Fight Aging!

Each year the SENS Research Foundation (SRF) brings on a summer crew of young researchers, capable undergraduate and graduate life science students who perform original research to assist in building the foundations of future rejuvenation biotechnologies. This is a great opportunity for anyone interested in molecular biology and the potential for aging research to reshape itself into the largest and most important branch of medical science in the years ahead. These are the early days of the next big thing, and working with the SRF is a great way to build connections and show your worth in this field.

The Foundation staff have been posting a series on this year's interns and their thoughts on the recent SENS6 conference, and the latest few articles are up:

SRF Intern Brandon Frenz Models the Effect of Systemic Aging Factors

Aging is defined as the gradual loss of a tissue's functional stability, or homeostasis. Loss of tissue homeostasis ultimately results in tissue failure, disease, and the eventual death of the whole organism. Recent studies have shown that the rate of this decline is not an independent phenomenon but rather is regulated through systemic factors. For example, in one type of study known as heterochronic parabiosis, the circulatory systems of an old and young mouse are linked together. The reversal of several key indicators of age observed in the older mouse coupled with tissue homeostasis decline in the young mouse provides evidence that aging is regulated by systemic factors.

During my internship, I helped develop a model in the fruit fly Drosophila melanogaster to study systemically regulated aging. By creating DNA damage in a specific tissue in the fly (the primary tissue), I was able to study the effect it has on tissue elsewhere in the fly (the distal tissue). I also tested the system ex vivo (outside the fly) and was able to generate a stress response in the distal tissue when it was cultured in a media with the damaged primary tissue. The experiments I conducted during my internship indicate that our systemic aging model appears to be robust and functioning as intended. This model will now be used to determine precisely which systemic factors are driving the stress response observed in the distal tissue and ultimately better characterize how systemic signaling factors from an individual tissue can drive the rate of aging.

SRF Intern Brandon Frenz on SENS6

One presentation of particular note was given by Associate Professor of Chemistry at Yale Dr. David Spiegel. Dr. Spiegel's lab studies advanced glycation end products (AGEs). AGEs are by-products of aging that accumulate in the area between cells, called the extracellular matrix (ECM). AGEs have been implicated in a number of age-related diseases, including Alzheimer's Disease, cardiovascular disease, diabetes, and stroke. One major hurdle to develop technology to break down AGEs is obtaining sufficient chemically pure quantities for experimentation. During his presentation, Dr. Spiegel explained how his lab is chemically synthesizing AGEs, such as glucosepane, the most abundant AGE found in aged tissue, using thirteen-step synthetic sequence.

A new institute focused on protein design is being created at the University of Washington, where I am a biochemistry graduate student. I am particularly excited that synthetically designed AGE-breaker proteins easily could be tested and screened in vivo using Spiegel's breakthrough technology. I have begun talks with Dr. Spiegel about a potential collaboration and am hopeful that his synthesis protocol has provided the means to develop a method to clear glucosepane from the human body and thus alleviate some age-related diseases.

SENS6 Intern Research Award Winner Ethan Sarnoski Establishes a Link Between Senescence and Mitochondrial Dysfunction

Cellular senescence is invoked by normal dividing cells to prevent excessive cell growth. This protective mechanism prevents cells experiencing genomic stress, such as DNA damage, from becoming cancerous. However, senescent cells continue to persist and accumulate as we age. The secreted molecules from these accumulated senescent cells are hypothesized to contribute to chronic inflammation and overall aging of the organism.

Dr. Campisi's lab seeks to understand the cause of senescence as well as the effect senescence associated secreted proteins (SASPs) have on the aging process. One phenomenon associated with aging is an increased number of cells that exhibit mitochondrial dysfunction. Mitochondria are the cellular structures which convert our food into a form of cell energy known as ATP (or adenosine triphosphate) through a process called cellular respiration. ATP is produced during the final stage of cellular respiration, known as the electron transport chain. During a key step in the electron transport chain, the enzyme NADH (nicotinamide adenine dinucleotide) is oxidized into NAD+, an essential cofactor in an earlier step in cellular respiration known as glycolysis.

My research project sought to understand the role mitochondrial dysfunction can play in senescence and ultimately aging. I indeed observed that mitochondrial dysfunction is able to induce senescence in cultured cells. I also determined that the senescence response was triggered by depletion of NAD(P)+. This insight into the link between mitochondrial dysfunction and senescence is an important step in the development of interventions for preventing the accumulation of senescent cells and their adverse aging effects.

SRF Intern Ethan Sarnoski on SENS6

I'd like to tell you about one particularly engaging presentation: that of the founder and CEO of Immusoft Matthew Scholz's description of the current state of Immusoft's Immune System Programming (ISP) technology. [This] involves the genetic modification of specialized protein-secreting cells called plasmablasts. Plasmablasts are partially mature B lymphocytes with substantial but limited ability to proliferate. The Immusoft research team reprograms these cells, instructing them to secrete a therapeutic protein in addition to their normal products. Ultimately, the team hopes to translate this process to human medicine by collecting plasmablasts from a patient, modifying and expanding their numbers outside the body, and then reintroducing the modified plasmablasts as therapeutic protein factories. In other words, the Immusoft technology will program a patient's own immune cells to produce a therapeutic protein.

Preparations are currently underway for a clinical trial in collaboration with researchers at the University of California, San Francisco, where programmed plasmablasts will be used to secrete broadly neutralizing antibodies to HIV. These antibodies have been observed in HIV-resistant elite controllers, but have not been successfully elicited through conventional vaccine strategies. Production of these antibodies with ISP cells represents a promising prophylactic measure for the prevention of HIV. Further studies may allow Immusoft's ISP technology to address such issues as age-related degeneration, optimization of blood cholesterol levels, and multiple rare diseases.

Studies of exercise show that moderate regular exercise produces meaningful benefits in health and longevity. Life expectancy is improved by five years, give or take, incidence of age-related disease is lower, and lifetime medical costs are lower. The challenge here when trying to put numbers to the benefits of exercise is that day to day activity for many people rises to the level of moderate regular exercise. Quantifying this activity can be hard, however, and may greatly increase the cost of a study. Even in the old, activities that wouldn't ordinarily be counted as deliberate exercise have an impact on health. This has only become very clear in recent years, with the emergence of small, widely available accelerometers that study participants can wear throughout the day.

Here, for example, is a study to show that non-exercise activity does is correlated with health and longevity, as you might expect:

Sedentary time is increasing in all societies and results in limited non-exercise physical activity (NEPA) of daily life. The importance of low NEPA for cardiovascular health and longevity is limited, especially in elderly. [This study examines] the association between NEPA and cardiovascular health at baseline as well as the risk of a first cardiovascular disease (CVD) event and total mortality after 12.5 years. Every third 60-year-old man and woman in Stockholm County was invited to a health screening study; 4232 individuals participated (78% response rate). At baseline, NEPA and exercise habits were assessed from a self-administrated questionnaire and cardiovascular health was established through physical examinations and laboratory tests. The participants were followed for an average of 12.5 years for the assessment of CVD events and mortality.

At baseline, high NEPA was, regardless of regular exercise and compared with low NEPA, associated with more preferable waist circumference, high-density lipoprotein cholesterol and triglycerides in both sexes and with lower insulin, glucose and fibrinogen levels in men. Moreover, the occurrence of the metabolic syndrome was significantly lower in those with higher NEPA levels in non-exercising and regularly exercising individuals. Furthermore, reporting a high NEPA level, compared with low, was associated with a lower risk of a first CVD event (hazard ratio of 0.73) and lower all-cause mortality (hazard ratio of 0.70). A generally active daily life was, regardless of exercising regularly or not, associated with cardiovascular health and longevity in older adults.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24167194

Stem cell populations decline in activity and possibly size with aging. This is most likely an evolved response to rising levels of damage that works to reduce cancer risk but causes increasing frailty and degeneration of tissue function. The exact mechanisms are probably different in different cell types and organs, but researchers have been making some progress in uncovering ways to trigger various types of stem cells to return to work. This can produce considerable benefits in terms of improved regeneration and tissue maintenance, but is probably going to come with an associated raised risk of cancer. For best effect we want researchers to work on removing the underlying damage that causes stem cells to go silent, rather than try to boost the activity of a damaged engine.

Here is an example of recent research of this type, in which a way to revive some of the heart's stem cells is found, and the proximate cause of their quiescence identified:

Hypoxia favors stem cell quiescence, while normoxia is required for their activation; but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown. A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal.

Here we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot reenter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy.

Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggests that a pool of functionally-competent CSCs persists in the senescent heart and this stem cell compartment can promote myocyte regeneration effectively, correcting partly the aging myopathy.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24170267

Telomeres are caps of repeating DNA sequences at the end of chromosomes. They shorten with each cell division, a little lost when DNA is replicated, and are lengthened by the activity of the enzyme telomerase, which adds additional repeating sequences. When telomeres become very short cells cease to replicate or self-destruct. Thus average telomere length in the cells of any given tissue is a function of how frequently those cells replicate, local levels of telomerase activity, how frequently new cells with long telomeres are created by the stem cell population supporting that tissue, and most likely a range of other factors. Average telomere length tends to decline and the proportion of very short telomeres increase with stress, illness, and advancing age, the latter being effectively just another form of becoming ill.

Telomere length may or may not be an important contributing cause of aging. From where I stand it looks very much like a secondary marker of aging, a consequence of other forms of damage. But researchers have demonstrated extension of life in mice through use of telomerase to extend telomeres - so there is the possibility that in and of itself loss of telomere length is doing further harm.

Measuring telomere length is a business these days. A few young companies have launched to bring to the clinic the laboratory techniques developed for measuring telomere length in blood samples. The hope here is that this has some predictive or diagnostic value, and it certainly seems at first sight that something useful can be found in the data. But straightforward comparisons of telomere length and health do not tend to yield useful results, as illustrated by this and similar studies:

Longitudinal Changes in Leukocyte Telomere Length and Mortality in Humans

Leukocyte telomere length (LTL) ostensibly shortens with age and has been moderately associated with mortality. In humans, these findings have come almost solely from cross-sectional studies. Only recently has LTL shortening within individuals been analyzed in longitudinal studies. Such studies are relevant to establish LTL dynamics as biomarkers of mortality as well as to disentangle the causality of telomeres on aging.

We present a large longitudinal study on LTL and human mortality, where the 10-year change of LTL is analyzed in 1,356 individuals aged 30-70 years. We find age, smoking status, and alcohol consumption to be associated with LTL attrition and confirm a strong association with baseline LTL. The latter association might be an epiphenomenon of regression to the mean. We do not find an association of mortality with either absolute LTL or LTL attrition. This study establishes that certain lifestyle factors influence LTL dynamics. However, it questions the applicability of LTL dynamics as a predictor of mortality.

Other research groups have found that more complex measures, such as looking at the proportion of very short telomeres and changes in that metric over time, can produce better results in animal studies. So there may be ways to slice the data so as to produce a useful outcome.

Epigenetics is the study of how genetic blueprints are turned into proteins, a process called gene expression, and how this process is regulated to create dynamic variations in levels of protein production. Protein production shifts in response to diet, environment, aging, and other factors, and can have a large impact on long-term health. The practice of calorie restriction produces sweeping epigenetic changes for example, leading to significantly longer healthy lives in laboratory animals.

Here researchers review work on the epigenetics of exercise in humans. Cataloging epigenetic alterations that occur in response to exercise is an early step on the road to trying to reproduce these changes using drugs or other techniques. At some point it will be possible for all of us to have optimal operation of metabolism for long-term health without actually undertaking exercise or calorie restriction or having good genes. But it is worth considering that this outcome is still a long way distant, and the old-fashioned methods of achieving the same goals are free, proven, and presently available to everyone.

Most human phenotypes are influenced by a combination of genomic and environmental factors. Engaging in regular physical exercise prevents many chronic diseases, decreases mortality risk and increases longevity. However, the mechanisms involved are poorly understood. The modulating effect of physical (aerobic and resistance) exercise on gene expression has been known for some time now and has provided us with an understanding of the biological responses to physical exercise.

Emerging research data suggest that epigenetic modifications are extremely important for both development and disease in humans. In the current review, we summarise findings on the effect of exercise on epigenetic modifications and their effects on gene expression. Current research data suggest epigenetic modifications (DNA methylation and histone acetylation) and microRNAs (miRNAs) are responsive to acute aerobic and resistance exercise in brain, blood, skeletal and cardiac muscle, adipose tissue and even buccal cells. Six months of aerobic exercise alters whole-genome DNA methylation in skeletal muscle and adipose tissue and directly influences lipogenesis. Some miRNAs are related to maximal oxygen consumption (VO2max) and VO2max trainability, and are differentially expressed amongst individuals with high and low VO2max.

Remarkably, miRNA expression profiles discriminate between low and high responders to resistance exercise (miR-378, -26a, -29a and -451) and correlate to gains in lean body mass (miR-378). The emerging field of exercise epigenomics is expected to prosper and additional studies may elucidate the clinical relevance of miRNAs and epigenetic modifications, and delineate mechanisms by which exercise confers a healthier phenotype and improves performance.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24163284

Here is an example of the sort of correlations that emerge on a regular basis from human studies of degenerative aging and variations in genes and gene expression:

The lipocalin apolipoprotein D (Apo D) is upregulated in peripheral nerves following injury and in regions of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, during aging and progression of certain neurological diseases.

In contrast, few studies have examined Apo D expression in the brainstem, a region necessary for survival and generally less prone to age-related degeneration. We measured Apo D expression in whole human brainstem lysates by slot-blot and at higher spatial resolution by quantitative immunohistochemistry. In contrast to cortex, hippocampus, and cerebellum, apolipoprotein D was highly expressed in brainstem tissue from subject with no history of neurological disease, and expression showed little variation with age. Both neurons and glia expressed Apo D, particularly neurons with larger somata and glia in the periphery of these brainstem centers. We propose that strong brainstem expression of Apo D throughout adult life contributes to resistance against neurodegenerative disease and age-related degeneration, possibly by preventing oxidative stress and ensuing lipid peroxidation.

Link: http://dx.doi.org/10.1371/journal.pone.0077852

I'm pleased to note that the latest Longecity crowdfunding initiative has met its goal: $7,000 raised from the community and a further $14,000 provided by Longecity will go towards a mitochondrial gene therapy research project carried out by SENS Research Foundation staff. One of the wonders of our modern age is that meaningful life science research at the cutting edge is now so very cheap: things that would have required a fully staffed laboratory and tens of millions of dollars twenty years ago can be now be accomplished by a single researcher with $20,000 to spend. This new state of affairs is reflected in the pace of progress in medical research.

LongeCity Research Support 2013: Mitochondrial Gene Therapy

Mitochondria, the power plants of the cell, contain their own DNA. Unlike the nucleus, mitochondria lack an efficient system to repair damaged DNA, and this damage accumulates over time. As we age, these accumulated mutations result in an increase in oxidative stress throughout the body. It is no coincidence that organisms which age more slowly consistently display lower rates of mitochondrial free radical damage. Reversing and/or preventing damage to mitochondrial DNA may be a key factor in slowing the aging process. In this project, engineered mitochondrial genes will be used to restore function to cells that contain defective mitochondrial genes.

There is a good discussion of the research and its details going on in the project Q&A thread. You should take a look: this is the model for the future of a great deal of research funding, in which enthusiasts in the public fund the work they want to see accomplished, talking directly with the scientists who carry out this research. Openness, transparency, and continuous communication are powerful tools. The Longecity folk are justifiably pleased at another addition to their fundraising record:

Congratulations everyone. Once again LongeCity/Imminst has reached the fundraising goal of $7,000. This will now be matched with a $14,000 grant and the research can begin. In case you were not counting, our organization still has a 100% success rate of funding life extension research. Every fundraising goal for the last 5 years has been met or exceeded.

More of this will be welcome, and I expect to see more of this in the years ahead as the community grows, side by side with growth in traditional forms of funding for SENS and SENS-like rejuvenation research.

Between our cells is the complex support structure of the extracellular matrix. It becomes extensively damaged in aging by the formation of cross-linked proteins, stuck together by sugars and other metabolic byproducts that the body fails to clear. This causes loss of elasticity in tissues like skin and blood vessels, as well as numerous other forms of harm. Glucosepane is by far the most important of these cross-linking compounds, but there is comparatively little work being done on ways to break down glucosepane, and thus reverse its effects on tissues, and remove this contribution to degenerative aging.

Here one of the researchers involved in present work on clearing glucosepane advances another target cross-link compound that might also be addressed:

Ageing of the extracellular matrix (ECM), the protein matrix that surrounds and penetrates the tissues and binds the body together, contributes significantly to functional aging of tissues. ECM proteins become increasingly cross-linked with age, and this cross-linking is probably important in the decline of the ECM's function. In this paper I review the role of EGGL, a cross-link formed by transglutaminase enzymes, and particularly the widely expressed isozyme TG2, in the aging ECM.

There is little direct data on EGGL accumulation with age, and no direct evidence of a role of EGGL in the aging of the ECM outwith pathology. However, several lines of circumstantial evidence suggest that EGGL accumulates with age, and its association with pathology suggests that this might reflect degradation of ECM function. TG activity increases with age in many circumstances, ECM protein turnover is such that some EGGL made by TG is likely to remain in place for years if not decades in healthy tissue, and both EGGL and TG levels are enhanced by age-related diseases.

If further research shows EGGL does accumulate with age, removing it could be of therapeutic benefit. I review blockade of TG and active removal of EGGL as therapeutic strategies, and conclude that both have promise. EGGL removal may have benefit for acute fibrotic diseases such as tendinopathy, and for treating generalized decline in ECM function with old age. Extracellular TG2 and EGGL are therefore therapeutic targets both for specific and more generalized diseases of aging.

Link: http://dx.doi.org/10.1089/rej.2013.1452

Sarcopenia is the characteristic loss of muscle mass and strength that occurs with aging. Among the suspected root causes are lack of exercise, failing blood vessel function, increasing levels of inflammation due to immune system aging and fat tissue, and changes in the ability of the body to process leucine from the diet. Interestingly the practice of calorie restriction is shown to mitigate the progress of sarcopenia, which might be taken as another vote for fat-related and inflammation-related causes, as calorie restricted individuals are lean and excess visceral fat tissue contributes considerably to levels of chronic inflammation.

Human aging is associated with a progressive loss of muscle mass and strength and a concomitant fat accumulation in form of inter-muscular adipose tissue, causing skeletal muscle function decline and immobilization. Fat accumulation can also occur as intra-muscular triglycerides (IMTG) deposition in lipid droplets, which are associated with perilipin proteins, such as Perilipin2 (Plin2). It is not known whether Plin2 expression changes with age and if this has consequences on muscle mass and strength.

We studied the expression of Plin2 in the vastus lateralis (VL) muscle of both healthy subjects and patients affected by lower limb mobility limitation of different age. We found that Plin2 expression increases with age, this phenomenon being particularly evident in patients. Moreover, Plin2 expression is inversely correlated with quadriceps strength and VL thickness. To investigate the molecular mechanisms underpinning this phenomenon, we focused on IGF-1/p53 network/signalling pathway, involved in muscle physiology. We found that Plin2 expression strongly correlates with increased p53 activation and reduced IGF-1 expression.

To confirm these observations made on humans, we studied mice overexpressing muscle-specific IGF-1, which are protected from sarcopenia. These mice resulted almost negative for the expression of Plin2 and p53 at two years of age. We conclude that fat deposition within skeletal muscle in form of Plin2-coated lipid droplets increases with age and is associated with decreased muscle strength and thickness, likely through an IGF-1- and p53-dependent mechanism. The data also suggest that excessive intramuscular fat accumulation could be the initial trigger for p53 activation and consequent loss of muscle mass and strength.

Link: http://dx.doi.org/10.1371/journal.pone.0073709

Ames dwarf mice are genetically engineered to lack growth hormone, and as a result are small, comparatively vulnerable to cold, and live much longer than their peers. The biochemistry of these mice has a number of similarities to that of calorie restricted mice, who also live much longer than their peers. Study of these and other forms of long-lived mice is shedding light on an overlapping collection of mechanisms that link the operation of metabolism with differences in the pace of degenerative aging. The hope here is that at some point this will lead to therapies to produce similar benefits in we humans, but most researchers think that such a result is comparatively distant from where we are now. The changes produced in mice through either growth hormone knockout or calorie restriction are sweeping, and it will be challenging to prove that any artificial alteration of human metabolism on the same scale is safe over the long term.

Nothing is stopping you from practicing calorie restriction, of course, and indulging in your own self-created sweeping and beneficial change to the operation of your metabolism. The human studies show that the benefits to a basically healthy individual exceed any other presently available strategy for improving long-term health. But the rules and chances of a positive outcome are very different when you want to try altering human genes and biological processes with medical technologies. Nonetheless, the enumerated benefits are good enough to keep research funds flowing, albeit at a very low level in comparison to fields such as stem cell medicine or cancer research.

