Mitochondrial Function and Cellular Senescence

The myriad mechanisms of cellular biology are a seething pool of feedback loops and interactions. Every protein that plays a role has half a dozen other roles on the side: evolution produces promiscuous reuse of every new component that arises. Thus little if anything happens in isolation in our cells, and changes produce reactions. So when we say that degeneration in aging is produced by the accumulation of a variety of forms of damage, we refer to a very complicated progress that spirals out from comparatively simple beginnings. Consider the SENS model for the causes of aging, for example. Broadly, the operation of metabolism produces waste byproducts that are not always entirely cleaned up or recycled. Separately, some important cellular components can become damaged in the course of normal operation in ways that resist the otherwise highly efficient recycling machinery. Further, evolution has adapted certain quiescent cell states used in embryonic development into a way to resist cancer. These senescent cells behave in ways that may well suppress cancer risk in the short term, but are not good at all for tissues over the long term. Separately again, some larger and more complex structures, such as the thymus or the immune system considered as a whole, become misconfigured or less useful over the course of time as an inevitable consequence of their structure and modes of operation. Even if all of their cellular components continued to work perfectly in and of themselves, some of our biological systems cannot operate well indefinitely.

These are all discrete sources of damage and gradual failure, distinct processes and harms that must be addressed separately by any suite of rejuvenation treatments. Damage doesn't accumulate in isolation, however. The harms interact. Persistent metabolic waste products degrade the effectiveness of cellular recycling systems, for example, and that probably exacerbates other sources of damage that arise from damaged cell components, misfolded proteins, and the like. There are many other examples of the way in which forms of damage might interact with one other, but there is also a lot of room for theory and speculation, since a complete map is lacked of the detailed progression of aging from its root causes through to age-related disease and death. Researchers have a catalog of the simple forms of damage at the beginning of the road, a catalog of complex diseases at the end of the picture, and only the first sketches of the story in between. Fortunately, if you have the catalog of damage you don't need the full picture in order to build treatments based on repair. Unfortunately the majority of the scientific community is more interested in filling in the gaps in the picture than in producing treatments.

As to speculation: given the list of forms of damage outlined in the SENS vision of aging, it is interesting to consider which of them are working in concert. If mitochondrial DNA damage was repaired throughout the body, would it result in diminished levels of misbehaving senescent cells, for example? Generally cells become senescent in response to a tissue environment that appears more damaged, or in response to the presence of toxins that might have that effect. Does the presently partially understood set of influences include the state of mitochondrial damage in a straightforward way? That is hard to tell in absence of good ways to control that damage experimentally. The fastest approach to answering this sort of question at the present point in time is probably to implement mitochondrial repair treatments in mice and see what happens.

Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored.

The free radical theory of aging has been adapted to the study of cellular senescence. Many studies show that reactive oxygen species (ROS) can induce cellular senescence. Indeed, hydrogen peroxide (H2O2), which is considered as the major ROS within the cell, is a potent inducer of cellular senescence in many cell types. While exogenous treatment with H2O2 can promote cellular senescence, endogenous ROS (such as superoxides and hydroxyl radicals) is also implicated in the establishment and maintenance of the irreversible growth arrest.

While several studies implicate the role of ROS during cellular senescence, others also suggest that mitochondrial ROS generation may not necessarily be the primary cause of cellular senescence. One [study] suggests that increased mitochondrial ROS production in replicative senescent cells is a consequence of the senescence phenotype rather than the reverse. Because mitochondria influence many cellular processes, accumulation of mitochondrial oxidative damage, as proposed in the free radical theory of aging, may be an oversimplification of the signaling mechanisms involved in the establishment of cellular senescence. It is also possible that mitochondrial ROS can act as signaling molecules to trigger cellular senescence, independent of mitochondrial oxidative damage, although this hypothesis still needs to be proven.

It is then necessary to go beyond the free radical theory and examine other mitochondrial effectors that may be involved in the irreversible cell growth arrest. Multiple mitochondrial factors, such as excessive mitochondrial ROS production, aberrant mitochondrial dynamics, defective electron transport chain, imbalanced bioenergetics, activated AMPK, decreased NAD+ levels, altered metabolism, and dysregulated mitochondrial calcium homeostasis, contribute to the establishment of irreversible growth arrest. All of these different mitochondrial signaling pathways can regulate each other, but how these factors cooperate to promote cellular senescence, and whether these pathways are conserved in all senescent cells still remains unclear.

As you can probably tell, this is one of those "look at all these things we don't know yet!" papers. I see a lot of these day in and day out. There is indeed a great deal that is still a big blank space on the map of how exactly we age, and that is exactly why more of a focus should be placed on the development of repair technologies based on what is presently well known.

Suppressing a Stroke Damage Mechanism

Researchers have found a way to make neurons more resistant to the oxidative damage that occurs in the restoration of blood flow following a stroke. An effective way to resist this particular form of damage may have broader applications than just the treatment of stroke:

Researchers have discovered a mechanism linked to the brain damage often suffered by stroke victims - and are now searching for drugs to block it. Strokes happen when the blood supply to part of the brain is cut off but much of the harm to survivors' memory and other cognitive function is often actually caused by "oxidative stress" in the hours and days after the blood supply resumes. "Until now, much of the drug research has been focusing on the direct damage caused by the loss of blood flow, but this phase can be hard to target. The patient may not even be in the ambulance when it is happening. We have found a mechanism that is linked to the next phase of damage that will often be underway after patients have been admitted to hospital."

[The researchers] looked at the damage caused by the excessive production of chemicals called "reactive oxygen species" in brain tissues immediately after blood supply is re-established. In a healthy brain, there are very low levels of reactive oxygen species, but the quantity dramatically increases after a stroke to levels that are harmful to neurons. "We identified an 'ion channel' in the membranes of neurons, called TRPM2, which is switched on in the presence of the reactive oxygen species. Basically, an ion channel is a door in the membrane of a cell that allows it to communicate with the outside world - TRPM2 opens when the harmful levels of reactive oxygen species are present and we found that removing it significantly reduced neuronal cell damage."

The researchers compared the effects of strokes on mice with TRPM2 with a transgenic strain without it. "In the mice in which the TRPM2 channel does not function, the reactive oxygen species are still produced but the neurons are very much protected. The neuronal death is significantly reduced. More importantly, we observed a significant difference in brain function, with the protected mice demonstrating significantly superior memory in lab tests. This study has pinpointed a very promising drug target. We are now screening a large chemical library to find ways of effectively inhibiting this channel."


Just Like All Aspects of our Biology, Age-Related Damage in the Brain is Complicated

There are many ways in which age-related damage emerges in the brain, and the details of any one individual's cognitive function decline with age is a result of the interactions between all of the processes and specific dysfunctions involved. It is very complicated, which is what you get as the result of simple degenerative mechanisms operating in a complex machine. Think of rust in an intricate metal structure: the complexity of the many possible failure modes is a function of the structure, not the rust. Rust is simple. Aging research aimed at producing therapies should focus on manipulating and fixing the simple things, in other words work on ways to periodically repair the causative damage. If the focus is on the complex things, such as trying to fully understand and manipulate the operation of the brain in a damaged state, then progress will be slow, expensive, and produce only marginal benefits.

Owing to increased life expectancy, understanding the pathogenesis of age-associated cognitive decline is becoming more and more important. There are many causes of dementia, but neurodegenerative diseases are thought to be one of the most prevalent in the aging population. Indeed, during the last century neuropathological examinations, based mostly on silver stainings, have demonstrated that the brains of the majority of the individuals with cognitive decline show Alzheimer's disease (AD)-related pathologies, including neurofibrillary tangles and senile plaques.

The spectrum of mixed brain pathologies expands beyond accompanying vascular pathology in brains with Alzheimer's disease-related pathology. Co-occurrence of neurodegenerative non-Alzheimer's disease-type proteinopathies is increasingly recognized to be a frequent event in the brains of symptomatic and asymptomatic patients, particularly in older people. Owing to the evolving concept of neurodegenerative diseases, clinical and neuropathological diagnostic criteria have changed during the last decades. Autopsy-based studies differ in the selection criteria and also in the applied staining methods used.

The present review summarizes the prevalence of mixed brain pathologies reported in recent community-based studies. In these cohorts, irrespective of the clinical symptoms, the frequency of Alzheimer's disease-related pathology is between 19 and 67%, of Lewy body pathology is between 6 and 39%, of vascular pathologies is between 28 and 70%, of TDP-43 proteinopathy is between 13 and 46%, of hippocampal sclerosis is between 3 and 13% and, finally, of mixed pathologies is between 10 and 74%. Some studies also mention tauopathies. White-matter pathologies are not discussed specifically in all studies, although these lesions may be present in more than 80% of the aging brains.

In summary, community-based neuropathology studies have shown that complex constellations of underlying pathologies may lead to cognitive decline, and that the number of possible combinations increases in the aging brain. These observations have implications for the prediction of the prognosis, for the development of biomarkers or therapy targets, or for the stratification of patient cohorts for genome-wide studies or, eventually, for therapy trials.


The Ridiculous Cost of Medical Research Regulation

The much-touted ballpark estimate of a billion dollars to produce a modern pharmaceutical from start to finish is about a decade old now - that figure is adjusted for today's diminished dollar value, eroded by inflation. You can replace "pharmaceutical" with any medical technology that is going to require a fair amount of original research and further tinkering in the laboratory to obtain the first working prototypes and the result is much the same. This large round number is the kitchen sink cost across a decade of work, including failed attempts and the opportunity cost of investment. The lion's share of the direct expenditures are imposed by regulatory requirements: trials, data, and more trials.

It has long been my position that almost all of the work carried out in the US at the behest of the FDA to prove safety is unnecessary. In fact it is counter-productive, as the immense imposed costs on development shut out a great deal of the experimentation and small-scale initiatives needed for rapid progress. Much of what the FDA demands is not demanded by similar regulatory bodies in other parts of the world, and even their requirements are very onerous in comparison to the standards in place fifty years past, a time when medical development seems to me to have worked just fine. It is a question of balances and choice: it is better to err in favor of faster progress and informed patient choice, but that is very far from the present state of affairs.

The result of an excessive and growing regulatory burden is that many potential medical technologies languish, are rejected outright, or are never developed at all, and patients suffer as a result. Our future health is determined by the pace of progress, and a slowdown across the board harms all of us considerably. Unfortunately that cost is invisible to the public at large and thus bureaucrats suffer very little as a result of the harms they cause by blocking progress. Meanwhile even comparatively small harms caused by an approved treatment that turns out to be overwhelmingly beneficial save for some negative effects for some people can snowball in the media to cause great damage to a career in the FDA bureaucracy. So you can see that the incentives are very much aligned with ever greater demands for proof and ever greater costs imposed on medical research and development. This is in fact what has happened over the past few decades, with the present result that in an age of radical progress and plummeting costs in the laboratory it is nonetheless the case that medicine is ever more expensive and the introduction of new applications of medical research has slowed down. This is well known and widely commented on, but so entrenched that this detrimental trend shows no signs of slowing.

So, to return to the cost of developing a modern pharmaceutical product: estimated at a billion dollars (in today's dollars) ten years ago, the same approach results in an estimated $2.5 to $2.8 billion dollars now. Interestingly the bulk of that is apparently not due to the increased time required to run the regulatory gauntlet, but rather largely due to other increases in the demands of regulators: much larger trials and more data. Via In the Pipeline, here are a couple of items on this topic. The second includes a very educational model and cost breakdown - you might take a look at that to see that initial research to the prototype stage, many failures included, is a fraction of the full cost of development and approval. That is something to think about as we raise money to help fund SENS research into the foundations of near future rejuvenation treatments.

Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion

Developing a new prescription medicine that gains marketing approval, a process often lasting longer than a decade, is estimated to cost $2,558 million, according to a new study by the Tufts Center for the Study of Drug Development. The $2,558 million figure per approved compound is based on estimated: 1) Average out-of-pocket cost of $1,395 million. 2) Time costs (expected returns that investors forego while a drug is in development) of $1,163 million. Estimated average cost of post-approval R&D - studies to test new indications, new formulations, new dosage strengths and regimens, and to monitor safety and long-term side effects in patients required by the U.S. Food and Drug Administration as a condition of approval - of $312 million boosts the full product lifecycle cost per approved drug to $2,870 million. All figures are expressed in 2013 dollars.

In a study published in 2003, Tufts CSDD estimated the cost per approved new drug to be $802 million (in 2000 dollars) for drugs first tested in human subjects from 1983 to 1994, based on average out-of-pocket costs of $403 million and capital costs of $401 million. The $802 million, equal to $1,044 million in 2013 dollars, indicates that the cost to develop and win marketing approval for a new drug has increased by 145% between the two study periods, or at a compound annual growth rate of 8.5%.

A Billion Here, A Billion There: The Cost Of Making A Drug Revisited

At first principles, there are several items that need to be factored in: direct costs of moving a drug forward, paying for failures along the way, and the time value of money (forgoing other investments). Since they haven't shared their model, I've built a quick-and-dirty version using their public assumptions to recreate in a ballpark fashion their $2.5B drug cost estimate. The distribution of costs (30-33% of spending into pre-clinical phases) is similar to their report. Here is my "estimated" model that you can download and play with.

The silver lining in all of this is that the greater the demands of the regulators, the more that development will move to much less costly regions of the world. We've seen this in the initial growth of the stem cell field, with proficient clinical industries established in Asia and elsewhere years prior to the first therapies eventually obtaining approval in the US - and we'd likely still be waiting on that approval if not for the fact that the existence of establish clinical networks and research groups elsewhere in the world puts increasing public pressure on US regulators to speed things up. Travel halfway around the world is cheap in comparison to the initial cost of most new medical technologies, which ultimately means that regulators set on ever-increasing demands will paint themselves out of the picture. Given yet more regulatory costs, the US research community will only thrive in the years ahead to the extent that it forges bridges to developers and clinics in other parts of the world - but that will definitely become the new normal if the trend continues.

Exercise Improves Cognitive Function in Older People

Here is a little more evidence to suggest that regular moderate exercise is worth the effort at any age, and even if you are already quite far advanced along the path of age-related degeneration:

A decline in cognitive ability commonly occurs among older individuals. This study sought to explore the restorative effects of exercise in older patients with existing cognitive disabilities. Ninety-six patients with mild cognitive impairment were placed in an exercise program for six months. Following completion of the program, participants were assessed via the Chinese Mini Mental Status Examination (MMSE), Activity of Daily Living (ADL) assessment, and body movement testing and compared to a control group of patients with mild cognitive impairment who did not participate in the exercise program (N = 102).

Compared with the control group, patients who exercised showed improved cognitive function in immediate memory and delayed recall function. In addition, activities associated with daily living showed improvement, as did body movement, arm stability, and the appearance of rotation. Based on these results, we conclude that participation in an exercise program can improve patients' cognitive function, physical abilities, and body movement capacity.


Inhibiting IFN-1 to Partially Restore Lost Cognitive Function

Researchers are expanding their exploration of signal molecules in the blood that differ in abundance between old and young individuals. Changing the levels in an old individual can somewhat restore stem cell function and partly turn back some other measurable declines that occur with aging, possibly through enhanced stem cell activities, possibly through other mechanisms. In considering aging as an accumulation of damage, these environmental changes are a reaction to that damage, a part of the evolved loss of stem cell activity with age that likely exists because it suppresses the risk of increasingly damaged cells spawning a cancer. The present human life span is a balance between diminished tissue maintenance on the one hand and cancer on the other. So it remains to be seen as to how to manage potential risks if this and other similar research is to produce useful treatments in the near term, though the benefits demonstrated in recent studies are large enough to make it well worth the effort:

Brain function declines in aging mammals. Recent work has identified dysregulation of key blood-borne factors whose altered expression during aging diminishes brain function in mice. Increased chemokine CCL11 expression with aging is detrimental to brain function. On the other hand, plasma levels of trophic factor GDF11 decrease with aging. Restoration of youthful levels of GDF11 by injection partially restores brain function and neurogenesis by improving endothelial cell function and vasculature. Moreover, GDF11 has a rejuvenative effect on cardiac and skeletal muscle.

Decreased IFN-II and increased IFN-I signaling during aging at the choroid plexus (CP), which constitutes the brain-cerebrospinal fluid barrier (B-CPF-B), negatively effects brain function. Blood from young mice contains factors that restore IFN-II levels. IFN-II is required for maintenance of the CP and low IFN-II levels are associated with decreased cognitive abilities.

IFN-1 levels appear to drive increased CCL11 expression through the cerebrospinal fluid (CSF). Blood from young animals does not restore IFN-1 levels. However, injecting anti-IFNAR antibodies into the CSF inhibits downstream IFN-I gene and protein expression, and decreases expression of CCL11, partially restoring neurogenesis and cognitive function. These results suggest that IFN-1 plays a critical role to increase CCL11 during aging of brain. An emerging theme is that aging-associated loss of function in mammals may involve a set of defined, potentially reversible changes in many tissues and organs, including the brain, permitting development of potential rejuvenative therapies.


An Interview with Bob Hariri of Human Longevity, Inc.

Bob Hariri is a cofounder of Human Longevity, Inc., the present exemplar of the mainstream focus on genetics when it comes to aging and longevity. I've had my say as to why I think this sort of effort is likely only to incrementally improve the present state of medicine rather than actually deliver meaningful extension of healthy life. It is much the same argument as I've made for initiatives aimed at slowing aging through altering the operation of metabolism: that research is slow, expensive, the primary output is knowledge of the detailed operation of metabolism rather than useful therapies, and even if successful beyond the expectations of those involved, it will still result in treatments that are near useless for old people. What good does it do to slightly slow the pace at which damage accumulates in your tissues if you are already very old and damaged? What good does it do to change some of your epigenetic patterns to those of a longer-lived human, when the difference in outcome is only a few years of extra health, and probably not even that if you are already old?

The only way to effectively add decades to healthy life spans and help the old is to produce rejuvenation treatments. From where I stand, the only viable way forward, a path likely to produce useful results within a short enough span of time to matter for those in middle age today, is to repair the various forms of damage that cause aging. The catalog of fundamental differences between old tissues and young tissues is well known, and detailed proposals exist on how to build repair treatments for each of these types of damage. But that work is for the most part very poorly funded, excepting those portions relating to stem cells and cancer. Genetics on the other hand is the flavor of the decade and it is comparatively easy to raise funds for any work in that field, regardless of its relative merits in the bigger picture.

So genetics is what we get. On the one hand this is work that is necessary for the future of medicine as a whole and should indeed be accomplished, and the sooner the better. On the other hand there seems to be an ambition to move the needle on aging and longevity that is simply unrealistic given the tools to hand in this field. Adding decades to healthy human life spans within the next few decades is not a plausible outcome of genetic research over that time scale, but it is for the less acknowledged and far less well funded work on rejuvenation treatments carried out by groups like the SENS Research Foundation. If SENS-like repair research had the funding and attention of the genetics field, I'd feel a lot more confident about the timeline for future rejuvenation treatments.

So all that said - again - what are the founders of Human Longevity, Inc. going to do with the vast mountain of genetic data they plan to accumulate? How do they tie the data gathering to their vision of improving human longevity and intervening in the aging process? Below are some interesting snippets from a recent interview with cofounder Bob Hariri, and as you can see there is a lot of emphasis placed on stem cell therapies as the treatment mode:

The Regeneration Generation: A Conversation With Bob Hariri, Vice-Chairman and Co-Founder of Human Longevity Inc.

RS: How did you get together with Craig Venter and Peter Diamandis?

BH: The three of us realized that we shared many common passions, among which was a desire to impact human health and society by exploring aging as a targetable disease. All of us have ventured, failed and succeeded by seeking to answer scientific questions based in real-world experience and offering solutions. We all took paths that were challenged, in some cases ridiculed and rejected, by established scientific institutions. In part that's because invention without relevance or context has less impact than true innovation. We all saw aging as an opportunity to innovate, not as an obstacle to human progress and prosperity.

RS: Can stem cells prevent aging and even turn back the clock?

BH: We believe that stem cells that are functioning well can play an important role in extending health and improving physical and cognitive performance and cosmetic vitality. Our work in stem cells has shown that if you can identify and measure individual variation for specific markers of disease at particular ages, you can identify the factors that predict the variability in how cells change over the lifespan. Then, using the information derived by interrogation of the genomics, proteomics and metabolomics, we can tailor treatments to how individuals get sick and improve their health.

RS: What is the game plan for the years ahead?

BH: Our goal is to sequence over 1 million full human genomes, microbiomes, MRI body-image scans, metabolomes, etc. We will commercialize therapies for diseases that are associated with the biological and molecular breakdown associated with aging. And we will develop a preventive healthcare model that will take baseline measures of stem-cell function, monitor that in real time and correct any drift from optimal activity with stem-cell therapy.

RS: How do you feel about Google's Calico venture? Are they competition for you?

BH: We are thrilled and excited that a remarkable company like Google has invested so actively in biomedicine and see Calico as part of what will be a rapidly expanding enterprise of age management or wellness. I hope there are many more companies who participate in helping people live longer, healthier lives.

RS: What do you think the field looks like 20 years from now?

BH: I believe stem-cell innovations will have a quantum impact on the kind of people we can be. Throughout our short history on this planet, our progress can be measured by our ability to thrive. By this, I don't just mean the fact that we will live longer and live better or that, as a result, we will spend less on health care. Rather, I believe the technological and physical evolution of our species will increase the capacity to share, and to be more flexible, inventive and determined in the face of uncertainty. Living longer at a time when the supply of ideas and inventions increase more quickly will exponentially increase the opportunity to pursue many more possibilities.

