidity into a shorter period later in life. This paradigm (Compression of Morbidity) contrasts with the old, where increasing longevity inevitably leads to increasing morbidity.

We have focused our research on controlled longitudinal studies of aging. The Runners and Community Controls study began at age 58 in 1984 and the Health Risk Cohorts study at age 70 in 1986. We noted that disability was postponed by 14 to 16 years in vigorous exercisers compared with controls and postponed by 10 years in low-risk cohorts compared with higher risk. Mortality was also postponed, but too few persons had died for valid comparison of mortality and morbidity. With the new data presented here, age at death at 30% mortality is postponed by 7 years in Runners and age at death at 50% (median) mortality by 3.3 years compared to controls. Postponement of disability is more than double that of mortality in both studies. These differences increase over time, occur in all subgroups, and persist after statistical adjustment.


The Mechanism of Blind Mole Rat Cancer Immunity

Blind mole rats, like naked mole rats, do not appear to suffer from cancer - an aspect of their biology that probably drives more research interest at the moment than their exceptional longevity. The cancer suppression mechanism in naked mole rats has been explored in recent years, but here researchers discover that blind mole rats have evolved a different method of achieving the same end:

Blind mole rats and naked mole rats - both subterranean rodents with long life spans - are the only mammals never known to develop cancer. Three years ago, [researchers] determined the anti-cancer mechanism in the naked mole rat. Their research found that a specific gene - p16 - makes the cancerous cells in naked mole rats hypersensitive to overcrowding, and stops them from proliferating when too many crowd together.

"We expected blind mole rats to have a similar mechanism for stopping the spread of cancerous cells. Instead, we discovered they've evolved their own mechanism."

[The researchers] made their discovery by isolating cells from blind mole rats and forcing them to proliferate in culture beyond what occurs in the animal. After dividing approximately 15-20 times, all of the cells in the culture dish died rapidly. The researchers determined that the rapid death occurred because the cells recognized their pre-cancerous state and began secreting a suicidal protein, called interferon beta. The precancerous cells died by a mechanism which kills both abnormal cells and their neighbors, resulting in a "clean sweep." [The next step is] to find out exactly what triggers the secretion of interferon beta after cancerous cells begin proliferating in blind mole rats.

"Not only were the cancerous cells killed off, but so were the adjacent cells, which may also be prone to tumorous behavior. While people don't use the same cancer-killing mechanism as blind mole rats, we may be able to combat some cancers and prolong life, if we could stimulate the same clean sweep reaction in cancerous human cells."


More Researchers Should Speak Openly of Bold Goals in Extending the Healthy Human Lifespan

It's been a good few years since Aubrey de Grey first put forward his view of the political and social processes that inhibit progress in longevity science: the short summary is that a sort of logjam is created and sustained by the silence of researchers. When scientists don't talk openly about bold goals in their field then there can be no broad public support for funding of those goals, and conservative funding organizations will assign resources to other projects. There are many players in the grand game of scientific progress, but it ultimately falls to the researchers to define the bounds of the possible in the public eye, and it is their pronouncements - or lack thereof - that set the limits of what can be easily funded.

When researchers sit back and say nothing, or restrict themselves to visions of incremental gain when far more is possible, then progress suffers. There are many reasons as to why members of the aging research community were for decades very reluctant to talk about extending human life at all: fear of being associated with the fraudulent "anti-aging" marketplace, the normal reluctance to place a flag far out on the field even in an age of radical change, and so forth. Until very recently, the ethos of aging research was observation and little more, amounting to a stifling of research into extending the healthy human life span. Who can say how much of an opportunity was lost? Certainly the chance to build an aging research community with the same breadth and eagerness to produce measurable results as the cancer research community; that opportunity was squandered, and that task still lies ahead.

The old attitudes have largely thawed, however, in the face of a combination of persistent advocacy (such as that of the Methuselah Foundation and supporters) and many demonstrations of extended healthy life in laboratory animals. It has been welcome, these past few years, to see more researchers willing to step up to the plate to talk in public about radical life extension and pushing the boundaries of what can be achieved through biotechnology. Here is an example:

World leading laboratory aims to make life expectancy of 130 a normality:

Overshadowed by the white expanse of Edinburgh's Royal Infirmary, clinical trials, scientific research and medical advancements are taking place, out of sight and outwith the grasp of many minds. These lab coated magicians might not grab the headlines, [but] their pioneering projects could soon change life as we know it - starting with a life expectancy of over 100 years. This is the Scottish Centre for Regenerative Medicine (SCRM), whose discoveries surrounding the multiplying and self-renewing cells are bringing us step-by-step closer to organ regeneration, tissue repair and longer-lasting life.