Prevention of Neuromusculoskeletal Frailty in Slow-Aging Ames Dwarf Mice: Longitudinal Investigation of Interaction of Longevity Genes and Caloric Restriction

The hypopituitary Ames Dwarf Mouse was the seminal example of single-gene regulation of mammalian longevity. They are deficient in the production of growth hormone (GH), thyroid stimulating hormone, and prolactin. The deficiency in somatotrophic signaling results in mice that are approximately half the size (length or weight) of their littermate controls. These mice outlive their normal littermate counterparts by approximately 40-60%. These results of longevity have been confirmed on different diets, on different genetic backgrounds, and in independent laboratories utilizing differing animal husbandry conditions. Furthermore, multiple other growth hormone signaling-deficient mouse mutants exhibiting longevity have since been reported.

Studies dating back a century have reported the healthspan and lifespan benefits of diets restricted in caloric content yet sufficient in macro- and micro-nutrients. These diets of "undernutrition without malnutrition" have been documented to have the ability to slow the progression of aging in multiple organ systems and in multiple species. Of particular note to this study, caloric restriction (CR) increases circulating GH levels in rats, dogs, and humans. To date, few reports have investigated the effects of this feeding paradigm on functional metrics of physical function.

The vast majority of studies on neuromusculoskeletal functioning in experimental gerontology deal with charting the prevalent, well-documented, aging-associated decline in neuromuscular or skeletal structure, strength, quality or performance. Save for studies with CR animals or on exercising animals, evidence of genetic or environmental factors that might improve physical functioning is limited; and, to the best of our knowledge, no combinatorial analysis of the interaction of two different factors has been conducted.

In this study, we conducted a longitudinal investigation of the individual and combined effects of Ames dwarfism or CR on measures of neuromusculoskeletal ability in senescing mice. Our initial hypothesis was that mice deficient in an anabolic process, such as GH signaling, would be inferior in performance on tasks requiring an integration of nervous, muscular, and skeletal systems' functions; as GH is crucial to the ontogeny and maintenance of those physiological systems. Thusly, we hypothesized that GH signaling-inhibiting Ames dwarfism will correlate with impaired function on late-life neuromusculoskeletal tasks, whereas GH signaling-enhancing CR will accentuate that performance. Our overall aim of revealing differences in physical capability between slow-aging mice and their normally aging counterparts was achieved for grip strength, balance, agility, and motor coordination; yet, some results ran counter to our hypotheses.

Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age.

From this longitudinal study, we report beneficial effects of either [dwarfism], caloric restriction, or both for physical functioning in aging mice. The individual effects of either factor, in combination with the additive effects seen during the motor coordination and agility testing, suggest that it is not merely a change in body composition (as CR reduces adiposity and Ames dwarfism increases it), difference in size (as CR mice are just as long as their ad-libitum-fed counterparts), or uniqueness of experimental design (as the three tests exerted considerably different challenges on the animals) that results in the benefits seen. Rather, we posit that the decrease in the rate of senescence induced by either factor is primarily responsible for the retention of neuromusculoskeletal function observed.

For many researchers the grail is to find ways to slow aging through medicine, to reproduce the reduction in the rate of senescence noted above. This will extend human life and push back the degenerative conditions of aging. It is also, unfortunately, a slow and expensive path forward that cannot ultimately produce therapies capable of rejuvenating the old - only therapies that slightly slow the pace at which the young become old. If these therapies only emerge when we are old, then it will be too late for us.

So this is not the path that the research community should take. Something different is needed for the decades of research that lie ahead, a research program more likely to result in actual rejuvenation of the old, and soon enough to matter.

Several different lines of work aim at directing the immune system to remove proteins involved in causing Alzheimer's disease pathology. This is one example:

Since the first case of Alzheimer's was described, the disease has been associated with the presence of insoluble deposits called amyloid plaques. However, in the past decade researchers have been able to conclude that the neuronal death characteristic of the disease is not due to the presence of these plaques but to the toxicity of the soluble aggregates preceding them (and called oligomers).

Immunotherapy, consisting of the use of antibodies as a treatment for the disease, is turning out to be a encouraging tool in the treatment of certain types of cancer and has also been used in trials to treat Alzheimer's disease. Nevertheless, the clinical trial which had advanced most in treating Alzheimer's through passive vaccination - using the bapineuzumab antibody - was halted in 2012 during its last trial phase due to the adverse effects of the treatment. Many scientists believe the effects were the result of administering complete antibodies, which produce inflammation in the brain. For this reason, they propose to administer antibody fragments, which has been seen to be much safer.

The research group [thus] designed a recombinant antibody fragment (called scFv-h3D6: single-chain variable Fragment), a derivative of bapineuzumab, which only contains the active part that fights against the etiological agent of the disease: the domains of the antibody responsible for the union of Aβ oligomers. Scientists observed how, in human cell cultures, this antibody fragment protects from cell death and described the molecular mechanism by which this antibody fragment removes the Aβ oligomers that cause the disease.

Mice models of Alzheimer's have been treated successfully with [the] antibody fragment. One abdominal injection and only five days later the animals improved their memory and ability to learn as the result of less aggregated toxins and an increase in the number of neurons. At [the] molecular level, researchers demonstrated two important facts: first, the new treatment eliminates from the cerebral cortex [the] oligomers, the elements causing the disease; and second, that this elimination is linked to the recovery in levels of certain apolipoproteins which are suspected to be the natural eliminators of Aβ peptide aggregations.

Link: http://www.uab.es/servlet/Satellite/latest-news/news-detail/antibody-fragment-designed-by-the-uab-effectively-fights-alzheimer-s-in-mice-1096476786473.html?noticiaid=1345662577400

Much of the age-related decline of the immune system can be blamed on cytomegalovirus (CMV). Near everyone is exposed to this type of herpesvirus at some point in life, and because the immune system cannot effectively clear it from the body ever more immune cells become uselessly and redundantly specialized to attack it. Since the immune system is limited in the number of cells it can support at any given time, this means that there are ever fewer cells capable of responding effectively to new threats, or patrolling the body to destroy senescent or cancerous cells.

An effective cytomegalovirus vaccine or other method of clearance and prevention will be useful for the young, and research is progressing, but this isn't an effective treatment for the old. There, the damage is already done. The best approach for rejuvenation of the immune system in this case is something along the lines of introducing new cells and destroying existing CMV-specialized cells to free up space. Nonetheless, here is an example of progress towards an effective vaccine for CMV:

Identification of immune correlates of protection for viral vaccines is complicated by multiple factors, but there is general consensus on the importance of antibodies that neutralize viral attachment to susceptible cells. Development of new viral vaccines has mostly followed this neutralizing antibody paradigm, but as a recent clinical trial of human cytomegalovirus (HCMV) vaccination demonstrated, this singular approach can yield limited protective efficacy.

Since HCMV devotes more than 50% of its coding capacity to proteins that modulate host immunity, it is hypothesized that expansion of vaccine targets to include this part of the viral proteome will disrupt viral natural history. HCMV and rhesus cytomegalovirus (RhCMV) each encode an ortholog to the cellular interleukin-10 (cIL-10) cytokine: cmvIL-10 and rhcmvIL10, respectively. Despite extensive sequence divergence from their host's cIL-10, each viral IL-10 retains nearly identical functionality to cIL-10.

Uninfected rhesus macaques were immunized with engineered, nonfunctional rhcmvIL-10 variants, which were constructed by site-directed mutagenesis to abolish binding to the cIL-10 receptor. Vaccinees developed antibodies that neutralized rhcmvIL-10 function with no cross-neutralization of cIL-10. Following subcutaneous RhCMV challenge, the vaccinees exhibited both reduced RhCMV replication locally at the inoculation site and systemically and significantly reduced RhCMV shedding in bodily fluids compared to controls. Attenuation of RhCMV infection by rhcmvIL-10 vaccination argues that neutralization of viral immunomodulation may be a new vaccine paradigm for HCMV by expanding potential vaccine targets.

Link: http://dx.doi.org/10.1128/JVI.01925-13

There has been more discussion of the future of medicine and human longevity in the print media of late. I attribute this to a combination of Google's announcement of their Calico initiative and an ongoing low-key advertising campaign run by Prudential, wherein that company seeks to differentiate itself through displaying an awareness of the potential for large increases in human life span in the years ahead.

There is also a larger than usual fraction of articles that take longevity science and medical development seriously, which is pleasant. Though I'm sure that this is at least partially because it is a lot harder to do otherwise without looking like an idiot these days, given that ever more scientists are willing to talk in public about extending health life spans. It is much easier to find scientific literature, reviews, and interviews with researchers in which they talk favorably about a future of longer lives. Beliefs and opinions change step by step, one increment at a time. That said, while it's harder to dismiss the science out of hand nowadays, there are still plenty of people willing to tell us that it is better for countless millions to die horribly and slowly than for any of those people to survive to risk being bored sometimes, or that old people are too dangerous to be permitted to live any longer:

Why No One Actually Wants to Live Forever

Depression runs high among retirees, and not just because of reduced income - in fact, the baby boomers who have recently retired are living a life of relative luxury compared with those of us still a few decades away. No, the reason they get depressed is because when you're retired, it is easy to feel like you have nothing to live for anymore, no purpose, nothing to get up for, no reason to even get dressed. In a word, they are bored.

What we forget when we focus on extending our lifespan as long as possible is that things make us happy because they are rare, finite, and therefore valuable and precious. Diamonds. Newborns. Laughter. Great first dates. Great third dates. Sunshine. (I live in London. Trust me, sunshine is very rare and very finite.) Make these things available to everyone all the time, and they would lose their glow, become mundane.

The problem with longevity? Old people.

Now consider radical life extension. It means that decision-making power, and economic and political authority, will be vested in a generation that is already obsolete and growing more so. People who find Facebook's and Twitter's popularity incomprehensible and more than slightly spooky will be making employment decisions based on outdated concepts of public and private personas. The young and innovative will be held at bay, prevented from creating new information forms and generating cultural, institutional, and economic breakthroughs. And where death used to clear the memory banks, there I stand ... for 150 years.

The social order of today versus that of the Roman Empire are remarkable for their similarities, not their differences, despite the much greater length of life we expect to enjoy today. Positions change, people change, and leaders are overturned on a timescale that is small compared to our life spans - and that timescale is much the same as it was two thousand years ago. I don't see it changing in the slightest if people lived twice as long as they do now, as the factors leading to social change have very little to do with overall length of life, proceeding as they do on a month-to-month and year-to-year basis, driven by what people want here and now, not ten years or twenty years away.

All in all it is odd that people are so willing to hold up such airy constructs of speculation as those above as viable arguments against efforts to prevent the very concrete cost of aging: the death of tens of millions every year and the ongoing suffering of hundred of millions more. But not every op-ed and article is negative these days; there are signs that more and more people are becoming accustomed to and even supportive of the idea that living longer in good health is the future, and that medical research aimed at increasing human longevity is a good and deserving cause.

Epigenetics is the study of mechanisms that cause changes in gene expression. Genes encode proteins, and gene expression is the complex multi-step process by which proteins are built from that blueprint. Changes in the amount of any specific protein in circulation or in a specific location in a cell can result in significant changes in the operation of metabolism, altering the operation of cellular machinery that in turn feeds back to further change gene expression. Our biology is a massively complex web of feedback loops and linkages between genes and proteins.

DNA methylation is of the mechanisms by which gene expression is altered. It involves the addition of a chemical tag to a gene. The pattern of DNA methylation changes with aging, a process sometimes called epigenetic drift, and some of those changes are characteristic enough to be used as a measure of age.

While a number of key signalling pathways (e.g. mTOR signalling) and biological processes (e.g. telomere attrition) affecting lifespan have been identified, other theories have argued that aging results mainly from accumulated molecular damage. Most likely, aging is determined by a complex cross-talk between multiple biological effects. Molecular damage itself can take many forms, including somatic DNA mutations and copy-number changes.

The advent of novel biotechnologies, allowing routine genome-wide quantitative measurement of epigenetic marks, specially DNA methylation, have recently demonstrated that age-associated changes in DNA methylation, a phenomenon now known as "epigenetic drift", may play an equally important role in contributing to the aging phenotype. Indeed, like telomere attrition, epigenetic drift has been associated with stem cell dysfunction, disease risk factors and common age-related diseases, such as cancer and Alzheimer's. Apart from extensive experimental work supporting a role for DNA methylation in aging, computational network biology approaches have recently shed further light into the potential role of epigenetic drift. For instance, one study has shown that drift appears to target WNT signalling, a key pathway in stem-cell differentiation and already known to be deregulated with age.

A more recent study mapped epigenetic drift occurring in gene promoters onto a human protein interactome and observed that most of the changes happen at genes which occupy peripheral network positions, i.e. those of relatively low connectivity. Although developmental transcription factors make up a significant proportion of "drift genes", the observed topological effect was not entirely driven by this enrichment. Crucially, the topological properties of genes undergoing epigenetic drift were highly distinctive from those which have been associated with modulating longevity, those undergoing age-related changes in expression, or those somatically mutated in age-related diseases like cancer. Moreover, essential housekeeping genes, many of which occupy highly central positions in the interactome, appear protected from epigenetic drift.

Although the overall functional significance of epigenetic drift remains to be established, a few instances of epigenetic drift causing silencing of key transcription factors have already been reported. Thus, it is plausible that epigenetic drift may gradually affect differentiation programs through functional deregulation of key lineage determining transcription factors, leading to well-known observations such as neoplastic formation.

Link: http://www.impactaging.com/papers/v5/n10/full/100610.html

Misfolded forms of alpha-synuclein have been identified as a proximate cause of dying brain cells in Parkinson's disease (PD), and so there is considerable interest in ways to remove this protein or block its mode of action. The research reported here is a good example of the platforms that researchers build in order to search for compounds that might be developed into drugs for this sort of task. Even when a specific protein or mechanism has been identified, at the present time it isn't yet possible to step directly to the answer and design the right molecule for the job. It remains more efficient to explore tens of thousands of candidates in the lab.

In the search for compounds that might alter a protein's behavior or function - such as that of alpha-synuclein - drug companies often rely on so-called target-based screens that test the effect large numbers of compounds have on the protein in question in rapid, automated fashion. Though efficient, such an approach is limited by the fact that it essentially occurs in a test tube. Seemingly promising compounds emerging from a target-based screen may act quite differently when they're moved from the in vitro environment into a living setting.

To overcome this limitation [researchers have] turned to phenotypic screens in which candidate compounds are studied within a living system. Yeast cells - which share the core cell biology of human cells - serve as living test tubes in which to study the problem of protein misfolding and to identify possible solutions. Yeast cells genetically modified to overproduce alpha-synuclein serve as robust models for the toxicity of this protein that underlies PD.

In a screen of nearly 200,000 compounds, [researchers] identified one chemical entity that not only reversed alpha-synuclein toxicity in yeast cells, but also partially rescued neurons in the model nematode C. elegans and in rat neurons. Significantly, cellular pathologies including impaired cellular trafficking and an increase in oxidative stress, were reduced by treatment with the identified compound. [Researchers then examined] neurons derived from induced pluripotent stem (iPS) cells generated from Parkinson's patients. The cells and differentiated neurons (of a type damaged by the disease) were derived from patients that carried alpha-synuclein mutations and develop aggressive forms of the disease. [The researchers] used the wealth of data from the yeast alpha-synuclein toxicity model to clue them in on key cellular processes that became perturbed as patient neurons aged in the dish. Strikingly, exposure to the compound identified via yeast screens [reversed] the damage in these neurons.

Link: http://wi.mit.edu/news/archive/2013/yeast-human-stem-cells-drive-discovery-new-parkinson-s-disease-drug-targets

When it comes to public discussion of extending healthy life spans through medical science, the tide is slowly turning. As a serious scientific goal, this used to be mocked when it was ever discussed at all. Now healthy life extension is discussed both seriously and more often. But it is still the case that the majority of the public puts little thought into the intersection of aging and progress in medicine, and when pushed for an opinion express disinterest in living longer. This is obviously problematic for those of us who do see the possibilities in longevity science: radical life extension could be achieved within our lifetimes given enough funding and support, but that support is slow in arriving.

There are a range of opinions as to why the broader public doesn't leap on the idea of living longer, healthier lives with great enthusiasm and approval. It is somewhat odd when seen from a logical perspective as, after all, there is widespread grassroots support for the development of better treatments for age-related diseases. The average person on the street thinks that progress is being made on the prevention and cure of heart disease, cancer, and so on, and that this is a good thing. But ask them about aging and extended life and you'll hear that nothing should be done, and they are set to die on the same schedule as their parents.

Most advocates for the development of rejuvenation therapies think that the biggest issue is that most people still think that living longer will mean being older for longer rather than being younger for longer - that it will mean more misery and pain and increasing decrepitude. Yet this has never been the message propagated by the scientific community: scientists are working on means to make people younger for longer, or to reverse aging so as to restore youthful vigor and capabilities to the old, and have always presented their research in terms of health and youth. "Older for longer" is a myth, and probably not even something that could be achieved at all, were someone foolish enough to try, but it persists nonetheless.

Why We Should Look Forward To Living To 120 And Beyond

Surprisingly, most people do not want to have their life spans extended. In my opinion, this pessimistic view stems from several factors. First, when forming a conscious and subconscious opinion about life expectancy, most people use as benchmarks their parents' and grandparents' life spans, and the national average. The line of thought is usually: "I am 40, my grandmother lived to 92, my dad is 70, and I heard that the average is about 78, so I should live to somewhere between 80 and 95. But I am not sure if I want to live that long, because my grandmother was very frail in her later years."

These perceptions are fostered by researchers who look at historic trends and project only marginal increases, or even decreases, in future life expectancy. These researchers predict that recent behavioral changes, like high-calorie diets and sedentary lifestyles, as well as pollution and other environmental factors, will outweigh life-extending advances in biomedical sciences. But the past 20 years have demonstrated that those relying on historical trends to make predictions about science and technology are often proven wrong.

People may also believe an extended life span will extend frailty and boredom in old age. But biomedical advances are not all the same. The current paradigm in biomedical research, clinical regulation and healthcare has created a spur of costly procedures that provide only marginal increases late in life. The vast percentage of lifetime healthcare costs today are spent in the last few years of patients' lives, increasing the burden on the economy and society and further contributing to the negative image of life extension. In the near future, however, the focus of biomedicine will shift to extending healthy, productive lives and keeping people young and occupied for as long as possible.

The preventive approaches available today, including improved diet and exercise and more advanced early diagnostics, may have the potential to add 10 to 20 years to our life spans. But future generations will more likely rely on biomedical interventions to prevent the loss of functionality with age and to maintain or even improve their performance on all levels. The lowest-hanging fruit is regenerative medicine, which will likely allow most of the organs in the body to be replaced or rejuvenated.

Sirtuin research continues despite disappointing results in mammals, and here leads to a new piece in the puzzle of linked protein mechanisms, and a novel way to extend life in nematode worms:

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan.

Sirtuins mandatorily convert NAD(+) into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1. We identify a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1, to generate MNA from NAM.

Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1-mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity. Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24077178

Insulin-like signaling is one of the better studied portions of the overlap between metabolism and aging, but even this alone is an enormously complex system. There is much left to discover:

Evolutionarily conserved insulin/insulin-like growth factor signaling (IIS) pathway governs growth and development, metabolism, reproduction, stress response, and longevity. In Drosophila, eight insulin-like peptides (DILPs) and one insulin receptor (DInR) are found, ended by dilp genes. Temporal, spatial, and nutrient regulation of DIPLS provides potential mechanisms in modulating IIS. Compensatory transcriptional regulatory mechanisms and functional redundancy that exist among DILPs make it difficult to dissect out their individual roles.

While the brain secretes DILP2, 3, and 5, fat body produces DILP6. Identification of factors that influence dilp expression and DILP secretion has provided insight into the intricate regulatory mechanisms underlying transcriptional regulation of those genes and the activity of each peptide. Studies involving loss-of-function dilp mutations have defined the roles of DILP2 and DILP6 in carbohydrate and lipid metabolism, respectively. While DILP3 has been implicated to modulate lipid metabolism, a metabolic role for DILP5 is yet to be determined.

Loss of dilp2 or adult fat body specific expression of dilp6 has been shown to extend lifespan, establishing their roles in longevity regulation. The exact role of DILP3 in aging awaits further clarification. While DILP5 has been shown associated with dietary restriction (DR)-mediated lifespan extension, contradictory evidence that precludes a direct involvement of DILP5 in DR exists. This review highlights recent findings on the importance of conserved DILPs in metabolic homeostasis, DR, and aging, providing strong evidence for the use of DILPs in modeling metabolic disorders such as diabetes and hyperinsulinemia in the fly that could further our understanding of the underlying processes and identify therapeutic strategies to treat them.

Link: http://www.frontiersin.org/Journal/10.3389/fphys.2013.00288/full

The thyroid gland produces a number of hormones that regulate metabolism, and as such both it and these hormones tend to show up in studies of aging and longevity. Variations in the operation of metabolism affect the pace of aging in individuals, and somewhere in the associated long chain of cause and effect can be found the thyroid and its activities.

One of the challenges inherent in building therapies based on data gathered about the operation of metabolism and variations between individuals is that it is hard to say whether what you are proposing to alter is a cause or a consequence. It is also presently a real challenge to discover all of the meaningful consequences of any particular metabolic alteration. So researchers can point to data and argue that longer-lived people tend to have characteristically similar levels of certain thyroid hormones, but you can't jump right from that to an assumption that trying to replicate this particular configuration of protein levels in other people will be beneficial.