An Update on Reprogramming Glial Cells into Neurons

Neuroglia are a variety of of types of support cell in the brain and nervous system. They perform all sorts of necessary tasks, some of which are still being uncovered, such as the recent discovery that recycling of damaged mitochondria in long axons is delegated to astrocyte glial cells rather than being performed by the nerve cell owning the axon. One of the possibilities opened up by the growing ability to reprogram cell state is to change some of these supporting glial cells into functional neurons, thus creating an increased supply of new cells to repair brain injuries and the damage of aging. Some inroads have already been made in animal studies, and basic proof of concept work has demonstrated that this is a potentially practical approach. Here is a more recent update:

The portion of the adult brain responsible for complex thought, known as the cerebral cortex, lacks the ability to replace neurons that die as a result of Alzheimer's disease, stroke, and other devastating diseases. A [study] shows that a Sox2 protein, alone or in combination with another protein, Ascl1, can cause nonneuronal cells, called NG2 glia, to turn into neurons in the injured cerebral cortex of adult mice. The findings reveal that NG2 glia represent a promising target for neuronal cell replacement strategies to treat traumatic brain injury.

[Researchers] have previously shown that Sox2, Ascl1, and other transcription factors - proteins that bind to specific DNA sequences to control the activity of genes - can induce the nonneuronal "support cells" known as glia to turn into neurons. It has been difficult, however, to convert glia into neurons after brain injuries such as stroke in the adult cerebral cortex of living animals. To test potential brain repair strategies, [the researchers] delivered transcription factors into the cerebral cortex of adult mice three days after traumatic injury. Surprisingly, they found that Sox2 alone or in combination with Ascl1 was sufficient to trigger the emergence of neurons, contrary to the widely accepted view that Sox2 prevents stem cells from turning into more mature cells such as neurons. Notably, the majority of cells that converted into neurons were NG2 glia. These glial cells have received relatively little attention in the past, even though they represent a promising cellular source for brain repair strategies because of their abundance and life-long capacity for proliferation.


Atherosclerosis Correlates with Cognitive Impairment

Aging is a global phenomenon of damage accumulation throughout the body. Different people age at modestly different rates due to their lifestyle choices and environment, so correlations between different manifestations of the aging process are easy to pull from the data even if there is no obvious way in which the known causative processes are linked. Yet since many bodily systems do in fact influence one another, that aging is global doesn't necessarily mean that any given set of age-related conditions are independent - so a correlation may be meaningful.

Atherosclerosis is a condition in which fat, cholesterol and other substances collect in the arteries, forming a substance called plaque that can build up, limiting blood flow. It can occur in any artery of the body, including the carotid, which supplies blood to the brain, coronary arteries and the aorta, which carries oxygenated blood from the heart through the abdomen to the rest of body. In a study of nearly 2,000 adults, researchers found that a buildup of plaque in the body's major arteries was associated with mild cognitive impairment. "It is well established that plaque buildup in the arteries is a predictor of heart disease, but the relationship between atherosclerosis and brain health is less clear. Our findings suggest that atherosclerosis not only affects the heart but also brain health."

In the study, researchers analyzed the test results of 1,903 participants (mean age, 44 years) in the Dallas Heart Study. The participants included both men and women who had no symptoms of cardiovascular disease. Study participants completed the Montreal Cognitive Assessment (MoCA), a 30-point standardized test for detecting mild cognitive impairment, and underwent magnetic resonance imaging (MRI) of the brain to identify white matter hyperintensity (WMH) volume. Bright white spots known as high signal intensity areas on a brain MR images indicate abnormal changes within the white matter.

Study participants also underwent imaging exams to measure the buildup of plaque in the arteries in three distinct vascular areas of the body: MRI to measure wall thickness in the carotid arteries and the abdominal aorta, and computed tomography (CT) to measure coronary artery calcium, or the amount of calcified plaque in the arteries of the heart. Using the results, researchers performed a statistical regression to correlate the incidence of atherosclerosis and mild cognitive impairment.


Not Everyone Likes Mitochondrial DNA Damage as a Theory of Aging

There are factions within the research community who argue against mitochondrial DNA damage as an important cause of aging. That said, I think I could pick any present hypothesis on the biochemistry of aging and find a faction whose members don't think much of it. For all that the mountains of data cataloging the differences between old tissues and young tissues are largely agreed upon, the field as a whole is a battleground of interpretations over the processes involved in moving from young to old. There are those who think damage akin to wear and tear at a cellular level causes change in metabolism, and those who think that evolved programs of changes in metabolism cause damage. Within the damage-as-root-cause school there are any number of debates over which forms of damage are more important, and which are primary causes of aging versus secondary consequences of other forms of damage.

After a decade following research I more or less agree with the SENS vision of aging and the approach of damage repair. But agreeing with the approach isn't the only reason to back a strategy that aims to repair identified forms of damage that differentiate old tissues from young tissues. The other good reason is that building the various clearly envisaged repair treatments is the fastest way to settle most of the arguments in the field. The past two decades of aging research have demonstrated that it is enormously expensive and very slow to try to figure out what is going on at a cellular and metabolic level in aging. Billions of dollars and thousands of researcher years have not produced any great advance in the big picture consensus: researchers still argue over quite fundamental matters of interpretation despite vast vaults of new data.

So I think it is past time to cut to the chase: implement some of the SENS repair biotechnologies, a task that could be accomplished for a fraction of what has been spent on investigations of calorie restriction alone in the past twenty years. So removal of senescent cells, clearance of metabolic waste, restoration of stem cell populations, destruction of misbehaving immune cells, repair of mitochondrial DNA, and so forth. Try out these technologies in mice: whether or not each type of treatment works, that effort will go a long way towards settling the debate over one particular form of age-related damage. In particular think of arguments over the relevance of mitochondrial DNA damage in aging; if we had a means to repair mitochondrial DNA, and any one of three or four such means is really only a few years distant given a sizable project fund, then there would be no real debate. Either removing the damage works, in the sense of meaningful improvement in measures of health, or it doesn't. There would be far less ambiguity possible after running that experiment a few times.

In any case, here is an open access paper whose authors are not hot on mitochondrial DNA damage in aging. While the mitochondrial theory of aging as originally envisaged is indeed becoming an outmoded viewpoint and is halfway overthrown, rejecting an important role for mitochondrial DNA damage seems like throwing out the baby with the bathwater. It is not hard to argue in opposition to some parts of their position, and I think there's a little of seeing what they want to see going on here. For every paper they could produce to support their points, there are others that undermine them. Mitochondrial dynamics are exceedingly complex, and there is a lot of subtlety in the relationship between mitochondria, generation of oxidative damage, and the possible means by which mitochondrial DNA might become damaged - of which oxidative reactions are but one mechanism. This is why I'd say focus on repair technologies as one of the primary methods of investigation at this time, and cut this Gordian knot - something that these authors would probably agree with, though they envisage an exploration conducted via better ways to induce defined levels and types of mitochondrial DNA damage.

Aging: A mitochondrial DNA perspective, critical analysis and an update

The mitochondrial theory of aging (MTA), a mainstream theory of aging which once included accumulation of mitochondrial DNA (mtDNA) damage by reactive oxygen species (ROS) as its cornerstone, has been increasingly losing ground and is undergoing extensive revision due to its inability to explain a growing body of emerging data. This, in turn, has resulted in both a growing skepticism towards the role of mtDNA mutations in aging, and in the transformation of some of our views on mtDNA, ROS, and aging.

Thus, the increased susceptibility of mtDNA to ROS-induced strand breaks (but not to oxidative base damage) is now viewed as a component of the mitochondria-specific mechanism for the maintenance of mtDNA integrity through abandonment and degradation of severely damaged mtDNA molecules, rather than as a mechanism for accelerated mtDNA mutagenesis. Also, we have begun to appreciate that increased ROS production in aging may represent evidence for adaptive signaling aimed at mitigating detrimental changes, rather than constituting an unwanted but unavoidable byproduct of respiration.

Even though its current status is controversial, it is the MTA that stimulated the research that advanced our understanding of aging and clarified the place of mtDNA in this process. While it is no longer plausible that mtDNA is either the sole or the main determinant of aging, epidemiological studies do still suggest a contribution of mtDNA variation to longevity. Also, it is becoming increasingly obvious that maternally transmitted low levels of germline mtDNA mutations can have a significant impact on health and lifespan. The random genetic drift theory has the potential to reconcile the observed mitochondrial dysfunction in aged organs with the low average levels of mtDNA mutations in some tissues. These and other findings demonstrate that despite dramatic advances, our understanding of the role of mtDNA in aging remains incomplete. This incomplete understanding persists in large part due to our limited ability to manipulate mitochondria in a meaningful way. The lack of approaches to introduce defined base lesions into mtDNA impedes our progress in understanding the specifics of mitochondrial processing of oxidative DNA damage. This, in turn, limits our ability to deconvolute and interpret the spectrum of mtDNA mutations observed in aging.

Initial Evidence for Glycogen Buildup in the Brain to Contribute to Aging

This research suggests another type of metabolic waste should be added to those already known to contribute to degenerative aging. Given where the researchers presently stand, one logical next step might be to run mouse life span studies to augment the data already gathered in flies, but those are quite expensive in comparison to other choices:

Glycogen is a branched polymer of glucose and the carbohydrate energy store for animal cells. In the brain, it is essentially found in glial cells, although it is also present in minute amounts in neurons. In humans, loss-of-function mutations in laforin and malin, proteins involved in suppressing glycogen synthesis, induce the presence of high numbers of insoluble polyglucosan bodies in neuronal cells. Known as Lafora bodies (LBs), these deposits result in the aggressive neurodegeneration seen in Lafora's disease. Polysaccharide-based aggregates, called corpora amylacea (CA), are also present in the neurons of aged human brains. Despite the similarity of CA to LBs, the mechanisms and functional consequences of CA formation are yet unknown.

Here, we show that wild-type laboratory mice also accumulate glycogen-based aggregates in the brain as they age. These structures are immunopositive for an array of metabolic and stress-response proteins, some of which were previously shown to aggregate in correlation with age in the human brain and are also present in LBs. Remarkably, these structures and their associated protein aggregates are not present in the aged mouse brain upon genetic ablation of glycogen synthase. Similar genetic intervention in Drosophila prevents the accumulation of glycogen clusters in the neuronal processes of aged flies. Most interestingly, targeted reduction of Drosophila glycogen synthase in neurons improves neurological function with age and extends lifespan. These results demonstrate that neuronal glycogen accumulation contributes to physiological aging and may therefore constitute a key factor regulating age-related neurological decline in humans.


Lysosomal Dysfunction in Atherosclerosis

Atherosclerosis is the build up of fatty plaques known as atheromas in blood vessel walls, leading to death or injury when blood vessels suffer structural failure or part of a plaque breaks loose to block a blood vessel elsewhere. Plaques start because damaged lipids cause a reaction in blood vessel walls, drawing in the immune cells called macrophages that ingest the lipids to remove them. Sometimes this doesn't work well enough, and the immune cells become stressed by intake of too many lipids and die. Plaques are comprised of the remnants of cells, and the presence of all this waste material causes further inflammation, producing a vicious cycle in which the plaques grow by attracting ever more immune cells.

This is a process that can be sped up by a number of factors, such as greater chronic inflammation or more lipids damaged by oxidation due to higher levels of oxidative stress in tissues. Both of these occur with aging and as a result of conditions such as obesity known to raise the risk of suffering atherosclerosis. Another item to consider is the degree to which immune cells are capable of digesting lipids. These molecules should be broken down in the cells' lysosomes, but lysosomal function is another aspect of cell biology that deteriorates with age.

Here, researchers show that spurring macrophages to generate more new lysosomes in reaction to the stress of ingesting lipids slows the development of atherosclerosis, which is much as expected. Even if they lysosomes are dysfunctional, more of them should still improve this particular situation:

Recent reports of a proatherogenic phenotype in mice with macrophage-specific autophagy deficiency have renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique ability to process both exogenous material, including lipids and autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to understand the effects of an atherogenic lipid environment on macrophage lysosomes and to evaluate novel ways to modulate this system.

Using a variety of complementary techniques, we show that oxidized low-density lipoproteins and cholesterol crystals, commonly encountered lipid species in atherosclerosis, lead to profound lysosomal dysfunction in cultured macrophages. We find that macrophages isolated from atherosclerotic plaques also display features of lysosome dysfunction. We then investigated whether enhancing lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied. Lysosomal stress [leads] to TFEB nuclear translocation and activation of lysosomal and autophagy genes. TFEB overexpression in macrophages further augments this prodegradative response and rescues several deleterious effects seen with atherogenic lipid loading.

Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program in macrophages has antiatherogenic effects.


Experimentation in Regenerative Reprogramming

Salamanders and zebrafish are among the species that can regenerate limbs and even large portions of vital organs after injury, and the regrown portions of their anatomy are just the same as the original. We mammals cannot do this: we can manage fingernails, occasionally fingertips at a very early age, and portions of the liver, but that is about it. One line of modern regenerative research asks whether it is possible to somehow induce the regenerative biochemistry of salamanders and zebrafish in mammals. Is mammalian incompetence in healing a matter of lost capabilities that originally evolved in a distant shared ancestor species, and thus the necessary biochemistry still exists, but is in some way dormant? The answer to that question, and the more important questions regarding whether or not it will be very hard to make use of anything learned about regeneration in species like salamanders, are only going to be revealed by more research. The present state of knowledge leaves a lot of room for speculation.

In recent years research has pointed to the importance of the immune system in enhanced regeneration: immune cell activity seems key to regeneration in both salamanders and zebrafish, and if suppressed injuries scar rather than regrowing lost tissues. Also some inroads have been made into finding protein machinery such as the ERK pathway that is vital to salamander-like regeneration, but different and less active in mammals. These are all still starting points for later research rather than answers in and of themselves, guideposts that may help focus other scientific groups on the right paths. All in all this is largely a matter of preliminary research aimed at understanding exactly how regeneration works in these species, and trying to do anything with this knowledge is still a fairly remote possibility for much of this work.

That isn't always the case, however. This research group has taken a more aggressive approach, cataloging microRNAs in heart tissue that are shared by zebrafish and mice, finding those that differ in amount between species after heart injury, and then artificially altering mouse microRNA levels to be more like those of the zebrafish. The result is positive, which suggests that this research is a step in the right direction. In particular it adds weight to the idea that at least some shared regenerative mechanisms from the deep evolutionary past remain dormant in mammals rather than lost entirely:

Salk scientists discover a key to mending broken hearts

[Researchers] have healed injured hearts of living mice by reactivating long dormant molecular machinery found in the animals' cells, a finding that could help pave the way to new therapies for heart disorders in humans. The new results suggest that although adult mammals don't normally regenerate damaged tissue, they may retain a latent ability as a holdover, like their distant ancestors on the evolutionary tree.

In a [2010 paper], the researchers described how regeneration occurred in the zebrafish. Rather than stem cells invading injured heart tissue, the cardiac cells themselves were reverting to a precursor-like state (a process called 'dedifferentiation'), which, in turn, allowed them to proliferate in tissue. Although in theory it might have seemed like the next logical step to ask whether mammals had evolutionarily conserved any of the right molecular players for this kind of regenerative reprogramming, in practice it was a scientific risk. "When you speak about these things, the first thing that comes to peoples' minds is that you're crazy. It's a strange sounding idea, since we associate regeneration with salamanders and fish, but not mammals."

The team decided to focus on microRNAs, in part because these short strings of RNA control the expression of many genes. They performed a comprehensive screen for microRNAs that were changing in their expression levels during the healing of the zebrafish heart and that were also conserved in the mammalian genome. Their studies uncovered four molecules in particular - MiR-99, MiR-100, Let-7a and Let-7c - that fit their criteria. All were heavily repressed during heart injury in zebrafish and they were also present in rats, mice and humans. However, in studies of mammalian cells in a culture dish and studies of living mice with heart damage, the group saw that the levels of these molecules were high in adults and did not decline with injury. So the team used adeno-associated viruses specific for the heart to target each of those four microRNAs, suppressing their levels experimentally.

Injecting the inhibitors into the hearts of mice that had suffered a heart attack triggered the regeneration of cardiac cells, improving numerous physical and functional aspects of the heart, such as the thickness of its walls and its ability to pump blood. The scarring caused by the heart attack was much reduced with treatment compared to controls, the researchers found. The improvements were still obvious three and six months after treatment - a long time in a mouse's life.

In Vivo Activation of a Conserved MicroRNA Program Induces Mammalian Heart Regeneration

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

Investigating Nail Stem Cells

Nails are one of the few parts of the human body that can regenerate completely after loss in adults. So why not dig deeper into the biology of the stem cells involved? Perhaps it will teach us something more about why only a few types of mammalian tissue are capable of such complete regeneration. This initial investigation is only the starting point for such a research program, but we'll no doubt hear more in the years ahead:

There are plenty of body parts that don't grow back when you lose them. Nails are an exception. [Researchers have] identified a new population of nail stem cells, which have the ability to either self-renew or undergo specialization or differentiation into multiple tissues. To find these elusive stem cells, the team used a sophisticated system to attach fluorescent proteins and other visible "labels" to mouse nail cells. Many of these cells repeatedly divided, diluting the fluorescence and labels among their increasingly dim progeny. However, a few cells located in the soft tissue attached to the base of the nail retained strong fluorescence and labels because they either did not divide or divided slowly - a known property of many stem cells.

The researchers then discovered that these slow-dividing stem cells have the flexibility to perform dual roles. Under normal circumstances, the stem cells contribute to the growth of both the nails and the adjacent skin. However, if the nail is injured or lost, a protein called "Bone Morphogenic Protein," or BMP, signals to the stem cells to shift their function exclusively to nail repair. The researchers are now wondering whether or not the right signals or environmental cues could induce these nail stem cells to generate additional types of tissue - potentially aiding in the repair of everything from nail and finger defects to severe skin injuries and amputations.


Restoring Function to Old Pancreatic Islets

Researchers here transplant pancreatic islets from old to young mice and see restored function. They conclude that replacing the through altered levels of signal proteins, for example. So this is an interesting result that needs further investigation to determine whether or not it is just blood vessel declines producing this effect:

Islets, which contain the beta cells responsible for secreting the blood-glucose-regulating hormones insulin and glucagon, typically decrease in function with age. The researchers hypothesized that the decrease in function might not be due solely to a decrease in glucose-sensing or hormone-secreting capacity, but also to a decrease in blood supply caused by inflammation and scarring of the vessels. Replacing the islet vasculature in grafts transplanted into young mice restored the islets to full function, even at an advanced age. The study finding is significant because it suggests that targeting inflammation and fibrosis in the small blood vessels of the islet may offer new treatment options for diabetes.

To determine how revascularization might affect islet function, the researchers transplanted pancreatic islets from 18-month-old mice into the eyes of 2-month-old diabetic mice. [This is the equivalent to ages 65 and 18 in humans.] The transplanted islets, which had been revascularized with healthy blood vessels, exhibited strong beta cell proliferation and regained control of blood glucose levels within three months of transplantation. "This is an unexpected but highly important finding that we predict will have a significant impact on diabetes research in the future. The results indicate that beta cell function does not decline with age, and instead suggest that islet function is threatened by an age-dependent impairment in islet vascular function."


Why Do We Advocate for Rejuvenation Research?

Yesterday, I had occasion to spend six hours or so in the emergency room of a medical center largely focused on treating serious conditions that are most prevalent in old people. A part of that experience by necessity involved listening to the comings, goings, and conversations of those present. These are not private places: they are typically divided visually by screens but with no way to avoid overhearing the staff and patients. The people there are generally not too concerned about privacy in the immediate sense in any case, having far more pressing matters to focus upon.

So, by proxy, one gets to experience small and somewhat wrenching slices of other people's lives. It is very easy for even those who follow aging research and speak up for rejuvenation treatments to forget just how hard it is to be very old. It's one thing to know about the catalog of pain, suffering, and loss of capabilities, the conditions we'd like to find ways to turn back, and another to watch it in action. It is, really, a terrible thing to be frail.

A fellow was brought in a little while after I arrived, a 90-something man who looked a lot better on the exterior than perhaps your mental picture of a 90-something individual might be. Tall, and surprisingly lacking in wrinkles stretched out on the rolling gurney under blankets, a mess of cables, and an oxygen mask. That he had had fallen was what I heard from the conversation of the medics, and was in pain. He cried out several times as he was moved from the gurney. It took some time and care to do it without hurting him more, given his weakness.

He seemed confused at first, but that was just my misperception: you try being 90 and in pain some time and see how well you do while you're being moved around and told to hold this and let go of that. The fellow answered the bevy of questions the receiving staff had for him, but the thing that caught at me was the time he took with the answers, and the questions he just missed. He was coherent, even quite sharp at times, not on any more painkillers than a handful of Tylenol, as I later heard, but he clearly struggled with something that we younger folk all take for granted: parse the question, find the information, form up a reply and speak it. Cognitive ability in all these areas becomes ever less efficient with old age, and there's something hollowing about hearing what is clearly a capable guy set back for a dozen seconds by a short question about one of the details of his fall. The medic repeated the question a few times and in different ways, which was clearly just making the information overload worse.