"The average lifespan of the human being should be 130 years - that's what we're working towards," says Professor Bruno Péault, who has been internationally recognised for his research into stem cells. ... Professor Bruno Péault, who specialises in vascular regeneration, has been leading research into stem cells found in blood vessels, and their role in tissue development and repair.

"One day it would be the ultimate goal to be able to stimulate stem cells directly in situ, with the appropriate drug or hormone, to get them to regenerate. But this is science fiction at the moment," he says.

Science fiction only stays science fiction when the research community stands aside and remains silent. One of the important early steps in turning the vision of greatly extended healthy human life spans into reality is for scientists in relevant fields to loudly declare this to be a viable, desirable, plausible goal.

Lifestyle Choices and the Pace of Age-Related Memory Decline

Longitudinal studies generally show the anticipated results when it comes to physical activity and age-related decline - if you are more active, you tend to exhibit a slower pace of decline. Education, intelligence, and wealth are also correlated with longer life and slower onset of frailty and disability, but unlike physical activity it is less clear as to what the root causes of these correlations might be:

[Data on] one thousand nine hundred fifty-four healthy participants aged 35 to 85 at baseline from the Betula Project [was used] to reveal distinct longitudinal trajectories in episodic memory over 15 years and to identify demographic, lifestyle, health-related, and genetic predictors of stability or decline.

Memory was assessed according to validated episodic memory tasks in participants from a large population-based sample. ... Of 1,558 participants with two or more test sessions, 18% were classified as maintainers and 13% as decliners, and 68% showed age-typical average change. More educated and more physically active participants, women, and those living with someone were more likely to be classified as maintainers, as were carriers of the met allele of the catechol-O-methyltransferase gene. Less educated participants, those not active in the labor force, and men were more likely to be classified as decliners, and the apolipoprotein E ɛ4 allele was more frequent in decliners.


Another Example of a Mitochondrially Targeted Antioxidant

Mitochondria, the powerplants of the cell, generate damaging reactive oxygen species as a side-effect of their operation. Unfortunately, they are vulnerable to those very same reactive compounds, and some forms of resulting damage to proteins and genes can create dysfunctional cells that contribute to degenerative aging. The longer you live, the more of these dysfunctional cells you have, and the larger their harmful effects.

This contribution to aging can be modestly slowed by use of antioxidants targeted to the mitochondria, as they will soak up some fraction of the oxidants generated before they cause damage. It is also the case that the effects of mitochondrial damage could be reversed entirely by some form of repair or replacement technology, and that would be a far better outcome.

Nonetheless, a number of research groups are working on targeted antioxidants, compounds that are very different from generic antioxidants sold in stores. Ingested antioxidants that you can buy today do nothing for this issue of mitochondrial damage, and are arguably a net negative for long-term health because they interfere with the signaling processes that produced increased cellular maintenance in response to exercise or other forms of mild stress.

Here is news of a recent addition to the research groups working on mitochondrially targeted antioxidants:

[Researchers] have designed a compound that suppresses symptoms of [Huntington's] disease in mice. The compound is a synthetic antioxidant that targets mitochondria, an organelle within cells that serves as a cell's power plant. Oxidative damage to mitochondria is implicated in many neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's. The scientists administered the synthetic antioxidant, called XJB-5-131, to mice that have a genetic mutation that triggers Huntington's disease. The compound improved mitochondrial function and enhanced the survival of neurons. It also inhibited weight loss and stopped the decline of motor skills, among other benefits. In short, the Huntington's mice looked and behaved like normal mice.

Defending mitochondria from reactive oxygen species is a tall order. That's because mitochondria are both the main target of these molecules, and a cell's primary source of them. In other words, mitochondria produce the very thing that damages them. Researchers have studied whether dietary supplements of natural antioxidants such as vitamin E and coenzyme Q can mitigate the harmful effects of reactive oxygen species on mitochondria. Natural antioxidants don't target specific tissue within the body, however. And they've been shown to yield only marginal benefits in human clinical trials. These lackluster results have driven scientists to develop synthetic antioxidants that specifically target mitochondria. A few years ago, [researchers] synthesized an antioxidant called XJB-5-131 that zeroes in on bacterial membranes, which are very similar to mitochondrial membranes.