This open access paper is a quick tour through published research, present consensus, and open questions regarding the thyroid and aging. A few of the more directly relevant portions are quoted below, but the whole thing is worth at least skimming for the examples of other associations with specific age-related conditions:

Thyroid and Aging or the Aging Thyroid? An Evidence-Based Analysis of the Literature

There has been long standing controversy about the thyroid function test results in the elderly. Serum thyroid-stimulating hormone (TSH), free thyroxine (T4), and free triiodothyronine (T3) concentrations change with aging. There is an increasing wealth of data suggesting that serum TSH levels increase with age, particularly after 70 years, but the data on free T4 is conflicting. This might reflect reduced end organ sensitivity, reduced turnover, and clearance, a genetic trait conferring a survival benefit or a combination of factors. In addition, no clear benefit is seen in treating a high TSH on a multitude of outcomes in the elderly. In fact, there is a possibility that treatment in the very elderly may lead to adverse outcomes. On the other hand, a low TSH has been associated with worse outcomes in the older age group.

The Leiden 85+ study showed that higher TSH concentrations and lower free thyroxine levels were associated with a survival benefit. In this study, participants with low levels of TSH at baseline had highest mortality rate, and participants with high TSH levels and low FT4 levels had the lowest mortality rate. The authors speculated that lower thyroid function may lead to lower metabolic rate which in turn could cause caloric restriction. Lower metabolic rate and caloric restriction have both been shown to be associated with improved survival in several animal studies.

There have been few recent studies exploring longevity with raised TSH and familial/genetic basis for this phenomenon. Data from the Leiden Longevity Study showed that when compared with their partners, the group of offspring of nonagenarian siblings showed a trend toward higher serum TSH levels in conjunction with lower free T4 levels and lower free T3 levels. In their extension to this study, they found that lower mortality in the parents of nonagenarian siblings was associated with higher serum TSH levels, lower free serum T4 levels, and lower free T3 levels in the nonagenarian siblings.

The comment on thyroid function leading to calorie restriction is interesting, because the relationship has been shown to go the other way: calorie restriction alters thyroid hormone levels in ways that appear similar to what is seen in longer-lived people. All these things are feedback loops in a connected system, of course, so it's quite possible to have cause and consequence in both directions.

This is the age of discovery for cellular control: cells are just complex machines, and with the right environment and chemical instructions the behavior and even type of a cell lineage can be radically changed. A lot of time and funding presently goes into discovering how to achieve these goals, as greater control over cells opens up many new vistas in medicine. At present, and in parallel to research into induced pluripotency as a path to generating any type of cell from easily obtained patient samples, such as skin or fat tissue, scientists are exploring the possibilities of transdifferentiation. At least some types of cell can be coerced into directly becoming other types of cell, without having to pass through an embryonic-like pluripotent stage, and researchers are becoming better at making this happen:

Scientists have developed a fast, efficient way to turn cells extracted from routine liposuction into liver cells. The scientists performed their experiments in mice, but the adipose stem cells they used came from human liposuction aspirates and became human, liver-like cells that flourished inside the mice's bodies.

Liver cells are not something an adipose stem cell normally wants to turn into. The [researchers] knew it was possible, though. Another way of converting liposuction-derived adipose stem cells to liver-like cells had been developed in 2006. But that method, which relies on chemical stimulation, requires 30 days or longer and is inefficient; it could not produce enough material for liver reconstitution. Working with induced pluripotent (iPS) cells takes even longer; they must first be generated from adult cells before they can be converted. Using a different technique [known] as spherical culture [researchers] were able to achieve the conversion within nine days with an efficiency of 37 percent, as opposed to the vastly lower yield obtained with the prior method (12 percent) or using iPS cells.

When they had enough cells, the investigators tested them by injecting them into immune-deficient laboratory mice that accept human grafts. Only the livers of these mice contained an extra gene that would convert the antiviral compound gancyclovir into a potent toxin. When these mice were treated with gancyclovir, their liver cells died off quickly. At this point the investigators injected 5 million [of the newly generated cells] into the mice's livers. Four weeks later, the investigators examined the mice's blood and found the presence of a protein (human serum albumin) that is only produced by human liver cells and was shown to be an accurate proxy for the number of new human liver cells in these experimental mice's livers. The mice's blood had substantial human serum albumin levels, which nearly tripled in the following four weeks. These blood levels correspond with the repopulation of roughly 10-20 percent of the mice's pre-destroyed livers by new human liver tissue.

Blood tests also revealed that the mice's new liver tissue was discharging its waste-filtration responsibility. Examination of the livers themselves showed that the transplanted cells had integrated into the liver, expressed surface markers unique to mature human hepatocytes and produced multi-cell structures required for human bile duct formation.

Link: http://med.stanford.edu/ism/2013/october/liver.html

Calcification appears to be one of the causes of increasing vascular stiffness with age, a form of functional deterioration in blood vessels that contributes to numerous age-related conditions. Here, researchers investigate means to remove this calcium:

Elastin-specific medial vascular calcification, termed "Monckeberg's sclerosis," has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium from calcified tissues into soluble calcium complexes.

We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to nanoparticles regressed elastin-specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23963635

Alzheimer's disease is perhaps the most studied form of age-related neurodegeneration. About 40% of the yearly budget of the US National Institute on Aging goes towards research into Alzheimer's disease, for example, and that is just the easily discovered funding. Where there is work on treating Alzheimer's rather than further investigating it, that research tends to focus on clearing clumps and fibrils of misfolded proteins known as amyloid. Alzheimer's is accompanied by a characteristic build up of amyloid beta, which many researchers think is the proximate cause of the harm the condition does to the brain. You might look at ongoing attempts to direct a patient's immune system to clear amyloid from the brain, for example.

Neural biochemistry is enormously complex, however, and there is plenty of room for uncertainty and argument over the root causes of Alzheimer's, how it progresses, and exactly which mechanisms are damaging and destroying brain cells. Why do some people suffer Alzheimer's while others do not, for example, even though we all appear to progress down the same path general of amyloid buildup and cellular damage? Here is an open access review paper that surveys the current range of plausible theories:

What causes alzheimer's disease?

Ever since the first description of pre-senile dementia by Alois Alzheimer in 1907, the presence of cognitive impairment together with the formation of senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the [defining] features of Alzheimer's disease (AD). Many theories as to the cause of AD have [been] proposed. It is not the intention to discuss every theory but to concentrate on those most likely to be involved. Hence, the theories are discussed in eight categories: (1) acceleration of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3 environmental factors such as exposure to aluminium, head injury, and malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes, and allelic variation in apolipoprotein E (Apo E), (5) a metabolic disorder resulting from mitochondrial dysfunction, (6) vascular factors such as a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these hypotheses and develops a general theory as to the cause of AD.

That AD may be an accelerated form of natural aging is based on the observation that the many pathological changes in AD are similar to those present in normal aging apart from their severity. Hence, in cognitively normal brain, there is an age-related reduction in brain volume and weight, enlargement of ventricles, and loss of synapses and dendrites in selected areas. Accompanying these changes are the characteristic pathological features of AD, including SP and NFT. Studies of Aβ deposition have also demonstrated a clear overlap between AD and normal aging. It was concluded that it was not possible to distinguish early-stage AD from normal aging at post-mortem. Similarly, SP have been observed in 60% of normal elderly cases, albeit at lower density than in AD. Moreover, [researchers have] concluded that there could be a 'continuum' of pathological change from elderly non-demented brains, early stage AD, to advanced AD.

Whether NFT occur as a result of normal aging is more controversial, [however]. Two further aging processes may be involved in AD. First, an age-related breakdown of myelin, although other studies suggest that myelin loss occurs late in AD and is secondary to neuronal degeneration. Second, the loss of cells in the locus caeruleus (LC), which provides noradrenaline to the cortex [and] stimulates microglia to suppress production of Aβ.

These studies suggest that the differences between AD and the normal elderly are largely quantitative rather than qualitative and there may be a 'continuum' of pathological change connecting these cases. Nevertheless, the distribution of the pathology may differ in AD and control brain, being more localised to areas of the temporal lobe in aging and with a more extensive spread into the hippocampus and cortical association areas in AD. An important question, therefore, is whether AD is an exacerbation of normal aging resulting from enhanced spread of the pathology along anatomical pathways.

The immune system declines with age, its army of cells capable of meeting new threats diminishing in number and capacity. One possible form of palliative therapy for immune system aging, intended to produce benefits to the condition of the patient without addressing the underlying causes of this degeneration, is to create large numbers of new immune cells and infuse them into the patient. It is well within the present capabilities of the stem cell research community to grow new immune cells from a patient's stem cells - and indeed this has been accomplished for some years in various forms of clinical trial.

Here is a study that tries this sort of approach in mice, but with mixed results: no harm is done, and it looks like the therapy is having the intended effect under the hood, but equally the most obvious measure of whether it's doing any good in terms of boosted immune response isn't reliably improved either. More work is needed here:

Transfusion of autologous leukocytes after prolonged storage has been proposed as a means of rejuvenating the immune system of older individuals. The rationale for this approach is that age related immune decline is associated with a diminished pool of naïve T cells following atrophy of the thymus and reduction in thymic output. The presence of high levels of naïve T cells within the blood of young individuals could provide a boost to the immune system of an older "self" through a rejuvenation of the naïve T cell pool.

However what remains unresolved is whether the cells could be incorporated effectively into the T cell pool of the host and whether effectors could be generated. Using CD45 congenic mice in our experiments we show that the transfusion of young donor cells into older congenic host animals leads to their successful incorporation into the peripheral T cell pool. When the recipients were challenged with influenza virus, specific effector CD8 cells were generated which were of both host and donor origin.

This would suggest that the environment provided by the host is not lacking and that effectors could be generated in an immune response to antigenic challenge. However the functional response as judged by viral load would appear to be variable, muted in some animals and showing greater effectiveness in others. Our results reveal that although there was a five-fold difference between the lowest and the highest number of cells transferred, at the time of assay there was no major difference in the numbers of donor cells in the hosts when compared with the numbers injected. Our experiments would suggest that there appears to be no direct correlation between the number of cells injected and the number of cells present within the host at the time of assay, implying that cell dose was not a critical factor in incorporation into the peripheral T cell pool.

Link: https://dx.doi.org/10.1186/1742-4933-10-34

The search for ways to measure both chronological and biological age from tissue samples is producing interesting early results. Chronological age is how old you are by the clock, but biological age is a measure of how rapidly the processes of degenerative aging are progressing in your case: different people slide down the slippery slope at somewhat different rates, whether because of genes, luck, or lifestyle choices. DNA methylation is one line of research: it occurs across the whole genome and changes with age as metabolism reacts to rising levels of cellular damage. Combining measurements of the methylation of many different genes seems to produce fairly good results when it comes to identifying the age of individuals and tissues:

"To fight aging, we first need an objective way of measuring it. Pinpointing a set of biomarkers that keeps time throughout the body has been a four-year challenge," said Steve Horvath, a professor of human genetics at the David Geffen School of Medicine at UCLA and a professor of biostatistics at the UCLA Fielding School of Public Health. "My goal in inventing this age-predictive tool is to help scientists improve their understanding of what speeds up and slows down the human aging process."

To create his age predictor, Horvath focused on a naturally occurring process called methylation, a chemical modification of one of the four building blocks that make up our DNA. He sifted through 121 sets of data collected previously by researchers who had studied methylation in both healthy and cancerous human tissue. Gleaning information from nearly 8,000 samples of 51 types of tissue and cells taken from throughout the body, Horvath charted how age affects DNA methylation levels from pre-birth through 101 years. For the age predictor, he zeroed in on 353 markers linked to methylation that change with age and are present throughout the body.

Horvath tested the predictive tool's effectiveness by comparing a tissue's biological age to its chronological age. When the tool repeatedly proved accurate in matching biological to chronological age, he was thrilled - and a little stunned. "It's surprising that one could develop a predictive tool that reliably keeps time across the human anatomy. My approach really compared apples and oranges, or in this case, very different parts of the body - including brain, heart, lungs, liver, kidney and cartilage."

Link: http://newsroom.ucla.edu/portal/ucla/ucla-scientist-uncovers-biological-248950.aspx

Despite more than a decade of finding numerous ways to slow aging in mice, the longest-lived genetically altered mice are still those that lack the genes for growth hormone receptor (GHR), one of the earliest demonstrations of a longevity mutation. They are small and have very little body fat, and as a result have to be carefully husbanded because they are vulnerable to cold - they wouldn't do well in the wild, but are otherwise healthy. These mice live 60-70% longer then their unmodified peers. But why?

A decade of research has not produced a definitive answer to that question, but rather a set of plausible contributions and theories proposed with varying amounts of confidence and supporting evidence. This mutation has a sweeping effect on metabolism, altering many areas thought to be important in aging and longevity. Producing any of these individual changes in isolation, so as to evaluate its effect, has proven challenging: metabolism is a web of linked systems and feedback loops, and changing any one item will cause reactions in all linked subsystems and mechanisms. One of the few definitive successes here is the removal of visceral fat: it is possible to surgically remove some of that fat from mice and show extension of life as a result, so we can reasonably conclude that some portion of the GHR knockout effect results from lower levels of visceral fat.

There are other ways to impact growth hormone beyond removing its receptor. Researchers can eliminate the gene for growth hormone itself, for example, or as in the work noted below they can add a gene for a growth hormone receptor antagonist (GHA), producing a protein that to some degree blocks the normal interaction between growth hormone and its receptor. Comparing the results on mouse metabolism and life span produced by these varied approaches might help to identify the importance of different contributing mechanisms to the life extension effect of GHR knockout.

Repression of GH signaling: One extended life to live!

Noteworthy is the fact that GHA mice do not experience significantly longer lifespans as do other mouse lines with a reduction in the GH/IGF-1 axis, such as the aforementioned GHR-/- mice. As a result, GHA mice have not been as extensively studied. Regardless, comparing the phenotype of GHA mice with other long-lived lines, such as GHR-/- mice, should reveal the most important traits caused by reduced GH action that are responsible for lifespan extension. An important distinction between GHA mice and GHR-/- mice is that the GHA does not completely inhibit GH signaling, while inhibition of GH signaling in GHR-/- mice is complete. Thus, we have generated two dwarf mice each with either low or no GH induced intracellular signaling (and each with low levels of IGF-1) yet only one has extended longevity.

Again, what molecular mechanisms account for this difference in lifespan between these two dwarf lines? GHA mice generally have a phenotype intermediate between that of control and GHR-/- mice, especially as it relates to size, readouts of the GH/IGF-1 axis and measures of glucose homeostasis. For example, GHA mice are dwarf, but not as dramatic as seen in GHR-/- mice. As compared to controls, circulating IGF-1 are reduced in both lines but by only ~25-40% in GHA mice as opposed to more than 80% in GHR-/- mice. While GHR-/- mice are extraordinarily insulin sensitive, glucose homeostasis is moderately improved in young GHA mice with low to normal plasma levels of glucose and insulin. However, insulin levels deteriorate with advancing age in male GHA mice. Perhaps the more marginal decreases in IGF-1 or the lack of dramatic alterations in glucose metabolism are sufficient in GHA mice to curb significant gains in longevity.

Interestingly, while dwarf throughout life, the body weight of male GHA mice gradually catches up to that of control mice with advancing age [due to] marked increases in adipose tissue. Where do GHA mice deposit their adipose tissue and could that be relevant to longevity? Like GHR-/- mice, GHA mice display dramatic increases in the subcutaneous fat depot. However, unlike GHR-/- mice, intra-abdominal fat pads (including visceral depots) become enlarged with advancing age in GHA mice, which may contribute to their deterioration in glucose homeostasis over time.

So here again is something to point to the accumulation of visceral fat as a bad thing for health and longevity. This is one of the few aspects of our biochemistry that we can reliably do something about today, and some portion of the demonstrated long-term health benefits of exercise and calorie restriction probably stems from the presence of lesser amounts of visceral fat tissue. Studies show that maintaining even a modest excess of body fat has a detrimental effect on future health and life expectancy.

Regular readers will no doubt recall that TTR amyloidosis, also known as senile systemic amyloidosis, is a prime suspect for the mechanism that limits human life span to the 110-120 range. Based on evidence from autopsies performed on supercentenarians, those who through luck, genes, and lifestyle manage to survive past the age of 110, these outliers are largely slain by a buildup of amyloid deposits that leads to clogging of blood vessels and ultimately to heart failure.

Transthyretin, or TTR is a protein involved in the transport of a thyroid hormone through the bloodstream. It produces amyloid when it misfolds, something that only becomes threatening in the young for the few unfortunate individuals who inherit a faulty TTR gene. There is some research aimed at producing a therapy for this inherited form of TTR amyloidosis, and the SENS Research Foundation has funded it with an eye to also producing ways to address the age-related form. If there was a good way to periodically clear this amyloid from our tissues, that is all that would need to be done for most people in order to eliminate this very slow-moving contribution to degenerative aging.

Here is an eye-opening piece of research that shows a significant correlation between a minor variant of the TTR gene and life expectancy differences driven by cardiovascular disease and other risks. The effect is surprisingly large for a minor genetic variation, from what I recall of similar research in recent years, and I'd certainly want to see this result replicated before taking it as read. It is still a good argument for bumping up the priority for research into amyloid clearance therapies, though one could argue that perhaps other mechanisms are also at work here, since levels of thyroid hormones seem to be important in longevity:

Transthyretin can cause amyloidosis attributable to destabilization of transthyretin tetramers in plasma. We tested the hypothesis that genetic stabilization of transthyretin associates with reduced risk of vascular disease and increased life expectancy. We included 68,602 participants from 2 prospective studies of the general population. We genotyped for 2 stabilizing genetic variants in the transthyretin gene (TTR), R104H and T119M, and determined the association of genotypes with plasma levels of transthyretin, measures of thyroid function, risk of vascular disease, and life expectancy.

During a mean follow-up of 32 years, 10,636 participants developed vascular disease. We identified 321 heterozygotes for T119M (frequency, 0.47%); R104H was not detected. First, mean plasma transthyretin and thyroxine levels were increased by 17% and 20%, respectively, in heterozygotes versus noncarriers, demonstrating functionality of this variant in the general population. Second, corresponding hazard ratios were 0.70 for all vascular diseases, 0.85 for cardiovascular disease, 0.45 for cerebrovascular disease, 0.47 for ischemic cerebrovascular disease, and 0.31 for hemorrhagic stroke. The cumulative incidence of cerebrovascular disease as a function of age was decreased in heterozygotes versus noncarriers.

Third, median age at death from all causes, from vascular and cerebrovascular diseases, and after diagnosis of vascular disease, and median age at diagnosis of vascular disease, was increased by 5 to 10 years in heterozygotes versus noncarriers.

Link: http://dx.doi.org/10.1161/ATVBAHA.113.301273

Last year researchers uncovered one of the controlling portions of the process by which the hematopoietic stem cells (HSCs) that form blood decline with age. This is a part of the age-related decline of all stem cell types: researchers who subscribe to a programmed view of aging see this a part of the program of aging, a primary cause of frailty and degeneration. Researchers who theorize that aging is a non-programmed accumulation of damage, the more mainstream view at this time, see the decline of stem cell capacity as an evolved response to rising levels of cellular and molecular damage, one that evolved in order to reduce the risk of cancer arising from the actions of damaged cells.

This difference of interpretation is important. In programmed aging world, the right thing to do given the discovery of such a mechanism is to build a therapy to adjust the levels of critical controlling proteins in order to restore a youthful mode of operation - and this is all you have to do in order to halt this part of degenerative aging. In aging-as-damage world, trying to make this change happen is a largely futile endeavor, and certainly not what should be the primary focus of the research community. Such a therapy may produce short-term benefits, as it will temporarily minimize a secondary contribution to the frailty of aging. However, since it fails to address the underlying damage that causes aging and stem cell decline, it is like revving up a worn engine. The outcome will most likely be a greatly raised risk of cancer.

In any case, here is an update on last year's research. The scientists are making progress in following the chain of proteins involved in shutting down stem cell activity in older tissues:

"Although there is a large amount of data showing that blood stem cell function declines during aging, the molecular processes that cause this remain largely unknown. This prevents rational approaches to attenuate stem cell aging. This study puts us significantly closer to that goal through novel findings that show a distinct switch in a molecular pathway is very critical to the aging process." The pathway is called the Wnt signaling pathway, a very important part of basic cell biology that regulates communications and interactions between cells in animals and people. Disruptions in the pathway have been linked to problems in tissue generation, development and a variety of diseases.

Analyzing mouse models and HSCs in laboratory cultures, the scientists observed in aging cells that a normal pattern of Wnt signaling (referred to in science as canonical) switched over to an atypical mode of activity (called non-canonical). They also noticed that the shift from canonical to non-canonical signaling was triggered by a dramatic increase in the expression of a protein in aged HSCs called Wnt5a. When the researchers decided to test this observation by intentionally increasing the expression of Wnt5 in young HSCs, the cells began to exhibit aging characteristics.

Interestingly, the dramatic increase of Wnt5a in aged HSCs activated another protein called Cdc42, which turned out to be critical to stem cell aging. Cdc42 is the same protein the scientists targeted in their 2012 study. In that study, the authors showed that pharmacologically inhibiting Cdc42 reversed the aging process and rejuvenated HSCs to be functionally younger.