It sticks with you to be the observer in this situation and clearly and suddenly realize that one day that faltering older person will be you, trying and often failing to force your mind into the necessary connections rapidly enough for the younger people around you. I know this, but knowing it and having it reinforced by being there are two very different things. An aged person is no less intelligent, far more experienced, wiser and all the rest, but the damage to the structure of the brain that occurs even in those without dementia means that making use of all of that in the way it deserves is near insurmountable.

The fellow's 60-something daughter arrived a little later to provide support and fill in more of the details. A story was conveyed in bits and pieces: that he was near blind now, and just about too frail to walk safely, even with a frame. The blindness explained a great deal of what had sounded to my ignorant ears as confusion in the earlier part of the fellow's arrival: we assume all too many things about those around us, such as the use of sight in an unfamiliar environment, or the ability to walk, or think quickly - and all of this is taken from us by aging. The fellow lived with his wife still, and she was of a similar age to him. His wife was not there because she herself was too frail to be undertaking even a short trip at such short notice. That seemed to me a harsh blow on top of the rest of what old age does to you. At some point you simply cannot do everything you'd want to as a partner. You are on the sidelines and at the point at which your other half is most likely to die, you are most likely unable to be there.

In this case the fellow was in no immediate danger by the sound of it. By good luck this was in no way likely to be a fatal accident, but rather another painful indignity to be endured as a part of the downward spiral of health and ability at the end of life. Once you get to the point at which simply moving from room to room bears a high risk of accident, and this is by no means unusual for a mentally capable person in their 90s, then it really is just a matter of time before you cannot live for yourself with only minimal assistance.

When talking with his daughter while he waited on a doctor and medical assistants to come and go with tests and updates, the fellow was much faster in his responses, though this was interrupted by a series of well-meaning but futile attempts to ease his pain by changing his position, each as much an ordeal as the move from the gurney had been. The conversation between father and daughter had the sense of signposts on well-worn paths, short exchanges that recapitulated the high points of many discussions that had come before. She wanted her father to move into an assisted living facility, and this fall was the latest in a line of examples as to why it was past the time for this - she simply could not provide all of the support needed on her own. She wasn't even strong enough herself to be able to safely get him back up on his feet after a fall. He was concerned about cost and the difficulties of moving, uncertainties and change. They went back and forth on this for a while. "We have to accept that it's just going to be more expensive as we get older," she said at one point, and he replied "I think you're getting the picture now," and laughed. There wasn't much to laugh about, but we can all do it here and there under these circumstances. I believe it helps.

I walked out of there after my six hours of hurry up and wait was done. They were still there, and whenever it is he leaves to go home it is unlikely it will be on his own two feet. But this is a scene I'll no doubt be revisiting at some point in the future, some decades from now, playing the other role in this small slice of life. What comes around goes around, but I'd like it to be different for me, and more importantly to be different for millions of others a lot sooner than my old age arrives.

Which leads to this: why does Fight Aging! exist? Why do we do this? Why advocate, why raise funds for research programs into ways to treat aging that may take decades to pay off? We do this because we can help to create a future in which there will be no more emergency rooms like the one I visited, no conversations about increasing disability, no pain, and no struggles to answer questions as quickly as one used to. No profound frailty. All these things will be removed by the advent of therapies that can effectively repair the causes of aging, curing and preventing frailty and age-related disease, and the sooner this happens the more people will be spared.

Lamin-B and Immunosenescence

The aging of the immune system isn't just a matter of damage, it is also inherent in the structure of a limited number of immune cells over time becoming ever more devoted to remembering threats rather than fighting them. As this research suggests there is the damage to think about as well, however:

As animals age, their immune systems gradually deteriorate, a process called immunosenescence. It is associated with systemic inflammation and chronic inflammatory disorders, as well as with many cancers. The causes underlying this age-associated inflammation, and how it leads to diseases, are poorly understood. Insects have an immune organ called the fat body, which is roughly equivalent to the mammalian fat and liver. It is responsible for many immune functions.

[Researchers] found that the fruit fly fat body experiences a great deal of inflammation in aged flies. [The] gradual reduction of a protein called lamin-B in the fat bodies of aging flies is the culprit behind fat body inflammation. Lamin-B is part of the lamin family of proteins, which form the major structural component of the material that lines the inside of a cell's nucleus. Lamins have diverse functions, including suppressing gene expression, and they are found in an array of tissues and organs. In humans, diseases caused by mutations in lamins are called laminopathies and include premature aging.

B-type lamins have long been suspected to play a role in gene suppression by binding to segments of DNA. The team's work revealed that when the fruit fly fat body was depleted of lamin-B, the normal suppression of genes involved in the immune response is reversed, just as it would be in response to bacterial infection or injury, but in this case there is no apparent infection or injury. The un-suppressed immune response initiates the inflammation.


More Investigations of Calorie Restriction in Long-Lived Mice

Calorie restriction extends healthy life in mice, and so does removing or blocking the activity of growth hormone through genetic engineering. The reasons for enhanced longevity in both of these cases are well studied but still far from fully understood, as both produce very broad alterations in the enormously complex processes of cellular metabolism. Trying both methods together is a way to perhaps shed some light on the more important mechanisms involved, however.

Ames dwarf (df/df) mice are homozygous for a spontaneous recessive mutation of the prophet of pituitary factor-1 (Prop1) gene, which inhibits development of three specific anterior pituitary cell types - somatotrophs, lactotrophs and thyrothrophs. The absence of these cell types in the df/df mice leads to deficiency of growth hormone (GH), prolactin (PRL) and thyrotropin (TSH). Interestingly, however, these mutants live significantly longer (40-60%) and healthier lives compared to their normal siblings. Ames dwarf mice phenotypically appear normal at birth but they grow at a slower rate and reach only half of the normal adult body weight, compared to their normal littermates. These mutant mice also exhibit very low levels of insulin-like growth factor-1 (IGF-1) and thyroid hormones. Furthermore, they have a reduced body temperature, but their food and oxygen consumption per gram of body weight are increased. Ames dwarf mice are less prone to cancer. These mutants show increased insulin sensitivity and glucose tolerance, thus displaying no diabetic phenotype. Furthermore, Ames dwarf mutants have reduced response of skeletal muscle to high levels of insulin, which might be important for their control of glucose homeostasis and as well their positive effects in extended longevity

Calorie restriction (CR), is the only efficient intervention which delays aging and extends lifespan. Laboratory animals subjected to reduced caloric intake, exhibit a number of beneficial effects including extension of lifespan, reduced body weight, plasma glucose and insulin levels; and improved insulin sensitivity and health span. Studies in various animal species revealed that CR delays aging, decreases cholesterol levels and blood pressure. Studies involving mice and rats support the concept that CR delays the aging process and reduces the incidence of several age-related diseases including type 2 diabetes and cancer. In addition, it has been shown that the prolongation of life can be greater than 40% in mice under CR regimen; with even greater extension of longevity in non-mammalian models.

Based on extensive studies of CR and Prop1 mutation on insulin signaling, metabolism and aging there is some evidence that indicates that Ames dwarfism and CR may act through similar mechanisms but they are certainly not identical. We studied the effects of calorie restriction (CR) on the expression of insulin signaling genes in skeletal muscle and adipose tissue of normal and df/df mice. The analysis of genes expression showed that CR differentially affects the insulin signaling pathway in these insulin target organs. Moreover, results obtained in both normal and Ames dwarf mice indicate more direct effects of CR on insulin signaling genes in adipose tissue than in skeletal muscle. Interestingly, CR reduced the protein levels of adiponectin in the epididymal adipose tissue of normal and Ames dwarf mice, while elevating adiponectin levels in skeletal muscle and plasma of normal mice only.


The Role of 3-D Printing in the Future of Medicine

3-D printing is a tool that has blossomed given the cheap computing resources to control it. It has long been possible to print three-dimensional structures in a variety of mediums, but efficient automation makes it cheaper to do this reliably and repeatedly, and also allows for the accurate manufacture of objects with very small scale features. Since cheap computing resources also drive progress in biotechnology, it is only natural that advances in tissue engineering go hand in hand with 3-D printing. These possibilities had to occur at the same time, as they depend on the same underlying technological capabilities. Tissue engineers want the ability to produce structures that mimic the collagen scaffold of the extracellular matrix, webbed with blood vessels and all sorts of other structural features on scales varying from millimeters to micrometers. As a goal that is yet to be achieved completely, but so far good enough attempts have been produced to create several less complex forms of tissue: a scaffold is printed and in the process of its construction is seeded with cells and proteins that encourage growth.

Researchers have been working with 3-D printers for some years now. Some of the formative research programs and first companies in the space are on their way to being a decade old, such as Organovo, whose founders count the Methuselah Foundation among their investors. The focus today is still largely on the production of products for research groups, producing small tissue structures such as printed blood vessels that can speed up the research process. Later, we will see more in the way of larger organs and tissue sections printed for transplant, not research. That is not too many years ahead.

Print Thyself: How 3-D printing is revolutionizing medicine

Central to the lab's work are three customized 3-D printers, each worth a quarter of a million dollars. Lewis led me through a warren of corridors and offices to a room where one of the printers sat on supports. It was immense. The base of the printer was a granite block five feet long, four feet deep, and a foot high, weighing a ton and a half. The printer does such fine-scale work that a stable base is essential, Lewis said. Resting on the block was a flat stage or platform, above which, in a vertical row, stood four rectangular steel containers, each a foot or so tall - the ink dispensers. A tangle of colored wires connected the dispensers to some machinery behind them, and each dispenser was controlled at the top by a robotic arm. To the side sat a large monitor and a computer, which controlled the printer.

Each dispenser contained a different biological material, Lewis explained. One held an aqueous suspension of chemically treated collagen, which serves as the matrix on which many of the body's tissues take shape. Two others held suspensions of fibroblasts, the gristly cells that form the body's connective tissue. The last dispenser contained the fugitive ink that Lewis had developed to create channels within materials. On the computer, Kolesky called up a software program and found an image representing the block of tissue that he would be printing. It looked like a rectangle of semi-clear gelatin, within which was a vascular network: a channel entered at one end and branched into smaller vessels, which looped around and ultimately joined back into a single vessel that exited at the other end. It was a simple network, approximating the way that an artery divides into smaller capillaries that eventually recombine into a vein.

The dispenser with the fugitive ink moved quickly and almost imperceptibly, releasing an exceptionally thin stream of what looked like agar onto the glass slide. The printer clacked and clattered like a busy riveting machine. In a minute or so, the job was done; the printer had left a trail of gelatinous ink that exactly matched the pattern on the computer. The stream of ink was about a tenth of a millimetre in diameter, and the entire pattern covered an area a little larger than a matchbook. The printer wasn't rigged to finish the job, but Kolesky explained what would typically happen next. The other ink dispensers would take their turn, laying down a lattice of collagen and fibroblasts that would solidify around the network of fugitive ink, encasing it in tan-colored living tissue. To drain the fugitive ink, Kolesky would place the tissue on a chilled stone cube; this would cause the ink to change from a gel to a liquid, after which he could then extract it with a small suction device. The end result would be a block of living tissue suffused with intricate vessels capable of carrying nutrients to the cells within.

The last step was to me the most remarkable. Once the vessels were empty, Kolesky would take a suspension of endothelial cells - the cells that line the insides of blood vessels - and inject it into the vessel network. The cells would settle in and multiply to line the insides of the channels, effectively turning the channels into blood vessels. And then the cells would spread - they would begin to branch off the existing vessels and form new ones. In effect, Lewis and her team have created an environment that the cells consider home - it is far more natural to them than a petri dish or the inorganic scaffolds that had previously played host to cultured tissues.

"I like to say that we design the highway and then get out of the way and let the endothelial cells create their own driveways," Lewis said. "It's better to rely on the intelligence of the cells themselves in terms of how they like to sprout."

Delivering Stem Cell Factor into Damaged Heart Tissue

In the years ahead stem cell medicine will most likely transform into a field largely based on manipulating existing cell populations in situ in the body rather than generating cells outside the body for transplantation. In many types of transplantation it appears that benefits are produced because the transplanted cells alter the local signaling environment in ways that cause native cells to better maintain and repair tissues, not because the transplanted cells are actually doing any of the work themselves. So ultimately researchers will want to directly issue those signals or otherwise alter native cells so as to change their behavior for the better. Some of the necessary work on that front is already taking place:

Researchers administered stem cell factor (SCF) by gene transfer shortly after inducing heart attacks in pre-clinical models directly into damaged heart tissue to test its regenerative repair response. A novel SCF gene transfer delivery system induced the recruitment and expansion of adult c-Kit positive (cKit+) cardiac stem cells to injury sites that reversed heart attack damage. In addition, the gene therapy improved cardiac function, decreased heart muscle cell death, increased regeneration of heart tissue blood vessels, and reduced the formation of heart tissue scarring. cKit+ cells are a critical cardiac cytokine, or protein receptor, that bond to stem cell factors. They naturally increase after myocardial infarction and through cell proliferation are involved in cardiac repair.

"It is clear that the expression of the stem cell factor gene results in the generation of specific signals to neighboring cells in the damaged heart resulting in improved outcomes at the molecular, cellular, and organ level. Thus, while still in the early stages of investigation, there is evidence that recruiting this small group of stem cells to the heart could be the basis of novel therapies for halting the clinical deterioration in patients with advanced heart failure."


Suppressing PERK Improves Memory in Mice

There is a fair amount of work taking place these days on ways to manipulate the efficiency of memory processes:

The brain's process of formulating memory is linked to the synthesis of proteins; high rates of protein production will lead to a strong memory that is retained over the long term, while a slow rate of protein production leads to weak memories that are less likely to be impressed on a person's long-term memory and thus forgotten. [Researchers] sought to examine the activity of a protein called elF2 alpha, a protein that's known as the "spigot" or regulator that determines the pace of protein synthesis in the brain during memory formation.

From earlier studies the researchers knew that there are three main molecules that act on the protein and either make it work, or stop it from working. During the first stage they sought to determine the relative importance and the task of each one of the molecules that control the activity of efF2 alpha and as a result, the ability to create memories. After doing tests at the tissue and cell levels, the researchers discovered that the main molecule controlling the efF2 alpha's activity was the PERK molecule. "The fact that we identified the PERK as the primary controller had particular significance. Firstly, of course, we had identified the dominant component. Secondly, from previous studies we already knew that in generative diseases like Alzheimer's, PERK performs deficiently. Third, PERK acts on various cells, including neurons, as a monitor and controller of metabolic stress."

After paralyzing PERK's activity or reducing its expression through gene therapy the researchers measured a 30% increase in the memory of either positive or negative experiences. The rats also demonstrated improved long-term memory and enhanced behavioral plasticity, becoming better able to "forget" a bad experience. "With this study we proved that we are capable of strengthening the process of protein synthesis in the brain and of creating stronger memories that last a long time. We have paved the way for the possible development of drugs that can slow the progress of incurable diseases like degenerative brain conditions, Alzheimer's chief among them."


"We should not regard aging as a fact of life."

It is not correct to view aging as set in stone, an immutable part of the human condition. Degenerative aging is just another medical condition, an unpleasant one at that, caused by biochemical processes in the body that are just as open to discovery, cataloging, and intervention as those of any disorder. The only thing that separates us from real, working rejuvenation treatments capable of restoring youthful vigor and health to the old is the same thing that once separated humanity from a cure for smallpox or effective management of infant mortality. In other words medical technology. Bringing aging under medical control and extending healthy lives indefinitely is just a matter of progress in applied biotechnology, and the research community is actually much closer to meaningful advances on this front than most people imagine to be the case.

However, precisely because the public are largely in the dark when it comes to the promising state of longevity science, that research community could very well simply remain ever close to promising advances for decades with little meaningful progress towards breakthroughs and commercialization. At the large scale, and over the score or more of years needed to forge entire new fields of medicine and bring them to maturity, funding and progress very much depend on public awareness and support for the cause. Currently the majority of the most promising scientific programs based on repair of the damage of aging, such as those coordinated by the SENS Research Foundation, are funded at exploratory levels only. In the broader research community it is still considered somewhat novel and adventurous to publicly back the strategy of treating the mechanisms of aging as a cause of disease rather than the traditional approach of engaging in ultimately futile attempts to patch over the diseases that are the end results of aging, one by one, and in isolation.

Thus while the stem cell and cancer research edifices include factions that are doing the right things and heading in the right directions for their slices of treating aging, there is definitely a way to go yet towards a research community and a public that are enthusiastically in favor of the most effective means to treat the causes of aging. That level of support will be needed if we are to ultimately remove from the human condition all of the pain, suffering, and death that aging causes. Getting to that point of widespread support is a slow grind: thousands of years of myth and tradition, and the modern education everyone receives both formally and informally, produce people who believe wholeheartedly that aging is a fact of life, something set in stone, a thing that is what it is. Yet that simply isn't true anymore. In an age of revolutionary progress in biotechnology, aging is as much a part of the human condition as we choose to let it be, and that starts now by choosing to support the right research programs.

"We should not regard aging as a fact of life"

The European: Dr. de Grey, for many years, people thought of human aging as inevitable, as part of our biology. Is that still true?

de Grey: I would not say that it is wrong. Aging is certainly a side effect of being alive. It is the accumulation of damage that the body does to itself as a by-product of its normal operations. In that sense it is exactly the same as the aging process of a car or an airplane. So really it is not even biology, it is just physics. The big mistake that people make is not in their understanding of what aging is, but in the misunderstanding of what the diseases of old age are: things like Alzheimer's, cancer, or cardiovascular disease.

The European: How are they mistaken?

de Grey: Most people think of those diseases as like infections - things that could be eliminated from the body using sophisticated medicine. An enormous amount of money and effort is being spent on that, although it is impossible to cure them because these things are part of aging and of being alive in the first place. The only way we can ever tackle those diseases is by tackling the whole package. By preventative maintenance against the damage of being alive.

The European: With stem cell therapies, for example?

de Grey: That is one part of it. But aging is not one single process but an accumulation of a lot of different types of damage in different organs and body parts as a result of different processes. In order to comprehensively tackle all of these types of damage, we have to do a lot of different things at the same time.


The European: Who would be able to afford these therapies?

de Grey: That's a good question. These therapies will not be expensive. They will be made available to everybody who needs them. Because unlike today's high-tech medicine which is very expensive, these therapies will pay for themselves. They will save us all of the money we are currently spending trying to keep people alive with medicine that doesn't work. This will also have an enormous number of very effective indirect economic benefits. One is that the children of the elderly will be more productive because they won't have to spend any time looking after their sick parents. The older but healthy people themselves will be continuing to contribute wealth to society instead of just consuming wealth. Any way you look at it, it would be economically suicidal at the national level for any country not to make these therapies available for everyone who is old enough to need them.

The European: How soon could these therapies be made available?

de Grey: In 2004, I first started making predictions about how quickly we would develop them. Back then, I said it would probably take around 25 years. But it was simply a 50/50 probability. I always acknowledged that there is at least a 10% chance that we won't get them ready for another hundred years in case we found new problems. But a 50/50 chance is enough to be worth fighting for. But what it really depends on is funding. At the earlier stages of the research, the funding is of course the most difficult to obtain, because people are not yet convinced that the research will eventually succeed. So over the past ten years, during which I would have hoped that we would have gotten to obtain a really decisive dramatic result, we only made about three years of progress. But that's about the amount of progress that I would have expected to make with the amount of money that we have actually received.

A point on the cost of treatments for aging: it is odd that many people believe that such treatments would be very expensive. Perhaps it is instinctive to associate great benefit with great cost, or perhaps people immediately think of the most expensive treatments available today, such as complex surgeries that need teams of highly trained professionals and lengthy aftercare. Those highly trained professionals are exactly why complex surgeries are expensive, however. You are paying for their time in a market that, for various reasons good and bad, has far too few highly trained medical professionals. Compare that situation with some of the most technically advanced treatments presently in widespread use, such as the so-called biologics used to control some autoimmune conditions. The cost of developing that technology was vast, yet infusions of mass-produced biologics cost a tiny fraction of a complex surgery, and that is because they are delivered in a half-hour appointment by a clinical assistant whose fee is a tiny fraction of that commanded by a surgeon. All of the complexity is baked into the research and initial development of a manufacturing industry, and so the eventual cost in the clinic is low and falling.

All of the potential treatments for aging, means to repair the cellular and molecular damage that causes degeneration, frailty, pain, and suffering, will be much more like the mass produced biologic infusion than the surgery. They will be drugs and custom proteins that clear out metabolic waste, replacement cells, gene therapies, and similar items. Everyone suffers the same forms of damage, and little customization of treatments will be needed. Where there is customization it will likely involve the use of your own tissue samples to generate a supply of your own cells that can be formed into the types needed to replenish aging stem cells and other diminished cell populations. That is a service that is even today in the process of becoming an industrial-scale industry, creating cells to order, and prices will fall just as for all other widely used biotechnologies.

So in short, effective treatments for aging will be expensive on the front end, in research and development, briefly expensive during clinical trials when the details are still being worked out and those costly and all too rare trained medical professionals are required in large numbers, and then cheap when mass-produced for the clinic.

Increasing Interest in DNA Methylation in Aging

Epigenetic mechanisms such as DNA methylation alter the pace at which specific proteins are manufactured. Epigenetic patterns are constantly in flux in our cells, changing in response to circumstances, the most interesting of which is the accumulation of cellular and molecular damage that causes aging. Now that researchers have demonstrated that some patterns of DNA methylation change in a fairly reliable way with age, reliable enough to be used to determine age from tissue samples in fact, there is perhaps a greater interest in exploring the details:

Although every person's DNA remains the same throughout their lives, scientists know that it functions differently at different ages. As people age, drastic changes occur in their DNA methylation patterns, which are thought to act as a "second code" on top of the DNA that can lock genes in the on or off position. However, what the consequences of these changes are remains a mystery. To begin deciphering this process, [scientists] studied methylation patterns in the blood cells of 1,264 persons ages 55 to 94 who participated in the Multi-Ethnic Study of Atherosclerosis (MESA).