The scientists first injected Huntington's mice with XJB-5-131 and tested the mice's motor skills. ... We saw improvements across the board. The difference was amazing. XJB prevented the onset of weight loss and the decline in motor skills.

Next, the researchers removed neurons from the Huntington's mice and cultured the cells in the presence of XJB-5-131. They found that XJB-5-131 significantly improved the survival of neuronal cultures compared to untreated neuronal cultures. [Researchers] studied the impacts of the compound on the mice's mitochondrial DNA. They discovered that XJB-5-131 dramatically lowered the number of lesions on the DNA, which is a sign of oxidative damage. They also tallied the number of mitochondrial DNA copies, which plummets in diseased mice. This number was restored back to normal in XJB-treated mice.


A Possible Metabolic Signature of Biological Age in Mice

A low-cost, reliable method of measuring biological age is greatly sought after by the research community. People and laboratory animals age at different rates - by which I mean that they accumulate damage and changes characteristic of aging at different rates. Thus two individuals of the same species and same chronological age might have different biological ages thanks to life style, environment, access to medicine, and so forth.

Some interventions, such as calorie restriction, can slow the pace at which an individual ages, but measuring this slowing is a challenging process. Biological age is a simple concept at the high level, but finding a quick and reliable way to actually measure it has yet to happen. Thus while researchers would like to have rapid answers as to how effective any given method of slowing aging might be, they must wait and run long-lasting studies. The bottom line measure for any slowing of aging is to wait for the individuals in question to live out their lives and thus measure by effect on life span. Even in short-lived mice this can require years and thus a great deal of money. In longer-lived animals, ourselves included, it is simply impractical to run the necessary studies.

When it comes to the forthcoming generation of therapies capable of limited rejuvenation - by repairing some of the damage that causes degenerative aging - the situation is much the same, as is the need for a quick and easy measure of biological age. A therapy that actually produces some degree of rejuvenation should make a laboratory animal biologically younger than peers with the same chronological age. But how to measure that change without employing the lengthy and expensive wait-and-see approach?

Given the present state of affairs, any quick measure of biological age will speed research, making it very much faster and cheaper to assess varied means of extending healthy life. Some experiments that would presently require a year or more could be conducted in a few weeks or months: apply the therapy and evaluate the resulting changes in measures of biological age.

Several lines of research look promising when it comes to yielding a way to reliably and consistently evaluate biological age. One involves measurement of DNA methylation levels, and despite initial setbacks it may yet prove possible to tease out a useful measure from changes in the dynamics of telomere length. There are others. Here, for example, is a recent paper in which researchers present a method based on measurement of metabolite levels:

A metabolic signature predicts biological age in mice

Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice.

In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that over-express telomerase, their metabolic score corresponded to younger ages than expected.

Importantly, telomerase reactivation late in life by using a TERT based gene therapy recently described by us, significantly reverted the metabolic profile of old mice to that of younger mice ... These results indicate that the metabolomic signature is associated to the biological age rather than to the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism.

This might turn out to be an indirect measure of telomerase activity and little else, as over-specific matching is always a potential issue when searching for patterns in a large and complex system such as mammalian metabolism. Testing this metabolic signature against other means of accelerating or slowing aging in mice - such as calorie restriction - is thus one obvious next step.

Investigating the Mechanisms of Cellular Senescence

Senescent cells are those that have left the cell cycle without being destroyed, either by the immune system or by one of the processes of programmed cell death. They remain active, however, exhibiting what is termed a senescence-associated secretory phenotype (SASP): these cells secrete all sorts of chemical signals that prove harmful to surrounding tissues and the body as a whole - through promotion of chronic inflammation, for example.

The number of senescent cells in tissue grows with age, and this increase in numbers is one of the root causes of aging. Researchers have demonstrated benefits in mice through destroying senescent cells without harming other cells. Regular targeted destruction of senescent cells could be the basis for therapies that remove this contribution to degenerative aging.