The researchers decided that for the current study, they would conduct experiments to see how blocking Wnt5a would affect HSC aging. To do so, they deleted Wnt5a from the HSCs of mice. They also bred mice to lack two functioning copies of the Wnt5a gene, which in essence blocked the protein's function in the HSCs of those animals. Deleting Wnt5 from cells functionally rejuvenated the HSCs. In mice bred to lack two functioning copies of the Wnt5a gene, the animals exhibited a delayed aging process in blood forming stem cells.

Link: http://www.eurekalert.org/pub_releases/2013-10/cchm-bsc101713.php

The programmed aging camp of aging research is a sizable minority in the field, and its members theorize that aging results from an evolved program of changes in metabolism, gene expression, and so forth. Some even think that aging processes are actively selected for rather than being a result of antagonistic pleiotropy, which occurs when a mechanism beneficial in early life is strongly selected despite the fact that it becomes harmful in later life. In later life the members of a species are no longer subject to the sort of evolutionary pressures that would lead to a better outcome for individuals. At the high level evolution only selects for reproductive success: the fate of individuals becomes irrelevant when they age beyond the point of providing meaningful contributions to the success of their offspring, and thus there is no further selection for sustaining, health- and longevity-enhancing adaptations.

Like the other big camp in aging research, the camp of those who theorize that aging is the result of a stochastic accumulation of damage to cells and molecules, programmed aging is divided into (a) researchers who think that there can be rapid progress towards radical extension of healthy life span, (b) researchers who think that only modest gains are plausible, and that even those will be hard to achieve, and (c) the silent majority who focus only on investigations of aging, not actually doing anything about it. The programmed aging approach to building therapies for aging involves altering gene expression and protein levels with the intent of changing the behavior of cellular machinery so as to turn back its operation to a more youthful mode. The researchers are often interested in furthering ongoing drug development programs such as investigations of rapamycin, as using drugs to enhance or suppress levels of specific proteins connected to aging is a step forward to their eyes, one that should lead to more sophisticated manipulations of the aging program in the future.

If you are in the aging as damage camp, as I am, this all looks like the slow road to nowhere, however. The cart is before the horse: damage causes change in gene expression and metabolic operations, not vice versa. This is an important distinction to make, because the research and development strategy that works well in a world in which aging is damage works poorly in a world in which aging is an evolved program - and vice versa. Thus one of these groups is achieving little other than to expand our knowledge of biology and aging.

In any case, this recently published book, while written from a programmed aging perspective, comes recommended. The interesting thing about the divide between the programmed aging and aging as damage camps is that their members largely agree on all of the fundamental observations and science of aging as established to date - the facts are what they are, and the difference is all in the interpretation of those facts. The book is an easy read, aimed at the layperson, but still educational, and the author holds that agelessness can be achieved in the decades ahead with sufficient funding of suitable research programs. I'm always pleased to see more people in the community espousing ambitious views, as ambition for radical change is the first step towards actually making progress.

Why we age: Insight into the cause of growing old

Why are we mortal? What are the causes of aging, and how, if at all, can the process be halted? The issue of aging, which so thoroughly consumes our youth-loving culture today, has only gained traction in the last century. Prior to this, disease, accident, or other misfortune caused the majority of deaths, rather than the effects of old age. As medicine advanced, vanquishing many diseases and adding decades to life expectancies, so old age and the natural shutting down of the human body became a trial for all to bear.

Dr Walker brings to light a real possibility in this age of advanced scientific prowess: the extension of the biological human lifespan beyond its current natural limits. By examining the aging process, scientists can isolate what causes our bodies to age, and therefore, also learn how to control this mechanism. Dr Walker believes that we could be seeing huge advances in this area before the end of the century, and here he explains why.

The book is organized into sections which each deal with a specific theory or question of aging, progressing historically through the often misunderstood relation between aging and death, the effects of aging, the theories on why we age, and ending with a tantalizing glimpse of a future without aging. Dr Walker takes a measured look at these complex issues, giving weight to each discussion with key evidence from several scientific fields. He discusses how "biological immortality" could be possible, by systematically examining evidence and theories to show why this concept could be achievable sooner than we think. The book is not designed as an academic thesis; rather, it is aimed at the average reader keen to understand their own experiences of aging and learn about the exciting advances scientists are making into this field of research.

I notice that Aubrey de Grey wrote a short review:

Although I myself am a proponent of the current mainstream view that aging is a non-programmed, damage-driven process, and I dispute Walker's arguments in this book for rejecting that view, I nonetheless believe that the book has great value: firstly because the model set out here is not one that I believe can be rejected out of hand, secondly because in the event (however unlikely in my view) that it is correct it would point the way to a far simpler and more easily implementable approach to medical postponement of age-related ill-health than would otherwise be available, and last but by no means least that the book is extremely well-written for a general audience, expounding in highly accessible but yet detailed terms a wide variety of aspects of this fascinating and vitally important field. I therefore recommend this book to anyone who is seeking a basic introduction to the biology of aging.

Between them tissue engineering and prosthetics offer replacement parts for a fair number of organs, but none yet as good as the original. This article somewhat overstates of the case with regard to how far the research and development has progressed, but it is certainly true that both biological and artificial replacement organs as good as or better than the evolved versions lie not so very far in the future:

Growing a human organ is a bit like baking a layer cake, says Dr. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine. Let's say the "cake" we want is a kidney. After harvesting cells from the patient's kidney and coaxing them to multiply - mixing up the cake batter - Atala's team bastes those cells onto a biodegradable scaffold, one painstaking layer at a time. "Once there's the right amount," he says, "we put it in an oven-like device that has the same conditions as the human body." The kidney "bakes" inside the bioreactor for a couple of weeks, where it's also exercised. Then it's ready for implant. Eventually, the scaffold melts away, leaving the new organ.

A donor kidney was the first organ to be successfully transplanted into a patient, in 1954. Five decades later, we're building new ones from scratch - growing them on scaffolds or printing them with modified desktop printers that shoot cells instead of ink. About 14 years ago, Atala's team implanted bioengineered bladders into patients and, he says, "they've lasted all these years." He and other scientists are moulding jumbles of cells into heart valves, ears, stomachs and skin. They're building advanced prosthetics, including bionic hands and legs, which mimic natural function and can even be controlled by our minds. More and more people will live their lives with these artificial parts integrated into their bodies.

To Atala, human organs fall into one of four categories, ranging from simplest to make to most difficult. First come flat parts, like skin. Then there are tubular organs, including the windpipe and blood vessels. Next are hollow, non-tubular parts, such as the stomach or bladder. The last, and most difficult to create, are solid organs, like the heart, liver, lung and kidneys. "Up to this point, we've implanted the first three types," says Atala. "We have not yet implanted a solid organ." But it can't be all that far off. In his lab, he's growing human fingers.

Link: http://www2.macleans.ca/2013/10/15/building-a-better-human/

Researchers continue to find new potential applications in regenerative medicine based on the transplantation of stem cells:

A source of gut stem cells that can repair a type of inflammatory bowel disease when transplanted into mice has been identified by researchers. The findings pave the way for patient-specific regenerative therapies for inflammatory bowel diseases such as ulcerative colitis. The team first looked at developing intestinal tissue in a mouse embryo and found a population of stem cells that were quite different to the adult stem cells that have been described in the gut. The cells were very actively dividing and could be grown in the laboratory over a long period without becoming specialised into the adult counterpart. Under the correct growth conditions, however, the team could induce the cells to form mature intestinal tissue.

When the team transplanted these cells into mice with a form of inflammatory bowel disease, within three hours the stem cells had attached to the damaged areas of the mouse intestine and integrated with the gut cells, contributing to the repair of the damaged tissue. "We found that the cells formed a living plaster over the damaged gut. They seemed to respond to the environment they had been placed in and matured accordingly to repair the damage. One of the risks of stem cell transplants like this is that the cells will continue to expand and form a tumour, but we didn't see any evidence of that with this immature stem cell population from the gut."

Link: http://www.sciencedaily.com/releases/2013/10/131017135210.htm

Crowdfunding is evolving, and it will in time make its way beyond being near-entirely devoted to the production of games, art, and gadgets. Arguably games, art, and gadgets make up the bulk of the first wave of crowdfunding growth because some parts of these industries have been discussing and trying out new business models pretty aggressively for the past decade, empowered by the communication infrastructure of the internet. They headed up the exploration and it was only a matter of time before one of those sparks led to a wildfire. Research in medicine and the life sciences, on the other hand, is an industry dominated by top-down decision-making and large, conservative funding structures. Considerably stigma attaches to scientists who step outside the ivory tower to start businesses and gather popular support for their work. I would hope that one of the consequences of the present success of crowdfunding is that any stigma associated with explaining and advocating your work as a scientist to the broader public will go away. Money talks, after all, and grant-writing is arguably a harder road for novel research, and more fraught with conflicts of interest, than obtaining funds directly from interested supporters.

So I'm pleased to see that modest-sized research projects that are somewhat relevant to aging, longevity, and related areas of medical science are starting to arrive and become funded. The present behemoth in the room, Kickstarter, wants nothing to do with medicine or science at this time and is ceding that part of this still-growing industry to competitors, both dedicated research crowdfunding sites like Microryza, anything-goes platforms like Indiegogo, and of course established communities that raise funds for specific goals without the benefit of flashy new dedicated crowdfunding sites, such as Longecity.

So right now, today, I can point out the successfully funded mouse lifespan study at Indiegogo, the ongoing fundraising for a SENS mitochondrial gene therapy study at Longecity, and I thought I'd also point out this brace of projects at Microryza, of varying relevance and degrees of success in funding:

Can we use 3-D printing to engineer organs affordably?

The cost of obtaining human organs for either transplant or research is a barrier in both healthcare and academia. Using off the shelf components along with common non-toxic materials used to grow in vitro blood vessels and potentially organs can significantly reduce that barrier. [The goal of this project is] to investigate the efficiency of the methods of printing carbohydrate glass for use as a sacrificial tissue structure, and replicate previous studies on printing vascularity. This research will also attempt to address whether or not the human engineered vascularities are sufficient to prevent necrosis in the resulting organ.

Targeted Drug Delivery by using Magnetic Nanoparticles

We are initially developing a patch for treating cancer, by injecting microscopic particles (or nanoparticles) into the bloodstream that can pinpoint, attach themselves to, and kill cancer cells. They are then naturally disposed by the body. This technology could potentially revolutionise health care and medicine and save millions of lives around the world as well as allow treatment of new types of cancer.

Developing A New Treatment For Neurodegenerative Diseases

In 2011, a previously unknown mechanism was discovered to control the disease characteristics of the rare genetic disorder Niemann Pick Type C (NPC). NPC is also nicknamed "Childhood Alzheimer's", because the neurological symptoms are remarkably similar to Alzheimer's disease (AD). By re-activating the mechanism, disease characteristics in NPC patient cells were successfully reversed to look like normal cells. As a proof-of-concept, normal cells developed similar characteristics to those seen in NPC patient cells when the mechanism was inhibited. This suggests that this mechanism controls the underlying cause of the disease. The goal of this research is to identify a therapeutic agent that is mechanism specific for the treatment of NPC and AD.

Can Modified Adult Stem Cells Reverse Neurological Pathologies?

Gene-modification of stem cells by transfection allows us to over-express (over-produce) neurotrophic factors (neuronal cell loving proteins) that may alleviate neurological deficits associated with disease. One protein we are interested in transfecting and over-expressing stem cells with is brain derived neurotrophic factor or BDNF. BDNF has been shown to contribute to the recovery of ischemic stroked rats. BDNF mRNA expression is reduced in the Parkinson's disease substantia nigra and improves cognition in an Alzheimer mouse model. Lastly, BDNF is neuroprotective to retinal ganglion cells (RGCs) in a rat glaucoma model.

Researchers should take note of this and do their own exploration. From the litter of failed and poorly funded relevant science projects you can find at Indiegogo it's clear that you can't just put something up and wait for people to notice. You have to go about this as the mouse lifespan project team did, and as the Longevity community does: the project site is only a business card and a place to donate, nothing more. It's a flag, and you have to put in the work to wave that flag, to talk to the community, to find your supporters and motivate them, provide updates, videos, and dialogs with the scientists involved. As more and more research groups try this, however, and establish watering holes like Microryza or Indiegogo, the halo of supporters with overlapping interests will grow, and it will become ever easier to find people who want to fund specific scientific goals.

I think that this is a grand future, one in which funding and advocacy merge naturally at the grassroots level to help advance a thousand needful projects that would otherwise have languished in the old-style funding infrastructure. It is good to see even slow progress towards that end: initial successes will encourage other forward-thinking researchers to join in and experiment, and so the landslide begins.

The protein p53 is involved in many cellular mechanisms, and seems to be an important part of the evolved balance between cancer risk and degenerative aging. This balance manifests as an ongoing decline in the activity of stem cell populations, and thus a progressive failure of tissue maintenance - but the lowered activity of these cell populations reduces the chances of damaged cells spawning cancer. In recent years researchers have demonstrated clever ways to manipulate p53 levels that can both reduce cancer risk and slow aging, so it is possible to both have your cake and eat it too in the case of this mechanism.

p53 is well known for suppressing tumors but could also affect other aging processes not associated with tumor suppression. As a transcription factor, p53 responds to a variety of stresses to either induce apoptosis (cell death) or cell cycle arrest (cell preservation) to suppress tumor development. Yet, the effect p53 has on the non-cancer aspects of aging is complicated and not well understood. On one side, p53 could induce cellular senescence or apoptosis to suppress cancer but as an unintended consequence enhance the aging process especially if these responses diminish stem and progenitor cell populations. But on the flip side, p53 could reduce growth and growth-related stress to enable cell survival and ultimately delay the aging process. A better understanding of diverse functions of p53 is essential to elucidate its influences on the aging process and the possibility of targeting p53 or p53 transcriptional targets to treat cancer and ameliorate general aging.

There are multiple ways to target p53 as an anti-cancer therapeutic. However, directly targeting p53 to suppress aging phenotypes would be difficult considering the delicate balance that is needed among arrest, senescence, and apoptosis. Animal models highlight these complexities [and] imply that specific and narrow interventions to either up or downregulate p53 activity might be suitable for cancer but not effective for general aging. Instead, broad interventions that reduce growth (rapamycin, calorie restriction, resveratrol) or mimic reduced growth (metformin, AICAR) may be the best candidates to alter p53 function in a manner that ameliorates or slows aging.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794078/

If you have a therapy that supposedly slows or reverses aging, how do you determine whether or not it works? Waiting to evaluate life span and health trajectory is the only presently available methodology, and that makes studies in mice very expensive and studies in humans impractical. If there were instead a range of short-term measures that could be reliably mapped to the state of degenerative aging, then research could proceed that much faster. So there is some interest in the search for biomarkers of aging, and this is an example of the sort of work presently taking place:

To investigate general health deterioration and loss of homeostasis in aging, we attempted to determine 1) the dynamics of biological processes during aging and 2) correlate patho-physiological aging end points to transcriptomic responses, which are generally believed to determine the cellular phenotype. Previously, large scale studies provided valuable new insights into aging mechanisms in multiple species, tissues and genotypes. Several of these studies focused on young versus old comparisons, making correlation studies difficult to execute.

We attempted to fill part of the hiatus between chronological aging rate and its associated patho-physiological patterns in the mouse by full genome gene expression profiling of five organs at six ages covering the entire lifespan in mice. Firstly, using the intercurrent gene expression profiles from the six time points, we were able to follow the dynamics of biological processes during chronological aging. For instance, energy homeostasis, lipid metabolism, IGF-1, PTEN and mitochondrial function in liver were slightly up-regulated during the first half of the lifespan but declined during the last 25% of the lifespan. These processes have previously been correlated to chronological aging by others, but interpreting the dynamics of biological functions throughout the lifespan in multiple tissues has been proved difficult so far. Our data can contribute to unravelling the dynamics of functional pathways throughout time in several tissues.

Results indicate that, besides existing overlap between chronological and pathological aging processes (e.g. mitochondrial processes and lipid metabolism), many divergent functional responses were revealed using a (often tissue-specific) pathological scale. These divergent responses leave us with numerous interesting anchor points for future aging research to correlate age-related biological pathways to actual patho-physiological end-points and reveal possible underlying mechanisms, as exemplified for hepatic lipofuscin accumulation.

We hope our results contribute to a new paradigm in aging and medical research taking into account individual and tissue-specific aging levels. For this however, as a next step, a systems biology approach is required to decipher causal age-related mechanisms. Correlating pathophysiological aging endpoints to gene expression and other cellular signatures will become a focus in current aging research to explore loss of homeostasis and general health decline on individual or organ-specific level.

Link: http://www.impactaging.com/papers/v5/n10/full/100606.html

One of the programs undertaken by the SENS Research Foundation is to cultivate the next generation of molecular biologists and other life scientists who will work on the foundations of rejuvenation biotechnology. The future of medicine for aging will focus on manipulating, cleaning, and repairing the protein machinery of cells, using gene therapies and carefully designed molecular machines. Working to treat and prevent degenerative aging will be just another part of the broad spectrum of advanced medical research into cells and cellular machinery - but in order for that to be the case, a research community must exist. A sizable number of today's students must decide that cutting-edge longevity science is both interesting and a growth opportunity. Which it is, but you still have to sell that to people who might have inherited the old view of gerontology as a staid field of palliative clinical medicine rather than the hotbed of new knowledge that it is today, complete with barnstorming displays of hacking living cell biology.

Hence the SRF education initiative, with online coursework and a video lecture series from noted researchers. The Foundation also accepts young researchers into intern positions: these are capable undergrads and postgrads who conduct original research and help to push the current state of the art towards readiness to implement the SENS vision for rejuvenation therapies. In the process they make the connections that will help them further their future careers in this expanding field of medical research. The SENS Research Foundation is at the center of a very wide web of relationships that spans the major aging research laboratories and scientific groups of the US and beyond: it's a very good place to be seen doing good work.

Here are recent posts by some of the last set of SRF interns, discussing the SENS6 conference and looking at the work they performed at the Foundation:

Firsthand account of Dr. Rigdon Lentz's and Dr. Jean Hebert's SENS6 presentations by intern Ariana Mirzarafie-Ahi

Everyone knows that cancer is the result of cells multiplying out of control. Our bodies have ways of identifying these cells and destroying them. However, what goes wrong in cancer? More specifically, what happens in large tumours that allows them to evade our natural defenses? Two kinds of protein, tumour necrosis factor (TNF) and interleukin-2 (IL-2) are responsible for binding to the surface of tumour cells and inducing their death. The problem, however, is that these cells continually produce too many receptors on their surface for these proteins, then shed them, so that they effectively bypass TNF- and IL-2-induced apoptosis (cell death).

Dr Lentz presented his solution to this problem at SENS6. The therapy involves cycling the patient's blood through a device outside the body, so ligands (molecules which attach the receptors) can remove all those extra receptors in the blood. Once the procedure is complete and the blood returned to the patient, TNF and IL-2 should be able to bind to the cell-surface receptors of tumour cells and destroy them.

SRF Intern Ariana Mirzarafie-Ahi Improves a Protocol to Study Age-Related Cross-Linking Molecules Threefold

During her 2013 SENS Research Foundation Summer Internship, Ariana worked with the research group of Dr. William Bains at the University of Cambridge, which specializes in seeking compounds for degrading advanced glycation end-products (AGEs). AGEs are by-products of aging that accumulate in the area between cells called the extracellular matrix (ECM). The 'cross-linking' of AGEs causes wrinkles, stiff joints, hypertension, blindness, and other age-related conditions. Ariana's project focused on optimizing the decellularization step that precedes quantitation of AGEs.

"My project sought to significantly shorten the period of time required for the decellularization of tissue samples. To analyze the contribution of specific AGE cross-links to tissue aging and test possible means of breaking those cross-links, it is first important to have a quick, simple procedure for decellularizing the tissue being studied. This procedure preserves all the major ECM proteins while removing the vast majority of cellular proteins. The run-time of the original decellularization protocol was 10 days. To determine if any steps could be truncated, I measured the progress of decellularization each day during the 10-day protocol. I noted that no significant increase in decellularization occurred during several days of the protocol. Using this data, I devised a new protocol which reduces the decellularization process from 10 days down to just 3."

Ariana presented her work at the SENS6: Reimagine Aging Conference held at Queens' College, Cambridge in September 2013. The new decellularization protocol will be published in the April 2014 special edition of Rejuvenation Research.

How small molecule intervention by the Chen and Madeo labs may reverse the aging process by intern Navneet Ramesh

I was particularly drawn to two presentations at the conference, that of Dr. Danica Chen from the University of California, Berkeley and that of Dr. Frank Madeo from the University of Graz. The SENS approach calls for damage repair to maintain and restore cellular function. Both presentations focused on small molecule interventions that could reverse the effects of aging.

Dr. Chen explained how sirtuin 3 (SIRT3) can slow the rate of damage to stem cells. Sirtuins are a group of seven proteins that affect many cellular processes by activating metabolic pathways. For example, sirtuins are believed to play a role in slowing the aging process via calorie restriction. However, a direct role in repair of cellular damage has remained poorly understood until now.