The researchers found age-related differences in DNA methylation in 8 percent of the 450,000 sites tested across the genome. Most of these changes did not seem to affect which cellular genes were turned on or off. However, [the team] did find a small subset of age-linked DNA methylation changes - 1,794 of the 450,000 sites tested - that were associated with altered gene expression. Out of this subset, 42 sites were associated with pulse pressure, a measure of vascular health that is known to change with age. "Our work suggests that most of the age-associated changes in DNA methylation do not have an obvious effect on cellular function, in this case altering gene expression, and some of them may just amount to noise. The methylation sites that are linked to altered gene expression are good candidates as potential drivers of the negative effects of aging, especially the small subset linked to pulse pressure. Our findings provide new insights into the aging process."

Future studies will try to test the relationship between these methylation sites and specific health outcomes. Eventually, the scientists hope to be able to target and reverse specific sites that are involved with age-related diseases.


A Discussion of Modest Goals in Treating Aging

Many researchers involved in longevity science initiatives have very modest goals. They are looking into how to alter metabolism to modestly slow the progression of aging, which is an enormously complex task and the research community is presently barely at the outset of obtaining a sufficient understanding to proceed effectively. Even with success, the possible benefits that can be achieved via slowing aging as much as, say, calorie restriction does are small in humans - and no-one has come close to achieving that target yet despite fifteen years of work and at least a billion dollars in funding. So the researchers involved here accurately predict expensive, slow, and gradual progress.

When I say "small" in connection with what calorie restriction can provide I mean a greater benefit to long term health than any presently available medical technology can produce in basically healthy people, and a few years added to overall life spans. This is nothing in the grand scheme of what is possible through other approaches, however. Instead of trying to alter an enormously complex system such that it wears and damages at a slower pace, researchers should be trying to fix that damage. Let us keep the metabolism we have, but regularly repair it. Aging is nothing more than damage, and repair would mean rejuvenation, an approach that is limited only by its effectiveness in how many years of healthy life it can add. Further, the damage that causes aging is already known and cataloged: the only research needed is to develop the means to remove it, and in most cases research groups already have strategies in mind.

So the future can be one of expensive, slow progress to a mediocre end goal that will provide very little help to old people, or a faster path to rejuvenation treatments that can actually reverse the frailty and suffering of aging. Sadly the research community remains largely fixated on the former path rather than the latter at this time, which is why it is very important to support the work of disruptive research groups like the SENS Research Foundation who are working on the better approach to treating aging and gathering allies in the scientific community.

Most scientists say we are no closer to eternal life today than we were all those years ago. The word "immortality" elicits a mixture of laughter and earnest explanations about the difference between science and science fiction. Conversations about longevity, however, are an entirely different story. Researchers are optimistic about recent efforts to delay the effects of aging and, perhaps, extend life spans. But at the same time, the scientific community is wary of how quickly these findings are packaged and resold by companies promising a fountain of youth. "It's probably worse today than it's ever been. As soon as the scientists publish any glimmer of hope, the hucksters jump in and start selling."

Understanding the process of aging and developing treatments that might slow the rate at which people grow old could help doctors keep patients healthy longer. We won't be able to stop or reverse aging, but researchers are interested in slowing its progress, such that one year of clock time might not equal a year of biological time for the body. That could delay the onset of diseases like cancer, strokes, cardiovascular disease and dementia, which become more prevalent as people age. "By targeting fundamental aging processes, we might be able to delay the major age-related chronic diseases instead of picking them off one at time. For example, we don't want to have situation where we, say, cure cancer and then people die six months later of Alzheimer's disease or a stroke. It would be better to delay all of these things together."

This is where the field known as the biology of aging is moving - to develop drugs that will increase life span and what researchers refer to as health span, the period of life when people are able to live independently and free from disease.


Regenerative Medicine and the Future of Healthy Longevity

One of the many possible future banners for applied longevity science is to call these treatments capable of extending healthy life span simply "regenerative medicine." In past years, regenerative medicine has referred to the output of the stem cell research community: ways to manipulate and transplant cells in order to create regrowth and healing to a degree that would not normally occur. But why not broaden the usage to include repair of damage within cells, and removal of metabolic waste in tissue structures between cells? It isn't such a leap. The stem cell research community is presently largely focused on building treatments for the old, and thus these researchers will have to solve many of the issues affecting old cells one way or another in order to render their therapies effective.

Looked at this way, "regeneration" and "rejuvenation" are really not so different in meaning. Aging is a matter of accumulated damage that is beyond the capacity of the body to heal, and regenerating old tissue by removing some that damage might as well be called rejuvenation. Such a treatment would remove some of the differences between old tissue and young tissue, and would aim to restore function to a point closer to that of a youthful, healthy individual. In isn't hard to think of aging as an illness, a progressive medical condition, when looking at things in these terms, and that seems to me to be a good viewpoint on the situation if it inspires more people to help do something about it.

Here is an enthusiastic two part piece that mentions regenerative medicine, advanced research such as the SENS programs, as well as other work on immunotherapies and clearance of senescent cells. All of this is in the context of looking ahead to the near future of new therapies and improvements in maintenance and restoration of human health:

Can Regenerative Biotechnology Extend Our Productive Lives?

"It's obvious to me that university laboratories can't do it alone," says University of Southern California professor of gerontology and biological sciences Caleb Finch. "Big Pharma can't do it alone. A marketplace of ideas has to be developed. Those of us who come to these meetings have an increasingly broader set of professional alliances. You get a high table of very smart people around you who represent different disciplines and technologies."

"Disease-modifying cell therapy is very quickly becoming a reality," declares Stephen Minger, chief cellular scientist at GE Healthcare in the United Kingdom. "We're all piling on this now. Until recently, pharma and biotech had no interest in the field - now everybody and his brother is setting up a cellular therapy program. There are a lot of Phase I and Phase II trials under way, with patients getting benefits. We're progressing very rapidly. A lot of money is being pumped in."

"Chronic diseases of aging account for the vast majority of health care expenditures," points out biochemist Judith Campisi, of Lawrence Berkeley National Laboratory and the Buck Institute for Research on Aging in Novato, Calif. "Traditionally, medicine has dealt with them by specializing. But people who study cancer, or neurodegenerative diseases like Alzheimer's, or painful osteoarthritis, or chronic obstructive pulmonary disease or congestive heart failure ... they don't talk to each other. The evidence in medicine is growing, however, that old age is malleable. It may not be inevitable. There are underlying basic processes, and if we could intervene [at that level], no longer treat [separate diseases] but treat aging processes like cellular senescence, it would totally transform medicine." Campisi has been experimenting with a recombinant drug that successfully flushes senescent cells from elderly transgenic mice - a far cry from proving efficacy in humans. And even the lifetime of these mutant lab mice is extended by only another 20 to 25 percent, she notes.

The Big Breakthrough in Rejuvenative Medicine

Immunotherapy is a revolutionary "personalized" medical technique by which blood is harvested from a patient; and the genetic machinery of its T cells - the body's potent main defense against most pathogens but normally unreactive to cancer cells - is altered by introducing an inactivated, genetically modified HIV virus. The souped-up blood is reinfused. The patient's own T cells now can detect signature proteins on the cancer cells and swarm to destroy them.

Several immunotherapeutic approaches such as chimeric antigen receptor therapies are under active investigation for a variety of cancers. Results in initial trials have been highly encouraging - in some instances, astonishing. Moreover, notes Stephen Minger, major pharmaceutical companies and niche startups are "piling on this now." "Individualized cell therapy is at the inflection point," he maintains. "It's going to change fundamentally the way we treat cancer ... [but it also holds promise for] orthopedic indications, repair of bone and cartilage ... organogenesis ... autoimmune diseases like multiple sclerosis, lupus, inflammatory bowel disease and Crohn's disease, where there's been very little therapy available and patients are sick all the time and in a lot of pain ... .

"We're starting to see clinical benefits from targeted immune therapies that spare normal tissue and are completely curative," he summarizes. "It's not just a niche. We're looking at treating very large patient populations to whom we've had very little to offer before. Now we have to address how to deal with millions of them a year. There's a huge amount of excitement around this. We're all ecstatic. But the hard stuff is ahead of us. It's going to be totally, totally disruptive."

Calorie Restriction and Age-Related Gene Expression Changes in the Brain

The practice of calorie restriction with optimal nutrition, a lowered calorie intake while maintaining necessary dietary micronutrient levels, slows near all measures of aging in laboratory animals such as mice. The human studies of calorie restriction show pretty impressive results on shorter term measures of health, greater benefits than any presently available medical technology can provide to an essentially healthy individual at any age. If calorie restriction was a drug, it would be a household name, which probably explains why so much effort is devoted to the development of calorie restriction mimetic drugs. Sadly that is actually a very poor approach to producing treatments for aging, as the calorie restriction response is exceedingly complex: near everything in the operation of metabolism changes in response to lowered food intake, researchers are nowhere near the level of understanding required to proceed effectively, and even if successful the end results will be of only slight benefit.

Thus we shouldn't take our cues for the future of longevity science from its past investigations of natural variations in longevity: the future must look more like engineering, an undertaking in which researchers attempt to repair the cellular and molecular damage that causes aging rather than work on ways that merely gently slow down the damage accumulation. You can't use calorie restriction to reliably live to age 90 and beyond, it just modestly improves your odds. The only way to reliably live much longer in good health is to develop actual, working rejuvenation treatments based on damage repair as a strategy.

In any case, here is an example of the sort of research that helps to maintain the presently high level of interest in calorie restriction mimetic development among researchers:

Neuroscientists [have] shown that calorie-reduced diets stop the normal rise and fall in activity levels of close to 900 different genes linked to aging and memory formation in the brain. Researchers say their experimental results, conducted in female mice, suggest how diets with fewer calories derived from carbohydrates likely deter some aspects of aging and chronic diseases in mammals, including humans. "Our study shows how calorie restriction practically arrests gene expression levels involved in the aging phenotype - how some genes determine the behavior of mice, people, and other mammals as they get old. [It adds] evidence for the role of diet in delaying the effects of aging and age-related disease."

While restrictive dietary regimens have been well-known for decades to prolong the lives of rodents and other mammals, their effects in humans have not been well understood. Benefits of these diets have been touted to include reduced risk of human heart disease, hypertension, and stroke, [but] the widespread genetic impact on the memory and learning regions of aging brains has not before been shown. Previous studies [have] only assessed the dietary impact on one or two genes at a time, but [this] analysis encompassed more than 10,000 genes. For the study, female mice, which like people are more prone to dementia than males, were fed food pellets that had 30 percent fewer calories than those fed to other mice. Tissue analyses of the hippocampal region, an area of the brain affected earliest in Alzheimer's disease, were performed on mice in middle and late adulthood to assess any difference in gene expression over time.


New Theorizing on Teleomere Length and Gene Regulation

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. They shorten with each cell division, one part of a limiting mechanism for the number of times that somatic cells can replicate. Average telomere length in tissues is a function of pace of cell division, activity of the telomere-lengthening enzyme telomerase, and the pace at which stem cells deliver fresh new long-telomere replacement cells. All of this varies widely by tissue type and other factors, and average telomere length in easily measured tissues tends to decrease with ill health and age, most likely as a result of declining stem cell activity.

All of this tends to suggest that telomere length is a measure of secondary and later consequences of aging, and is not in and of itself a primary cause of aging. The counterargument to that is provided by studies in which enhanced telomerase activity lengthened life span in mice, but it isn't clear at this point whether lengthening telomeres is the reason for that outcome, versus other functions of telomerase or cellular reactions to altered levels of that enzyme. Continuing this theme, these researchers suggest a mechanism by which changing telomere length could alter the regulation of gene expression, and thus cellular behavior, for a wider range of genes than previously suspected:

[Researchers] found that the length of the endcaps of DNA, called telomeres, form loops that determine whether certain genes are turned off when young and become activated later in life, thereby contributing to aging and disease. "Our results suggest a potential novel mechanism for how the length of telomeres may silence genes early in life and then contribute to their activation later in life when telomeres are progressively shortened. This is a new way of gene regulation that is controlled by telomere length."

Even before the telomeres shorten to the critical length that damages the DNA, the slow erosion in length has an effect on the cell's regulation of genes that potentially contributes to aging and the onset of disease. The [findings] required the researchers to develop new methods for mapping interactions that occur near the endcaps and to use an extensive array of methodologies to verify the impact. Specifically, the team showed that when a telomere is long, the endcap can form a loop with the chromosome that brings the telomere close to genes previously considered too far away to be regulated by telomere length. Once the telomere and the distant genes on the same chromosome are close to each other, the telomere can generally switch those genes off.

Conversely, when telomeres are short, the chromosome does not form a loop and the telomere can no longer influence whether target genes are switched on or off. The researchers were able to identify three genes whose expression patterns are altered by telomere length but believe this number is the just the tip of the iceberg. "We have developed the concept that telomere shortening could be used as a timing mechanism to respond to physiological changes in very long-lived organisms, such as humans, to optimize fitness in an age-appropriate fashion."


Recent Investigations into the Mechanisms of Atherosclerosis

Atherosclerosis is a particularly unpleasant age-related condition not because it causes great suffering along the way but because it is comparatively invisible right up until the point at which it kills you suddenly. In atherosclerosis the blood vessel walls are thickened by material that is largely composed of immune cells and the fatty remnants of dead cells. Eventually this material becomes unstable enough to cause major blood vessel failure or for a piece to break off and catastrophically block a blood vessel elsewhere in the body, leading to stroke or heart attack.

Once atherosclerotic plaques exist in earnest, they become a ongoing industry of inflammation, cell death, and restructuring on the inside of your blood vessels. The immune cells present in the area act to maintain inflammatory conditions that help to make things worse and attract more immune cells, creating an ever larger mess as time goes by. The starting point for this process involves cholesterols, however. Low-density lipoproteins (LDL) can become damaged by oxidative reactions and in large enough numbers their presence causes a response in blood vessel walls, wherein the tissues issue a call for immune cells to turn up and remove the unwanted damaged LDL molecules. Sometimes this all proceeds according to plan and the harmful LDL is removed, but sometimes the immune cells cannot cope with the ingestion of LDL and die. This can snowball into precursor fatty structures that will grow to become atherosclerotic plaques.

So progression of atherosclerosis is one of the many aspects of aging that can be sped by an environment of greater chronic inflammation in the body. But it is also driven by levels of damaged LDL. That second item is the link between causes of chronic oxidative stress in tissues, rising levels of oxidative molecules roaming to cause unwanted reactions and damaged proteins, and damage such as that of atherosclerosis. Damage caused to mitochondria over the course of aging in particular is thought to drive rising levels of oxidative molecules such as reactive oxygen species: some cells in every tissue become very dysfunctional as a result of this, overtaken by damaged mitochondria and turned into exporters of oxidative molecules. That flow of oxidative molecules can react with and damage important proteins such as LDL that travel far in the body via the circulatory system - and thus contribute to the roots of atherosclerosis over the years.

So I've sketched a picture here, but the reality is that these are complex mechanisms and in absence of repair technologies to remove one or another contribution to atherosclerosis it is hard to prove the degree to which various different sources contribute to the pathology of the condition. For example, there are other ways to modify LDL so as to cause pathology, but this is all the more reason to work harder on repair biotechnologies, as I see it. They are an investigative tool that compares favorably in projected cost and time at this point in comparison to the slow and painfully expensive approach of gathering a full understanding of any process in the aging of metabolism. That all said, here is an example of present research aimed at improving understanding of the causes of atherosclerosis, a paper that touches on some of those other means to alter LDL in harmful ways:

New immunological findings provide possible therapy for cardiovascular disease

Atherosclerosis is an inflammatory process where lipids in the form of LDL cholesterol (also called 'bad cholesterol') are stored in the artery walls. The activation of the immune system in the form of T-cells, among others, plays a vital role, particularly for rupturing the atherosclerotic plaques which, the primary cause of myocardial infarction and stroke. LDL is only taken up in the artery wall after modification, a process where oxidation is one probable underlying cause. Enzymes in the artery walls can also modify LDL making it inflammatory. Most basic scientific studies in the field are based on mouse models with genetic changes as mice cannot develop arteriosclerosis or cardiovascular disease.

[The researchers] studied inflammatory and immune defence reactions in atherosclerosis and cardiovascular disease using plaque cells and blood from patients with cardiovascular disease. The researchers have observed that the lipids (phospholipids) in modified LDL appear to be one of the primary causes. The research team has shown that LDL that is modified by enzymes in the artery walls can activate dendritic cells, which in turn play a key role in activating the T-cells. Non-modified, regular LDL on the other hand had no effect on these cells in the study. The research also indicates the possible existence of a mechanism, namely that stress proteins (also called heat shock proteins) are expressed, which is decisive when modified LDL activates the dendritic cells and T-cells. The study shows that a plasma protein Annexin A5 decreases inflammation and modulates immune reactions to modified LDL, which creates a protective effect.

Induction of Dendritic Cell-Mediated T-Cell Activation by Modified but Not Native Low-Density Lipoprotein in Humans and Inhibition by Annexin A5

Atherosclerosis is an inflammatory disease, where activated immunocompetent cells, including dendritic cells (DCs) and T cells are abundant in plaques. Low-density lipoprotein modified either by oxidation or by human group X-secreted phospholipase A2 (LDLx) and heat shock proteins (HSP), especially HSP60 and 90, have been implicated in atherosclerosis.

We previously reported that Annexin A5 inhibits inflammatory effects of phospholipids, decreases vascular inflammation and improves vascular function in apolipoprotein E−/− mice. Here, we focus on the LDLx effects on human DCs and T cells. Our data show that modified forms of LDL such as LDLx but not native LDL activate human T cells through DCs. HSP60 or 90 contribute to such T-cell activation. Annexin A5 promotes induction of regulatory T cells and is potentially interesting as a therapeutic agent.

You can clearly see the standard research approach here: look for ways to interfere in the details of the process of development (tinker with levels of Annexin A5 to try to reduce the inflammation levels caused by the presence of damaged molecules) rather than address the root cause (the presence of that damaged LDL in the first place). When you work from the end state backwards, points at which the process might be altered are the first things to be discovered. That doesn't mean it is a good approach, however. What it means is that it is the approach most likely to win further funding and a prospect of entering the drug development and regulatory pipeline as they are presently instantiated. Effectiveness of the research strategy as a whole is a much lower priority, sad to say.

An Interesting Presentation on Aging Research

There are a number of people, researchers and advocates, in the longevity science community who have a good understanding of present research and knowledge, but who then build on that understanding to assemble what look to me to be completely the wrong conclusions about how best to proceed towards extending healthy life spans. The fellow who writes Anti-Aging Firewalls is one such individual. He is very much in favor of dietary supplements and other presently available means of metabolic alteration to impact aging, which seems to me to be a huge waste of time and effort. It is massively complex, the data is always ambiguous, and nothing in this area can be demonstrated to approach calorie restriction and exercise in terms of benefits delivered.

Note that neither calorie restriction nor exercise, despite the proven benefits for human health, will reliably let you live to age 90. Three quarters of each new aging cohort will be dead by that point and that includes a majority of those who led exemplary lifestyles. So no, tinkering with supplements is not the path to the future of longevity. Instead all that wasted effort should be focused on supporting and expanding work like that carried out by the SENS Research Foundation: building the rejuvenation technologies that don't presently exist, and which could offer the ability to reliably live in good health to age 90 and beyond. Too many people spend their time in the futile search for something that works now, when they only thing that will do any good is to work on making the treatments that will work tomorrow.

So all that said, here are a pair of presentations where the first is really quite good, being an opinionated view of aging research and its prospects, and the second is not, being a dive into largely pointless approaches that can do little for long-term health even in the best of outcomes.

Aging is multilayered. The aging of a living organism is both a manifestation and a result of complex changes in composition, structure and function across all levels of biological organization from molecular pathways, cell components and cells, to organs and tissues, to whole-body systems. Yet it is rarely studied that way: almost all research investigations have been carried out at a specific single level of organization and often in isolation with a relatively narrow focus. Research is reductionist and highly focused. This is the methodology and culture that dominates biological and biomedical research across the entire spectrum of research activities internationally. This traditional strategy has unquestionably led to significant progress and remarkable insights. But a more integrated approach is needed if we are ever to have a fully developed, fundamental understanding of aging and longevity and their relationship to health.

So, how does science speak with regard to aging? With many tongues. Important findings about aging can come from cancer research, Alzheimer's disease research, genetics and epigenetics research, studies of animals and plants, population health studies, and aging research studies. They can come from just about everywhere in the life sciences. They can be inconsistent, pushing different viewpoints. The contributing scientists mostly do excellent work. But they don't always talk with each other. It is a Tower of Babel! Understanding aging takes us into just about every area of human biology and medicine. The field is incredibly broad and deep and consists of many disparate areas of studies. Most scientists are only partially aware of what other scientists producing related results are doing, and can be unaware that others have solved part of the problem that they are addressing. So, what is presented here is my own story of what is known about aging.