Any other approach would require understanding more about SASP and how to control or reverse the unpleasant effects of senescence - and here is an example of this sort of research, aimed at identifying controlling mechanisms with an eye to building therapies to reduce SASP:

With advancing age, senescent cells accumulate in tissues and the SASP-elicited proinflammatory state is believed to have a complex influence on age-related conditions. For example, two major SASP factors, IL-6 and IL-8, together with other SASP factors, attract immune cells to the tissue in which senescent cells reside; depending on the tissue context, this immune surveillance can promote processes such as wound healing, the resolution of fibrosis, and tumor regression. At the same time, SASP factors can compromise the integrity of the ECM, thus facilitating cancer cell migration. In addition, the systemic proinflammatory phenotype seen in the elderly is believed to affect a broad range of age-related pathologies, including diabetes, cancer, neurodegeneration and cardiovascular disease and contributes to an age-related decline of the adaptive immune system (immunosenescence).

Despite the great potential impact of the SASP on the biology of senescence and aging, the mechanisms that regulate SASP are poorly understood. ... Here, we report the identification of NF90 as an RNA-binding protein that binds to numerous mRNAs encoding SASP factors (collectively named SASP mRNAs) and coordinately influences their post-transcriptional fate in a senescence-dependent manner.

In young, early-passage, proliferating fibroblasts, high NF90 levels contributed to the repression of SASP factor production. This repression was elicited mainly via reduction in SASP factor translation ... By contrast, in senescent cells NF90 levels were markedly reduced, which allowed increased expression of numerous SASP factors. Our results are consistent with a role for NF90 as a coordinator of the inhibition of SASP factor production in early-passage, proliferating fibroblasts; in senescent cells, the lower levels of NF90 lead to SASP de-repression, permitting higher expression of SASP factors


Creating Myelin-Producing Cells to Order

Myelin sheaths the axons of nerve cells, but the integrity of this sheathing degrades with age. Transplants of neural stem cells can be used to encourage myelin formation, and researchers are exploring this approach as a therapy for conditions involving more profound myelin loss.

There is always a demand in this sort of research for better and cheaper ways to obtain cells that have the desired effect. It is not trivial, for example, to isolate the right sort of neural stem cell, or establish a protocol for producing these cells from embryonic or induced pluripotent stem cells. A great deal of stem cell research these days involves the discovery of chemical signals, growth environments, and other necessary items to guide the growth of specific cell types.

Here is an example for myelin-forming cells, which will no doubt contribute to the next round of research and development of cell therapies aimed at regrowth of myelin:

Researchers have unlocked the complex cellular mechanics that instruct specific brain cells to continue to divide. This discovery overcomes a significant technical hurdle to potential human stem cell therapies; ensuring that an abundant supply of cells is available to study and ultimately treat people with diseases.

"One of the major factors that will determine the viability of stem cell therapies is access to a safe and reliable supply of cells. This study demonstrates that - in the case of certain populations of brain cells - we now understand the cell biology and the mechanisms necessary to control cell division and generate an almost endless supply of cells."

The study focuses on cells called glial progenitor cells (GPCs) that are found in the white matter of the human brain. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons.

One of the barriers to moving forward with human treatments for myelin disease has been the difficulty of creating a plentiful supply of necessary cells, in this case GPCs. Scientists have been successful at getting these cells to divide and multiply in the lab, but only for limited periods of time, resulting in the generation of limited numbers of usable cells. ... Overcoming this problem required that [researchers] master the precise chemical symphony that occurs within stem cells, and which instructs them when to divide and multiply, and when to stop this process and become oligodendrocytes and astrocytes.


Not All Longevity Manipulations Play Nice Together

One of the pleasant aspects of the repair approach to intervention in aging, such as that proposed in the Strategies for Engineered Negligible Senescence (SENS), is that all distinct forms of repair therapy can reasonably be expected to complement one another. Undergo a procedure to fix mitochondrial damage or break down an AGE such as glucospane, for example, and you are better off. Undergo both therapies and you will gain a commensurately greater benefit.

Unfortunately, this expectation of complementary therapies is very much not the case when it comes to attempts to slow down aging by genetic, epigenetic, or other metabolic manipulation. Metabolism is enormously complex, and even the well-studied phenomenon of calorie restriction isn't yet fully understood in terms of how the machinery of genes, proteins, and controlling signals all ties together to increase life span and improve health. Varied methods of extending life by slowing aging often turn out to operate on different portions of the same mechanism, or harmful when used together even though they are beneficial on their own.

One thing often tried by research groups that discover a novel way of slowing aging in laboratory animals is to try out the new method in calorie restricted animals: will the effects on life span complement one another and thus lead to a greater extension of life than is the case for either method on its own? Few presently known genetic alterations or other methods of slowing aging produce more than a 30% life extension in mice, and the standing record is 60-70% for growth hormone deficient mice - so at this point in time, it seems unlikely that any new life span record will be set through slowing aging without employing some complementary combination of techniques.