Another highlight of SENS6 for me was Dr. Frank Madeo's demonstration that a compound called spermidine promotes longevity. Spermidine belongs to a class of organic compounds known as polyamines, which have been shown to decline with age. They have been identified as key regulators of genes involved in aging, but the specific details as to how they interact with these genes remains unknown. Dr. Madeo noted that spermidine treatment promoted autophagy, which is the process of degrading and destroying unneeded cellular components through the lysosome. This discovery is particularly interesting to rejuvenative medicine because diminished autophagic activity is thought to play a crucial role in the aging process.

SRF Intern Navneet Ramesh Attempts to Inhibit a Key Pathway in Tumor Cell Maintenance of Telomere Length

In most cases, tumor cells owe their indefinite longevity to the enzyme telomerase, which continuously extends their telomeres. However, 10 to 15% of tumor cells can maintain telomere length without telomerase function. This second method of telomere maintenance is referred to as "alternative lengthening of telomeres," or ALT. The exact mechanism by which ALT occurs remains unknown, but several chromatin remodeling genes have been implicated. Several types of cancer cells, especially in tissues of mesenchymal origin, exhibit the ALT phenomenon.

During my internship, I attempted to determine how the ALT mechanism could be overcome. Previous studies have demonstrated that a transcriptional regulator involved with chromatin remodeling, known as ATRX, is either deleted or abnormally expressed in cells which use the ALT mechanism. I hypothesized that introduction of ATRX could inhibit ALT activity. Therefore, I predicted that expression of ATRX in ALT-regulated cells would lead to a reduction in markers of ALT activity, such as C-circles, ALT-associated PML nuclear bodies (APBs), and, of course, telomere length. To test this hypothesis, I transfected three cell lines that utilize the ALT mechanism with an ATRX expression construct and measured the resulting effect on ALT activity. Preliminary data indicates that ATRX expression does indeed reduce ALT activity.

Tissue engineers have demonstrated the ability to grow small amounts of structured organ tissue called organoids in recent years, and have done so with liver, kidney, and now pancreatic cells, among others:

[Researchers] have developed a three-dimensional culture method which enables the efficient expansion of pancreatic cells. The new method allows the cell material from mice to grow vividly in picturesque tree-like structures. The method offers huge long term potential in producing miniature human pancreas from human stem cells. These human miniature organs would be valuable as models to test new drugs fast and effective - and without the use of animal models.

The cells do not thrive and develop if they are alone, and a minimum of four pancreatic cells close together is required for subsequent organoid development. "We found that the cells of the pancreas develop better in a gel in three-dimensions than when they are attached and flattened at the bottom of a culture plate. Under optimal conditions, the initial clusters of a few cells have proliferated into 40,000 cells within a week. After growing a lot, they transform into cells that make either digestive enzymes or hormones like insulin and they self-organize into branched pancreatic organoids that are amazingly similar to the pancreas."

"We think this is an important step towards the production of cells for diabetes therapy, both to produce mini-organs for drug testing and insulin-producing cells as spare parts. We show that the pancreatic cells care not only about how you feed them but need to be grown in the right physical environment. We are now trying to adapt this method to human stem cells."

Link: http://news.ku.dk/all_news/2013/2013.10/new_3d_method_used_to_grow_miniature_pancreas/

Cells are constantly suffering damage, the protein machinery harmed by reactive metabolic byproducts, other waste chemicals building up, and various subsystems failing. Efficient repair processes run continually, but at varying paces in response to circumstances. Degenerative aging is nothing more an accumulation of unrepaired damage in and between cells, and many of the ways to slow degenerative aging in laboratory animals are associated with a higher level of the cellular repair and housekeeping processes known as autophagy.

Here is a short open access review that providing an introduction to the processes of autophagy and their significance, with diagrams to clarify some of the descriptions:

Cellular damage occurs in response to genetic perturbations, nutrient deprivation, aging, and environmental toxins. The task of managing general and specific cellular damage is largely under the control of the highly regulated process called autophagy. The term autophagy is used to describe lysosomal-mediated degradation of intracellular contents, which can be divided into 3 basic mechanisms: (1) chaperone-mediated autophagy, (2) microautophagy, and (3) macroautophagy.

Macroautophagy is the most extensively studied autophagy process. One major function of macroautophagy is the control of accumulation of over-produced, long-lived or damaged proteins. Deficiencies of macroautophagy may contribute to accumulation of protein aggregates, which are apparent in a number of neurodegenerative diseases.

Chaperone-mediated autophagy, initiated by chaperone Hsc70, recognizes one protein at a time, and Hsc70 carries the protein to the lysosomes via binding to the lysosomal associated membrane protein (LAMP2A). Whether additional chaperones and lysosomal receptors participate in chaperone-mediated autophagy is unknown.

Microautophagy is achieved by invagination of lysosomal membranes. Lipid, protein or organelles can be degraded through this pathway. Whether lipid, organelles and other proteins are marked by specific modifications to be recognized by the lysosomes is highly likely but the majority of these have yet to be defined.

Autophagic removal of mitochondria is important for mitochondrial quality control. Poor quality mitochondria may enhance cellular oxidative stress, generate apoptosis signals, and induce cell death. Because healthy mitochondrial function is essential for cell survival, selective removal of a subset of dysfunctional mitochondria is a highly regulated process and requires coordinated functions of mitochondrial and cytosolic proteins. This is controlled by a complex array of proteins which are constantly being revised and enhanced.

Link: http://dx.doi.org/10.1016/j.redox.2012.11.008

The Longecity community is presently raising funds for a modestly-sized rejuvenation research project to be undertaken by a SENS Research Foundation team. Grand goals are made of many small steps, and these days any given small step in the life sciences can take the form of a six month project, a few skilled post-graduate researchers with access to an established lab, and $10-30,000. Meaningful research that pushes forward the boundaries of medical science is becoming very cheap, with that fall in prices driven by accelerating progress in the tools and capabilities of biotechnology. We can see this process at work here, as this significant and useful gene therapy research can be conducted with a proposed budget of $21,000.

LongeCity Research Support 2013: Mitochondrial Gene Therapy

In this project, engineered mitochondrial genes will be used to restore function to cells that contain defective mitochondrial genes.

The SENS team is developing a unique method for targeting these genes to the mitochondria; this step has been the bottleneck in research on this topic over the last decade. In their system, the mRNA from the engineered mitochondrial gene is targeted to the mitochondrial surface before it is translated into a protein using a co-translation import strategy. Once imported, it is incorporated into the correct location in the inner mitochondrial membrane. The long-term goal of this project is to utilize this improved targeting strategy to rescue mutated mitochondrial DNA and thereby prevent and cure one of the major causes of cellular aging.

There is an open question and answer thread dedicated to the project in the Longecity forums, and the researchers have started to discuss the research in some detail. I think that you'll find it interesting:

Mitochondrial Gene Therapy: Questions

One reason [that we chose to work with the genes CyB and ATP8] that these may be both the easiest and hardest genes to achieve efficient import with. CyB has a reputation (whether or not it is deserved is a matter for some debate) in the field of being the most difficult and hydrophobic protein to import into the mitochondria. It is one of the bigger mitochondrially encoded genes, so at the very least it is a challenge. ATP8, on the other hand, is tiny and so may be considered the easiest to import. Thus we've set ourselves a task that spans the range of challenges that we think we'll encounter.

The second reason is that, strategically, OxPhos complexes III and V are the most interesting for proof of concept rescue of the entire mito genome. The reason is that they have the fewest genes that are encoded by the mitochondria. Complex III has only CyB (and thus ONLY CyB is needed to rescue the entire complex) and Complex V has only 2: ATP6 and ATP8. So if we want to study functional rescue of entire complexes then III and V are the easiest.

A third of the needed project funds - $7,000 - will be raised from the community while the remaining $14,000 will matched by Longecity: $2 for every $1 donated. Since I last mentioned this project, donors have contributed a little over $5,000 - so just $2,000 left to go, with a November deadline. If you've been on the fence about donating, then jump in! It's never too late to help build a future that we'd all like to live in, one that involves far longer, healthier lives, and complete prevention of the diseases of aging.

This mitochondrial gene therapy project is exactly the sort of crowdfunded science initiative that I like to see succeed - and that I'd like to see succeed again many times over in the years ahead. A future in which the SENS Research Foundation obtains a significant amount of its science budget from the community on a project by project basis is a bright one, I think. It isn't just a matter of money and connecting with supporters: it also generates publicity, materials, and broader interest in the research itself. At this stage in the game it is still very important to talk to the rest of the world about longevity science and the prospects for progress in the near future, and crowdfunding rejuvenation research via Longecity, Microryza, and Indiegogo - and their successors - blends fundraising, organizational transparency, advocacy, education, and persuasion in a very useful way.

Every detrimental change that occurs with aging is directly caused by some collection of cellular mechanisms, but that is only the second to last link in the chain. The deeper cause is an accumulation of unrepaired molecular damage, spiraling outward to create that chain of changes, reactions, and forms of secondary damage. While the list of fundamental damage that causes aging is enumerated and well understood, the final proximate cause of an age-related condition can be challenging to identify and understand - our biology is very complex indeed. You might look at the amount of work and funding that has gone into Alzheimer's research, for example, and the decades it has taken to make any sort of meaningful progress there. Sometimes an immediate cause can turn out to be fairly clear and localized, however, given sufficiently advanced tools for investigation:

[Researchers] have new insight into the age-old question of why maximum heart rate (maxHR) decreases with age. This decrease in maxHR not only limits the performance of aging athletes but it is also a leading cause for nursing home admittance for otherwise-healthy elderly individuals who no longer have the physical capacity required for independent living.

One of the reasons for the age-dependent reduction in maximum heart rate is that aging depresses the spontaneous electrical activity of the heart's natural pacemaker, the sinoatrial node. "I utilized a method to record ECGs from conscious mice and found that maximum heart rate was slower in older mice, just as it is in older people. This result wasn't unexpected. But what was completely new was that the slower maxHR was because the individual pacemaker cells - called sinoatrial myocytes, or 'SAMs' - from old mice just couldn't beat as fast as SAMs from young mice."

The slower beating rate was due to a limited set of changes in the action potential waveform, the electrical signal that is generated by the cells. The changes were caused by altered behavior of some ion channels in the membranes of the older cells. Like most initial discoveries in basic science, this study opens many more questions and avenues for further research. But the significance of the study is that it raises the possibility that sinoatrial ion channels and the signaling molecules that regulate them could be novel targets for drugs to slow the loss of aerobic capacity with age.

Link: http://www.eurekalert.org/pub_releases/2013-10/uocd-wdm101113.php

Reseachers and advocates associated with Heales and the International Longevity Alliance successfully crowdfunded a modest mouse life span study via Indiegogo. It's worth looking at how they went about structuring the research (a short term project using old mice, which benefited from having a group of suitably aged mice to hand now) and managing publicity. Now if we could just manage the same sort of outcome for a range of more ambitious SENS-related mini-projects in rejuvenation research rather than combinatorial drug tests for slowing aging...

Here, we step on the shoulders of giants : by contributing you can help us test a combination of drugs shown to extend healthy lifespan in mice. The largest life extension in mice so far resulted from a similar effort, where one mouse lived very close to 5 years (mice usually live 2-3 years)! The result should be key to to optimally search for additional years of healthy life.

This experiment has something unique. It is the first time in the world that crowdfunding is used to test a combination of the most potent nongenetic-interventions known to extend the lifespan. The results will help in the search for life prolonging treatments for both animals and humans. Analogous experiments have hardly been done in mammals and have usually been done only for the immediate short-term effects, without checking the effects on the animal's entire lifespan. For these reasons in many cases you never know for sure whether the drugs you take shorten your lifespan or make you live longer and healthier.

There are *right now* in the lab a sufficient number of aged mice (~20 months old) - male and female - which belong to the C57Bl6 strain to start a lifespan test. The mice will be divided into 2 test groups (females and males) and 2 control groups (24 animals per each group). The test will be blind.

The food of the treated mice will contain: 1) An α-adrenergetic receptor blocker (metoprolol). Potential action: Prevents too fast heart beats. 2) An mTOR inhibitor (everolimus, similar action as rapamycin). Potential action: Puts cells in an active and resistant mode. 3) Metformin. Potential action: Normalizes blood and IGF-1 values at low levels. It also has potential similarities with everolimus. 4) Simvastatin. Action: Decreases the amount of LDL cholesterol (considered as 'bad' by some) in the blood. 5) Ramipril: an ACE inhibitor. Action: Prevents hypertension. 6) Aspirin. When small doses are used, it is believed to have reduced side effects while improving blood flow and therefore reducing cardiovascular risks, and potentially also preventing incidence of some cancers.

Link: http://www.indiegogo.com/projects/i-am-a-little-mouse-and-i-want-to-live-longer

Each of our cells contains a herd of mitochondria, the evolved descendants of ancient symbiotic bacteria that now work to generate chemical energy stores used to power the rest of the cell. Mitochondria malfunction in aging, causing their cells to malfunction also, and it is though that this stems from damage to the comparatively fragile mitochondrial DNA. This DNA specifies essential protein machinery used in mitochondrial energy generation, but it sits right next to the ongoing and energetic set of chemical reactions that occur inside each mitochondrion. These reactions generate reactive byproducts - free radicals, reactive oxygen species, and so on - that are most likely to harm the mitochondria rather than any other portion of the cell.

Mitochondria, their state of damage, and their resistance to becoming damaged appear to be very important in determining the pace of aging and longevity of different individuals and species. In particular damage to mitochondrial DNA is important: per the mitochondrial free radical theory of aging, the chain of harm starts with chance mutations that remove just a few essential protein blueprints, but which also allow the damaged mitochondrion to evade cellular quality control mechanisms - so it can reproduce and spread its form of dysfunction.

All of this is why technologies that can replace mitochondrial DNA or move it into the cell nucleus are so important: they will repair and reverse a contributing cause of degenerative aging. Unfortunately it has proven technically challenging to obtain a good picture of what exactly is going in the mitochondrial DNA of laboratory animals, let alone people in clinics. This has probably dampened enthusiasm for the development of means to replace mitochondrial DNA over the past few decades - clinical development proceeds only after great certainty in the underlying science these days, arguably far more certainty than is actually needed to produce good, working therapies. Only comparatively recently has data started to accumulate in earnest, to the point at which it can be seriously applied to support or disprove various different forms of the mitochondrial free radical theory of aging. Here is a whole raft of data to take a look at, however, an example of what researchers are turning out today in terms of mapping mitochondrial DNA damage:

Mitochondrial DNA Rearrangements in Health and Disease - A Comprehensive Study

Mitochondrial DNA (mtDNA) rearrangements cause a wide variety of highly debilitating and often fatal disorders and have been implicated in aging and age-associated disease. Here we present a meta-analytical study of mtDNA deletions (n = 730) and partial duplications (n = 37) using information from more than 300 studies published over the last 30 years.

We show that both classes of mtDNA rearrangements are unequally distributed among disorders and their breakpoints have different genomic locations. We also demonstrate that 100% of cases with sporadic mtDNA deletions and 97.3% with duplications have no breakpoints in the 16 071 breakage hotspot site, in contrast with deletions from healthy and aged tissues. Notably, most deletions removing a section of the D-loop are found in tumours. Deleted mtDNA molecules lacking the origin of L-strand replication (OL ) represent only 9.5% of all reported cases, while extra origins of replication occur in all duplications. As previously shown for deletions, imperfect stretches of homology are common in duplication breakpoints.

mtDNA Rearrangements Database

We provide a dedicated website with detailed information on deleted/duplicated mtDNA regions to facilitate the design of efficient methods for identification and screening of rearranged mitochondrial genomes.

MitoBreak - The mitochondrial DNA breakpoints database

A comprehensive on-line resource with curated datasets of mitochondrial DNA (mtDNA) rearrangements, MitoBreak provides a complete, quality checked and regularly updated list of breakpoints.

Damage to the mitochondrial genome might occur in the form of point mutations, large deletions or duplications and DNA breakage with subsequent linearization of the mtDNA molecule. As eukaryotic cells contain many copies of mtDNA, a mutated type of mtDNA must first reach a threshold level by clonally expanding within a cell before it can cause adverse effects. The accumulation of damaged mtDNA molecules in tissues is an important cause of mitochondrial disease, a clinically heterogeneous group of disorders related with OXPHOS dysfunction. Moreover, mutated mtDNAs are suspected to contribute to the etiology of a number of age-related disorders, by accumulating with age in a variety of tissues.

Autophagy is the name given to a collection of housecleaning and recycling processes that take place within cells. Research indicates that more autophagy is a good thing, leading to fewer damaged cellular components and metabolic waste products lingering to cause issues. Most of the methods demonstrated to extend life in laboratory animals are linked to enhanced levels of autophagy, and artificially increasing levels of autophagy might form the basis for future medical therapies.

Here, however, researchers show that extracellular levels of amyloid in Alzheimer's disease are reduced in mice with deficient autophagy, which is not the expected result, but nonetheless makes sense in context:

Pathological hallmarks of Alzheimer's disease (AD) include the aggregation of amyloid beta (Aβ) peptides inside neurons and the accumulation of extracellular Aβ plaques. Previously, the mechanisms by which Aβ leaves neurons were unknown, and it has been controversial whether the intracellular or extracellular accumulation of Aβ plays a larger role in AD-associated symptoms.

[Researchers] crossed mice deficient in autophagy in forebrain neurons with transgenic animals that produce abnormally high levels of the Aβ precursor protein. They found that the offspring had far fewer extracellular Aβ plaques than the transgenic mice that showed normal autophagy. "We know that autophagy is the cleaning system within the cell. Our expectation was that if we delete autophagy, we would get more of the Aβ plaques outside the cell. But we saw the contrary, so we were really surprised by that, and we had to work hard to understand why."

In order to understand the reason that autophagy-deficient mice had fewer Aβ plaques, the researchers measured Aβ release from neurons isolated from the mice. They observed a drastic decrease in Aβ secretion, which led to accumulation of Aβ inside the cells. [This in turn] led to neurodegeneration and memory impairment in the mice, consistent with earlier reports "that intracellular Aβ is toxic, or is at least contributing to the toxicity" in neurons. "We have brought some light to the issue, but of course it is not known yet how the toxicity is mediated. That remains to be elucidated." But the question of whether intracellular versus extracellular Aβ accumulation mediates the effects of AD remains contentious. "The field is divided."

"What this study is telling us, too, is that one of the mechanisms that protects the cells is getting rid of the Aβ that's in the cells and putting it outside the cell. Sure, it may still be toxic under those conditions, but the real toxicity is being generated by its accumulation and disruption of intracellular processes."

Link: http://www.the-scientist.com/?articles.view/articleNo/37769/title/Autophagy-s-Role-in-Alzheimer-s/

Here is an experimental methodology that I haven't seen advocated recently, though it bears on some of the theorizing regarding the evolutionary origins of naked mole rat longevity, since they live in comparatively oxygen-poor tunnel environments.

The negative relation between metabolism and life span is a fundamental gerontological discovery well documented in a variety of ontogenetic and phylogenetic models. But how do the long-lived species and populations sustain lower metabolic rate and, in more general terms, what is the efficient way to decline the metabolism?

The suggested 'pull and push back' hypothesis assumes that decreased O2 (hypoxia) and/or increased CO2 (hypercapnia) may create preconditions for the declined metabolic and aging rates. However, wider implementation of such ideas is compromised because of little advances in modification of the metabolic rate. Artificial atmosphere with controlled O2 and CO2 levels could be a promising approach because of the minimal external invasions and involvement of the backward and forward loops ensuring physiological self-regulation of the metabolic perturbations.

General considerations and existing data indicate that manipulations of CO2 levels may be more efficient in life span extension than O2 levels. Thus, maximum life span of mammals positively correlates with the blood CO2 and HCO3- but not with O2 levels. Yet, proportional decease of the body O2 and increase of CO2 seems the most optimal regime ensuring lower losses of the energy equivalents. Furthermore, especially rewarding results could be expected when such changes are modeled without major external invasions using the animals' inner capacity to consume O2 and generate CO2, as it is typical for the extreme longevity.

Link: http://dx.doi.org/10.1007/s10522-013-9472-1

The immune system can be broadly divided into adaptive and innate components, both of which decline with age. A failing immune system is one of the most serious aspects of frailty in the elderly, leaving them vulnerable to pathogens that a young person would shrug off, and suffering from reduced monitoring activities aimed at the destruction of potentially cancerous, senescent, and other harmful cells.

Focusing just on the adaptive immune system, there are a range of contributing causes identified by researchers to date. Firstly, new T cells, the workers and killers of the immune system, are only created in large numbers when an individual is young. The thymus, where these immune cells mature, atrophies early in adult life, its evolved task of setting up the immune cell population done. The supply of new immune cells diminishes to a trickle thereafter, a fraction of what it was. This effectively caps the T cell population associated with the active immune system: the body only supports so many.

This soft limit on the number of T cells leads to the second cause of immune system decline, which is structural, inherent in the nature of the immune system's organization and mode of operation. The adaptive immune system remembers threats, and it does do by maintaining a converted population of memory cells, one for each threat. Unfortunately some threats, like herpesviruses, cannot be cleared from the body: they keep coming back, again and again, each time leading to more cells becoming specialized to remember them. The main culprit here appears to be cytomegalovirus (CMV), which the majority of people have been exposed to by the time they are old: aside from its effects on the immune system's memory cell contingent it is largely harmless, and you probably didn't even notice your initial infection. But ultimately your immune system becomes overpopulated by memory cells dedicated to CMV, with too few naive T cells left to do its other jobs.