Anti-Aging Medicine: Notes on a Controversy

The "anti-aging" marketplace demonstrates that it is quite possible to build a successful business, even a successful industry, on the basis of delivering something that doesn't actually exist. In this case, that phantom product is the means to reliably slow or turn back the aging process. Many of those in the industry are - or at least were at the outset - quite sincere about seeking to help people and produce meaningful benefits for their customers, but unfortunately once money starts rolling in due to substitutes and shams those original noble goals are always subverted.

Historically, the existence of the "anti-aging" marketplace has a lot to do with why the legitimate research community long suppressed public discussion of and work on interventions in the aging process. They did not want to be associated with snake oil salesmen in any way, shape, or form. This is becoming a matter of recent history now, increasingly irrelevant in the face of a zoo of long-lived laboratory animals and public support from notable scientists for the goals of slowing aging through metabolic alteration or reversing aging by repairing the cellular and molecular damage that causes degeneration.

Those who do not learn from history are doomed to repeat it, however, so while the conflict between the scientific establishment and the "anti-aging" market is no longer dragging down and isolating legitimate longevity science in the same way it was, it is good to understand what happened over the past few decades: why progress was much slower than it might have been, and why it required a considerable struggle within the research community to open up public discussion of extending healthy human life spans. There is, after all, still a very strong "anti-aging" movement based on the same old lies and fraudulent products - it just isn't as much of an impediment to real scientific progress as was once the case, but that won't necessarily continue the way we'd like it to. This open access paper is in Portuguese, and the automated translation is of mixed quality, but still worth reading:

In academic and medical circles, it is certain that the strengthening of geriatrics and gerontology contributed to a much greater attention to aging. However, the path to a greater community for geriatrics and gerontology and aging sciences did not happen without setbacks. Despite the US community of biogerontologists (as well as geriatricians and other gerontologists) having developed since the late 1930s, some forty years later it was still stigmatized by the historical legacy of mythology and quackery that characterized the aspirations and practices of prolongevity. An aura of disbelief lasted until the mid-1970s in initiatives aimed at prolongevity, affecting any scientists that worked on aging, including gerontologists and geriatricians.

Now, in 1970, the demographic transition was already under way in the US, as in other core countries, and even then, the idea prevailed that a medicine and science of aging were illegitimate. However, since then, such an assumption is not longer the case, that change occurring alongside the growing number of seniors who demand specific attention, and who are attended by professionals of aging. In other words, one can say that the geriatric-gerontological field was a franchisee with access to the fields of science, and its legitimacy has been recognized as more was learned about aging.

But here we come to the year 2010, and a new course of events unexpectedly rushes over what seemed stabilized. The geriatric-gerontological field rid itself of the question of legitimacy, but this now returns, and from a direction in which it is least expected: since the mid-1990s, doctors - peers - are questioning whether the practice in geriatrics and gerontology are indeed the most effective in preventing the complications of aging. Announcing themselves to be in possession of something more innovative in terms of scientific action on aging, and identifying themselves as questioning the mainstream, practitioners of antiaging medicine are causing a stir among geriatricians and gerontologists. The latter accused the former of charlatanism and bad faith; the first and the second accused of denying patients the chances of aging well (an ideal of aging that has been carefully constituted and supported on the shoulders of geriatrics / gerontology to have legitimacy and recognition!).

In this article we will explore the roots of this controversy, with the intent to understand what is their place in the field of knowledge about aging and what it shows us about the production of our sociotechnical collective term that emphasizes the importance of science for the constitution of modern society. We start by explaining how geriatrics and gerontology were structured and legitimized as the science of aging, emphasizing the points that are targets of questioning by anti-aging medicine. We then look at the emergence of that other way of thinking about aging, which will allow us to get into the history of the controversy itself.


Old Stem Cells Not So Good at Repairing Heart Attack Damage

One of the areas in which stem cell therapies have shown promise right from the beginning is in the treatment of various forms of heart disease and the tissue damage caused by a heart attack, or myocardial infarction. Benefits have been evident enough for a broad clinical industry to flourish in many parts of the world well in advance of the exceedingly slow and largely unnecessary process of pushing treatments through the regulatory gauntlet in the US. A trend in the development of therapies has been from the use of transplanted stem cells obtained from donors to the use of stem cells isolated or reprogrammed from a patient's tissue samples, something that should produce a better class of result because it removes concerns regarding transplant rejection and other issues that can arise when the tissues from one person are used in another.

If using the patient's own cells in a regenerative therapy, the question of age immediately arises, however. Most people in need of regenerative treatments are in need exactly because they are old and suffering from age-related degenerative medical conditions. Their organs falter and fail, and the leading use case for present and future regenerative medicine is to at least partially compensate for or ideally turn back this downward spiral. We age because we become damaged, the machinery of cells and tissues degraded in various ways to the point of malfunction, and a part of that damage accrues to stem cell populations. Work on understanding why stem cell activity declines with aging has in recent years placed a great deal of emphasis on the state of the surrounding tissue environment rather than the cells themselves. The muscle stem cells known as satellite cells recover much of their ability to maintain tissues when moved from old tissue to young tissue, for example. This, of course, leads to more optimism for the near future of regenerative treatments for old people, provided that sizable benefits can indeed be obtained by coaxing stem cells into a more youthful and active behavior through altered levels of signal proteins such as GDF-11.

Not all types of stem cells do as well as aged satellite cells, however. Mesenchymal stem cells (MSCs), usually obtained from bone marrow or fat tissue in adults, are at present one of the most-used cell types in treatments under development as well as those available in clinics or trials. Unfortunately, there is fairly robust evidence to show that these cells don't work as well in regenerative therapies when obtained from older donors. The research group quoted below have investigated the mechanisms involved, which is the first step on the road to understanding whether or not there is a practical way to fix this problem in the near term, and thus make cells from old patients just as effective as those from young patients:

Aging Increases the Susceptivity of MSCs to Reactive Oxygen Species and Impairs Their Therapeutic Potency for Myocardial Infarction

In the last decade, great successes been achieved in transplanting MSCs to treat myocardial infarction (MI) in animal models as well as in clinical trials. Previously, lower efficacy of old MSCs than the young ones in myocardial repair has been confirmed by independent studies and furthermore different potential mechanisms have been proposed, such as deteriorated paracrine capacity and impared angiogenic capacity. However, the causes why the efficacy of MSCs on myocardial repair after ischemia was attenuated with aging were far from thoroughly demonstrated. In the current study, our purpose is to determine whether other causes existed in addition to the previous findings that aging influenced the therapeutic efficacies of MSCs. We show that aging increases the susceptivity of MSCs to reactive oxygen species (ROS) and impairs their therapeutic potency for myocardial infarction. To our knowledge, this is the first evidence that MSCs from old donors were more susceptible to ROS induced adhesion impairment and apoptosis, leading to a more rapidly decreased survival rate, and thus resulting in a dampened therapeutic effectiveness.

Back to 2001, two landmark studies showed transplantation of bone marrow cells could generate de novo myocardium. Thereafter, MSCs transplantation was carried out by several clinic trials, and a promising therapeutic potential was reported. However, as autologous MSCs transplantation was favoured in clinic, and most patients were over 60 years old, one question arises - are MSCs from old donors qualified to do the job? We found an impaired therapeutic efficiency of transplantation using MSCs from old donors. Furthermore, our data suggest that this impairment may be caused directly by a significantly decreased viability of old MSCs engrafted, in which the micro-environmental ROS in the MI region may play important roles.

The co-injection of MSCs with the free radical scavenger, NAC (N-acetyl-L-cysteine) has been shown to protect MSCs from ROS and enhanced their therapeutic efficiency. In our study, in order to investigate whether MSCs from old donors were more vulnerable to the micro-environmental ROS in the MI region in vivo, besides the old and young MSCs transplantation groups, we introduced a group in which 1 mM NAC was co-injected with the old MSCs. Interestingly, we found a similar number of NAC treated old MSCs and young MSCs remained one week after transplantation, whereas the number of survived MSCs from old donors was only about a half of that of survived MSCs from young donors. In addition, judging by the histology and function of heart, we found an impaired therapeutic efficiency transplanting MSCs from old donors. Since the NAC plays its role as a ROS scavenger but does not have a significant therapeutic effect in treating MI without MSCs, we may safely indicated that MSCs from old donors has lower viability in vivo in the MI region due to their increased susceptivity to the environmental ROS.

To survive, cells require an adequate interaction between them and the extracellular matrix, otherwise they will undergo apoptosis, known as anoikis. Thus, the viability of engrafted MSCs also depends on cell adhesion. However, the infarction of myocardium created a harsh micro-environment, including an accumulation of ROS, which has been reported to hinder cell adhesion. Therefore, we postulated that the low survival rate of MSCs from old donor may be caused by an enhanced susceptibility to environmental ROS. By adhesion assay and apoptosis assay, we found that ROS caused more damage in the adhesion of old MSCs than of the young ones, which further increase the old MSCs' apoptosis indirectly.

The Overlap Between Vascular Disease and Alzheimer's Disease

The flexibility and structural integrity of blood vessel networks declines with age. Metabolic waste products accumulate in blood vessel walls, and separately a combination of damaged cells, damaged proteins, and chronic inflammation leads to harmful restructuring. Other mechanisms are at work also, such as those involved in hypertension. This all means that ever more tiny blood vessels fail in one way or another, either bleeding into brain tissue or not delivering oxygen efficiently. The resulting damage builds up, a bit at a time. Thus there is every reason to consider a causal link between vascular issues and forms of dementia such as Alzheimer's: vascular problems eating away at the brain's integrity are going to worsen the effects of an emerging dementia even if it is caused by entirely different mechanisms. Further, there is the possibility that issues with blood flow in the brain can directly impact clearance of the misfolded proteins called amyloids implicated in the progression of Alzheimer's disease. Other links may yet be discovered.

The interaction between cerebrovascular disease (CVD) and Alzheimer's disease (AD) is a topic of considerable current interest. With age there is an increasing prevalence of coincident AD and CVD that is well recognized. Since 50% to 84% of the brains of persons who die aged 80 to 90+ show appreciable cerebrovascular lesions (CVL), a specific problem is their impact in relation to AD pathology. CVD frequently occurs in brains of both non-demented elderly and AD patients. The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly, suggesting additive or synergistic effects of both types of lesions on cognitive impairment.

The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds, while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent. Small infarcts in patients with full-blown AD have no impact on cognitive decline but are overwhelmed by the severity of Alzheimer pathology, while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia.


Selective Removal of FXR1P Enhances Memory

As researchers make progress in understanding how memory works, they will also find ways to enhance its operation. A class of therapies that attempt to compensate for age-related memory impairment may arise as a result, but note that compensation is never a true replacement for addressing the actual causes of dysfunction. Still, even after the causes of memory issues with age are understood and prevented, there is still a place for options to enhance memory in healthy people. Who doesn't want better control over memory, even in youth?

This is an example of the sort of results currently emerging from studies of memory mechanisms in laboratory animals. Like all work at this early stage it is a long way from any practical implementation as an enhancement, but very interesting nonetheless:

[Researchers] used a mouse model to study how changes in brain cell connections produce new memories. They demonstrated that a protein, FXR1P (Fragile X Related Protein 1), was responsible for suppressing the production of molecules required for building new memories. When FXR1P was selectively removed from certain parts of the brain, these new molecules were produced that strengthened connections between brain cells and this correlated with improved memory and recall in the mice.

"The role of FXR1P was a surprising result. Previous to our work, no-one had identified a role for this regulator in the brain. Our findings have provided fundamental knowledge about how the brain processes information. We've identified a new pathway that directly regulates how information is handled and this could have relevance for understanding and treating brain diseases. Future research in this area could be very interesting. If we can identify compounds that control the braking potential of FXR1P, we may be able to alter the amount of brain activity or plasticity. For example, in autism, one may want to decrease certain brain activity and in Alzheimer's disease, we may want to enhance the activity. By manipulating FXR1P, we may eventually be able to adjust memory formation and retrieval, thus improving the quality of life of people suffering from brain diseases."


The Lung Can Regenerate

One of the ongoing themes in stem cell research is the discovery that numerous tissues thought to be static or poor at regeneration are in fact generating new cells, and can in fact naturally regenerate under some circumstances. If the rudiments of these regenerative mechanisms exist, then why not build therapies based on reliably activating and steering them? Or so the thinking goes. At the present time work hasn't progressed much past discovery and experimentation, even for nerve tissues where the crucial discoveries that neurogenesis occurs in adults were solidified and accepted fifteen years ago. Most of the progress in the broader field of regenerative medicine to date has been a case of improving on regenerative mechanisms that have long been well recognized and are consistently at work in ordinary adults. That will change soon enough, however, as improved technologies and capabilities in working with cells are leading to rapid progress in all areas of cell research. The equipment and knowledge present in the labs of today is far advanced over that of even a decade ago, and the pace is picking up.

Here is a great example of the sort of discoveries taking place in recent years regarding the regenerative capabilities of tissues that normally recover from damage only poorly. In this case the focus is on the lung. Like much of this work, it seems very promising - that there are mechanisms that could with just comparatively simple manipulations greatly enhance the normal state of tissue regeneration. "Comparatively simple" is usually still a major research project in any form of cell biology, unfortunately, but this and similar results in other tissues show the path ahead. Regenerative medicine will undergo a great deal of improvement in near future:

Lung regeneration mechanism discovered

The idea that the lung can regenerate has been slow to take hold in the biomedical research community, in part because of the steady decline that is seen in patients with severe lung diseases like chronic obstructive pulmonary disease (known as COPD) and pulmonary fibrosis. Nevertheless, there are examples in humans that point to the existence of a robust system for lung regeneration. Some survivors of acute respiratory distress syndrome, or ARDS, for example, are able to recover near-normal lung function following significant destruction of lung tissue.

Mice appear to share this capacity. Mice infected with the H1N1 influenza virus show progressive inflammation in the lung followed by outright loss of important lung cell types. Yet over several weeks, the lungs recover, revealing no signs of the previous lung injury. Using this mouse model system, [researchers] previously identified a type of adult lung stem cell known as p63+/Krt5+ in the alveoli found within the lung.

The research team reports that the p63+/Krt5+ lung stem cells proliferate upon damage to the lung caused by H1N1 infection. Following such damage, the cells go on to contribute to developing alveoli near sites of lung inflammation. To test whether these cells are required for lung regeneration, the researchers developed a novel system that leverages genetic tools to selectively remove these cells from the mouse lung. Mice lacking the p63+/Krt5+ lung stem cells cannot recover normally from H1N1 infection, and exhibit scarring of the lung and impaired oxygen exchange - demonstrating their key role in regenerating lung tissue. The research team also showed that when individual lung stem cells are isolated and subsequently transplanted into a damaged lung, they readily contribute to the formation of new alveoli, underscoring their capacity for regeneration.

p63+Krt5+ distal airway stem cells are essential for lung regeneration

Lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia or acute respiratory distress syndrome often recover full pulmonary function within six months.

Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5 (Krt5) to this process. Here we show that [these cells] undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation.

Pascal's Wager as Applied to the Defeat of Aging

There are two choices: do nothing and probably age to death, or support research into longevity science and live for much longer in good health if it is successful. Since you are here and reading this, the dice are already rolling for the rest of your life. Why not do what you can to improve the odds of a good outcome, a future in which effective rejuvenation treatments for age-related frailty and disease exist by the time you need them?

The choice comes down to doing nothing - except hoping that you have the right religious beliefs - or doing something - buying a cryonics policy and/or supporting scientific research. So what should you do? Perhaps the best way to illuminate the choice is to consider a previous choice human beings faced in their history. What should they do about disease? Should they pray to the gods and have faith that the gods will cure them, or should they use science and technology to find the cures themselves? In hindsight the answer is clear. Praying to the gods makes no difference, whereas using modern medicine has limited death and disease, and nearly doubled the human lifespan in the last century. Other examples also easily come to mind. What is the best way to predict weather, harness energy, communicate instantly over great distances, or fly to far off planets?

These examples highlight another advantage to making [the] wager - the incremental benefits that accrue as we live longer and better lives as we approach the holy grail of blissful immortality. Such benefits provide assurance that we are on the right path, which should increase our confidence that we are making the correct wager. In fact, the benefits already bestowed upon us by science and technology confirm that it is the best path toward a better future. As these benefits accumulate, and as we become aware of them, our existence will become increasingly indistinguishable from the most enchanting descriptions of any afterlife.

So we should throw off archaic superstitions and use our technology. Will we do this? Yes. I say with confidence that when an effective pill that stops or reverses aging becomes available at your local pharmacy - it will be popular. Or if, as you approach death, you are offered the opportunity to have your intact consciousness transferred to your younger cloned body, a genetically engineered body, a robotic body, or a virtual reality, most will use such technologies when they are demonstrated effective. By then almost everyone will prefer the real thing to a leap of faith.


Whole-Genome Sequencing of Supercentenarians

The search for longevity-associated genes continues, and the evidence taken as a whole suggests that the situation is very complex. It looks to be the case that potentially hundreds or thousands of genes each provide a tiny, environment- and lineage- specific contribution, and associations between single genes and natural variations in longevity are almost all either statistically weak or fail to replicate in different study populations. So the genetics of longevity looks like one of the many presently popular areas of study in which there is little to gain but knowledge of the details of our metabolism. The cellular and molecular damage that distinguishes old tissues from young tissues is well known and is the same in everyone. The best path towards treating aging is to repair this damage, not spend all our time figuring out how differences in the reaction to this damage causes some few very damaged people to live longer:

Supercentenarians (110 years or older) are the world's oldest people. Seventy four are alive worldwide, with twenty two in the United States. We performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity. We found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in supercentenarian compared to control genomes.

We followed up on the gene most enriched for rare protein-altering variants in our cohort of supercentenarians, TSHZ3, by sequencing it in a second cohort of 99 long-lived individuals but did not find a significant enrichment. The genome of one supercentenarian had a pathogenic mutation in DSC2, known to predispose to arrhythmogenic right ventricular cardiomyopathy, which is recommended to be reported to this individual as an incidental finding according to a recent position statement by the American College of Medical Genetics and Genomics. Even with this pathogenic mutation, [this supercentenarian] lived to over 110 years.

The entire list of rare protein-altering variants and DNA sequence of all 17 supercentenarian genomes is available as a resource to assist the discovery of the genetic basis of extreme longevity in future studies.


SENS Research Foundation Newsletter, November 2014

The SENS Research Foundation is perhaps the only group in the world to presently focus on organizing, advocating, and carrying out research into the biotechnologies required for treatments capable of reversing degenerative aging. The pains and frailties of aging are the consequence of unrepaired damage to cells and tissues. While it is true that the forms of damage are well understood and there are several clear paths to develop means to repair this damage, it is still the case that someone has to do the initial proof of concept work and persuade the rest of the research community to join in. Without bold steps there will be no progress.

The latest newsletter from the SENS Research Foundation arrived in my in-box today, along with a reminder that we're in at present right in the middle of the Fight Aging! 2014 matching fundraiser to support the Foundation's research programs, and all the help we can get to hit the target will be greatly appreciated:

Everyone at SENS Research Foundation would like to thank all our contributors who have helped us reach $19,159 - well on the way to our $50,000 challenge goal. Fight Aging! has pledged to us that for every $1 you give they will add $2 - tripling your donation. The challenge goal is to reach $50,000 by December 31st. So please join the more than 300 donors who have shown their support for SENS Research Foundation and our work and donate today.

We are also looking for additional challenge grant sponsors. If you are interested in offering up a challenge please contact us.

One of the important activities undertaken by the Foundation is to help build the rejuvenation research community of tomorrow. A generation of well-connected, organized researchers who see the treatment of aging as an exciting, cutting-edge field of science won't come about by accident. The defeat of age-related pain, suffering, and disease is a long-term project, and the people who will in years ahead, at the height of their careers, put the capstone on the first generation of rejuvenation treatments are still in college today, deciding which academic path to pursue:

SENS Research Foundation invites all qualifying students to apply for the 2015 Summer Scholars Program. The online application will be available starting December 1, 2014. Completed applications will be accepted through February 2, 2015. If you are an undergraduate interested in rejuvenation biotech, this is your chance to gain valuable experience in the field.

The first in a series videos profiling the students who participated in the 2014 SRF Summer Scholars Program is now available for viewing on the SRF website. This video features our 2014 scholars in action at the SRF Research Center (SRF-RC). View the video to meet Christine Wu, Summer Wang, and Karina Liker and learn about their experiences in the program.

As is usually the case, the question of the month section makes for interesting reading:

Question of the Month #7: What's Menopause Got To Do With It (Rejuvenation Biotechnology)?

Q: SENS Research Foundation Chief Science Officer Dr. Aubrey De Grey recently made a comment to the media suggesting that "rejuvenation biotechnology could eliminate menopause within twenty years." How does intervening in the process of menopause fit in with SRF's agenda to ameliorate age-related disease?

A: SENS Research Foundation works to catalyze the development of rejuvenation biotechnology: a new class of medicines that will keep us young and healthy and forestall the disease and debility that currently accompany a long life, by targeting the root causes of age-related ill health.

Menopause shares much in common with major age-related health problems, inasmuch as they all result from the accumulation of cellular and molecular damage in our tissues over time. Because this damage takes our tissues' microscopic functional units offline, aging damage gradually degrades each tissue's capacity to carry out its normal function with time. When enough of this damage accumulates in a particular tissue, specific diseases and disorders of aging characteristic of that tissue emerges, whether it's in the brain (Alzheimer's and Parkinson's disease), or the heart and circulatory system (atherosclerosis and heart failure), or the machinery controlling cellular growth (cancer) - or the ovaries (menopause). The corollary of this is that by removing and repairing this damage, rejuvenation biotechnology will restore the proper structure of the cellular machinery that keeps our tissues functioning, restoring their ability to keep us alive and with the good health that most of us enjoy at earlier ages.