That this hasn't yet happened suggests that we shouldn't hold out much hope for the next five to seven years - there has, after all, been a lot of experimentation in mice over the past decade, and especially since the record set using growth hormone deficient mice. Unfortunately purely negative results don't tend to be published as often as positive results, so it's not a straightforward matter to find out which combinations of the various known methods to slow aging in mice have been tried only to fail.

Nonetheless, one example showed up recently in work on extending mouse longevity with AC5 knockout (AC5 KO) and calorie restriction, and here is a commentary on that research that clearly makes the point:

Models of longevity (Calorie Restriction and AC5 KO): Result of three bad hypotheses

Third Incorrect Hypothesis: The most widely studied model of longevity is calorie restriction (CR). Our hypothesis was that combining these two models would produce a super longevity model. Accordingly, we placed AC5 KO mice on CR. Within a month we found that all the AC5 KO mice on CR had died. Accordingly, we had to change our hypothesis to include that the AC5 KO and CR models share similar protective and metabolic mechanisms, which could mediate longevity and health, but when superimposed are actually lethal.

This might be taken as a cautionary note on metabolic manipulation as a path to slowing aging: there are pitfalls, it is enormously complicated, and there isn't much of a roadmap in comparison to the path to repair-based strategies of the sort outlined in the SENS vision.

Promoting Remyelination by Blocking Hyaluronidase

Myelin is the material sheathing axons in nerve cells. A number of conditions involve loss of myelin, such as multiple sclerosis (MS), but loss of myelin integrity occurs to a lesser degree for all of us as we age, and is thought to contribute to the characteristic cognitive decline of later years. Thus research into ways to regenerate myelin sheathing has broad potential application and is worth keeping an eye on:

We have identified a whole new target for drugs that might promote repair of the damaged brain in any disorder in which demyelination occurs. Any kind of therapy that can promote remyelination could be an absolute life-changer for the millions of people suffering from MS and other related disorders.

In 2005, [researchers] discovered that a sugar molecule, called hyaluronic acid, accumulates in areas of damage in the brains of humans and animals with demyelinating brain and spinal cord lesions. Their findings at the time [suggested] that hyaluronic acid itself prevented remyelination by preventing cells that form myelin from differentiating in areas of brain damage. The new study shows that the hyaluronic acid itself does not prevent the differentiation of myelin-forming cells. Rather, breakdown products generated by a specific enzyme that chews up hyaluronic acid - called a hyaluronidase - contribute to the remyelination failure.

This enzyme is highly elevated in MS patient brain lesions and in the nervous systems of animals with an MS-like disease. The research team [found] that by blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the MS-like disease. Most significantly, the drug that blocked hyaluronidase activity led to improved nerve cell function. The next step is to develop drugs that specifically target this enzyme.


Deepening the Puzzle

One of the many oddities in the way in which the public at large approaches aging is captured by the existence of a thriving "anti-aging" marketplace, full of people selling fake silver bullets and fraudulent potions, alongside a pervasive lack of interest in scientific research aimed at extending human life, and outright rejection of the goal of extending human life in many quarters. One would think that a market claiming to sell ways to turn back the clock - or at least disguise the fact that the clock is ticking - could not thrive without interest in the supposed goal of their products, yet there is little manifestation of that interest when it comes to actually, really doing something about slowing or reversing aging, rather than just throwing money at faking it.

Here is another data point to add to the existence of the "anti-aging" marketplace when trying to understand what is going on here:

A study [finds] that in 2011 spending on medications for aging conditions - such as mental alertness, sexual dysfunction, menopause, aging skin and hair loss - ranked third in annual prescription-drug costs of the commercially insured, surpassed only by the cost of treating diabetes and high cholesterol.

The research found that among these insured individuals use of drugs to treat the physical impact associated with normal aging was up 18.5 percent and costs increased nearly 46 percent from 2006 to 2011. Increased use of these drugs was even more pronounced for the Medicare population (age 65+), up 32 percent from 2007 to 2011. The largest utilization jump among Medicare beneficiaries was from 2010 to 2011, up more than 13 percent and outpacing increases in the use of drugs for diabetes, high cholesterol and high blood pressure combined.