These outlines are simplifications of a complex set of issues, and omit any discussion of how the array of cellular and molecular damage that accumulates with aging also impacts the immune system negatively. The important point to take away from this is that the research community has near-term options available to reverse these contributions to immune system frailty. For example: the use of tissue engineering to restore thymic tissue to the role of generating a flow of new T cells; regular infusions of fresh T cells created from the patient's own stem cells; the use of new cancer therapy technologies to target and kill memory T cells specialized to CMV, freeing up space for new T cells. None of these are beyond the capacity of today's technology - as is so often the case, it's just a matter of devoting research and development resources to the problem for a few years, in a world in which funding sources lack the vision to support even the obvious bold advances.

Here is a good, conservative, and very readable open access review of the role of CMV in immune system decline:

Human T cell aging and the impact of persistent viral infections

Aging is associated with a dysregulation of the immune response, loosely termed "immunosenescence." Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual.

In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people.

We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity.

Dissecting the effects on immune alterations in elderly individuals with respect to age, low grade-inflammation, disease and CMV seropositivity remains a big challenge. We are currently approaching this challenge by assessing individual variations in responses to CMV, namely antibody titer, specificity, and neutralizing activity and determination of the specific CMV cell reservoirs (e.g., monocytes) rather than just "infected vs. not infected." This approach appears to us more likely to yield informative data in populations where almost all subjects are infected with the virus, for instance elderly individuals even in industrialized countries and essentially everyone in developing countries. Furthermore, longitudinal studies are needed including young and elderly healthy individuals to dissect the effects of age vs. CMV infection.

This is the sort of data gathering exercise that I would like to see augmented in medical research by more aggressive experiments in intervention, an area in which I think the research community is far less active than it could be. In the past you could argue costs, but costs are plummeting in the life sciences as biotechnology advances rapidly. It seems to me that just as much could be learned by augmenting T cell numbers or destroying memory T cells in animal studies as by exploring human data in more detail - and moreover it would also move the world closer to working therapies should the results be positive, which won't happen in the data gathering default mode of modern research.

Most human dietary studies gather data via participant self-reporting, which has its limitations. Using biomarkers to examine levels of specific dietary components is a step up from that, but it doesn't remove the core issues inherent in looking at specific dietary components in isolation. For example, we know that overall calorie intake level is enormously important in determining health and longevity, and that correlates with levels of different dietary components. Also, people who make better efforts to take care of their health tend to have better diets, but that effort extends beyond just diet. So levels of specific dietary components in human studies are going to correlate with all sorts of other line items that can impact health and longevity, such as exercise, calorie intake, amount of visceral fat tissue, conscientiousness in use of medical resources, and so on.

Correlation is not causation, but invariably when it comes to diet there are all sorts of vested interests willing to sell you the idea that you should believe otherwise. This study reports a large enough result to awake that contingent:

Polyphenols are naturally occurring compounds found largely in fruits, vegetables, coffee, tea, nuts, legumes and cereals. More than 8,000 different phenolic compounds have been identified in plants. Polyphenols have antioxidant, antiinflammatory, anticarcinogenic, etc. effects.

Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy.

In conclusion, the research proves that overall mortality was reduced by 30% in participants who had rich-polyphenol diets (greater than 650 mg/day) in comparison with the participants who had low-polyphenol intakes (less than 500 mg/day). "[The] results corroborate scientific evidence suggesting that people consuming diets rich in fruit and vegetables are at lower risk of several chronic diseases and overall mortality." Moreover, the research stresses the importance of evaluating - if possible - food intake by using nutritional biomarkers, not only food frequency questionnaires.

Link: http://dx.doi.org/10.3945/jn.113.177121

Here are the results of an analysis of the effects of exercise on aging and longevity in mice: it is expected to slow the onset of age-related frailty, but unlike the practice of calorie restriction it fails to extend either average or maximum life span.

Exercise has been unequivocally associated with a slowing of age-specific mortality increases in rats and with an increased median lifespan. However, the results in mice [to date] are not that clear.

Male C57Bl/6J mice, individually caged, were randomly assigned to one of two groups: sedentary (n = 72) or spontaneous wheel-runners (n = 72). We evaluated longevity and several health parameters including grip strength, motor coordination, exercise capacity (VO2max) and skeletal muscle mitochondrial biogenesis. We also measured the cortical levels of the brain-derived neurotrophic factor (BDNF), a neurotrophin associated with brain plasticity. In addition, we measured systemic oxidative stress and the expression and activity of two genes involved in antioxidant defense in the liver (that is, glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD)). Genes that encode antioxidant enzymes are considered longevity genes because their over-expression may modulate lifespan.

Exercise does not cause an increase in either average lifespan or maximal lifespan. Maximal lifespan was defined as the age at which the longer-lived animal died. In our mice it was 950 days. Average lifespan was defined as the age at which 50% of the animals died. It was 750 days for sedentary mice and 770 for wheel-runners. Aging was associated with an increase in oxidative stress biomarkers and in the activity of the antioxidant enzymes, GPx and Mn-SOD, in the liver in mice. Life-long spontaneous exercise did not prolong longevity but prevented several signs of frailty (that is, decrease in strength, endurance and motor coordination). This improvement was accompanied by a significant increase in the mitochondrial biogenesis in skeletal muscle and in the cortical BDNF levels.

Link: http://www.longevityandhealthspan.com/content/2/1/14

The New Organ Prize is an initiative of the Methuselah Foundation, and has been under development for a little while - an open beta for trying out crowdfunding strategies, building alliances, and so forth. This is an evolution of the organization's experience with research prizes and their use in spurring a scientific community to achieve greater and more rapid progress. The Foundation's past work on the Mprize for longevity science, and associated networking behind the scenes, helped to speed the transformation of aging research from a field in which any public discussion of life extension was likely to be career-threatening into a community that now embraces the quest for longer healthy lives. Much of the publicity for longevity science that you see today would never have happened even as recently as a decade ago, as back then researchers were much more circumspect and funding sources much more conservative.

The New Organ Prize exists in a different, more liberated, and openly ambitious scientific environment and has a different aim: to accelerate the development of whole organ tissue engineering, creating functional long-lasting organs just as good as the natural variety, built from a patient's own cells, and to make this happen far sooner than it otherwise would. The Methuselah Foundation staff have already built a range of important alliances, such as with tissue printing company Organovo, and the arrangement outlined in the announcement that I found in my in-box today:

We're thrilled to announce that Methuselah has now secured an official launch date and partner for the New Organ Prize - the World Stem Cell Summit (WSCS), taking place in San Diego, CA on December 4-6, 2013. As the premier annual forum for regenerative medicine, there's no better place than WSCS to unveil New Organ to the scientific community and the world. And we'd love for you to join us.

WSCS and Methuselah Foundation aspire to build an enduring partnership that will contribute to the realization of whole organ engineering, preservation, and regeneration for the benefit of millions. With attendees from more than 40 countries, the Summit's interdisciplinary agenda for the global stem cell community explores everything from disease updates and new research directions to cell standardization, regulatory pathways, and economic development.

This year, New Organ will be an integral part of WSCS. During this three-and-a-half day event that includes a variety of speaker presentations, ongoing exhibitions, small group events, and social opportunities, WSCS chairman Bernie Siegel will join Methuselah CEO Dave Gobel on stage in a joint announcement celebrating the official launch of the New Organ Prize.

Our whole team will be there ... and we wouldn't be here without you. Just like the leaders of the World Stem Cell Summit, you're committed to New Organ's success, and we'd be honored to mark this milestone together. To learn more about WSCS and register, visit www.worldstemcellsummit.com.

Thanks again for your ongoing support. Here's to the upcoming launch of New Organ!

One aspect of the frailty of being old is the loss of healing capacity. Stem cell activity diminishes, probably as a part of an evolved response to accumulated cellular damage that minimizes cancer risk, and even minor injuries become troubling. Researchers are investigating the details of this process with the intent of reversing the signaling systems involved, restoring some of the youthful ability to heal. This, unfortunately, doesn't do anything to address the underlying damage of aging - it is in some ways like removing the safety features that prevent overuse of a worn engine - but the end result is better than not having the ability to do this.

Researchers working with elderly mice have determined that combining gene therapy with an extra boost of the same stem cells the body already uses to repair itself leads to faster healing of burns and greater blood flow to the site of the wound. Their findings offer insight into why older people with burns fail to heal as well as younger patients, and how to potentially harness the power of the body's own bone marrow stem cells to reverse this age-related discrepancy.

To heal burns or other wounds, stem cells from the bone marrow rush into action, homing to the wound where they can become blood vessels, skin and other reparative tissue. The migration and homing of the stem cells is organized by a protein called Hypoxia-Inducible Factor-1 (HIF-1). In older people [fewer] of these stem cells are released from the bone marrow and there is a deficiency of HIF-1.

[Researchers] first attempted to boost the healing process in mice with burn wounds by increasing levels of HIF-1 using gene therapy, a process that included injecting the rodents with a better working copy of the gene that codes for the protein. That had worked to improve healing of wounds in diabetic animals, but the burn wound is particularly difficult to heal, and that approach was insufficient. So they supplemented the gene therapy by removing bone marrow from a young mouse and growing out the needed stem cells in the lab. When they had enough, they injected those supercharged cells back into the mice. After 17 days, there were significantly more mice with completely healed burns in the group treated with the combination therapy than in the other groups. The animals that got the combination therapy also showed better blood flow and more blood vessels supplying the wounds.

Link: http://www.sciencedaily.com/releases/2013/10/131009132235.htm

Investigations continue into what can be done with comparatively simple transplantation of various different types of stem cell:

Damaged or diseased organs may someday be healed with an injection of blood vessel cells, eliminating the need for donated organs and transplants, according to scientists. Researchers show that endothelial cells - the cells that make up the structure of blood vessels - are powerful biological machines that drive regeneration in organ tissues by releasing beneficial, organ-specific molecules. They discovered this by decoding the entirety of active genes in endothelial cells, revealing hundreds of known genes that had never been associated with these cells. The researchers also found that organs dictate the structure and function of their own blood vessels, including the repair molecules they secrete.

"Our work suggests that that an infusion of engineered endothelial cells could engraft into injured tissue and acquire the capacity to repair the organ. These studies - along with the first molecular atlas of organ-specific blood vessel cells - will open up a whole new chapter in translational vascular medicine and will have major therapeutic application. Scientists had thought blood vessels in each organ are the same, that they exist to deliver oxygen and nutrients. But they are very different." Each organ is endowed with blood vessels with unique shape and function and delegated with the difficult task of complying with the metabolic demands of that organ.

The scientists postulated that endothelial cells derived from embryonic stem cells [are] able to be taught how to act like an organ-specific blood vessel, [and the] team generated endothelial cells from mouse embryonic stem cells that were functional, transplantable and responsive to microenvironmental signals. These embryonic-derived endothelial cells "are versatile, so they can be transplanted into different tissues, become educated by the tissue, and acquire the characteristics of the native endothelial cells."

Researchers can propagate these cells in large numbers in the laboratory. "We now know what it takes to keep these cells healthy, stable and viable for transplantation." The researchers transplanted these generic endothelial cells [into] the liver of a mouse and found that [they] became indistinguishable from native endothelial cells. This also occurred when cells were grafted into kidneys. "These naive endothelial cells acquire the phenotype - the molecular profile and signature - of the native pre-existing endothelial cells due to the unique microenvironment in the organ. These transplanted endothelial cells are being educated by the unique biophysical microenvironment organ in which they are placed. They morph into endothelial cells that belong in the organ, and that can repair it. If you have a heart injury and you need to reform some of your cardiomyocytes, the endothelial cells that are around the heart secrete factors that are specific for helping a heart repair itself."

Link: http://weill.cornell.edu/news/releases/wcmc/wcmc_2013/blood-vessel-cells-can-re.shtml

I'm definitely not going to run up a quick post every time that a journalist thinks he or she has something new to say about Calico, Google's recently announced and only just underway initiative aimed at pushing forward the bounds of longevity science and extending human life. If I did that it would be Calico day and and day out until Google finally revealed the details of their research and funding agenda - which, frankly, I can't imagine is more than a long internal white paper at this point, and subject to change. But I'll indulge just this once, since it's been a couple of weeks, long enough for someone in the profession to actually have done some legwork and come up with something that we outsiders don't yet know.

New details on Google's anti-aging startup

Calico is considered the brainchild of Bill Maris, the Google Ventures managing partner who once was a biotech portfolio manager at Investor AB. Sources says that Maris looked at the life sciences landscape, and saw hundreds of companies all focused on curing or minimizing various diseases and conditions. In all cases, the goal was either to prolong life and/or improve the quality of life. What didn't exist, however, were companies focusing on the root cause of so much of this disease and death. Namely, that we all keep getting older. Or, put another way, that our bodies begin to fail on a cellular level - largely due to degradation of our genetic materials.

Now that the entire genome had been coded, Maris wondered if it was possible to actually study the genetic causes of aging and then create drugs to address them (a question that was heavily influenced by talks with futurist and Googler Ray Kurzweil). For example, what if you examined the genomes of thousands of healthy 90 year-olds from all parts of the world? What genetic similarities do they have? Or, perhaps, what happens to most of us that didn't happen to them. Even if this didn't result in longer life, it perhaps could at least lead to an improved quality of life for folks on the back nine.

One of those Maris called on was Google co-founder and director of special projects Sergey Brin, who expressed interest in investing. But as conversations progressed between Brin, Maris and Google CEO Larry Page, a consensus began to form that the best course of action would be to fund the entire project off of Google's balance sheet (the board would later agree). I have heard various numbers as to the exact Google commitment, but for now can only really say that we're talking about a minimum of hundreds of millions (tranched out, of course). The company itself still isn't commenting, although it's possible that there will be some specifics in its next quarterly earnings report (due next week).

You might recall that Maris made some interesting comments on the direction of Google Ventures late last year.

Maris said some of the areas he is interested in include businesses that are focused on radical life extension, cryogenics and nanotechnology.

At present some observers are joining the perhaps-too-obvious dots to suggest that Calico will fund programs focused on the data side of medical research, as Google is a Big Data company. If so, then I wouldn't expect Calico to directly contribute much to the bottom line of (a) the number of years of healthy life gained by you and I, and (b) just how long it takes to develop and deploy longevity-enhancing therapies. The obvious places to start with data are genetic studies of longevity or comparative studies of biology between long-lived and short-lived people and species - and that's all a sideshow, really, far removed from research programs capable of producing human rejuvenation.

Google Calico details emerge: Immortality, Obamacare, and millions of dollars

According to insiders familiar with Calico's formation, Maris was inspired by the work of the Human Genome Project, which had coded the entire DNA sequence. The combination of that, and an understanding of how Big Data crunching could be implemented, led to suggestions that Calico could compare the genome of healthy older people - such as those who had made it to their 90s without encountering any significant health issues - and see how, in aggregate, they differed from others.

Really this is all just more reading of tea leaves. It is very good that large sums of money are sliding towards longevity science: the avalanche that began ten years ago with a few advocates and small foundations has started in earnest. But it should be expected that Google will probably follow the present mainstream distribution of funding for longevity science, which is to say that most of it will go towards things like calorie restriction mimetic development, or the next drug candidate after rapamycin thought to slightly slow aging, or the study of centenarian genomes, and so on. None of these are paths to human rejuvenation, and only some of them are even slow, hard paths to slightly extending healthy human life.

So the arrival large-scale funding doesn't bypass the need to ensure that rejuvenation research (such as SENS, the Strategies for Engineered Negligible Senescence) dethrones slowing aging (such as rapamycin development) as the dominant strategy for the aging research community. That process is underway, and many noted researchers are SENS supporters, but it has a long way to go yet.

I don't spend my time advocating for the development of SENS-style repair therapies, ways to reverse the known root causes of degenerative aging, because I'm some kind of longevity science counter-culture hipster, supporting the minority view in the field because it's the minority view in the field. I advocate repair-based research aimed at reversal of aging because, based on my decade of reading research and observing the biotechnology community, I'm convinced that it's the only plausible and cost-effective way to produce large gains in healthy life span soon enough to matter to those of us in middle age today.

At this point any high-level strategy for longevity science will lead to some form of first generation therapies twenty years or so from now. If the present mainstream focus on drug development and gently slowing aging by metabolic manipulation continues to be the dominant approach, then the therapies of the 2030s will be weak medicine, and will do little for those of us who by then have become old, aging and dying on much the same schedule as our parents. What use is slowing the damage of aging when you are already old and damaged? But equally over those twenty years the research community could instead choose to work on repairing the root causes of aging - choose to produce rejuvenation therapies that reverse age-related frailty and effectively treat age-related disease, resulting in large gains in healthy life span even for people who are already old.

This is the most important debate in medical research today, as the outcome will determine whether we die as did our parents, or whether we have the opportunity to live in good health for centuries. Yet the broader public are oblivious to it.

Cryonics as presently practiced is the low-temperature storage of a patient on death, so as to preserve the structure of the mind and offer a chance at being revived by a future medical community capable of rejuvenation, repair, and restoration to life. Cryonics as a medical technology has been under development at a slow pace since the early 1970s, with a steady delivery of improvements in process and methodologies. This piece from a recent issue of Cryonics Magazine discusses strategies and goals for future improvements in the cryopreservation process:

Let's start with the following definition of cryonics: "Cryonics is the stabilization of critically ill patients at ultra-low temperatures to allow resuscitation in the future." As you can see, nothing in this definition says that repair is an intrinsic feature of cryonics. But is this a reasonable perspective? Yes, cryonics patients will require a second look at their condition by a future doctor who will have more advanced medical technologies at his/her disposal. This could conceivably be called "repair." Most cryonics patients will also require rejuvenation biotechnologies. After all, it makes little sense to cure the patient's disease but leave him/her in a fragile, debilitated state. This could be called "repair" too, in particular if you believe that aging is the progressive accumulation of damage.

The repair that I want to discuss here is repair of the damage that is associated with the cryopreservation process itself. If we can eliminate this kind of damage, and the associated requirement of repair in the future, we will make the idea of cryonics a whole lot more attractive. Perhaps the most obvious advantage is that cryonics could not be dismissed solely by pointing to the (irreversible) damage caused by the cryopreservation process itself. In essence, such a form of cryonics would be akin to putting a critically ill patient in a state of true suspended animation. This would strengthen the legal position of cryonics patients because a decision to abandon a patient in such a condition would be more akin to murder (or at least serious neglect).

Another advantage would be that the absence of cryopreservation damage would increase the likelihood of the patient being restored to good health in the future. Less damage is also likely to translate into lower costs, too, and it is rather obvious that such an advantage can mean more security for the patient. Reversible cryopreservation may also lead to earlier treatment and resuscitation attempts, which may reduce challenges associated with re-integration [into society]. Cryonics without repair also matters in the here-and-now. Without the goal of reversible cryopreservation there are no objective, empirical criteria to evaluate the quality of care in a cryonics case. Last, but not least, we should do no harm. Allowing unnecessary injury of the patient because future advanced technologies should be able to fix it is a morally suspect gamble with a person's life.

Link: http://www.alcor.org/magazine/2013/10/07/cryonics-without-repair/

Here is a better article covering recent advocacy for the Longevity Dividend. A group of researchers have been seeking large-scale public funding of ways to slow aging for some years now, aiming for a sweeping alteration in the strategy for research into aging and age-related disease, and this is one of their periodic calls to action:

Slowing aging is no fantasy. Researchers can delay how rapidly lab animals such as mice and roundworms grow old with a variety of measures, from genetic tinkering to extremely low-calorie diets. So far, however, nobody has shown that any drug or diet can postpone human senescence. But some scientists, including demographer S. Jay Olshansky of the University of Illinois, Chicago, argue that we now know enough about aging to start an intensive, multiyear search for ways to delay it in people - a sort-of Manhattan Project for longevity. "Aging is the underlying risk factor for most of the things that go wrong with us" as we grow older, he says. That means slowing the process would not just add years to our lives, but it would also postpone illnesses such as cancer, diabetes, and heart disease that primarily strike the elderly.

An extra couple of years might not be very attractive if you're going to be sick and decrepit. But slowing aging would also allow about 5% more seniors to avoid infirmity between 2030 and 2060 than would reductions in cancer or heart disease alone. "To my friends who want to live forever, I say it makes for great science fiction," Olshansky says. "Our goal is to extend healthy life, not necessarily life itself."

Olshansky belongs to the Longevity Dividend Initiative (LDI), a group of researchers and organizations that has been talking up the payoffs of postponing human aging. [He] and his colleagues are ready to take the next step, he says. In 2014, the LDI plans to start raising money, mainly from nongovernmental organizations and private individuals, to fund research to develop age-fighting measures, Olshansky says. Although researchers are already studying many potential options, the LDI's goal is to usher them into human studies and possible use.

As you can see, this is the position taken by researchers who think that some modest gains can be made, but who - for whatever reason - don't see repair of the root causes of aging leading to rejuvenation per the SENS model as a viable path forward. In many ways this is a competition for attention and funding: work on rejuvenation and its backers versus work on modestly slowing aging and its backers. That said, funding isn't a fixed bucket, and the more that aging, longevity, and medical research are discussed in public the larger that bucket might become.