So maintaining a woman's fertility and postponing or eliminating menopausal symptoms comes down to a mixture of repairing and replacing damaged cells (notably egg cells) and tissues (follicles) whose age-related degradation leads to menopause in the first place, bringing the whole system back to its youthful, functional norm. Today, researchers are pursuing several "damage-repair" approaches to realize this goal, and that's what we'll discuss in an article at the SEN Research Foundation website.

No Benefit to Survival from Injections of Young Blood Plasma Provided to Old Mice

The practice of heterochronic parabiosis, linking the circulatory systems of old and young mice and observing the results, produces measurable beneficial changes in the tissues of the old mice. Researchers have identified a few proteins such as GDF-11 where changes in the circulating levels occur with age, and artificially resetting these levels - such as via parabiosis - can alter the behavior of stem cells to make them more active in tissue maintenance. A range of other experiments are currently ongoing to try to better understand and catalog these results first identified via parabiosis studies. Some of these experiments are going to produce null or ambigious results, as is the case here, because nothing in biology is simple or straightforward. You'll probably want to skip ahead to the discussion section at the end of this open access paper, as that is where the interesting information can be found:

Aging is for now an irreversible process that affects multiple organs and is the leading cause of age-associated mortality and morbidity. The search for an efficient way to counter age-related changes in an organism is a task of high importance. Recently, scientific evidence of a rejuvenating effect of young blood on different tissue and organ functions was published. Among these studies, heterochronic parabiosis was particularly interesting: the model demonstrates the possibility of constant exchanges of cellular and humoral factors through the blood between animals of different ages.

Still, after such mostly positive reports, the question of the overall beneficial effect becomes extremely intriguing: Instead of looking at a specific parameter or a short period of time, is maintaining a young milieu globally beneficial over time? This can be asked through a simple measure: Does it increase lifespan? In previous experiments, we looked at the survival of mice following temporary isochronic and heterochronic parabiosis (unpublished data). It was found that aged mice tended to live longer after a period of heterochronic parabiosis than isochronic parabiosis, suggesting a globally beneficial effect of the young milieu. However, the difference was not statistically significant, and lifespans were not in the range of those of untreated animals, possibly due to the traumatic condition of parabiosis. Therefore, general conclusions were very uncertain regarding "anti-aging" effects, and another model for long-term effects was sought, namely, plasma injections.

To assess the anti-aging effect of young blood we tested the influence of repeated injections of plasma from young mice on the lifespan of aged mice. One group of 36 CBA/Ca female mice aged 10-12 months was treated by repeated injections of plasma from 2- to 4-month-old females. Their lifespan was compared to a control group that received saline injections. The median lifespan of mice from the control group was 27 months versus 26.4 months in plasma-treated group; the repeated injections of young plasma did not significantly impact either median or maximal lifespan.


Another Look at Blood Groups and Longevity

Evidence for blood group differences to be meaningfully involved in natural variations in longevity is nebulous at best. Nonetheless, papers emerge every so often on this topic to theorize and collect more evidence, but continue to reinforce the lack of compelling data:

ABO antigens have been known for a long time and yet their biological meaning is still largely obscure. Based on the available knowledge of the genes involved in their biosynthesis and their tissue distribution, their polymorphism has been suggested to provide intraspecies diversity allowing to cope with diverse and rapidly evolving pathogens. Accordingly, the different prevalence of ABO group genotypes among the populations has been demonstrated to be driven by malaria selection. In the similar manner, a particular ABO blood group may contribute to favour life-extension via biological mechanisms important for surviving or eluding serious disease.

There are only five reports suggesting a possible association between ABO blood groups and ageing/longevity features, among those only two performed on centenarians and only one performed by molecular methods. In the first one, a significant increase of A blood type was observed in the healthy elderly male population over 64 years of age from UK, but it is not possible to consider this study for the very low age taken into account. In a study carried out on a small sample of very longevous Turkish population, no association was found; however, the validity of age claims was very questionable because birth certificates were not available, so also this study cannot be considered.

A more recent study investigated the association between blood groups and life expectancy in the Japanese population. The authors compared frequencies of ABO blood groups in 269 centenarians living in Tokyo and those in 7153 regionally matched controls. Group B was observed more frequently in centenarians than in controls, suggesting that group B might be associated with exceptional longevity. The authors suggested that group B individuals are more likely to survive age-related diseases rather than escape them, since 33% of the centenarians were free of age-related diseases, but this did not correlate with the group B.

In a further study, to validate these results, [researchers] collected data on the ABO blood groups of patients who died in a United States tertiary care hospital over a 1-year period. If group B was a marker for a longer lifespan, it would be expected that the percentage of group B patients would rise with age at the time of death and those of other blood groups would decline. A total of 772 patients were included in the study and data were presented as ABO proportion stratified by age. The authors found that the percentage of group B patients declined with age, and this result was statistically significant. None of the other blood groups showed a statistically significant increase or decrease when plotted against decade of death. Overall, these results suggest that group B is not a marker for longevity, at least in US.

We have recently investigated the relationship between ABO group and longevity in a small sample of homogeneous Sicilian centenarians (n = 38) and young controls (n = 59). Our group of centenarians (age range 100-107) had no cardiac risk factors or other age-related diseases. The control group (age range 45-65) was recruited from blood donors and judged to be healthy on the basis of clinical history and blood tests. Samples were genotyped by molecular biology to determine ABO blood group and Chi Square analysis was used to determine the statistical significance of differences in ABO of centenarians and controls. Our pilot study shows a not-significant increase of A1 allele in Sicilian centenarians.

In the generation of centenarians under study, the control of cardiovascular disease, in fact plays a key role in the longevity attainment. So, the Sicilian results, that need to be confirmed in a larger sample of centenarians, also taking into account the gender due to its relevance in immune-inflammatory responses, are in line with the previous statements. So, people carrying A1 allele should be advantaged in attaining longevity because of the lower levels of the serum soluble inflammatory marker E-selectin linked to this blood group, so avoiding or delaying cardiovascular events.


Recent Interviews with Aubrey de Grey

Aubrey de Grey is originator of the SENS rejuvenation research programs and presently Chief Science Officer at the SENS Research Foundation, the umbrella organization dedicated to ensuring that therapies to treat and reverse degenerative aging are developed as soon as possible. The Foundation funds a range of research into the underlying biotechnologies needed to produce regenerative medicine for aging, and is supported by a number of noted philanthropists and luminaries in the scientific community.

Success here is as much a matter of convincing the broader medical research community as it is of proving the case via scientific research: like all sweeping changes in the making, this is a bootstrap process of growing the funding and the research results until SENS effectively becomes the mainstream of aging research. This will happen because SENS research programs will prove capable of delivering far better results than the present approaches to aging, and at a fraction of the cost. SENS is based on repair of damage, while today's mainstream is much more interested in finding ways to alter the operation of our metabolism to slightly slow down the accumulation of further damage. It doesn't take a scientist to understand that repair will always win out in terms of cost-effectiveness, and that repair is the only way to rejuvenate the old, those who will benefit very little from ways to slow down the damage of aging.

Yesterday de Grey appeared on CNBC in a short segment to summarize some of his views. It is always good to see a broader audience get a taste of these things, but I should note that in the past decade television has shown itself to be a terrible medium to convey the exciting prospects for longevity science. Even fairly involved treatments of the research and researchers involved produced very little in return: no great visitation of web sites, no donations, no follow up. No doubt we can all theorize as to why this is the case, but it is what it is.

Do you really want to live to 1,000?

At this year's Exponential Medicine conference, CNBC was present to probe faculty about some of the exciting developments within accelerating technologies. One of the most eye-opening speakers is Aubrey de Grey, cofounder and Chief Science Officer of the SENS Research Foundation, who was interviewed about longevity and the prospect of regenerative medicine extending our lives to 1,000 years or more.

By way of a contrast here is a longer audio podcast interview with de Grey from last month, in which he covers the established SENS vision and the long-term goal for the entire research community of eliminating degenerative aging from the human condition:

Eliminating aging (it's more obvious than it sounds) with Aubrey de Grey

It sound crazy when you put it into perspective but at the moment there is a 100% chance of death. I don't want to sound too morbid but this includes you, your friends and your family...

Aubrey de Grey joins me [to] discuss his work on resolving the issue of aging which at it's fundamental level is just a problem with our mechanics breaking down over time. We cover neurodegenerative diseases to mitochondrial damage and he gives us the 7 key targets his research as suggested will have the biggest impact on the aging process. The interview was a fascinating insight into Aubrey's work and he will be appearing again soon do to a show about cancer and the potential to solve it.

Suppressing Mitochondrial Fission as a Potential Treatment for Parkinson's Disease

Mitochondria are bacteria-like organelles that swarm in their thousands in each of our cells, and they are important in aging because they can suffer forms of damage that negatively impact the functionality of their host cell. The mitochondrial population of any given cell is very dynamic: they swap protein machinery, fuse with one another, divide like bacteria, and are destroyed by cellular quality control mechanisms. Cells can even transfer mitochondria between one another, and all this takes place constantly at a very rapid pace. It has made it very challenging to prove exactly how damage to mitochondria occurs and propagates, which is one of the reasons why the SENS rejuvenation research approach is to jump over that question and focus on repair strategies that will work no matter how the damage is caused and spreads.

Mitochondrial dysfunction leading to higher rates of cell death or malfunction is implicated in a variety of specific age-related conditions, Parkinson's disease among them, and for reasons that may or may not run in parallel to the damage of aging. This has placed a spotlight on mitochondrial dynamics and the ability to manipulate their activities, as here. It is interesting to speculate on why less fission is beneficial; perhaps it allows mitochondrial quality control processes more chances to destroy damaged mitochondria before they replicate, or perhaps an increase in the rate of fusion over fission allows for more of the mitochondria in a cell to have all of the necessary proteins for complete function rather than just a damaged set:

The inhibition of a particular mitochondrial fission protein could hold the key to potential treatment for Parkinson's Disease (PD). The debilitating movement symptoms of the disease are primarily caused by the death of a type of brain cell that produces a chemical called dopamine. Understanding why these nerve cells die or do not work properly could lead to new therapies for PD.

Mitochondria are small structures within nerve cells that help keep the cells healthy and working properly - they are, in effect, the power generators of the cell. Mitochondria undergo frequent changes in shape, size, number and location either through mitochondrial fission (which leads to multiple, smaller mitochondria) or mitochondrial fusion (resulting in larger mitochondria). These processes are controlled mainly by their respective mitochondrial fission and fusion proteins. A balance of mitochondrial fission/fusion is critical to cell function and viability.

The research team found that when a particular mitochondrial fission protein (GTPase dynamin-related protein-1 - Drp1) was blocked using either gene-therapy or a chemical approach in experimental models of PD in mice, it reduced both cell death and the deficits in dopamine release - effectively reversing the PD process. The results suggest that finding a strategy to inhibit Drp1 could be a potential treatment for PD.


An Interview with Michael Fossel

One of the roles of the enzyme telomerase is to extend the repeating telomere DNA sequences at the ends of chromosomes, thus lengthening the replicative life span of cells. Telomere length is a part of the clock mechanism limiting the life span of ordinary cells, and it decreases with each cell division. Telomerase is active in different tissues to different degrees, most notably in the stem cells that provide fresh cells with long telomeres to maintain tissues. The mix of these dynamics helps to determine the rate of cell turnover in any given tissue and the current average length of telomeres. This turnover rate varies greatly throughout the body, from a few days for the lining of the gut to essentially never for some of the central nervous system. The average length of telomeres tends to decline with aging or ill health, most likely due to a slowdown in the activity of stem cells and their delivery of new cells with long telomeres. As such these measures are probably a secondary aspect of aging, a marker rather than a root cause.

That said, increasing telomerase activity in mice has been shown to extend life, though there are several plausible reasons why this might be the case, only one of which involves enhanced tissue function due to longer-lived cells. The potential upside here has to be balanced with a concern over cancer: forcing cells into longer lives than evolution has settled on may or may not tip the balance in favor of much more cancer. This hasn't happened in the mouse studies, but mice have quite different telomere dynamics in comparison to humans.

Michael Fossel is one of the more noteworthy advocates for telomerase therapy as an important research direction for the treatment of aging. Here is an interview:

Michael Fossel's dream is to reverse human aging and since 1996 he has been a strong and vocal advocate of experimenting with telomerase therapy as a potential way of intervention in a wide variety of medical conditions related to aging. During our 1 hour discussion with Michael we cover a variety of interesting topics such as: his dream to reverse aging and the desirability and feasibility thereof; the Hayflick limit of cell division and Aubrey de Grey's concerns that telomerase therapy may cause cancer; the distinction between reversing aging and living forever; his "non-sexy" tips on healthy living; his take on cryonics and transhumanism.

"Ageing is dynamic, not static. Never mind the low-hanging fruit. [...] Go for the important one! The reason to [reverse aging] is not to double somebody's lifespan. The reason to do this is because people out there are hurting. They are frightened. They are terrified by the things that happen to them when they get disease. The reason to do this is because we are human and we should be working at this. It's not playing God, it is working at being human. It's compassion. It's not a matter of living longer, it is a matter of making people healthy again."


The Seven Pillars of Aging

Aging research is still mostly a matter of investigation, gathering data and validating theories without a hint of any intent to build treatments to help the aged. This terrible state of affairs is changing, however, and the prospects look increasingly good for serious levels of funding to arrive over the next decade at established research programs aimed at intervening in the aging process. Hence a lot of researchers are now interested in establishing such programs, and the existing programs are solidifying their positions and networks. It is often thought that scientists have a poor instinct for finance and competition, but the people who think that have evidently never seen the long game of grant management in action. A great deal of planning, positioning, and forethought takes place among those who manage sizable research portfolios.

Most of today's longevity science programs with an aspiration to producing therapies are presently focused on very modestly slowing aging through metabolic manipulation of one kind or another, such as the development of calorie restriction mimetic drugs. This is unfortunate, but I suppose that there has to be a start somewhere. When those programs are raising funds at five or ten times their present level, despite the poor prospects for any sort of meaningful extension of healthy life to emerge from their work, the same multiplier in funding levels will be attainable for SENS rejuvenation research. SENS-style biotechnologies that can repair the underlying cellular and molecular damage that causes aging are the approaches that actually matter if what you care about is adding decades of healthy life and restoring the old to vigor and health. SENS is still the young, disruptive movement in the field, but a rising tide floats all boats.

That said, SENS has rather set the tone for how researchers are choosing to present their research strategies: plans of development leading towards specific therapies to treat the aging process itself. This is a departure from the present state of medicine, in which only the symptoms of aging are treated, the various age-related diseases. Pushing the research community towards a growing consensus that aging can and should be treated as a condition (or rather collection of identifiable conditions) is a great victory in and of itself: now it's just a matter of steering in the right direction, funding the best strategies. SENS is presented as a set of seven classes of damage that causes aging, each with its own attendant proposed paths to treatments. The influence of that vision can be seen in the noted Hallmarks of Aging polemic published last year, which followed the same model but with a different, overlapping emphasis on what in aging is thought to be cause versus consequence.

Now here again we have another new position statement on treating aging that echoes the SENS model. It is put forward by leading figures in the research community, with yet another another take on what is cause versus consequence, and which research strategies to pursue, also overlapping to some degree with the SENS vision - though less so, I think. It is no doubt completely coincidental that there are seven pillars of aging, perhaps a reference to Proverbs 9:1, and it is certainly the case that all of these strategic considerations of aging research could be differently divided if the fancy takes you. But seven is a magic number it seems, and so seven it is:

Leading scientists identify research strategy for highly intertwined "pillars of aging" as next step in supporting the trans-NIH Geroscience Interest Group's efforts to integrate aging into research on chronic diseases

Scientists who have been successful in delaying mammalian aging with genetic, dietary and pharmacological approaches have developed a research strategy to expand Geroscience research directed at extending human healthspan. The scientists took part in the first summit of the NIH Geroscience Interest Group (GSIG) held last year on the NIH campus. The National Institutes of Health is made up of 27 different components called Institutes and Centers. Each has its own specific research agenda. The GSIG is aimed at promoting new pathways for collaboration, both within the NIH and with its funded researchers, specifically within the context of aging.

The "Pillars of Aging" and research goals are detailed in the following table:

Adaptation to Stress

  • Bridge continuum from psychological to molecular stresses.
  • Differentiate hormesis from toxic stress.
  • Better align human and animal studies.


  • Biomarker development: chronological vs. biological aging.
  • Link age-related environmental inputs to epigenetic signatures.
  • Test small molecules that regulate enzymes controlling epigenetic events.


Macromolecular Damage


  • Define role of signal transduction pathways linked to metabolism in aging processes.
  • Understand contribution of circadian clocks to aging and metabolism.
  • Connect metabolic dysfunction with tissue-specific decline in aging.


  • Identify proteostatic pathways that are overwhelmed in specific chronic disease states.
  • Examine crosstalk between proteostasis machineries.
  • Understand non-cell-autonomous signaling and activation of proteostasis pathways.

Stem Cells and Regeneration

"We have high hopes that our research strategy will help move collaborative efforts to the next level. What has come out of our work is a keen understanding that the factors driving aging are highly intertwined and that in order to extend healthspan we need an integrated approach to health and disease with the understanding that biological systems change with age. The trans-NIH GeroScience Interest Group (GSIG) and this Geroscience initiative hope to mobilize the research community about considering prevention of multiple age-related chronic conditions by targeting common mechanisms underlying these conditions, rather than improving the management of diseases one by one. Our current approach to researching and treating chronic diseases is inadequate and fragmentary. By the time chronic diseases are diagnosed, much damage is done and undoing it is difficult. Targeting aging may allow early intervention and allow us to maintain vigor and activity, while offsetting the economic burdens of a burgeoning aging population hampered by multiple chronic diseases."

I see much of this, such as the focus on epigenetics, metabolism, stress, and proteostasis, as being largely a case of looking at the consequences of damage and the detailed operation of damaged machine. It is vastly complex, and not a path to prevention or reversal of aging. Nonetheless, that is where the overwhelming majority of today's research takes place. Still, most of the research community does see aging as being the result of damage, even though you might not be able to discern as much from their research work, and so there are components of these pillars that are pointed in the right general direction.

Improved Synthetic Blood Platelets Spur Clotting

Present work on artificial blood tends to focus on narrow areas of functionality in which short-term augmentation of the capabilities of natural blood are useful, such as oxygen transport and clotting. From these diverse paths a wholly artificial blood substitute will no doubt eventually arise, but bear in mind that this line of development faces stiff competition from the use of cell technologies to produce biological blood as needed. One way or another blood donation will be a thing of the past not so many years from now:

An additive nanoparticle manufacturing process has been used to design and realize a synthetic platelet for the first time. The platelets are "super mimics", matching the natural shape, size, flexibility, and surface biochemistry of real platelets unlike prior incarnations that match only one or two qualities. The synthetic plates are made by a layer-wise build-up of synthetic polymers and biological proteins, some of which include polystyrene, polyallylamine hydrochloride, and bovine serum protein (a generic protein). The surfaces are conjugated to natural clotting factors such as von Willebrand Factor binding peptide, and fibrinogen-mimetic peptide. The new nanoparticle-derived synthetic platelets have a natural, flexible "discoid" shape rather than a rigid spherical shape that overcame the margination problem. Nanoparticles have been developed previously for solving the same challenges but thus far have been hampered by deficiencies such as poor circulation in the blood stream, poor margination (the migration from central bloodstream to extremities), and poor targeting.

The synthetic platelets also display preferential attachment to injury sites because they are decorated on the exterior with the right proteins including von Willebrand Factor and collagen. In animal experiments, the synthetic platelets were introduced into the blood stream after injury to the tail of the model animal - mice. The platelets circulated broadly and then settled on the site of physical insult. In the animals that received the synthetic platelets with the biological mimic of the surface, the accumulation of platelets was three times higher than without for synthetic platelets with unmodified surfaces, accompanied by the same accelerated stopping of bleeding.

The immediate application is imagined for control of bleeding in people who have suffered traumatic injury, and patients who are undergoing surgery or suffer from a clotting disorder due to problems with platelets. But in addition, the new medical material is generating excitement for its potential as a therapeutic delivery vehicle for treating diseases that involve platelets, such as atherosclerosis (thickening of arterial wall leading to constriction of blood vessels) and thrombosis.


Use of Transdifferentiated Cells in Regenerative Therapy

When creating patient-matched cells for use in regenerative therapies the present approach is to generate pluripotent cells, such as induced pluripotent stem cells, from an easily obtained sample, and then guide those cells to differentiate into the desired cell type. Researchers are finding it is possible in some cases to directly transform one cell type into another, however, a process called transdifferentiation. In theory this might prove more efficient and less costly, but at this point it is very early in the development of regenerative therapies that use transdifferentiated cells:

[Scientists] learned that fibroblasts - cells that causes scarring and are plentiful throughout the human body - can be coaxed into becoming endothelium, an entirely different type of adult cell that forms the lining of blood vessels. The new method [starts] with exposing fibroblasts to poly I:C (polyinosinic:polycytidylic acid), a small segment of double-stranded RNA that binds to the host cell receptor TLR3 (toll-like receptor 3), tricking the cells into reacting as if attacked by a virus. Fibroblasts' response to a viral attack - or, in this case, a fake viral attack - appears to be a vital step in diverting fibroblasts toward a new cell fate. After treatment with poly I:C, the researchers observed a reorganization of nuclear chromatin, allowing previously blocked-off genes to be expressed. The fibroblasts were then treated with factors, such as VEGF, that are known to compel less differentiated cells into becoming endothelial cells.