Link: http://news.sciencemag.org/economics/2013/10/secret-antiaging-worth-looking

There is some debate over whether rapamycin, an immune suppressant agent that is presently being used in research to inhibit the activities of the protein produced by the mechanistic target of rapamycin (mTOR) gene, causes a slowing of aging or merely a reduction in cancer rates. The mTOR gene is a hot topic in research these days, as the extension of life in mice resulting from rapamycin is more reliable and easily replicated than is presently the case for any other line of longevity-enhancing drug development. The question of whether it actually slows aging or merely suppresses cancer is somewhat important for the future of this research, however. Both outcomes produce longer life in laboratory animals, but only one is of great interest to longevity science - if rapamycin is only a cancer suppressant, then its continued development will be picked up by the cancer research community, and the scientists aiming at aging will move on.

This runs the other way as well, of course. If there is debate over whether a cancer suppressant is slowing aging or not, then you will find researchers who think that perhaps it is time to take a closer look at how other known or suspected cancer suppressants work. Might they be slowing aging? This attitude is prevalent among researchers who subscribe to the programmed view of aging, seeing degenerative aging as something that might ultimately be stopped entirely through suitable alterations to genetic programming and protein levels. Digging through the enormous complexity of metabolism and its relationship with degenerative aging is much more attractive if you imagine that this sort of grail lies at the end of the road.

This research group advocates the hyperfunction theory of programmed aging, and its members see extension of life through inhibition of mTOR as supportive of that theory:

Selective anticancer agents suppress aging in Drosophila

According to our analysis of the literature more than 100 pharmaceutical substances that can prolong the lifespan of model organisms [have been discovered]. However, the increase of lifespan with aging-suppressor substances rarely exceeds 40%, which [is] greatly less than effects (up to 1000% or more) caused by mutations in the regulatory genes, which are the key switches of cell program to maintain growth or resist to stress, such as gene of PI3Ksubunit. We proceeded on the assumption that a more effective aging-suppressor drugs may be substances with specificity to the products of genes that control the evolutionarily conserved mechanisms of aging, mutations in which have the greatest effect on lifespan and the aging rate. In this regard, we investigated the aging-suppressive properties of specific pharmacological inhibitors of aging associated gene products TOR, PI3K, NF-κB and iNOS.

The aging process is associated with hyperactivation of TOR and PI3K, as well as NF-κB and iNOS, leading to cellular senescence, age-related pathologies, and oncogenesis. Therefore, many anticancer agents are inhibitors of the same enzymes as aging-suppressors, including TOR, PI3K, NF-κB and iNOS. This is entirely consistent with the theory that considers cellular senescence as age-dependent hyperactivation of pro-aging signaling pathways.

We studied the effects of inhibitors of PI3K (wortmannin), TOR (rapamycin), iNOS (1400W), NF-κB (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors [on] Drosophila melanogaster lifespan and quality of life (locomotor activity and fertility). Our data demonstrate that pharmacological inhibition of PI3K, TOR, NF-κB, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin and wortmannin (by 23.4%). The bioinformatic analysis showed the greatest aging-suppressor activity of rapamycin, consistent with experimental data.

The programmed aging viewpoint must be contrasted with the view that aging is an accumulation of damage. We see changes in protein levels and epigenetic alterations with aging because metabolism reacts to that damage - damage causes change, the reverse of the programmed aging view of change leading to damage. If, as I believe from my reading around the field, aging is indeed largely a matter of a stochastic accumulation of unrepaired damage, then manipulation of genes and metabolism to try to slow down aging is a very poor way forward in comparison to just fixing the damage. Building methods of repair for the known forms of damage that cause aging should be a far easier and faster development program - which is why I support SENS over mainstream work on the development of longevity drugs. It is the more optimal path forward, and the only one likely to lead to radical life extension in our lifetimes.

Many people believe that greatly increased population levels are the inevitable result of increased human longevity. Separately, many people believe that overpopulation is presently happening, and will lead to catastrophe in the near future. I and many others have noted in the past that overpopulation doesn't exist today, that many multiples of today's population could exist on this one planet with a high standard of living using no more than today's technology, and that population models show that even radical life extension doesn't greatly increase the population size. Supporting any level of population is simply another engineering challenge, one well within our capabilities today for any plausible near future population size, never mind using the improved technologies of tomorrow.

What people point to today as overpopulation is more accurately labeled as poverty caused and maintained by bad governance: resources squandered, persistent war, kleptocracies, regulation, serfdom, and so on. It is not a matter of counting heads, but of greed and inhumanity. So little of the light and noise put out on the topic of overpopulation seems particularly rational to me, but here is a generally sensible piece from a pro-longevity author:

By far the most predominant criticism made against indefinite longevity is overpopulation. It is the first "potential problem" that comes to mind. But fortunately it seems that halting the global mortality rate would not cause an immediate drastic increase in global population; in fact, if the mortality rate dropped to zero tomorrow then the doubling rate for the global population would only be increased by a factor of 1.75, which is smaller than the population growth rate during the post-WWII baby-boom.

Finding innovative solutions to new and old problems is what humanity does. Thus while overpopulation is the most prominent and most credible criticism against continually-increasing lifespans, and the one that needs to be planned-for the most (because it will eventually happen, but it will lead to sustainability, resource and living space problems only if we do nothing about it), it is in no way insoluble, nor particularly pressing in terms of the time available to plan and implement solutions to shrinking living-space and resource-space (i.e. the space occupied by resources such as food, energy-production, workplaces, etc.). We have a host of potential solutions today, ones we can use to increase available living space without regulating the global birthrate, and decades following the achievement of indefinite lifespans to consider the advantages and disadvantages of the various possible solutions, to develop them and to implement them.

So then: wherefore from here? Overpopulation is still the most prominent criticism raised against indefinite longevity, and if combated, it could lead to an increase in public support for the longevity movement. You might think that the widespread concern with overpopulation due to increasing longevity won't really matter, if they turn out to be wrong, and overpopulation isn't so insoluble a problem as one is inclined to first presume. But this misses a crucial point: that the time it takes to achieve longevity is determined by and large by how widespread and strongly society and the members constituting it desire and demand it. If we can convince people today that overpopulation isn't an insoluble problem, then continually-increasing longevity might happen much sooner than otherwise. At the cost of 100,000 deaths due to age-correlated causes per day, I think hastening the arrival of indefinite longevity therapies by even a modest amount is somewhat imperative. Hastening its arrival by one month will save 3 million lives, and achieving it one year sooner than otherwise will save an astounding 36.5 million real, human lives.

Link: http://ieet.org/index.php/IEET/more/cortese20131003

Much of present research into longevity-enhancing genetic alterations is a matter of following the chains of association in protein machinery, looking for common mechanisms shared by different mutations. Since any given metabolic alteration that extends life can be induced or influenced by changing the levels of numerous different proteins, it is expected that (a) researchers will find many different longevity mutations beyond those already known, and (b) most of these will act through a much smaller number of common mechanisms. Identifying those common mechanisms is one path towards greater understanding of the way in which natural variations in longevity are determined by genes and the operation of metabolism.

While numerous life-extending manipulations have been discovered in the nematode Caenorhabditis elegans, one that remains most enigmatic is disruption of oxidative phosphorylation. In order to unravel how such an ostensibly deleterious manipulation can extend lifespan, we sought to identify the ensemble of nuclear transcription factors that are activated in response to defective mitochondrial electron transport chain (ETC) function.

Using a feeding RNAi approach, we targeted over 400 transcription factors and identified 15 that, when reduced in function, reproducibly and differentially altered the development, stress response, and/or fecundity of isp-1(qm150) Mit mutants relative to wild-type animals. Seven of these transcription factors - [including HIF-1 and] the CREB homolog-1 (CRH-1)-interacting protein TAF-4 - were also essential for isp-1 life extension.

When we tested the involvement of these seven transcription factors in the life extension of two other Mit mutants, namely clk-1(qm30) and tpk-1(qm162), TAF-4 and HIF-1 were consistently required. Our findings suggest that the Mit phenotype is under the control of multiple transcriptional responses, and that TAF-4 and HIF-1 may be part of a general signaling axis that specifies Mit mutant life extension.

Link: http://www.impactaging.com/papers/v5/n10/full/100604.html

The most conservative members of the aging research community don't believe that human life spans can be meaningfully extended any time soon, or that we should even make the attempt. Fortunately, they don't have much more to say on the matter, so don't contribute meaningfully to discussions on this topic within the scientific community. They are a part of the silent majority: researchers who only investigate aging, gathering data rather than attempting to do something about it.

Among scientists who do believe that lives can be lengthened, most - in public at least - adhere to the view that the only plausible goal is a gentle slowing of the pace of aging, and that even this is not going to happen any time soon. The proposed methodologies here generally involve ways to shift the operation of metabolism into more efficient states, such as that produced through the practice of calorie restriction, shown to extend healthy and maximum life spans in many different species. As the past few decades of research have demonstrated, this is an expensive and complex proposition. Despite billions of dollars in research funding, there is little to show yet beyond an increased understanding of the relationship between metabolism, genetics, and natural variations in longevity - and that present understanding is clearly just a starting point.

(Fortunately there is a much better way forward based on identifying and repairing the damage that causes aging. Such an approach doesn't require anywhere near as much new knowledge, and will lead to rejuvenation rather than just a slowing of aging. As yet this is a minority research program within longevity science, however, for all that it is the self-evidently better path forward. But that is not today's topic).

Among researchers who look with favor on work aimed at gently slowing aging, there is one group who have for some years promoted what they call the Longevity Dividend: a proposal for large-scale public funding to go towards methods of slowing aging. Their position is backed by models that show incrementally greater gains in health than can be achieved through the present modus operandi of trying to patch over age-related diseases in their late stages. At the highest level this is a matter of prevention versus cure: aging is the cause of age-related diseases, and thus efforts focused on treating aging should be far more efficient when it comes to raising quality of life and reducing the incidence and cost of frailty and disability in the old.

The Longevity Dividend camp has gathered supporters over the years, as open discussion of extending human life has become more acceptable within the scientific community, and this example of research and advocacy is their latest foray into the public funding arena:

The Pursuit Of Improved Physical And Mental Health

Medical advances, improved nutrition, and reductions in smoking have extended life expectancy and reduced the prevalence of diseases that stalk modern society. Paradoxically, though, for every success, an equally difficult challenge remains. As people age, they are less likely to suffer through a single disease but rather experience multiple maladies related to living longer. In this issue of Health Affairs we explore this paradox and many other subjects while conceding that humankind will never exhaust the quest for reducing mortality and relieving pain.

Are there other approaches to prolonging healthy living that could accompany these ongoing efforts? Dana Goldman, David Cutler, John Rowe, Pierre-Carl Michaud, Jeffrey Sullivan, Desi Peneva, and Jay Olshansky have developed a hypothetical alternative called "delayed aging." Their article reports that studies with animal models have shown real potential and concludes that greater investment in research on delaying aging appears to be an efficient way to forestall disease, extend healthy life, and improve public health.

Substantial Health And Economic Returns From Delayed Aging May Warrant A New Focus For Medical Research

Recent scientific advances suggest that slowing the aging process (senescence) is now a realistic goal. Yet most medical research remains focused on combating individual diseases. Using the Future Elderly Model - a microsimulation of the future health and spending of older Americans - we compared optimistic "disease specific" scenarios with a hypothetical "delayed aging" scenario in terms of the scenarios' impact on longevity, disability, and major entitlement program costs.

Delayed aging could increase life expectancy by an additional 2.2 years, most of which would be spent in good health. The economic value of delayed aging is estimated to be $7.1 trillion over fifty years. In contrast, addressing heart disease and cancer separately would yield diminishing improvements in health and longevity by 2060 - mainly due to competing risks. Delayed aging would greatly increase entitlement outlays, especially for Social Security. However, these changes could be offset by increasing the Medicare eligibility age and the normal retirement age for Social Security. Overall, greater investment in research to delay aging appears to be a highly efficient way to forestall disease, extend healthy life, and improve public health.

To live a longer, healthier life: delay aging, don't just cure disease, study concludes.

"When we treat someone with cancer, or heart disease, or stroke, we are treating a manifestation or byproduct of biological aging -- the underlying process marches on unaltered by this approach to disease," said Jay Olshansky, a professor at the University of Illinois School of Public Health in Chicago and a co-author of the study. "This means that even if we succeed for a time in extending life by treating disease, either that disease or another will emerge with time....Slowing aging alters the risk of all diseases simultaneously by attacking the origins of all of the things that go wrong with us as we grow older."

Delayed aging is better investment than cancer, heart disease

With even modest gains in our scientific understanding of how to slow the aging process, an additional 5 percent of adults over the age of 65 would be healthy rather than disabled every year from 2030 to 2060, reveals the forthcoming study. Put another way, an investment in delayed aging would mean 11.7 million more healthy adults over the age of 65 in 2060.

The analysis, from top scientists at USC, Harvard, Columbia, the University of Illinois at Chicago and other institutions, assumes research investment leading to a 1.25 percent reduction in the likelihood of age-related diseases. In contrast to treatments for fatal diseases, slowing aging would have no health returns initially, but would have significant benefits over the long term.

This is all very encouraging from the point of view that more public discussion of extended longevity through medical science is a good thing. A rising tide floats all boats. But attempting to slow aging is a great way to burn a lot of money and time with the expectation of very little to show for it at the end of the day. This isn't rejuvenation research of the sort advocated by the SENS Research Foundation, and only that type of repair-based strategies for treating aging have the possibility of producing the means of human rejuvenation soon enough to matter. The expected outcome for drug development to slow aging is that everyone in middle age today will age to death on much the same schedule as their parents: the emergence of treatments to slightly slow aging twenty years from now, produced at a vast cost, will do next to nothing to change that outcome.

Aging is damage, and only by repair of that damage can aging be reversed. So be appropriately pleased to see more discussion of extending healthy life in public, but recognize that only greater material support for SENS research and similar programs will help us live for decades longer in good health.

Researchers make progress in growing another tissue type from cells:

[Researchers have] created precursors to salivary and lacrimal glands that, when transplanted into mice, successfully connected to the host ducts and nervous system. Once connected, these lab-grown secretory glands helped to restore the production of saliva and tears in animals from which healthy salivary or lacrimal glands had previously been excised.

To create the secretory glands, [the researchers] built on previous work that used a bioengineering technique they developed to reconstitute organ germs from teeth and hair follicles via a 3-D cell processing method. First, they created the glandular precursors - or "germs" - in vitro using single epithelial and mesenchymal cells isolated from embryonic glands. After three days in organ culture, the bioengineered glands had undergone branching morphogenesis, followed by stalk elongation and cleft formation - three tell-tale signs of organogenesis. By that time, the researchers also observed an accumulation of saliva in the ducts of the bioengineered salivary gland germs.

[The researchers] next engrafted these secretory gland germs in mice - from which healthy salivary or lacrimal glands had been removed - using a nylon thread-guided, interepithelial tissue-connecting plastic method it published [last year]. Not only did the precursor secretory glands innervate, but in response to stimulation by the nervous system, they began to secrete saliva and tears, moistening dry mouths and eyes in the animal models.

Link: http://www.the-scientist.com/?articles.view/articleNo/37727/title/Replacement-Secretory-Glands/

One emerging strategy in medical research is to set up factories in the body to manufacture proteins and drugs in situ as needed. Taking advantage of existing cellular machinery to do this make sense, and so we see the production of technology demonstrations like this one:

The researchers inserted modified strands of messenger RNA into connective tissue stem cells - called mesenchymal stem cells - which stimulated the cells to produce adhesive surface proteins and secrete interleukin-10, an anti-inflammatory molecule. When injected into the bloodstream of a mouse, these modified human stem cells were able to target and stick to sites of inflammation and release biological agents that successfully reduced the swelling. "If you think of a cell as a drug factory, what we're doing is targeting cell-based, drug factories to damaged or diseased tissues, where the cells can produce drugs at high enough levels to have a therapeutic effect."

Mesenchymal stem cells have become cell therapy researchers' tool of choice because they can evade the immune system, and thus are safe to use even if they are derived from another person. [The messenger RNA] technique to program cells is harmless, as it does not modify the cells' genome, which can be a problem when DNA is used (via viruses) to manipulate gene expression. "This opens the door to thinking of messenger RNA transfection of cell populations as next generation therapeutics in the clinic, as they get around some of the delivery challenges that have been encountered with biological agents."

Link: http://www.hsci.harvard.edu/newsroom/stem-cells-engineered-become-targeted-drug-factories

The SENS Research Foundation funds and coordinates much-needed research into the foundation biotechnologies for human rejuvenation, as well as advocacy programs to encourage greater funding and progress in areas of longevity science that are presently neglected. This, sadly, is most of the list beyond cancer and stem cell medicine.

Among their many other activities, the Foundation staff are engaged in building a video library that will in time include a full lecture course from noted researchers aimed at students and young scientists, profiles of researchers and postgraduate interns working on rejuvenation biotechnology, and records of the SENS conference series at which new advances are presented in fields of research relevant to engineering greater human longevity.

The SENS6 conference was held last month, and some of the first few presentation videos are being posted to the SENS Research Foundation YouTube channel. Here, for example, is the keynote from George Church:

In the SENS6 Conference's keynote address, Harvard University's Dr. George Church describes recent advances in genomics and in the reading, writing, and interpretation of -omes fields. He also discusses PersonalGenomes.org, his initiative to glean new medical insights by gathering data on the genotypes, microbiomes, environments, traits, and stem cells of participants. He proceeds to cover various methods of improving RNA sequencing to gather data on transcriptomes, then provides additional detail on engineering therapeutics for individual patients. Before concluding, Dr. Church discusses protective alleles and offers a broad overview of genomic engineering strategies. In particular, he notes the considerable promise the CRISPR approach holds for the field.

A long and detailed piece from the SENS Research Foundation on the relevance of ongoing development of therapies for Parkinson's disease based on targeting α-synuclein, a protein thought to be important in the disease process:

A range of damaged proteinaceous aggregates accumulate intracellularly and extracellularly in the aging brain, with higher burdens of characteristic aggregates associated with diagnosed age-related neurodegenerative disorders. These include beta-amyloid protein (Aβ) and neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and other age-related dementias, and Lewy bodies and other intracellular α-synuclein (AS) aggregates in Parkinson's disease (PD) and other synucleinopathies. Additionally, it is increasingly clear that LB along with other neuronal protein aggregates are key drivers of "normal" cognitive aging.

Multiple lines of evidence from cell culture studies, transgenic model organisms, and genetic epidemiology link a person's steady-state AS levels and accumulation of LB to both clinical PD and subclinical age-related movement disorders. Mutations and genetic variants that increase the production or aggregability of AS are clearly linked to earlier onset and severity of PD.

Buoyed by the strong evidence from AS vaccination studies, an Austrian biotechnology firm with an unique development platform - with support from a major Parkinson's charity - has lept ahead of the pack. As of this writing, they are now in the midst of human clinical trials of a first-in-class immunotherapeutic agent targeting the removal of pathological AS species as a disease-modifying rejuvenation therapy to prevent, arrest, and reverse the ravages of Parkinson's disease.

The degenerative aging process is driven by the accumulation of multiple forms of cellular and molecular damage in the structures of our tissues, leading progressively over time to increasing disease, disability, and ultimately death. PD as a clinical entity emerges when the level of a specific subset of such lesions crosses of a clinical threshold. The key corollary of these facts is that when rejuvenation biotechnology matures to the point that this underlying damage is safely and effectively removed, repaired, replaced, or rendered harmless, then PD and the full spectrum of age-related disease and disability can be prevented, arrested in its course, and ultimately reversed.

AS vaccines will address one key driver of the PD phenotype: the accumulation of aggregated AS species in the brain and peripheral nervous system. But to fully arrest the progression of the disease, multiple rejuvenation biotechnologies will have to be brought to bear, each of them targeting specific cellular and molecular lesions involved in the constellation of pathology underlying PD.

Step by step, the rejuvenation biotechnologies needed to prevent and reverse the disabling neuropathology that drives PD are being developed, tested in rodents, and moved into clinical trials. The rejuvenation biotechnologies that emerge from these trials will initially be indicated for PD, but the lesions that these new therapies target are suffered by all aging people, driving the universal age-related loss of motor control, cognition, and autonomic dysfunction. Whether any individual suffers the obvious gait disturbances, tremors, and "masklike" loss of facial affect - these eventualities are in part a matter of individual variations in how rapidly the age-related lesions most specific to PD symptoms accumulate in our tissues, and in part a matter of the rate at which other aging damage accumulates in our bodies, overshadowing or pre-empting clinical PD with competiting forms of age-related morbidity and mortality.

An end to this, and to the misery of age-related ill health in all its forms, are what drives SENS Research Foundation's work in research, education, outreach, transdisciplinary networking, and advocacy. We are encouraged by the progress being made in clearance of AS aggregates from the aging brain, moving us one step closer to the day when humanity will move free of the mummification of the years.

Link: http://www.sens.org/research/unbinding-mummies-human-testing-rejuvenation-biotechnology-targeting-%CE%B1-synuclein-begins

That overpopulation exists at all is one of the most prevalent delusions in the modern world: thanks to the environmentalist movement, a cause that has ascended near to the status of civic religion, the average fellow in the street thinks that there are too many people alive today, that resources are stretched to breaking point, that the future is one of Malthusian decline, and that horrible poverty in the third world is caused by the existence of too many people. All of these points are flat-out wrong. Humanity is wealthier and has greater access to resources today than at any time in history, the variety and amounts of available resources are growing at an accelerating pace due to technological progress, the earth could support many times more people than are alive today, and where there is poverty it exists due to terrible, predatory governance and the inhumanity of man - it exists due to waste and aggression amidst the potential for plenty.

Even this pro-longevity piece subscribes, as many do, to the false idea that somehow we are consuming too many resources and will run out. This is silly: resources are infinite, because through technological progress we constantly develop new ones. People live in an age of change, with each new decade clearly different from the last, and yet live under the assumption that everything will remain the same going forward. Being worried about running out of anything that we use today is like being worried about running out of candle wax in 1810, or running out of room for horse breeding operations in 1840, or running out of food in 1940. All false concerns, and all false for exactly the same reasons: we are not static consumers of resources, we are net producers of resources.

Make no mistake, it'll take us a long, long time to get there, but we'll eventually find a way to halt the aging process. Owing to advanced medical, regenerative, and cybernetic technologies, future humans will enter into a state of "negligible senescence," a condition marked by the cessation of aging and the onset of everlasting youth. It sounds utopian, but as biogerontologist Aubrey de Grey has repeatedly noted, it's simply an engineering problem - one that's not intractable.

I've been debating this issue for the better part of a decade, and I've heard virtually every argument there is to be said both in favor of and in condemnation of the possibility. I'm not going to go over all of them here. But without a doubt the single most prominent argument set against radical life extension is the issue of overpopulation and environmental sustainability.

As a final note, there's a certain inevitability to radical life extension. It's the logical conclusion to the medical sciences. So rather than futilely argue against it, we should come up with constructive solutions to ensure that it unfolds in the most non-disruptive way possible.

Link: http://io9.com/no-extreme-human-longevity-won-t-destroy-the-planet-1440148751

Mutations in mitochondrial DNA (mtDNA) are at the center of the mitochondrial free radical theory of aging. Every cell has its herd of bacteria-like mitochondria, toiling to generate chemical energy stores and emitting reactive free radicals as a result of this activity. Each mitochondrion has its own copy of mitochondrial DNA, separate from the DNA in the nucleus of the cell. If mutations change or remove any one of a dozen or so of the most vital genes in a mitochondrion then it will malfunction in ways that can evade the cell's quality control mechanisms. That mitochondrion will divide to create more broken copies, and ultimately all the mitochondria in that cell and all its descendants will become defective. This creates malfunctioning, abnormal cells that export streams of harmful, reactive molecules into the surrounding tissues. This process is one of the root causes of aging, and is why you'll see a fair number of posts here on the repair of mitochondrial DNA as a part of any future toolkit of rejuvenation therapies.

There is some debate over the different types of mutational damage in mitochondrial DNA and their significance, however. Damage ranges all the way from comparatively minor point mutations, in which a single base is substituted, all the way up to catastrophic double strand breaks that require major intervention to restore correctly. To pick one example from past research, scientists have shown that mice loaded up with many more mitochondrial point mutations than usual don't seem to suffer for it. So are point mutations unimportant in mitochondrial function and we should focus more on deletions, in which breaks are poorly repaired or replication failed? Perhaps.

Here is a recent open access paper on this topic. These researchers speculate that it's not damage from free radicals at fault, but rather replication issues as mitochondria reproduce inside the cell. This is an interesting challenge to the prevailing paradigm, but the researchers would then have to explain how genetic changes that alter the levels of free radicals produced by mitochondrial can shift life span so readily in laboratory species. Where is the connection to replication rate and efficiency there? Again, it is worth noting that these researchers are predominantly looking at point mutations (and transitions, a form of point mutation) - and this might not be where the action is in the case of mitochondrial DNA and aging.

Ultra-Sensitive Sequencing Reveals an Age-Related Increase in Somatic Mitochondrial Mutations That Are Inconsistent with Oxidative Damage

Owing to their evolutionary history, mitochondria harbor independently replicating genomes. Failure to faithfully transmit the genetic information of mtDNA during replication can lead to the production of dysfunctional electron transport proteins and a subsequent decline in energy production. Cellularly-derived reactive oxygen species (ROS) and environmental agents preferentially damage mtDNA compared to nuclear DNA. However, little is known about the consequences of mtDNA damage for mutagenesis. This lack of knowledge stems, in part, from an absence of methods capable of accurately detecting these mutations throughout the mitochondrial genome.

Using a new, highly sensitive DNA sequencing strategy, we find that the frequency of point mutations is 10-100-fold lower than what has been previously reported using less precise means. Moreover, the frequency increases 5-fold over an 80 year lifespan. We also find that it is predominantly transition mutations, rather than mutations commonly associated with oxidative damage to mtDNA, that increase with age. This finding is inconsistent with free radical theories of aging.

The bottom line for the prospective longevity engineer is that the outcome of this sort of debate is probably moot. Mitochondrial DNA is getting damaged, this is a definite, well-established difference between old tissue and young tissue, and the prospective mechanisms for repair or replacement of mitochondrial DNA will revert the entirety of that difference regardless of how important or unimportant different forms of mutation happen to be. So the order of the day is to carry on building mitochondrial repair therapies: at this point it would be faster to create them and try them out to settle any debate over effectiveness than to do more research and measurement of mitochondrial mutation types and rates.

This article is pure speculation in absence of data, but it certainly can't hurt to have more serious discussions of longevity science appearing in the mainstream media:

But the question is, what will Calico actually do? At the moment the company isn't giving much detail away [and] repeated requests [to] interview either Page or Levinson were politely declined. In the absence of any real information, many commentators have speculated that Calico will pursue a 'big-data' approach to health: gathering massive amounts of information from patients and 'crunching it' to help speed the way to health care discoveries. Some have suggested that Calico's new CEO will take the view that the best way to tackle aging is to focus on preventing diseases.

Aubrey de Grey, an expert in the field of regenerative medicine, [says] that it is too soon to speculate on what Google's approach will be: "in relation to Calico, I think it's vital to keep in mind that there is essentially no concrete information about their planned direction and emphasis, and any guess that they will take a heavily data-driven approach is no more than a guess." However, he does think that Calico will not limit its focus to a single disease: "The statements from Page and Levinson thus far indicate quite strongly that the emphasis will not be just cancer, or even just a range of specific diseases, but will be 'aging itself': Page in particular has highlighted the paltry longevity gains that would arise even from totally eliminating cancer."

João Pedro de Magalhães, a Portuguese biologist who leads the Integrative Genomics of Aging group at the University of Liverpool, agrees: "From what I've read, I don't think the company will mostly focus on cancer. In the Time interview Larry Page clearly states that solving cancer is 'not as big an advance as you might think'. This is reminiscent of what experts studying aging have been saying for a while, which is that to really make a difference in human health and longevity you need to tackle the aging process rather than individual age-related diseases."

Link: http://www.cnn.com/2013/10/03/tech/innovation/google-calico-aging-death/

Gene expression, the process by which a protein is produced from the specification of a gene, is complicated and the early steps involve dynamic interactions between RNA sequences. MicroRNAs (miRNAs), for example, are small RNA sequences that regulate gene expression by targeting specific messenger RNAs (mRNAs), sequences that transfer information on the gene into the ribosome where the protein will be built.

A lot of work has gone into looking for genes and gene product proteins relating to aging or longevity, but work on finding microRNAs with the same associations has really only just started in comparison - there are few results to see so far. Here, researchers identify some microRNAs whose levels vary with age:

Altered expression of circulating miRNAs have been associated with age-related diseases including cancer and cardiovascular disease. Although we and others have found an age-dependent decrease in miRNA expression in peripheral blood mononuclear cells (PBMCs), little is known about the role of circulating miRNAs in human aging.

Here, we examined miRNA expression in human serum from young (mean age 30 years) and old (mean age 64 years) individuals using next generation sequencing technology and real-time quantitative PCR. Of the miRNAs that we found to be present in serum, three were significantly decreased in 20 older individuals compared to 20 younger individuals: miR-151a-5p, miR-181a-5p and miR-1248. Consistent with our data in humans, these miRNAs are also present at lower levels in the serum of elderly rhesus monkeys.

In humans, miR-1248 was found to regulate the expression of mRNAs involved in inflammatory pathways and miR-181a was found to correlate negatively with the pro-inflammatory cytokines IL-6 and TNFα and to correlate positively with the anti-inflammatory cytokines TGFβ and IL-10. These results suggest that circulating miRNAs may be a biological marker of aging and could also be important for regulating longevity. Identification of stable miRNA biomarkers in serum could have great potential as a noninvasive diagnostic tool as well as enhance our understanding of physiological changes that occur with age.

Link: http://www.impactaging.com/papers/v5/n10/full/100603.html

Cryonics Magazine is the in-house publication of cryonics service provider Alcor, available to members of the organization. Articles from recently issues sometimes make their way online to the magazine site, and are usually well worth reading.

What is cryonics? It is the provision of indefinite low-temperature storage for the body and brain immediately following death. For so long as the pattern of fine tissue structures that encode your mind survive intact, there is the chance that future technologies can restore you to life. This should be within the capabilities of a mature molecular nanotechnology industry, able to build sophisticated molecular machines to repair cells, remove cryoprotectant chemicals, and perform all the other myriad tasks needed to restore a cryopreserved individual to life. How long until that industry arrives? The answer to that question doesn't really matter when you are preserved: you have all the time in the world, for so long as the cryonics industry continues forward robustly.

Cryopreserved individuals are vitrified, not frozen, these days. Freezing tends to produce significant ice-crystal damage, while vitrification does not: tissues turn to a glass-like state, suffused by cryoprotectant chemicals, the structure well preserved at all levels. There is still the issue of potential fracturing, but that too can be addressed. Vitrification is under development in the broader cryobiology industry for use in long-term storage of organs for transplant, and reversible vitrification for that use isn't too far from prime time. Undoing vitrification for a human brain in the field is obviously a little way beyond doing so for blood vessels or an animal kidney under laboratory conditions - but it's just an advance.

One of the underlying assumptions in cryonics is that any future society capable of restoring a vitrified individual should have absolutely no problem with building a new body and rejuvenating old tissues - that being a much easier challenge. If you can mass-precision-engineer molecules and molecular robots to the degree needed to undo cryopreservation, then rearranging molecules to undo mere damage to cells is no great issue. That seems reasonable given what we expect to see in the next fifty years of development in medicine, nanotechnology, and related fields. Beyond that, of course, the sky is the limit.

Here are a few recent pieces from Cryonics Magazine, in no particular order. I think that you'll find them interesting:

Resuscitation Research Can Start Now!

A major obstacle to strengthening the case for cryonics is the perception that meaningful research aimed at resuscitation of cryonics patients cannot be done today. Attempts to be more specific than evoking the need for a technology that can manipulate matter at the molecular level are considered to be vague and unproductive. Clearly, such a stance is an open invitation for skeptics to claim that cryonics advocates have not much more to offer than hope and optimism. Nothing could be further from the truth. Not only is there a lot of relevant empirical research that can be conducted today, a focused investigation into the technical and logistical challenges of resuscitation can also define cryonics research priorities and refine the stabilization and cryopreservation procedures that we use today.

[Of interest] is the 1991 article "'Realistic' Scenario for Nanotechnological Repair of the Frozen Human Brain" where the individual forms of mechanical and biochemical damage (ice formation, protein denaturation, osmotic damage, etc.) are catalogued and repair strategies are discussed in biological terms. Describing the various forms of damage at such a detailed level provides a meaningful context within which to discuss the technical feasibility of cryonics in rather specific terms.

Effects of Temperature on Preservation and Restoration of Cryonics Patients

An understanding of probable future repair requirements for cryonics patients could affect current cryostorage temperature practices. I believe that molecular nanotechnology at cryogenic temperatures will probably be required for repair and revival of all cryonics patients in cryo-storage now and in the foreseeable future. Current nanotechnology is far from being adequate for that task. I believe that warming cryonics patients to temperatures where diffusion-based devices could operate would result in dissolution of structure by hydrolysis and similar molecular motion before repair could be achieved. I believe that the technologies for scanning the brain/mind of a cryonics patient, and reconstructing a patient from the scan are much more remote in the future than cryogenic nanotechnology.

Cryonicists face a credibility problem. It is important to show that resuscitation technology is possible (or not impossible) if cryonicists are to convince ourselves or convince others that current cryonics practice is not a waste of money and effort. For some people it is adequate to know that the anatomical basis of the mind is being preserved well enough - even if in a very fragmented form - that some unspecified future technology could repair and restore memory and personal identity. Other people want more detailed elaboration.

What Do We Really Know About Fracturing?

The goal of any credible cryonics organization is to develop reversible cryopreservation to avoid passing on problems with the cryopreservation process itself to the next generation. While there is a lot of recognition for the need to eliminate cryoprotectant toxicity, it is rather obvious that it will not be possible to restore integrated function in a fractured brain. Despite all the articles and discussions that have been devoted to the topic of intermediate temperature storage, we do not seem to know much yet about fracturing in (large) tissues that are well equilibrated with a vitrification solution and subjected to a responsible cooling protocol. While [the] data seem to support the use of the newer vitrification solutions for reducing fracturing, controlled studies of fracturing in vitrified tissues will need to be conducted in a lab to really understand what we can expect under ideal (non-ischemic) circumstances.

The shine has worn off sirtuin research, as extension of life span resulting from manipulation of sirtuin 1 has been hard to reproduce in mammals. Sirtuin 3 is looking more interesting, however, and there is a still a great deal of funding for investigative work on sirtuin 1 and its role in the extended longevity produced by calorie restriction:

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan. Sirtuins mandatorily convert NAD+ into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1.

We identify a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1, to generate MNA from NAM. Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1-mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity.

Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

Link: http://dx.doi.org/10.1038/nchembio.1352

Is the mineralization of connective tissue important in aging and something that should be addressed separately from other forms of change that occur in old tissues? These researchers think so:

When you open a 70-year old patient on the operating table and touch the aorta, the feeling may resemble touching an eggshell or sand paper. It is stiffer than the heart of a young person and the key reasons for this are the abundant calcium deposits in the connective tissue that accumulate with age. The many factors leading to mineralization of the connective tissue include genetic and acquired diseases, inflammation, reactive oxygen species, but the major problem is that it occurs spontaneously during aging as calcium-containing molecules are trapped in the extracellular matrix and develop into apatite over time.

"Aging inevitably leads to the loss of function on many levels. Mineralization of the connective tissue is one of the causes and consequences of aging and is a complex multifactorial process. Metabolic activity, diseases and external stress factors may cause calcification, but most importantly, it occurs spontaneously. Our goal is to identify least toxic ways to both prevent calcification and to repair the accumulated aggregates. Mineralization of connective tissue with age is one of the many aspects of aging that are examples of 'accumulation of eventually pathogenic extracellular material', an issue that attracts too little attention within the academic community. The accumulation of advanced glycation endproducts (AGEs) and of mineral deposits both result in increased stiffness of connective tissue, impair homeostasis and contribute to a broad range of age-related diseases."

Link: http://www.labfairy.com/2013/10/a-group-of-my-colleagues-proposed-novel.html

You might recall that the advocates of the International Longevity Alliance have declared October 1st to be International Longevity Day. They hope to gather official recognition and use this yearly event to raise awareness of longevity science, the need for greater funding of rejuvenation research, and the moral imperative to lengthen the healthy human life span, eliminate frailty, and defeat age-related disease:

International Longevity Day

Some time ago the idea was raised to celebrate a special day by the longevity movement - the LONGEVITY DAY. Now an excellent opportunity to do this is coming the 1st of October, the official United Nations International Day of Older Persons. Let us make the Longevity Day on that day - the 1st of October this year! Let us hold meetings and other events globally!

Longevity Day

Making the Longevity Day on October 1: So far, people in about 30 countries have expressed their willingness to hold dedicated meetings and other events on that day. The day is especially significant as, on that day, we have an excellent opportunity to link in the public mind the issue of AGING with the issue of ANTI-AGING research that is probably the only means to truly address and ameliorate the problem of aging.

Longevity Day Appeal - October 1

An additional way of promotion is: Support our petition to celebrate the International Longevity Day during the International Day of Older Persons. This can be done in several ways:

1) Sign the online petition and spread it among your friends and on social media. The petition is also featured on the newly established Longevity Intelligence Communications (LIC) site dedicated to promoting petitions related to longevity.

2) Participate in the physical signing and mailing of the petition (to be sent to International Organizations, Governmental Offices, Associations of the Elderly, Scientific Societies, etc.) As a first option, the petition will be sent to the UN (the authors of the "International Day of Older Persons"). If you are interested in doing so, please contact us.

3) Download a template of a flyer containing a short version of the petition. You can modify it as you see fit: change the text, affiliation, country, logo, slogan, links, etc. - as long as the spirit of support for Longevity and Longevity Research is maintained. Or print it out as it is and distribute it among friends, at your school, health club, etc. Engage people in the topic. Or upload it and spread it online.

You can download the flyer template from the Longevity Day Facebook page.

Please consider spreading this message. With some minimal effort we can create a series of highly influential and positive events, promoting the advancement of Healthy Longevity for All through Support of Scientific Research directed toward that goal!

Mitochondria are the cell's roving herd of power plants, producing chemical energy stores to power cellular processes, and mitophagy is the process by which damaged mitochondria are recycled for parts. If allowed to continue functioning and dividing like bacteria, damaged mitochondria can harm the cell - and in fact forms of damage that allow mitochondria to evade mitophagy are one of the root causes of degenerative aging. In older individuals many cells are overtaken by malfunctioning mitochondria, forcing them to operate abnormally and export damaging reactive molecules into surrounding tissues.

Here, researchers make inroads into understanding more of the mechanisms by which mitophagy operates, which may open the door to correcting failures in this process. This presents another potential avenue for treatments for aging based on mitochondrial repair to add to those that already exist and are under development.

Cardiolipins, named because they were first found in heart tissue, are a component on the inner membrane of mitochondria. When a mitochondrion is damaged, the cardiolipins move from its inner membrane to its outer membrane, where they encourage the cell to destroy the entire mitochondrion. "It's a survival process. Cells activate to get rid of bad mitochondria and consolidate good mitochondria. If this process succeeds, then the good ones can proliferate and the cells thrive."

[The newly identified part of this mechanism] turns out to be a protein called LC3. One part of LC3 binds to cardiolipin, and LC3 causes a specialized structure to form around the mitochondrion to carry it to the digestive centers of the cell. "There are so many follow-up questions. What is the process that triggers the cardiolipin to move outside the mitochondria? How does this pathway fit in with other pathways that affect onset of diseases like Parkinson's? Interestingly, two familial Parkinson's disease genes also are linked to mitochondrial removal." While this process may happen in all cells with mitochondria, it is particularly important that it functions correctly in neuronal cells because these cells do not divide and regenerate as readily as cells in other parts of the body.

"I think these findings have huge implications for brain injury patients. The mitochondrial 'eat me' signaling process could be a therapeutic target in the sense that you need a certain level of clearance of damaged mitochondria. But, on the other hand, you don't want the clearing process to go on unchecked. You must have a level of balance, which is something we could seek to achieve with medications or therapy if the body is not able to find that balance itself."

Link: http://www.sciencedaily.com/releases/2013/09/130930140518.htm

A long-form essay on priorities in advocacy and fundraising for longevity science:

I would like to address what I consider to be three common criticisms against the desirability and ethicacy of life-extension I come across all too often - three specters of immortality, if you will. These will be Overpopulation (the criticism that widely-available life-extension therapies will cause unmanageable overpopulation), Naturality (the criticism that life-extension if wrong because it is unnatural), and Selfishness (the criticism that life-extension researchers, activists and supporters are motivated by a desire to increase their own, personal lifespans than by a desire to decrease involuntary suffering in the world at large).

What makes them worrying is the fact that they deter widespread support of life-extension from the general public, because they stop many people from seeing the advantage and desirability of life-extension today. Just what is considered worthy of scientific study is to a very large extent out of the hands of the average scientist. The large majority of working-day scientists don't have as much creative license and choice over what they research as we would like to think they do.

Scientists have to make their studies conform to the kinds of research that are getting funded. In order to get funding, more often than not they have to do research on what the scientific community considers important or interesting, rather than on what they personally might find the most important or interesting. And what the scientific community considers important and worthy of research is, by and large, determined by what the wider public considers important.

Thus if we want to increase the funding available to academic projects pertaining to life-extension, we should be increasing public support for it first and foremost. We should be catalyzing popular interest in and knowledge of life-extension. Strangely enough, the objective of increased funding can be more successfully and efficiently achieved, per unit of time or effort, by increasing public support and demand via activism, advocacy and lobbying than by say direct funding, period. Thus, even if most of these criticisms, these specters of immortality, are to some extent baseless, refuting them is still important insofar as it increases public support for life-extension, thereby hastening progress in the field.

Link: http://ieet.org/index.php/IEET/more/cortese20130924