About 2 percent of the fibroblasts were transformed from fibroblasts into endothelial cells, a rate comparable to what other research groups have accomplished using viruses and gene therapy. Preliminary, as-yet-unpublished work [suggests] they may be able to achieve transformation rates as high as 15 percent. "That's about where we think the yield of transformed cells needs to be. You don't want all of the fibroblasts to be transformed - fibroblasts perform a number of important functions, including making proteins that hold tissue together. Our approach will transform some of the scar cells into blood vessel cells that will provide blood flow to heal the injury."

The scientists introduced the transformed human cells into immune-deficient mice that had poor blood flow to their hind limbs. The human blood vessel cells increased the number of vessels in the mouse limb, improving circulation. "The cells spontaneously form new blood vessels - they self assemble. Our transformed cells appear to form capillaries in vivo that join with the existing vessels in the animal, as we saw mouse red blood cells inside the vessels composed of human cells. One of the next steps will be to see if we can rescue an animal from an injury. We want to know if the therapy enhances healing by increasing blood flow to tissues that may have been damaged by a loss of blood because of ischemia."


The Goal is This: Suffering and Death Should Be Optional

The accelerating advance of technology and consequent growth in individual wealth created over the past few centuries can also be seen as an expansion of individual freedom and choice. Wealth is greater available choice, enabled by technology. All of the coins, numbers, and possessions, all of the details of our society and its capabilities are really just a way to enumerate that expanded opportunity for the individual: the choice to fly, the choice to communicate with people on the opposite side of the world, the choice to be warm rather than cold or cold rather than warm, and most importantly the choice to be alive and free of pain and disability rather than suffering or dead due to any number of medical conditions.

Taken as a whole, medicine is the march towards immortality as an ideal, never expecting to get there, but stolidly knocking down as many walls as it takes to move forward one step at a time, each new advance bringing us all just that little bit closer to a world without pain and death. This is a fine and noble thing, and the work of our ancestors has brought us a long, long way from the state of medicine just a few hundred years ago. Helping to continue and expand this progress in technology is the best of what we can do as individuals and as a species, and it is but one slice of what we might call paradise engineering: building the technologies needed to create a rich world of enormous choice and experience that nonetheless entirely lacks involuntary suffering and death.

Here is an eminently sensible article from a professional philosopher that I somehow missed when it was published earlier this year. It makes for a refreshing change in comparison to much of what emerges from philosophy and ethics on the subject of radical life extension and efforts to bring an end to suffering:

Death Should Be Optional

As a non-scientist I am not qualified to evaluate scientific claims about what science can and cannot do. What I can say is that plausible scenarios for overcoming death have now appeared. This leads to the following questions: If individuals could choose immortality, should they? Should societies fund and promote research to defeat death? The question regarding individuals has a straightforward answer - we should respect the right of autonomous individuals to choose for themselves. If an effective pill that stops or reverses aging becomes available at your local pharmacy, then you should be free to use it. My guess is that such a pill would be wildly popular! (Consider what people spend on vitamins and other elixirs on the basis of little or no evidence of their efficacy.) Or if, as you approach death, you are offered the opportunity to have your consciousness transferred to your younger cloned body, a genetically engineered body, a robotic body, or into a virtual reality, you should be free to do so. I believe that nearly everyone will use such technologies once they are demonstrated effective. But if individuals prefer to die in the hope that the gods will revive them in a paradise, thereby granting them reprieve from everlasting torment, then we should respect that too. Individuals should be free to end their lives even after death has become optional for them.

The argument about whether a society should fund and promote the research relevant to eliminating death is more complex. Societies currently invest vast sums on entertainment rather than scientific research; although the latter is a clearly a better societal investment. Ultimately the arguments for and against immortality must speak for themselves, but we reiterate that once science and technology have extended life significantly, or defeated death altogether, the point will be moot. By then almost everyone will choose to live as long as possible. In fact many people do that now, at great cost, and often gaining only a few additional months of bad health. Imagine then how quickly they will choose life over death when the techniques are proven to lead to longer, healthier lives. As for the naysayers, they will get used to new technologies just like they did to previous ones.

[Nonetheless], the defeat of death completely obliterates most world-views that have supported humans for millennia; no wonder it undermines psychological stability and arouses fierce opposition. Thus monetary and psychological reasons help to explain much opposition to life-extending therapies. Still people do change their minds. We now no longer accept dying at age thirty and think it a great tragedy when it happens; I argue that our descendants will feel similarly about our dying at eighty. Eighty years may be a relatively long lifespan compared with those of our ancestors, but it may be exceedingly brief when compared to those of our descendants. Our mind children may shed the robotic equivalent of tears at our short and painful lifespans, as we do for the short, difficult lives of our forebearers. In the end death eradicates the possibility of complete meaning for individuals; surely that is reason enough to desire immortality for all conscious beings. Still, for those who do not want immortality, they should be free to die. But for those of us that long to live forever, we should free to do so. I want more freedom. I want death to be optional.

The Funding Issues of Longevity Science

Aging research receives very little funding in comparison to other lines of medical research, which makes little sense given that it is the cause of the overwhelming majority of deaths in wealthier regions of the world with large research communities. Within aging research, very little funding is devoted towards intervening in the aging process, the work of producing treatments for aging. Within that set of funding, very little indeed is going towards research programs like SENS that have a shot at producing real results in the decades ahead.

Indeed, if one were to be cynical, one might view the past ten to fifteen years of research in sirtuins and longevity genes, work that ostensibly has the aim of slowing aging, as a successful attempt by metabolic researchers to find a flag to wave that will let them obtain much more funding for their work on cataloging the exceedingly complex operation of cells. Certainly the output from most so-called longevity research has been more data on cellular metabolism, and nothing of material use beyond that - and if you spend time watching the field, that is exactly what we should expect from this work.

Only comparatively new, disruptive approaches like SENS, based on repair of the cellular and molecular damage that causes aging rather than manipulating metabolism to slightly slow the onset of damage, have the plausible outcome of producing rejuvenation treatments at the end of the day. Even in the best of outcomes for work on sirtuins or calorie restriction mimetic drugs, the end result will be of little use for old people, and will have only marginal benefits for everyone else. That is not a path to add decades to healthy life spans, and such a result simply isn't within the bounds of the possible for current efforts aimed at slowing aging only. For more than that we need to focus on damage repair. Yet damage repair receives only a tiny sliver of funding within the field.

Today, in an increasingly ageing world, anyone who found a formula to prevent or just slow down the process would no doubt make a killing. But the controversial scientists working to engineer a fountain of youth claim that, despite an increased interest from Silicon Valley types over the past few years, they're still low on funds. Research on life extension doesn't have to be particularly expensive. Aubrey de Grey told me that to run his brainchild, SENS, "The procedures and machinery that are needed are very much the same as for any biology research," with high-precision equipment such as microscopes accounting for the biggest expenses. The often hostile response to life-extension work surely plays a role in the equation, with many suggesting the idea of curing ageing is simply snake oil or outright dangerous.

But even if you buy into the idea, there's a lack of foreseeable payoff. Investing in such ventures could potentially yield big returns - but only in the long term. While de Grey is convinced that the first person to live 1,000 years has already been born, the prospect that one of the laboratories working to beat ageing will hit the jackpot any time soon sounds farfetched to most. "People want to invest today to make money tomorrow, that's the thing. With life extension, things take a little longer."

Right now, life-extension research is still research, pure and simple. Scientists exploring the uncharted territories of longevity mainly tinker with cells and telomeres, or strive to spawn long-lived mice; so far the opportunities for life-extension institutes to churn out marketable products are virtually non-existent. If some breakthroughs along these lines were achieved, the life-extension sector has the potential to be a hugely profitable industry. In 2013 [people] worldwide spent $195.9 billion to keep the signs of ageing at bay with products aimed at countering such nuisances as wrinkles, hair loss, or faltering memory. Just imagine if feasible treatments emerged to tackle those problems at their root, eradicating ageing altogether. That's why the current dearth of funds doesn't make any sense. "My argument is the following: Health is a huge business, and illness is a huge business too. If we can offer products to live longer it'll be a huge business. What will the value of future gains be? It'll be huge. What is worth investing in it? Let's say 100 billion dollars a year, but actually any amount is worth spending."


Testing Dopamine Neuron Transplants in Rats

Parkinson's disease involves loss of a small population of dopamine generating neurons in the brain. The underlying processes causing this loss happen in all aging brains, but to a greater extent in those who ultimately manifest this condition. One approach to treatment under development is direct replacement of the lost cells, but like many types of cell therapy a lot of work and testing is involved to find the most useful strategies given the cell sources and technologies presently available:

Parkinson's disease is caused, in part, by the death of neurons that release a brain chemical called dopamine, leading to the progressive loss of control over dexterity and the speed of movement. [Researchers have shown] that transplantation of neurons derived from human embryonic stem cells (hESCs) can restore motor function in a rat model of Parkinson's disease, paving the way for the use of cell replacement therapy in human clinical trials.

Another approach involving the transplantation of human fetal cells has produced long-lasting clinical benefits; however, the positive effects were only seen in some individuals and can also cause involuntary movements driven by the graft itself. To rigorously assess an alternative hESC-based treatment approach, [scientists] transplanted hESC-derived dopamine neurons into brain regions that control movement in a rat model of Parkinson's disease. The transplanted cells survived the procedure, restored dopamine levels back to normal within five months, and established the correct pattern of long-distance connections in the brain. As a result, this therapy restored normal motor function in the animals. Importantly, the hESC-derived neurons show efficacy and potency similar to fetal neurons when transplanted in the rat model of Parkinson's disease, suggesting that the hESC-based approach may be a viable alternative to the approaches that have already been established with fetal cells in Parkinson's patients.


A First Look at the Bowhead Whale Transcriptome

Numerous research groups are involved in comparative genetic analysis of aging and longevity: investigating the biology of unusually long-lived species in search of the reasons why these animals are unusually long-lived in comparison to their peer. We humans actually fall into this category, having a greater longevity than our nearest primate cousins. Nonetheless, there are much more exceptional species out there, even if we restrict ourselves to the study of mammals. Some whales can live for centuries, and naked mole rats live for nine times as long as other similarly sized rodents.

There is the hope that beyond new knowledge the investigation of long-lived species might point the way towards means of slowing aging or treating age-related disease in humans. That really depends on the details, however: it is entirely possible for a mechanism of longevity (or regeneration as in salamanders, or cancer resistance as in naked mole rats, and so forth) to in the end turn out to be clear, well-understood, and nonetheless in no way useful to human medicine. The more likely outcome is that it takes a very long time and a lot of money to come to even a preliminary understanding, and at the end of the day those resources might have better been spent on directly advancing human medicine. If you've been following research into salamander regeneration over the past decade, for example, you'll see what I mean. Perhaps there is a grail there, perhaps not, and we won't know without a great deal more research - and this at a time when purely human regenerative medicine is advancing by leaps and bounds.

Nonetheless, comparative studies of aging and longevity are underway, and like all such research these days the scientists involved are producing mountainous vaults of data. The Methuselah Foundation, for example, presently provides a modest grant to a UK research group to sequence the genome of bowhead whale. On the basis of various direct and indirect evidence individuals of this species are thought to live for more than two centuries, and it seems only reasonable to ask how the whales manage this feat. The UK group are not the only researchers to work on answering this question. Another group that has studied bowhead whales for some years has recently published their first pass at the bowhead whale genome:

The transcriptome of the bowhead whale Balaena mysticetus reveals adaptations of the longest-lived mammal

Mammals vary dramatically in lifespan, by at least two-orders of magnitude, but the molecular basis for this difference remains largely unknown. The bowhead whale Balaena mysticetus is the longest-lived mammal known, with an estimated maximal lifespan in excess of two hundred years. It is also one of the two largest animals and the most cold-adapted baleen whale species. Here, we report the first genome-wide gene expression analyses of the bowhead whale, based on the de novo assembly of its transcriptome.

The bowhead's lifespan far exceeds that of other renowned long-lived species of mammals studied for molecular insights into aging. However, limited access to tissues of these animals has precluded detailed analyses of biological functions based on gene expression. As a first step in identifying such patterns, we present the liver, kidney and heart transcriptomes of the bowhead whale. Comparison of the bowhead whale transcriptome with that of the related minke whale and other mammals enabled us to identify candidate genes for the exceptional longevity of the bowhead whale.

It has been proposed that the difference in longevity between humans and other primates stems from differential expression of a small number of genes. A recent study comparing humans to eight other mammals, including primates, revealed that 93 liver and 253 kidney genes showed evidence of human lineage-specific expression changes. The number of genes differentially expressed in the bowhead whale liver (45 genes) and kidney (53 genes) compared to other mammals is similar, albeit using a different computational method. We speculate that the genes differentially expressed, with unique coding sequence changes and rapidly evolving in the bowhead whale, represent candidate longevity-promoting genes. We particularly stress the findings suggestive of altered insulin signaling and adaptation to a lipid-rich diet. The availability of a single heart tissue sample from the bowhead whale precluded identification of distinct gene expression patterns in the long-lived bowhead whale, but revealed that argininosuccinate lyase (Asl) may protect the heart of cetaceans during hypoxic events such as diving.

This is just a starting point, and other research groups will add to it in the years ahead. It is interesting to speculate on the role of hypoxia in the evolution of longevity, for example, as both whales and naked mole rats experience frequent long exposure to oxygen-poor environments: diving for the whales, and life underground in poorly ventilated tunnels for the naked mole rats. In fact these are not the only species in which hypoxia is theorized to spur the evolution of longevity, not directly, but as a side-effect of the class of cellular mechanisms needed for a complex animal to thrive in oxygen-poor environments.

Suggesting Impaired Quality Control as the Cause of Greater Mitochondrial DNA Damage in Aging

Thousands of mitochondria swarm within each of our cells, working to produce energy store molecules that power cellular processes. Mitochondria multiply by division, contain remnant DNA from their origin as symbiotic bacteria, and are culled when dysfunctional by cellular quality control mechanisms. Despite the destruction of faulty mitochondria, damage to their DNA nonetheless accumulates. More serious forms of this mutational damage can block the production of proteins necessary for mitochondrial function, leading to dysfunctional cells and contributing to a range of ultimately fatal age-related conditions.

There is a fair degree of debate over just how this damage originates, spreads, and increases with age, however. Whatever the process by which a single damaged mitochondrion can replicate its damage throughout all of the mitochondria in a cell in some circumstances, this transformation happens rapidly: researchers don't have intermediate states to study. The causes of increasing damage might include mitochondrial division, or the reactive oxygen species produced by the normal operation of mitochondrial processes, or some other process, such as a progressive failure of quality control as suggested here:

We review the impact of mitochondrial DNA (mtDNA) maintenance and mitochondrial function on the aging process. Mitochondrial function and mtDNA integrity are closely related. In order to create a protective barrier against reactive oxygen and nitrogen species (RONS) attacks and ensure mtDNA integrity, multiple cellular mtDNA copies are packaged together with various proteins in nucleoids. Regulation of antioxidant and RONS balance, DNA base excision repair, and selective degradation of damaged mtDNA copies preserves normal mtDNA quantities.

Oxidative damage to mtDNA molecules does not substantially contribute to increased mtDNA mutation frequency; rather, mtDNA replication errors of DNA PolG are the main source of mtDNA mutations. Mitochondrial turnover is the major contributor to maintenance of mtDNA and functionally active mitochondria. Mitochondrial turnover involves mitochondrial biogenesis, mitochondrial dynamics, and selective autophagic removal of dysfunctional mitochondria (i.e., mitophagy). All of these processes exhibit decreased activity during aging and fall under greater nuclear genome control, possibly coincident with the emergence of nuclear genome instability. We suggest that the age-dependent accumulation of mutated mtDNA copies and dysfunctional mitochondria is associated primarily with decreased cellular autophagic and mitophagic activity.


A Look at the State of Neuroprosthetics Development

Interfacing with the central nervous system is an important part of replacing many structures in the body, whether with new tissues or artificial structures that accomplish at least some of the same functions. Much of the work in this direction is concerned with the development of more functional artificial limbs and powered exoskeletons, but there is a lot more than just that going on in the research community:

Neural control of a prosthetic device for medical applications is now becoming commonplace in labs around the world. In its simplest form, a neuroprosthetic is a device that supplants or supplements the input and/or output of the nervous system. For decades, researchers have eyed neuroprosthetics as ways to bypass neural deficits caused by disease, or even to augment existing function for improved performance. Today, several different types of surgical brain implants are being tested for their ability to restore some level of function in patients with severe sensory or motor disabilities. [Perhaps] the most visible recent demonstration of the power of neuroprosthetics was a spinal cord-injured patient using a brain-controlled exoskeleton to kick off the 2014 World Cup in Brazil. In short, tinkering with the brain has begun in earnest.

When connecting an external device to the human nervous system, researchers have traditionally used a setup that records brain signals from the user, computationally analyzes those signals to infer the user's intentions, and then relays the information to an external effector that acts on those intentions. Inputs can be the firing of individual neurons in the brain, the cumulative voltages across areas of cortex encompassing millions of neurons, or the action potentials conducted by peripheral nerves anywhere in the body. In terms of output effectors, researchers have demonstrated that brain or nerve signals can be used to control computer cursor movements and robotic arms, or enable the reanimation of paralyzed limbs.

But information transfer via neuroprostheses is not a one-way street; some systems are able to convert environmental stimuli into perceptions by capturing an external input and translating it into an appropriate stimulus delivered directly to the nervous system. In this light, researchers have developed cochlear implants and functional retinal prostheses. Such reversal of information transfer can also be beneficial for limb prostheses. Under normal circumstances, meaningful movements of the body can only be accomplished in conjunction with appropriate sensation of the limb or body part. While this area of research is still young, researchers are beginning to create "bidirectional" brain-computer interfaces.


Further Investigations into FGF21 in Calorie Restriction

In most species examined to date reducing caloric intake while maintaining optimal levels of required dietary micronutrients extends healthy life spans and maximum life spans. In laboratory mice the effect can extend maximum life spans by up to 40% or more, but the consensus is that in humans lifelong calorie restriction would perhaps add just a few years to life spans even through the effects on health are quite similar. Even regular exercise is not quite as impressive in its benefits to long term health, however, which raises the question as to why it is that calorie restriction doesn't have the same effect on life span in humans as it does in mice.

The evolutionary argument for this conclusion is pretty straightforward: the calorie restriction response evolved in the deep past as a way to better survive periods of seasonal famine. A season is long for a mouse, short for a human, and therefore only the mouse evolves a very plastic life span. There are other considerations that pertain only to primates, as well. We humans are long lived in comparison to our neighboring species such as chimpanzees and gorillas, and that is a fairly recent development in the grand sweep of evolutionary time. It is thought that our growing intelligence and culture led to new selection effects that extended life because the old could contribute to the success of their grandchildren. Out of the set of switches and dials available to evolution on a shorter time frame, it is possible that many that would be affected by calorie restriction are already turned on all the time in our species, as it were.

I can speculate wildly in this way without great fear of contradiction because the metabolic response to calorie restriction is fantastically complex and still only understood in broad outline. The short summary is that near everything that can be measured in the operation of cell metabolism changes when there are fewer calories coming in. This makes it a real challenge to pull apart exactly what is going on in detail: what is important, what is secondary, which systems are driving which changes. A cell is a big mess of feedback loops based on changing abundances of various proteins, and everything interacts with everything else in a constant, dynamic dance of change. The research community has put serious time and money into the attempt to understand how calorie restriction works over the past fifteen years, and there isn't much to show for it yet - one can argue that most of that money and time has been spend on what turned out to be interesting dead ends. A vast amount of data has been generated, and yet just a few sentences can now be added to the summary of what was known at the turn of the century. A lot more work lies ahead.

One of the proteins implicated in the calorie restriction response is fibroblast growth factor 21 (FGF21). More of it extends life in mice, and more of it is generated during methionine restriction. Some researchers are looking on it as a possible calorie restriction mimetic due to these results. In general its ability to produce life extension on its own makes it seem worthy of further investigation, and here is a typical result of such investigation, which is to say that the situation is rendered more complicated than prior work suggested, and more questions are raised than answers are provided:

Fibroblast Growth Factor 21 Is Not Required for the Reductions in Circulating Insulin-Like Growth Factor-1 or Global Cell Proliferation Rates in Response to Moderate Calorie Restriction in Adult Mice

Calorie restriction (CR), reduced caloric intake without malnutrition, increases maximum lifespan and delays the onset of many age-related diseases in organisms ranging from worms to rodents, and possibly non-human primates. Decreased signaling through the somatotropic axis is one mechanism that has been suggested to mediate these effects of CR, perhaps through a reduction in cell proliferation, which is predicted to contribute to lifespan extension by delaying cellular replicative senescence and inhibiting the promotional phase of carcinogenesis. Several lines of evidence contribute to a strong case for this hypothesis. First, CR in mice leads to a reduction in circulating levels of insulin-like growth factor-1 (IGF-1) in association with reduced rates of proliferation in a number of cell types. Second, repletion of circulating IGF-1 levels in CR rodents attenuates the CR-induced reduction in cell proliferation. Last, disruption of IGF-1 signaling in several mouse models mimics many of the effects of CR including, increased maximum lifespan, reduced tumor progression, delayed cellular replicative senescence and reduced rates of cell proliferation. Thus, identifying mechanisms that regulate IGF-1 signaling and cell proliferation in response to CR in mice could provide insight into the biology of aging and offer therapeutic targets for treating age-related diseases.

Using FGF21-knockout mice, we asked directly whether FGF21 was necessary for the IGF-1 and cell proliferation responses to moderate CR in adult mice. In order to capture possible circadian fluctuations in mRNA and circulating levels of factors of interest, mice were euthanized at two different time points. We found that the relative levels of circulating FGF21 and hepatic FGF21 mRNA in ad libitum (AL) vs. CR mice exhibited characteristic circadian fluctuations. The pattern of FGF21 expression in response to CR was unexpected in light of previous observations that FGF21 expression is robustly up-regulated in fasted mice. In contrast to these studies, we found that at 1500 h, CR mice, which had essentially been without food for more than 20 h, had lower hepatic FGF21 mRNA levels and a trend towards lower circulating levels of FGF21 compared to AL mice. Furthermore, at 1900 h, CR mice, which were in a postprandial state, had higher circulating FGF21 and hepatic FGF21 mRNA levels compared to AL mice. These data underscore the fact that CR is not simply repeated fasting and that CR and fasting are two distinct dietary paradigms.

Interestingly in humans, long-term (1-6y) CR does not reduce circulating IGF-1 levels and a very low calorie diet in obese diabetics actually reduces circulating FGF21 levels, with the caveat that baseline circulating FGF21 levels are elevated in this population. More studies are needed to confirm and clarify the effect of varying degrees of CR on circulating IGF-1 and FGF21 levels and the potential interplay between these two hormones in healthy humans.

Suggesting that SCNT is Better than Induced Pluripotency for Producing Cells for Therapy

There are now several methods of producing pluripotent cells from a patient's tissue. These are cells that are similar to embryonic stem cells in that they can be used to produce any type of cell in the body. A supply of patient-matched cells enables a broader range of more effective regenerative therapies to be developed. The earliest methodology for the production of pluripotent cells is known as somatic cell nuclear transfer (SCNT), and over the years has proven to be technically challenging. Few groups even now can reliably use these techniques. A much easier method called induced pluripotency was developed more recently and has captured most of the effort in this field in recent years. However, there are some indications that SCNT produces better cells, free from some classes of abnormality that can be introduced by the induced pluripotency reprogramming process:

Human pluripotent stem cells hold potential for regenerative medicine, but available cell types have significant limitations. Although embryonic stem cells (ES cells) from in vitro fertilized embryos (IVF ES cells) represent the 'gold standard', they are allogeneic to patients. Autologous induced pluripotent stem cells (iPS cells) are prone to epigenetic and transcriptional aberrations.

To determine whether such abnormalities are intrinsic to somatic cell reprogramming or secondary to the reprogramming method, genetically matched sets of human IVF ES cells, iPS cells and nuclear transfer ES cells (NT ES cells) derived by somatic cell nuclear transfer (SCNT) were subjected to genome-wide analyses. Both NT ES cells and iPS cells derived from the same somatic cells contained comparable numbers of de novo copy number variations. In contrast, DNA methylation and transcriptome profiles of NT ES cells corresponded closely to those of IVF ES cells, whereas iPS cells differed and retained residual DNA methylation patterns typical of parental somatic cells. Thus, human somatic cells can be faithfully reprogrammed to pluripotency by SCNT and are therefore ideal for cell replacement therapies.


A Potential Way to Target Ras in Cancers

The future of effective cancer treatment will involve finding ways to selectively target and sabotage common mechanisms used by sizable fractions of the many different forms of cancer. The goal is to produce treatments that work well with few side effects, and can be applied to many cancers, so that the next generation of the commercial cancer therapy industry can be established on the back of, say, a dozen different broadly applicable therapies rather than hundreds of different treatments each specific to a subtype of cancer. Here is an example of incremental progress towards one such potential treatment:

[Researchers have] uncovered a new strategy and new potential drug to target an important signalling protein in cells called Ras, which is faulty in a third of cancers. When the Ras protein travels from the centre of a cell to the cell membrane, it becomes 'switched on' and sends signals which tell cells to grow and divide. Faulty versions of this protein cause too many of these signals to be produced - leading to cancer. Scientists have been attempting for decades to target Ras, but with little success. The reason the protein is so difficult to target is because it lacks an obvious spot on its surface that potential drug molecules can fit into in order to switch it off, like a key closing a lock.

But now the researchers have shown that instead of directly targeting the faulty protein itself they can stop it moving to the surface of the cell by blocking another protein which transports Ras - preventing it from triggering cancer in the first place. By targeting a link in the chain reaction that switches on the Ras protein, the scientists have opened opportunities to develop new treatments in the future. "We've been scratching our heads for decades to find a solution to one of the oldest conundrums in cancer research. And we're excited to discover that it's actually possible to completely bypass this cancer-causing protein rather than attack it directly. We're making new improvements on compounds for potential drugs, although the challenge still lies in developing a treatment that exploits this discovery without ruining the workings of healthy cells."


A Look at Age-Related Changes in Protein Abundance Throughout the Fibroblast Proteome

The proteome is the entire set of proteins generated by an organism under discussion. Here we'll use it in the more restricted sense of the entire set of proteins generated by a specific type of cell, the common fibroblast. Fibroblasts are connective tissue cells responsible in part for building the extracellular matrix that supports cell populations in a three-dimensional structure. We live in an age of rapidly advancing biotechnology, and the areas in which progress is most rapid are those related to genetics and proteomics: measuring, cataloging, and altering the thousands of different types of complex molecule present in and around cells. As the costs fall and the tools become ever more capable, researchers can now easily amass a great deal of data on the abundance of all proteins in specific tissues and under specific circumstances.

So to aging: it is now possible to compare cells from young tissue and old tissue in great detail - at least insofar as relative protein levels are concerned. From the perspective of aging considered as a process of damage accumulation, a snapshot of an old cell and a young cell created in this way is a comparison that shows the high level outcome of low level underlying processes. It tells us something about how the cell has altered its behavior, the pace at which it synthesizes different proteins, but not in great detail. That detail must be painstakingly inferred, a process that involves taking the catalog of changes in protein abundance and working backwards through what is presently known of what these proteins actually do.

Interestingly, we know already where researchers will end up at the end of this process should they follow it through to the very end, tracing back every change through nested layers of cause and effect. There is already a good, well-established list of the forms of damage to cells and tissues that are fundamental, not caused by some other change, but rather occurring as a natural result of the normal operation of cellular metabolism. There is a starting point and an ending, and a vast and very, very complicated blank space on the map in between.

Fortunately that blank space doesn't matter from the practical perspective of producing treatments: what researchers should do is to find ways to fix the fundamental damage and work forward to see what happens when it is fixed. That strategy should along the way generate effective treatments for aging. Unfortunately, this is not what 99% of the research community is actually doing. Rather, they are working backwards from the end, a process that will in the end come to the same filling in of the map, but has very little chance of generating effective treatments for aging along the way. Why little chance? Because their discoveries relate to proximate causes, changes in protein levels that are happening for very complicated reasons and are consequently hard to safely alter to try to make the situation less bad. Even if they are altered safely, that fails to address the underlying causes, which march on, and no doubt lead to all sorts of other forms of harm.

Here is a paper that demonstrates just how far the tools have come in the past two decades. Consider that the Human Genome Project kicked off in 1990 with a very long timeline, and then the whole thing was basically completed in a couple of years by Celera between 1998 and 2001 using newer technologies. The costs were staggering. Yet less than fifteen years later it is entirely unremarkable for genomes to be sequenced and the costs are small and falling rapidly. Proteome analysis is a much more complex affair, but the advance in capabilities has been similarly relentless. Today's machinery allows thousands of different proteins to be efficiently assessed and analysed per sample, and at costs that are tiny in comparison to event just a few years past. This paper isn't unusual at all in terms of what is taking place in the laboratory these days; be sure to read in far enough to find the diagrams:

Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts

We analyzed an ex vivo model of in situ aged human dermal fibroblasts, obtained from 15 adult healthy donors from three different age groups using an unbiased quantitative proteome-wide approach applying label-free mass spectrometry. Thereby, we identified 2409 proteins, including 43 proteins with an age-associated abundance change. Most of the differentially abundant proteins have not been described in the context of fibroblasts' aging before, but the deduced biological processes confirmed known hallmarks of aging and led to a consistent picture of eight biological categories involved in fibroblast aging, namely proteostasis, cell cycle and proliferation, development and differentiation, cell death, cell organization and cytoskeleton, response to stress, cell communication and signal transduction, as well as RNA metabolism and translation.

Our present analyses showed 43 proteins with altered expression in these cells according to the different donor age groups. Remarkably, we found no overlap between the mRNA and protein expression data for these 43 proteins. This could be due to the fact that individual proteins or transcripts may not meet the threshold for statistical significance as the used technologies have different noise levels. On the other hand, it has been shown and confirmed by our data that in mammalian cells approximately only one third of the mRNA abundance is reflected in the proteome. However, the fact that 77% of the age-associated proteins were not linked to expression changes of the corresponding transcripts suggested that most of the age-associated alterations detected at the proteome level are likely caused by other processes, such as post-transcriptional regulation, translation efficiency, protein stability or modifications, rather than by differential regulation of gene expression.

There is a lot more theorizing in that vein in the paper; this is characteristic of this approach of working down from the top. It generates as many questions and new leads to follow as it does answers. As you might note the generation of proteins from genetic blueprints is a process with a lot of distinct stages, all of which are quite capable of reacting to circumstances independently from the others, producing a net change in abundance. Personally I think the "protein stability or modifications" segment is worth looking at in more detail given the apparently falling levels of chaperone proteins and decline in other parts of the cellular housekeeping processes with age.

A Programmed Aging Point of View on Objectives in Treating Age-Related Degeneration

The majority of the research community sees aging as a consequence of damage, which leads to reactions in the form of changes in the operation of metabolism. Cells react with altered levels of gene expression, leading to different amounts of various proteins in circulation, and other more complex changes also take place. Not all of these reactions are a good thing, and many cause further harm. In the programmed aging viewpoint, the changes in protein levels are the fundamental cause of aging, an evolved system that causes aging and exists because it provided selection benefits in early life. Thus to one school of thought repair of damage is absolutely the best approach while to the other it is pointless, and vice versa for efforts to change protein levels directly in old tissues without repairing damage.

The strange thing about modern aging research, or the tragic thing depending on your viewpoint, is that despite the majority considering aging to be caused by damage, the research they undertake is actually far more suited to the programmed aging school of thought. The most common approach to research is to examine the end stage of a particular aspect of aging, and pick out proximate causes, or changes in protein levels and gene expression, and try to alter them. This is the path forced upon researchers by the regulatory structure they work within: commercialization of treatments is only permitted for named diseases, the late stages of age-related damage. So they must work from the end backwards, and thus the first things they find are always going to be proximate causes and reactions.

This must all change if we are to see effective treatments based on damage repair. Meanwhile the programmed aging theorists should be pretty pleased with the current state of affairs, since it is going in the direction they would recommend even though they are ostensibly having a tough time in winning over their colleagues to their hypotheses on aging. This is a slow moving debate that is only ever going to be settled by the establishment of rejuvenation treatments that actually work, and thereby demonstrate one view to be wrong. That goal is muddied by the fact that there are many layers of damage and reaction, and thus one can in fact achieve modest benefits in some cases by altering proximate causes.

It is my belief that the timing of development and aging is determined by chromatin state. The body knows how to be young, and it knows how to be old. The difference is coded in chromosomes, especially in telomere length of stem cells and epigenetic markers in endocrine cells. I am proposing that aging is, in large part, a matter of epigenetics. A different set of genes is turned on when we are young compared to when we are old, and that makes all the difference.

I believe that aging is controlled by several biological clocks. This is a strong claim, but I think it has good support, outlined in the references above. Biological clocks certainly control development, puberty and related schedules early in life. How the body knows its own age is yet incompletely understood. It's a good bet that the same clocks that control development have been re-purposed to control aging. There are three clocks we know something about. These are the epigenetic clock, shrinkage of the thymus, master gland of the immune system. A common way to construct a clock is with a feedback loop. A clock looks at itself to determine its next move. The body has a feedback loop between epigenetic state (at a cell level) and circulating hormones and RNAs (at a systemic level).

There is intriguing data from parabiosis that circulating factors may be able to reprogram the body's age state. (This is the "back end" of the feedback loop described above.) If we're looking for quick progress against aging, the circulating hormones are more accessible and make a more convenient target than trying to get inside the cell nucleus to reprogram epigenetic state directly. If we're lucky, then adding some factors to the blood while blocking others will have a long-lasting effect of re-programming epigenetics, and the body will take over by continuing to secrete a "young mix" into the blood stream. If we're not so lucky, it may be necessary to perform some epigenetic re-programming more invasively.


Molecular Chaperones Decline with Age

Chaperone proteins work to ensure correct protein folding and function in cells. The more chaperone activity taking place, the less damage in the form of dysfunctional protein machinery at any given time. Artificially boosting forms of chaperone activity is a potential form of treatment for some of the causes and consequences of age-related degeneration, as it could turn back the clock on rising levels of misfolded and otherwise damaged proteins.

Aging is the most significant and universal risk factor for developing neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's, Parkinson's and Huntington's diseases. This risk increases disproportionately with age, but no one really knows why. Now a team of [scientists] has uncovered some clues. The researchers are the first to find that the quality of protective genes called molecular chaperones declines dramatically in the brains of older humans, both healthy and not, and that the decline is accelerated even more in humans with neurodegenerative disease.

Molecular chaperones are a special set of highly conserved genes that watch over cells, keeping them and the entire organism healthy by preventing protein damage. The researchers specifically found the decline in 100 genes, approximately one-third of all human molecular chaperone genes. Then, with additional studies, they winnowed that number down to 28 human genes specifically involved in age-associated neurodegeneration. These critical genes provide a basis for a biomarker, an early indicator of disease and a target for new therapeutics.

"Imagine if we had biomarkers that tell doctors how you are doing in terms of aging, warning of any problems long before neurological deficits appear. This would be a remarkable tool, especially considering the increases in life expectancy in many parts of the world. Let's say a person is age 50, but we see his molecular chaperones have declined and aren't repairing proteins and cellular damage. The chaperones are acting more like age 85 or 90. That's a sign that medical intervention could help. Molecular chaperones really are the barrier we have between disease and no disease. If this critical system declines, it leads to misfolded and damaged proteins, and eventually tissues become dysfunctional and die. If we can keep the chaperones healthy, we should be able to keep the person healthy. The next step is to understand the basis for the decline of these specific chaperones and to develop treatments that prevent their decline. The goal is not to make people live forever but rather to match health span more closely with life span - to improve the quality of life being lived."


Fundraising Update: A Third of the Way

The Fight Aging! 2014 fundraiser to benefit the work of the SENS Research Foundation launched a month ago and will run for another two months - until the end of the year. Until the end of December a $100,000 matching fund waits to be drawn down by your donations: for every $1 given to the Foundation to help expand their rejuvenation research programs, $2 is drawn from the fund. So donate!

Why give to support the Foundation? The SENS Research Foundation funds research programs to produce the basic technologies required to build rejuvenation therapies, treatments that will be capable of repairing the various forms of cellular and molecular damage that cause age-related frailty, disease, and death. Some of this research already takes place in the mainstream, such as in the cancer and stem cell research communities, but these are only a few of the many lines of work needed to produce a working rejuvenation toolkit and the clinical community to support it. Despite great progress in biotechnology over the past decade, and despite a good understanding of the goals and the damage that must be repaired, that other research is still largely languishing. The SENS Research Foundation is perhaps the only organization in the world that is wholly focused on speeding all of these necessary threads by funding research groups and laboratories.

Stem cell based regenerative therapies and even a partial cure for most cancers alone will not greatly extend our lives, even though they provide significant improvements over the present state of affairs for people suffering age-related disease. Aging is caused by other processes as well, and if one doesn't get you then one of the others will. To help the old and to help prevent ourselves from suffering in same way as today's old people the research community must also tackle other important issues in the aging body and brain: metabolic waste products building up inside and around cells; growing levels of mitochondrial DNA damage; immune system dysfunction; and senescent cell accumulation. All of these produce eventually fatal medical conditions on roughly the same timescales, and thus removing frailty and disease from aging will require progress on all of these fronts.

As noted, however, far too little work takes place on most of these projects. That is why our assistance is so important; that is why we must have fundraisers and philanthropy and advocacy. The work funded and encouraged by the SENS Research Foundation represents the future, and the SENS vision of repair of the causes of aging is to my eyes the only viable replacement for the present day collection of poor strategies for tackling aging in medicine. There can and should be more than just palliative care, or attempts to slightly slow down aging, or the same old-style drug discovery programs attempting to do more good than harm for people in the very end stages of aging. The near future can and should be one of targeted, designed treatments that zero in on the known forms of cellular and molecular damage that cause aging. The more support we can provide to organizations like the SENS Research Foundation, the faster this future will arrive, and the better all of our lives will be as a result.

We're now a third of the way through our 2014 fundraiser and over the last month more than 300 people from the community have generously stepped up to provide more than $16,000 dollars of the $50,000 target. If you're on the fence, consider this: you'll probably spend more than most of these folk gave on coffee and cake this coming month, and what is that going to do for your future prospects? So invest a little in the rest of your life, in making the future a place you'd like to live in, I'd say. Small actions taken now will snowball, and make large differences down the line.

Smooth Muscle Cells in Blood Vessel Stiffening

Blood vessels lose their flexibility and structural integrity with age, which contributes to a range of ultimately fatal cardiovascular conditions, as well as loss of cognitive function caused by disruption of blood flow in the brain. This process of stiffening in blood vessels is thought to be at least partially due to cross-linking in the extracellular matrix, in which the mechanical properties of tissue degrade due to rising levels of advanced glycation endproducts, sugary metabolic wastes that can glue together proteins to disrupt their function.

Here, however, researchers look at another potential causative process for vascular stiffness, in this case connected to focal adhesion structures. These are built by cells in order to anchor to the extracellular matrix and hold steady in its tissue, but can be quite dynamic in some circumstances, destroyed and recreated as a cell shifts its position:

The aorta is the main artery of the body. It is connected to the heart and carries oxygen-rich blood pumped from the left ventricle to the rest of the circulatory system. Pumping blood from the heart causes pulsing waves that reverberate into the aorta. As it branches off into smaller blood vessels, the aorta acts as a shock absorber, blunting the impact of these waves. But with age, changes in the blood vessel wall can cause the aorta to lose some of its flexibility and its ability to buffer high-pressure waves as they travel to the smaller vessels. The reduced shock-absorbing capacity can lead to changes in microcirculations and negative effects on organ function.

The underlying cause of aortic stiffening is unclear. While much of the previous research pointed to the extracellular matrix (ECM) - a group of molecules secreted by the cells that support cell attachment and communication - as the culprit, a few studies suggest that vascular smooth muscle may play a role. [Researchers] directly measured the mechanical properties of the aortas of young and old mice to observe how smooth muscle cells factor into aortic wall stiffness. They also observed how focal adhesion signaling - which helps promote arterial flexibility in young mice - is impaired with aging. They used a novel biomechanical method to distend the aorta, mimicking circumferential strain, to measure how the smooth muscle affected arterial stiffness.

"A major finding of the present study is that the smooth muscle cell is a major source and regulator of vascular stiffness, in contrast with the often-assumed dominance of ECM in effecting changes in wall stiffness with aging. The decrease in the focal adhesion signaling mechanism led to higher stiffness in old vessels. We conclude from our results that the smooth muscle focal adhesions represent a potential therapeutic target in the context of preventing or reversing increases in aortic stiffness. An understanding of this mechanism may lead to an approach to reverse this aging-induced deficiency."


Proposing a Trial of Rapamycin in Dogs

Rapamycin has been shown to modestly extend life in mice, though there is some ongoing debate as to whether this is an effect caused by cancer risk reduction rather than a slowing of aging. Some researchers are now intending to embark on a small study using dogs:

Yeast, worms and mice: all have lived longer when treated with various chemical compounds in laboratory tests. But many promising leads have failed when tried in humans. This week, researchers are proposing a different approach to animal testing of life-extending drugs: trials in pet dogs. Their target is rapamycin, which is used clinically as part of an anti-rejection drug cocktail after kidney transplants and which has also been shown to extend the lives of mice by 13% in females and 9% in males.

The compound's effect on lifespan has not yet been tested in people - human trials are expensive and it takes a long time to learn whether a drug can extend a human life. Furthermore, rapamycin is no longer patentable, so pharmaceutical companies are unwilling to invest effort in it. The drug can also cause some serious side effects that might rule it out as a pharmaceutical fountain of youth. It has, for example, been linked to an increased risk of diabetes in people who have had kidney transplants. But at low doses, researchers suspect that the drug will not be a problem for healthy dogs.

[Molecular biologists] propose to give low doses of rapamycin to dogs in a study that would also test whether the drug can extend the animals' lives. The researchers hope to test rapamycin in large dogs that typically live for eight to ten years; they would start giving the drug to animals aged six to nine. A pilot trial would involve about 30 dogs, half of which would receive the drug, and would allow the researchers to dose the dogs for a short time and observe effects on heart function and some other health measures. The trial could be completed in as little as three years, but researchers will know long before that - perhaps in months - whether rapamycin improves cardiac function or other aspects of health.